Anti-infective agents
View Patent ↗The present invention provides HCV polymerase inhibiting compounds having the formula (I): where R 1 is cyclobutyl-N(R a )—, n is 1, 2, 3 or 4, and at least one R 5 is R a SO 2 N(R j )alkyl-. In a non-limiting example, a compound of the present invention is N-[(3-{1-[(cyclobutyl)amino])-4-hydroxy -2-oxo-1,2-dihydro-quinolin-3-yl}-1,1-dioxo-1,4-dihydro-1λ 6 -thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methane-sulfonamide. The present invention also features compositions comprising the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers or tautomers thereof, and methods of using the same to treat or prevent HCV infection.
1. A process for preparation of a compound, a stereoisomer of the compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound, stereoisomer, or tautomer, wherein:
the compound corresponds to formula (I):
A is thienyl;
R 1 is cyclobutyl-N(R a )—, wherein the cyclobutyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R e ), —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R e ), —C(O)R c , —C(O)OR c , and —C(O)NR c R e ;
as to R 2 and R 3 :
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, alkyl, aryl, arylalkyl, heteroaryl, heterocycle, heteroarylalkyl, cyano, halo, —N(R a )(R b ), R a R b NC(O)—, —SR a , —S(O)R a , —S(O) 2 R a , and R a C(O)—, wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R a , alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, -(alkyl)(OR k ), -(alkyl)(NR a R b ), —SR a , —S(O)R a , —S(O) 2 R a , —OR k , —N(R a )(R b ), —C(O)R a , —C(O)OR a , and —C(O)NR a R b , or, alternatively,
R 2 and R 3 , together with the carbon atoms to which they are attached, form a five- or six-membered ring selected from the group consisting of aryl, cycloalkyl, heteroaryl, and heterocycle, wherein each such substituent is optionally substituted with m independently selected R 6 substituents;
R 4 is selected from the group consisting of alkoxy, arylalkoxy, aryloxy, halo, hydroxy, R a R b N—, N 3 —, and R e S—, wherein each such substituent is optionally substituted with or 2 substituents independently selected from the group consisting of halo, nitro, cyano, —OH, —NH 2 , and —COOH;
as to R 5 :
at least one R 5 is R a SO 2 N(R f )alkyl-, and
each additional R 5 is independently selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, azidoalkyl, formyl, halo, haloalkyl, halocarbonyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, cycloalkyl, cyano, cyanoalkyl, nitro, R a R b N—, R a C(O)—, R a S—, R a (O)S—, R a (O) 2 S—, R a R b Nalkyl-, R a (O)SN(R f )—, R a SO 2 N(R f )—, R a (O)SN(R f )alkyl-, R a SO 2 N(R f )alkyl-, R a R b NSO 2 N(R f )—, R a R b NSO 2 N(R f )alkyl-, R a R b NC(O)—, R k OC(O)—, R k OC(O)alkyl-, R k Oalkyl-, R a R b NSO 2 —, R a R b NSO 2 alkyl-, (R b O)(R a )P(O)O—, and —OR k , wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R d ), —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R d ), —C(O)R c , —C(O)OR c , and —C(O)NR c R d ;
each R 6 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocyclealkyl, -(alkyl)(OR k ), -(alkyl)(NR a R b ), —SR a , —S(O)R a , —S(O) 2 R a , —OR k , —N(R a )(R b ), —C(O)R a , —C(O)OR a , and —C(O)NR a R b , wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, haloalkyl, cyano, nitro, —OR a , —NR a R b , —SR a , —SOR a , —SO 2 R a , —C(O)OR a , —C(O)NR a R b , and —NC(O)R a ;
as to R a and R b :
each R a and R b is independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylsulfanylalkyl, aryl, arylalkenyl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkenyl, heterocyclealkyl, hydroxyalkylcarbonyl, nitroalkyl, R c R d N—, R p O—, R p Oalkyl-, R c R d Nalkyl-, R c R d NC(O)alkyl-, R c SO 2 —, R c SO 2 alkyl-, R c C(O)—, R c C(O)alkyl-, R c OC(O)—, R c OC(O)alkyl-, R c R d NalkylC(O)—, R c R d NC(O)—, R c R d NC(O)Oalkyl-, and R c R d NC(O)N(R e )alkyl-, wherein each such substituent is optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R d ), —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R d ), —C(O)R c , —C(O)OR c , and —C(O)NR c R d , or alternatively,
R a and R b , together with the nitrogen atom to which they are attached, form a three- to six-membered ring selected from the group consisting of heteroaryl and heterocycle, wherein the heteroaryl and heterocycle are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R d ), -alkylSO 2 NR c R d , -alkylC(O)NR c R d , —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R d ), —C(O)R c , —C(O)OR c , and —C(O)NR c R d ; as to R c and R d :
each R c and R d is independently selected from the group consisting of hydrogen, —NR f R h , —OR f , —CO(R f ), —SR f , —SOR f , —SO 2 R f , —C(O)NR f R h , —SO 2 NR f R h , C(O)OR f , alkenyl, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, and heterocycloalkyl, wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR f ), -(alkyl)(NR f R h ), —SR f , —S(O)R f , —S(O) 2 R f , —OR f , —N(R f )(R h ), —C(O)R f , —C(O)OR f , —C(O)NR f R h , —C(O)N(H)NR f R h , —N(R e )C(O)OR f , —N(R e )SO 2 NR f R h , —N(R e )C(O)NR f R h , -alkylN(R e )C(O)OR f , -alkylN(R e )SO 2 NR f R h , and -alkylN(R e )C(O)NR f R h , or alternatively,
R c and R d , together with the nitrogen atom to which they are attached, form a three-to six-membered ring selected from the group consisting of heteroaryl and heterocycle, wherein the heteroaryl and heterocycle are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR f ), -(alkyl(NR f R h ), —SR f , —S(O)R f , —S(O) 2 R f , —OR f , —N(R f )(R h ), —C(O)R f , —C(O)OR f , and —C(O)NR f R h ;
each R c is independently selected from the group consisting of hydrogen, alkenyl, alkyl, and cycloalkyl;
as to R f and R h :
each R f and R h is independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocycle, heterocyclealkyl, heteroaryl, and heteroarylalkyl, wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O(alkyl), —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(alkyl), —S(O)(alkyl), —SO 2 alkyl, -alkyl-OH, -alkyl-O-alkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylN(alkyl) 2 , -alkylS(alkyl), -alkylS(O)(alkyl), -alkylSO 2 alkyl, —N(H)C(O)NH 2 , —C(O)OH, —C(O)O(alkyl), —C(O)alkyl, —C(O)NH 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), and —C(O)N(alkyl) 2 , or alternatively,
R f and R h , together with the nitrogen atom to which they are attached, form a three- to seven-membered ring selected from the group consisting of heterocycle and heteroaryl, wherein the heterocycle and heteroaryl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, halo, oxo, nitro, aryl, arylalkyl, cycloalkyl, cycloalkenyl, heterocycle, heteroaryl, heteroarylalkyl, —OH, —O(alkyl), —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —S(alkyl), —S(alkyl), —S(O)(alkyl), -alkyl—OH, -alkyl-O-alkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylS(alkyl), alkylS(O)(alkyl), -alkylSO 2 alkyl, -alkylN(alkyl) 2 , —N(H)C(O)NH 2 , —C(O)OH, —C(O)O(alkyl), —C(O)alkyl, —C(O)NH 2 , —C(O)NH 2 , —C(O)N(H)(alkyl), and —C(O)N(alkyl) 2 ;
each R k is independently selected from the group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, nitroalkyl, R a R b Nalkyl-, R a Oalkyl-, R a R b NC(O)—, R a R b NC(O)alkyl, R a S—, R a S(O)—, R a SO 2 —, R a Salkyl-, R a (O)Salkyl-, R a SO 2 alkyl-, R a OC(O)—, R a OC(O)alkyl-, R a C(O)—, and R a C(O)alkyl-, wherein each such substituent is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R d ), —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R d ), —C(O)R c , —C(O)OR c , and —C(O)NR c R d ;
each R p is independently selected from the group consisting of hydrogen, alkenyl, alkyl, aryl, arylalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, formylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, and nitroalkyl, wherein each such substituent is optionally substituted with 1, 2, or, 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halo, cyano, nitro, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, alkoxyalkoxyalkyl, -(alkyl)(OR c ), -(alkyl)(NR c R d ), —SR c , —S(O)R c , —S(O) 2 R c , —OR c , —N(R c )(R d ), —C(O)R c , —C(O)OR c , and —C(O)NR c R d ;
m is 1, 2, 3, or 4;
n is 1, 2, 3, or 4; and
the process comprises:
(a) contacting a compound of formula (26)
with a reagent selected from the group consisting of (1) carbon disulfide and a methylating agent, (2) tris(methylthio)methyl methyl sulfate, and (3) tris(methylthio)methyl methyl tetrafluoroborate, in the presence of a base, to provide a compound of formula (27)
(b) contacting the compound of formula (27) with a compound of formula (13)
2. The process of claim 1 , wherein the compound of formula (13) is 2-amino-4-(methane-sulfonylamino-methyl)-thiophene-3-sulfonic acid amide: