Polycyclic Agents for the Treatment of Respiratory Syncytial Virus Infections

Abstract

Compounds of formula (I), and their use as in the treatment of infections involving viruses of the Pneumovirinae sub-family (RSV) are disclosed. In the formula ring (A) may be phenyl, pyridyl etc., (B-C) may be CH 2 —CH 2 etc., (R 1 ) may be phenyl and substituted forms thereof, (R 2 ) may be assorted substituents.

1 . A method for treating a mammal infected with respiratory syncytial (RSV), which comprises administering to the mammal a therapeutically effective amount of one or more compounds of formula I 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts or derivatives thereof, in the treatment of infections involving viruses of the Pneumovirinae sub-family, wherein 
         A together with the atoms to which it is attached, forms an optionally substituted aromatic ring; 
         linker B-C together with the atoms to which they are attached, forms an optionally substituted heterocyclic ring having from 5 to 8 ring atoms; 
         R 1  is selected from C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, —(CH 2 ) n C 3-7  cycloalkyl, —(CH 2 ) n C 4-7  cycloalkenyl, —(CH 2 ) n  aryl, —(CH 2 ) n  arylC 1-12  alkyl, —(CH 2 ) n  arylC 2-12  alkenyl, —(CH 2 ) n  arylC 2-12  alkynyl, and —(CH 2 ) n  heterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; 
         R 2  is selected from —CH 2 R 3 , —C(Y)R 3 , —C(Y)OR 3 , —C(Y)N(R 4 )R 3 , —C(Y)C 2 H 2 N(R 4 )R 3 , —C(Y)CH 2 SR 3  and —S(O) w R 3 , where R 3  is selected from hydrogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, —(CH 2 ) m  arylC 3-7  cycloalkyl, —(CH 2 ) m C 4-7  cycloalkenyl, —(CH 2 ) m  aryl, —(CH 2 ) m  arylC 1-12  alkyl, —(CH 2 ) m  arylC 2-12  alkenyl, —(CH 2 ) m  arylC 2-12  alkynyl and —(CH 2 ) m  heterocyclyl; and when R 2  is —CH 2 R 3 , or —C(Y)R 3 , R 3  may also be selected from —S—R 5  and —O—R 5 ; m is 0-6; R 4  is hydrogen or C 1-6  alkyl; R 5  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; and 
         X and Y are independently selected from O, S and NR 6 , where R 6  is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy. 
       
     
     
         2 . The method according to  claim 1  wherein R 2  is not an unsubstituted —C 1-6 alkyl or unsubstituted —C(O)—C 1-6 alkyl. 
     
     
         3 . The method according to  claim 1  wherein ring A is an optionally substituted aryl ring. 
     
     
         4 . The method according to  claim 1  wherein ring A is an optionally substituted phenyl ring. 
     
     
         5 . The method according to  claim 1  wherein ring A is an optionally substituted heteroaryl ring. 
     
     
         6 . The method according to  claim 1  wherein ring A together with the atoms to which it is attached, represents an optionally substituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl or isoxazolyl ring. 
     
     
         7 . The method according to  claim 1  wherein ring A is an optionally substituted pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring. 
     
     
         8 . The method according to  claim 1  wherein ring A is optionally substituted pyridyl ring. 
     
     
         9 . The method according to  claim 1  wherein ring A is optionally substituted with one or more substituents independently selected from halo, —NH 2 , NO 2 , C 1-6  alkyl, aryl and heterocyclyl, the aryl and heterocyclyl groups optionally substituted with halo, C 1-6 alkyl or halo substituted C 1-6  alkyl and, when ring A contains one or more ring nitrogens, the optional substituents include N-oxides of one or more of the ring nitrogens and pyridinium salts thereof. 
     
     
         10 . The method according to  claim 1  wherein ring A is optionally substituted with a substituent selected from halo, alkyl, C 6 H 5 —CH 3 —C 6 H 4 —, CF 3 —C 6 H 4 —, pyridyl, NO 2  and when ring A contains one or more ring nitrogens, the optional substituent also include an N-oxide form of a ring nitrogen, and pyridinium salts thereof. 
     
     
         11 . The method according to  claim 1  wherein ring A is not substituted. 
     
     
         12 . The method according to  claim 1  of a compound of the formula IV 
       
         
           
           
               
               
           
         
         its salts, N-oxides and pharmaceutically acceptable derivatives thereof, wherein B-C, X, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         13 . The method according to  claim 1 , wherein R 2  is selected from —CH 2 R 3 , —C(Y)R 3 , —C(Y)OR 3 , —C(Y)N(R 4 )R 3 , —C(Y)CH 2 N(R 4 )R 3 , —C(Y)CH 2 SR 3  and —S(O) w R 5 , where R 3  is selected from hydrogen, —C 1-12 alkyl, —C 2-12 alkenyl, —C 2-12 alkynyl, —(CH 2 ) m C 3-7 cycloalkyl, —(CH 2 ) m C 4-7  cycloalkenyl, —(CH 2 ) m aryl, —(CH 2 ) m arylC 1-12  alkyl, —(CH 2 ) m arylC 2-12 alkenyl, —(CH 2 ) m arylC 2-12  alkynyl, —(CH 2 ) m heterocyclyl, and when R 2  is —CH 2 R 3 , or —C(Y)R 3 , R 3  may also be selected from —S—R 5  and —O—R 5 ; m is 0-6, R 4  is hydrogen or is C 1-6  alkyl, R 5  is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7  cycloalkenyl, benzyl, aryl and heterocyclyl, w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  alkoxy, C 2-6  alkenyl, C 2-6 alkynyl, halo, halo-C 1-6  alkyl (including CF 3 ), hydroxy, mercapto, nitro, cyano, NH 2 , mono or di((C 1-6 alkyl)amino, phenyl, benzyl and heterocyclyl. 
     
     
         14 . The method according to  claim 1  wherein R 2  is —CH 2 —R 3 , and R 3  is —(CH 2 ) m aryl or —(CH 2 ) m  heterocyclyl and m is 0 to 3 and the aryl or heterocyclyl ring is optionally substituted. 
     
     
         15 . The method according to  claim 1  wherein R 2  is —COR 3  and R 3  is aryl or heterocyclyl and is optionally substituted. 
     
     
         16 . The method according to  claim 1  wherein R 3  is optionally substituted phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl. 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl or pteridinyl. 
     
     
         17 . The method according to  claim 16 , wherein R 3  is optionally substituted with one or more substituents selected from C 1-6  alkyl, C 1-6  alkoxy, C 2-6  alkenyl, C 2-6  alkynyl, halo, halo-C 1-6  alkyl (including CF 3 ), hydroxy, mercapto, nitro, cyano. NH 2 , mono or di(C 1-6 alkyl)amino, phenyl, benzyl and heterocyclyl. 
     
     
         18 . The method according to  claim 1  wherein R 2  is —CON(H)R 3 , and R 3  is —(CH 2 ) m  aryl or —(CH 2 ) m  heteroaryl and m is 0 to 2 and the aryl or heteroaryl ring is optionally substituted with one or more substituents independently selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl. 
     
     
         19 . The method according to  claim 1  wherein link -B-C- is an optionally substituted link of the formula —CH 2 —(CH) z —, where z is 1-4. 
     
     
         20 . The method according to  claim 19  wherein z is 1 or 2. 
     
     
         21 . The method according to  claim 1  wherein -B-C- is a linker of the formula —CH 2 CH 2 —. 
     
     
         22 . The method according to  claim 1  wherein linker -B-C- is optionally substituted no more than three optional substituents, the substituents selected from halo, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl. 
     
     
         23 . The method according to  claim 1  wherein linker -B-C- is not substituted. 
     
     
         24 . The method according to  claim 1  wherein X is oxygen or sulphur. 
     
     
         25 . The method according to  claim 1  wherein R 1  is an optionally substituted aryl or heterocyclyl group. 
     
     
         26 . The method according to  claim 1  wherein R 1  represents phenyl, thienyl, pyrrolyl, pyridyl ring or a —C 1-6  alkylphenyl group, the rings being optional substituted with halo, hydroxy, nitro, —NR′R″ (where R′ and R″ are independently selected from hydrogen, lower alkyl and —C(O)R, where R is C 1-6  alkyl, phenyl or heterocyclyl), C 1-12 alkyl, phenyl and —O—R a , where R a  is —C 1-12 alkyl, —C 3-7 cycloalkyl, —C 1-12 alkylC 3-7 cycloalkyl, phenyl or —C 1-12 alkylphenyl; and the C 1-12 alkyl, phenyl or R a  group may be optionally substituted with halo, —CN, —NR′R″; —CO 2 R or —CONR′R″, where R, R′ and R″ are independently selected from hydrogen or lower alkyl. 
     
     
         27 . The method according to  claim 1  wherein R 1  is phenyl optionally substituted with a substituent selected from halo, —C 1-6 alkyl, —C 1-6 alkylhalo, —C 1-6 alkylCN, —OC 1-6 alkyl, —OC 1-6 alkylhalo, —OC 1-6 alkylCO 2 NH 2 , —OC 1-6 alkylCN, —OC 1-6 alkylC 3-7 cycloalkyl, —OC 1-6 alkylC 6 H 5 , —OC 1-6 alkylOCH 3 , —OC 6 H 5 , —OC 6 H 4 halo, —CF 3 , —OCF 3 , —NR′R″ (where R′ and R″ are independently selected from hydrogen, —C(O)C 1-6 alkyl, —C(O)C 6 H 5 , —C(O)CH═CHCO 2 H, —C(O)C 1-6 alkylCO 2 H, —C(O)C 1-6 alkylCO 2 CH 3 , —C(O)C 1-6 alkylC 6 H 5 , —C(O)C 1-6 alkylC 6 H 4 CH 3 , —C(O)C 1-6 alkylC 6 H 4 OCH 3  and —C(O)C 1-6 alkylC 6 H 4 halo), —CO 2 H, —CO 2 C 1-6 alkyl, —NO 2 , —OH, —C 6 H 5 , —C 6 H 4 C 1-6 alkyl, —C 6 H 4 halo and —OC(O)C 1-6 alkyl. 
     
     
         28 . The method according to  claim 1  wherein R 1  is phenyl substituted with halo, —OC 1-6 alkyl, —OC 1-6 alkylhalo, —OC 1-6 alkylCO 2 NH 2 , —OC 1-6 alkylCN, —OC 1-6 alkylC 3-7 cycloalkyl, —OC 1-6 alkylC 6 H 5  or —OC 1-6 alkylOCH 3 . 
     
     
         29 . The method according to  claim 1  wherein R 1  is 4-chlorophenyl. 
     
     
         30 . A method for the treatment of infections involving respiratory syncytial viruses (RSV) by the inhibition of the virus's fusion processes by the administration of a therapeutically effective amount of a compound of formula I as defined in  claim 1 , or a pharmaceutically acceptable salt or derivative thereof to a patient in need to treatment. 
     
     
         31 . A pharmaceutical formulation for the treatment of infections involving respiratory syncytial viruses (RSV) comprising a compound of formula I as defined in  claim 1 , or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         32 - 37 . (canceled) 
     
     
         38 . A compound of formula I 
       
         
           
           
               
               
           
         
         or a salt or pharmaceutically acceptable derivative thereof, wherein 
         A together with the atoms to which it is attached, represents an optionally substituted phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring; 
         B-C is an optionally substituted link of the formula —CH 2 —(CH) z —, where z is 1-4; 
         R 1  is selected from C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, —(CH 2 ) n C 3-7  cycloalkyl, —(CH 2 ) n C 4-7  cycloalkenyl, —(CH 2 ) n  aryl, —(CH 2 ) n  arylC 1-12  alkyl, —(CH 2 ) n  arylC 2-12  alkenyl, —(CH 2 ) n  arylC 2-12 , alkynyl, and —(CH 2 ) n  heterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; 
         R 2  is selected from —CH 2 R 3 , —C(Y)R 3 , —C(Y)OR 3 , —C(Y)N(R 4 )R 3  and —S(O) w R 5 , where R 3  is selected from hydrogen, C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, —(CH) m C 3-7 cycloalkyl, —(CH 2 ) m C 4-7  cycloalkenyl, —(CH 2 ) m  aryl, —(CH 2 ) m  arylC 1-12  alkyl, —(CH 2 ) m  arylC 2-12  alkenyl, —(CH 2 ) m  arylC 2-12  alkynyl and —(CH 2 ) m  heterocyclyl; and when R 2  is —CH 2 R 3 , or —C(Y)R 3 , R 3  may also be selected from —S—R 5  and —O—R 5 ; m is 0-6; R 4  is hydrogen or C 1-6 alkyl; R 5  is C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 4-7  cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted, 
         X and Y are independently selected from O, S and NR 6 , where R 6  is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy; 
         with the provisos that when A is phenyl and R 1  is 4-chlorophenyl or unsubstituted phenyl 
         (i) R 1  is not unsubstituted cyclopropyl, halomethyl, unsubstituted phenyl or phenyl with only halo, —CH 3  and/or —OCH 3  substituents when R 2  is COR 3 ; 
         (ii) R 3  is not unsubstituted phenyl or phenyl with only halo, —CH 3 , —OCH 3  and/or —C(O)OCH 2 CH 3  substituents when R 2  is C(O)NHR 3 ; 
         (iii) R 3  is not unsubstituted phenyl or phenyl with only halo, —CH 3 , —OCH 3  and/or —C(O)OCH 2 CH 3  substituents when R 2  is C(S)NHR 3 ; 
         and with the provisos 
         (iv) when A is phenyl and R 2  is CH 2 R 3 ; R 3  is not hydrogen, unsubstituted C 1-6  alkyl or C 1-6  alkyl only substituted with NH 2 , mono or di C 1-6  alkyl amino groups; 
         (v) when A is phenyl and R 1  is 4-methoxyphenyl, R 2  is not CHO; 
         (vi) when A is phenyl and R 1  is phenyl optionally substituted with only halo, C 1-6  alkyl and/or C 1-6  alkoxy and R 2  is COR 3 , R 3  is not methylene substituted with NH 2 , mono or di C 1-6  alkyl amino. N-piperidinyl or N-morpholinyl; 
         (vii) when A is phenyl and R 1  is 3-CH 3 ,4-CH 3 CH 2 CH 2 NHC(O)CH 2 O-phenyl, R 2  is not —S(O) 2 CH 2 SO 2 CH 3 , —CHO, —COCH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CO 2 C(CH 3 ) 3  or C 1-6  alkyl; 
         (viii) when A is pyridyl and R 1  is 3-CH 3 ,4-CH 3 CH 2 CH 2 NHC(O)CH 2 O-phenyl, R 2  is not CH 3 . 
       
     
     
         39 - 64 . (canceled) 
     
     
         65 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and salts thereof. 
       
     
     
         66 . A pharmaceutical formulation for the treatment of infections involving respiratory syncytial viruses (RSV) comprising a compound of formula I as defined in  claim 38 , or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         67 . A compound of formula 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         the pyridyl ring is optionally substituted; 
         B-C is an optionally substituted linker of the formula —CH 2 —(CH 2 ) z —, where z is 1-4; 
         R 1  is selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, —(CH 2 ) n C 3-7 cycloalkyl, —(CH 2 ) n C 4-7 cycloalkenyl, —(CH 2 ) n aryl, —(CH 2 ) n arylC 1-12 alkyl, —(CH 2 ) n arylC 2-12 alkenyl, —(CH 2 ) n arylC 2-12 alkynyl, and —(CH 2 ) n heterocyclyl; n is 0-6; and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; 
         X is selected from O, S and NR 6 , where R 6  is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy; 
         with the proviso that when -B-C- is —CH 2 CH(CH(CH 3 ) 2 )—, R 1  is not 3-CH 3 ,4-CH 3 CH 2 CH 2 NHC(O)CH 2 O-phenyl-. 
       
     
     
         68 - 77 . (canceled) 
     
     
         78 . Use of a compound of formula III, 
       
         
           
           
               
               
           
         
         and salts thereof, wherein R 1 , ring A, -B-C- and X are as defined in  claim 38 , as an intermediate for the production of a compound of formula I as defined in  claim 38 . 
       
     
     
         79 . A method of separating the enantiomers of a compound of formula III by forming diastereomeric salts of the compounds using an enantiomerically enriched chiral hydrogen phosphate. 
     
     
         80 - 82 . (canceled)