IP Library › Granted Patent US 7,538,105

Granted Patent B2

US 7,538,105 · App. 12/098,024 · Granted May 26, 2009

Anti-infective agents

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Patent No.: US 7,538,105
App. No.: 12/098,024
Granted: May 26, 2009
Kind: B2

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Abstract

Compounds having the formula are hepatitis C(HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C(HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.

Claims (217)

1. A compound, a stereoisomer of the compound, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, stereoisomer, or tautomer, or a combination thereof, wherein:

the compound corresponds to formula (I):

B is selected from the group consisting of

A is thienyl;

as to R 1 and R 2 :

R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —C(O)OR a , —C(O)NR a R b , and R 1p , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b ,—N(R e )C(O)R a , —N(R e )C(O)OR a , —N(R e )C(O)NR a R b , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —N═CR j R k , —C(R e )═CR j R k , and R 1q ; and

R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)OR a , —N(R e )C(O)NR a R b , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —N═CR j R k , and R 2q ; or, alternatively,

R 1 and R 2 , together with the carbon atom to which they are attached, form a monocyclic ring selected from the group consisting of cycloalkyl and cycloalkenyl, wherein:

each of the cycloalkyl and cycloalkenyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of halo, —OH, —O(alkyl), —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , alkyl, and haloalkyl;

as to R 3 and R 4 :

R 3 is selected from the group consisting of hydrogen, cyano, formyl, halo, oxo, nitro, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , alkyl, alkenyl, alkynyl, and R 3p , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 3q ; and

R 4 is selected from the group consisting of hydrogen, cyano, formyl, halo, oxo, nitro, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , alkyl, alkenyl, alkynyl, and R 4p , wherein:

R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycle, wherein:

each of the of aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycle is substituted with (R 8 ) m ;

R 5 is selected from the group consisting of —OR d , —SR d , —NR d R e , —N(H)C(O)R d , —N(H)C(O)OR d , —N(H)SO 2 R d , and —N(H)SO 2 NR d R e ;

R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and -alkylR 106 ;

R 7 at each occurrence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OP(═O)(R e )(OR e ), —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(═NH)R e , —N(R e )C(═Nalkyl)R e , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(═S)NR a R b , —N(R e )C(═S)N(R e )C(O)R a , —N(R e )C(O)OR a , —N(R e )SOR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)R a , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 7p , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, nitro, halo, —N 3 , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SOR a , —N(R e )SO a2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)R a , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 7q ;

R 8 at each occurrence is independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, alkyl, alkenyl, alkynyl, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 8p , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, nitro, oxo, halo, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , —N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 8q ;

R 9 at each occurrence is independently selected from the group consisting of alkyl, alkenyl, alkynyl, —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR a R b , —OSO 2 R a , —OSO 2 NR a R b , —SR a , —S(O)R a , —SO 2 R a , —SO 2 OR a , —SO 2 NR a R b , —NR a R b , N(R e )C(O)R a , —N(R e )C(O)NR a R b , —N(R e )C(O)OR a , —N(R e )SO 2 R a , —N(R e )SO 2 NR a R b , —N(R e )SO 2 N(R e )C(O)OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , and R 9p , wherein:

R 10 is selected from the group consisting of hydrogen and alkyl;

R 11 is selected from the group consisting of hydrogen and alkyl;

as to R a and R b :

R a at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R p , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, —OR c , —OC(O)R c , —OC(O)OR c , —OC(O)NR c R d , —OSO 2 R c , —OSO 2 NR c R d , —SR c , —S(O)R c , —SO 2 R c , —SO 2 OR c , —SO 2 NR c R d , —NR c R d , —N(R e )C(O)R c , —N(R e )C(O)NR c R d , —N(R e )C(O)OR c , —N(R e )SO 2 R c , —N(R e )SO 2 NR c R d , —N(R e )SO 2 N(R e )C(O)OR c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , —C(O)N(R e )NR c R d , and R q ; and

R b at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, hydroxyalkyl, alkoxyalkyl, and -alkylR 106 ; or, alternatively,

R a and R b , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein:

each of the heterocycle and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR c , —OC(O)R c , —OC(O)OR c , —OC(O)NR c R d , —OSO 2 R c , —OSO 2 NR c R d , —SR c , —S(O)R c , —SO 2 R c , —SO 2 OR c , —SO 2 NR c R d , —NR c R d , —N(R e )C(O)R c , —N(R e )C(O)NR c R d , —N(R e )C(O)OR c , —N(R e )SO 2 R c , —N(R e )SO 2 NR c R d , —N(R e )SO 2 N(R e )C(O)OR c , —C(O)R c , —C(O)OR c , and —C(O)NR c R d , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, or 2 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, —OR c , —OC(O)R c , —OC(O)OR c , —OC(O)NR c R d , —OSO 2 R c , —OSO 2 NR c R d , —SR c , —S(O)R c , —SO 2 R c , —SO 2 OR c , —SO 2 NR c R d , —NR c R d , —N(R e )C(O)R c , —N(R e )C(O)NR c R d , —N(R e )C(O)OR c , —N(R e )SO 2 R c , —N(R e )SO 2 NR c R d , —N(R e )SO 2 N(R e )C(O)OR c , —C(O)R c , —C(O)OR c , —C(O)NR c R d , and R q ;

as to R c and R d :

R c at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R 103 , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, oxo, halo, nitro, —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR f R g , —OSO 2 R f , —OSO 2 NR f R g , —SR f , —S(O)R f , —SO 2 R f , —SO 2 OR f , —SO 2 NR f R g , —NR f R g , —N(R e )C(O)R f , —N(R e )C(O)NR f R g , —N(R e )C(O)OR f , —N(R e )SO 2 R f , —N(R e )SO 2 NR f R g , —N(R e )SO 2 N(R e )C(O)OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , and R 103 ; and

R d at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, alkoxyalkyl, hydroxyalkyl, and -alkylR 106 ; or, alternatively,

R c and R d , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein:

each of the heteroaryl and heterocycle is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR f R g , —OSO 2 R f , —OSO 2 NR f R g , —SR f , —S(O)R f , —SO 2 R f , —SO 2 OR f , —SO 2 NR f R g , —NR f R g , —N(R e )C(O)R f , —N(R e )C(O)NR f R g , —N(R e )C(O)OR f , —N(R e )SO 2 R f , —N(R e )SO 2 NR f R g , —N(E e )SO 2 N(R e )C(O)OR f , —C(O)R f , —C(O)OR f , and —C(O)NR f R g , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, halo, nitro, oxo, —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR f R g , —OSO 2 R f , —OSO 2 NR f R g , —SR f , —S(O)R f , —SO 2 R f , —SO 2 NR f R g , —NR f R g , —N(R e )C(O)R f , —N(R e )C(O)NR f R g , —N(R e )C(O)OR f , —N(R e )SO 2 R f , —N(R e )SO 2 NR f R g , —N(R e )SO 2 N(R e )C(O)OR f , —C(O)R f , —C(O)OR f , —C(O)NR f R g , and R 103 ;

R e at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, and alkylR 106 ;

as to R f and R g :

R f at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and R 103 , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, —OH, —O(alkyl), —O(cyanoalkyl), —O(haloalkyl), —O(R 106 ), —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)(R 106 ), —N(alkyl)(R 106 ), —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , and R 103 ; and

R g at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 106 , haloalkyl, and -alkylR 106 ; or, alternatively,

R f and R g , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein:

each of the heterocycle and heteroaryl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OH, —O(alkyl), —O(cyanoalkyl), —O(haloalkyl), —OR 106 , —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)(R 106 ), N(alkyl)(R 106 ), C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), and —C(O)N(alkyl) 2 , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, —OH, —O(alkyl), —O(cyanoalkyl), —O(haloalkyl), —OR 106 , —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)(R 106 ), —N(alkyl)(R 106 ), —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , and R 103 ;

as to R j and R k :

R j at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , haloalkyl, and -alkylR 103 ; and

R k at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl; or, alternatively,

R j and R k , together with the carbon atom to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl, wherein:

each ring is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, cyano, formyl, halo, oxo, —OH, —O(alkyl), —O(cyanoalkyl), —O(haloalkyl), —OR 106 , —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)(R 106 ), —N(alkyl)(R 106 ), —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl) and —C(O)N(alkyl) 2 , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, nitro, halo, oxo, —OH, —O(alkyl), —O(cyanoalkyl), —O(haloalkyl), —OR 106 , —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —N(H)(R 106 ), —N(alkyl)(R 106 ), —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , and R 103 ;

m is selected from the group consisting of 0, 1, 2, 3, and 4;

n is selected from the group consisting of 0, 1, 2, 3, and 4;

p is selected from the group consisting of 0, 1, and 2;

t is selected from the group consisting of 0, 1, 2, 3, and 4;

R p , R q , R 1p , R 1q , R 2q , R 3p , R 3q , R 4p , R 4q , R 7p , R 7q , R 8p , R 8q , R 9p , and R 9q , at each occurrence, are independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; wherein:

each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, formyl, halo, nitro, oxo, —OR 101 , —OC(O)R 101 , —OC(O)OR 101 , —OC(O)NR 101 R 102 , —OSO 2 R 101 , —OSO 2 NR 101 R 102 , —SR 101 , —S(O)R 101 , —SO 2 R 101 , —SO 2 OR 101 , —SO 2 NR 101 R 102 , —NR 101 R 102 , —N(R 102 )C(O)R 101 , —N(R 102 )C(O)OR 101 , —N(R 102 )C(O)NR 101 R 102 , —N(R 102 )SO 2 R 101 , —N(R 102 )SO 2 NR 101 R 102 , —N(R 102 )SO 2 N(R 102 )C(O)OR 101 , —C(O)R 101 , —C(O)OR 101 , and —C(O)NR 101 R 102 , wherein:

each of the alkyl, alkenyl, and alkynyl is substituted with 0, 1, 2, or 3 substituents independently selected from the group consisting of cyano, formyl, halo, nitro, oxo, —OR 101 , —OC(O)R 101 , —OC(O)OR 101 , —OC(O)NR 101 R 102 , —OSO 2 R 101 , —OSO 2 NR 101 R 102 , —SR 101 , —S(O)R 101 , —SO 2 R 101 , SO 2 OR 101 , —SO 2 NR 101 R 102 , —NR 101 R 102 , —N(R 102 )C(O)R 101 , —N(R 102 )C(O)OR 101 , —N(R 102 )C(O)NR 101 R 102 , —N(R 102 )SO 2 R 101 , —N(R 102 )SO 2 NR 101 R 102 , —N(R 102 )SO 2 N(R 102 )C(O)OR 101 , —C(O)R 101 , —C(O)OR 101 , and —C(O)NR 101 R 102 ;

as to R 101 and R 102 :

R 101 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, R 103 , -alkylR 103 , -alkenylR 103 , -alkynylR 103 , haloalkyl, cyanoalkyl, -alkylC(O)R 104 , -alkylC(O)OR 104 , -alkylC(O)NR 104 R 105 , -alkyl-OR 104 , -alkyl-OC(O)R 104 , -alkyl-OC(O)OR 104 , -alkylSR 104 , -alkylS(O)R 104 , -alkylSO 2 R 104 , -alkylSO 2 OR 104 , -alkylSO 2 NR 104 R 105 , -alkylNR 104 R 105 , -alkylN(R 105 )C(O)R 104 , -alkylN(R 105 )C(O)OR 104 , -alkylN(R 105 )C(O)NR 104 R 105 , -alkylN(R 105 )SO 2 R 104 , and -alkylN(R 105 )SO 2 NR 104 R 105 ; and

R 102 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, and benzyl; or, alternatively,

R 101 and R 102 , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein:

each of the heterocycle or heteroaryl is substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, —OH, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , —SH, —Salkyl, —S(O)alkyl, —SO 2 alkyl, —C(O)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylN(alkyl) 2 , -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH 2 , -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl) 2 , -alkylSH, -alkylSalkyl, -alkylS(O)alkyl, -alkylSO 2 alkyl and -alkylC(O)alkyl;

R 103 at each occurrence is independently selected from the group consisting of cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle, wherein:

each of the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle is independently substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, nitro, cyano, oxo, formyl, haloalkyl, —OR 104 , —OC(O)R 104 , —OC(O)OR 104 , —OC(O)NR 104 R 105 , —OSO 2 NR 104 R 105 , —SO 2 R 105 , —S(O)R 104 , —NR 104 R 105 , —N(R 105 )C(O)NR 104 R 105 , —N(R 105 )COR 104 , —N(R 105 )SO 2 R 104 , —N(R 105)SO 2 NR 104 R 105 , —C(O)R 104 , —C(O)OR 104 , —C(O)NR 104 R 103 , -alkylOR 104 , -alkylOC(O)R 104 , -alkylOC(O)OR 104 , -alkylOC(O)NR 104 R 105 , -alkylOSO 2 NR 104 R 105 , -alkylSO 2 R 104 , -alkylS(O)R 104 , -alkylNR 104 R 105 , -alkylN(R 105 )COR 104 , -alkylN(R 105 )SO 2 R 104 , -alkylN(R 104 )C(O)NR 104 R 105 , -alkylN(R 105 )SO 2 NR 104 R 105 , -alkylC(O)R 104 , -alkylC(O)OR 104 , and -alkylC(O)NR 104 R 105 ;

as to R 104 and R 105 :

R 104 and R 105 , at each occurrence, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, and benzyl; or, alternatively,

R 104 and R 105 , together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of heterocycle and heteroaryl, wherein:

each of the heterocycle or heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, —OH, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , —SH, —Salkyl, —S(O)alkyl, —SO 2 alkyl, —C(O)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylN(alkyl) 2 , -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH 2 , -alkylC(O)N(H)(alkyl), —alkylC(O)N(alkyl) 2 , —alkylSH, -alkylSalkyl, -alkylS(O)alkyl, -alkylSO 2 alkyl, and -alkylC(O)alkyl; and

R 106 at each occurrence is independently selected from the group consisting of aryl and heteroaryl, wherein:

each of the aryl and heteroaryl is substituted with 0, 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, nitro, formyl, halo, cyano, —OH, —Oalkyl, —NH 2 , —N(H)(alkyl), —N(alkyl) 2 , —C(O)OH, —C(O)Oalkyl, —C(O)NH 2 , —C(O)N(H)(alkyl), —C(O)N(alkyl) 2 , —SH, —Salkyl, —S(O)alkyl, —SO 2 alkyl, —C(O)alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, -alkylNH 2 , -alkylN(H)(alkyl), -alkylN(alkyl) 2 , -alkylC(O)OH, -alkylC(O)Oalkyl, -alkylC(O)NH 2 , -alkylC(O)N(H)(alkyl), -alkylC(O)N(alkyl) 2 , —alkylSH, -alkylSalkyl, -alkylS(O)alkyl, -alkylSO 2 alkyl, and alkylC(O)alkyl.

2. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 1 , wherein:

R 5 is —OR d , and

R d is hydrogen.

3. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 1 , wherein R 3 and R 4 , together with the carbon atoms they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl.

4. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 1 , wherein:

R 5 is —OR d ,

R d is hydrogen, and

R 6 is selected from the group consisting of hydrogen and alkyl.

5. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 1 , wherein:

R 5 is —OR d ,

R d is hydrogen,

R 6 is selected from the group consisting of hydrogen and alkyl, and

R 3 and R 4 , together with the carbon atoms to which they are attached, form a ring selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl.

6. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 1 , wherein:

the compound corresponds to formula (III):

7. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 6 , wherein R 5 is —OR d , wherein R d is hydrogen.

8. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 6 , wherein:

R 5 is —OR d , wherein R d is hydrogen, and

R 6 is selected from the group consisting of hydrogen and alkyl.

9. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 6 , wherein:

R 5 is —OR d , wherein R d is hydrogen,

R 6 is selected from the group consisting of hydrogen and alkyl,

R 1 is selected from the group consisting of:

(1) alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of:

(a) halo,

(b) —OR a , wherein R a is hydrogen,

(d) —OC(O)NR a R b , wherein R a is alkyl and R b is hydrogen,

(e) —C(O)OR a , wherein R a is alkyl,

(f) —C(R e )═CR j R k , wherein R e is hydrogen and R j and R k , together with the carbon atom to which they are attached, form a cycloalkyl ring; and

(g) —R 1q , wherein R 1q is selected from the group consisting of aryl and cycloalkyl;

(2) alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of:

(a) —C(O)OR a , wherein R a is alkyl, and

(b) —R 1q , wherein R 1q is aryl,

(3) —C(O)OR a , wherein R a is alkyl, wherein the alkyl is unsubstituted or substituted with one R q , wherein R q is a heterocyclic ring, wherein the heterocyclic ring is unsubstituted or substituted with one —C(O)OR 101 , wherein R 101 is alkyl,

(4) —C(O)NR a R b , wherein:

R a is alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of —OC(O)R c and —OR c , wherein R c is selected from the group consisting of hydrogen and alkyl, and

R b is alkyl, or, alternatively,

R a and R b , together with the nitrogen atom to which they are attached, form a heterocyclic ring substituted with alkyl substituted with one substituent selected from the group consisting of —OR c and —OC(O)R c , wherein R c is selected from the group consisting of hydrogen and alkyl, or

(5) R 1p , wherein R 1p is heterocycle; and

R 2 is alkyl.

10. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 6 , wherein:

R 5 is —OR d , wherein R d is hydrogen,

R 6 is selected from the group consisting of hydrogen and alkyl,

R 1 is selected from the group consisting of:

(1) alkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of:

(a) halo,

(b) —OR a , wherein R a is hydrogen,

(d) —OC(O)NR a R b , wherein R a is alkyl and R b is hydrogen,

(e) —C(O)OR a , wherein R a is alkyl,

(f) —C(R e )═CR j R k , wherein R e is hydrogen and R j and R k , together with the carbon atom to which they are attached, form a cycloalkyl ring; and

(g) —R 1q , wherein R 1q is selected from the group consisting of aryl and cycloalkyl;

(2) alkenyl, wherein the alkenyl is unsubstituted or substituted with one substituent selected from the group consisting of:

(a) —C(O)OR a , wherein R a is alkyl, and

(b) —R 1q , wherein R 1q is aryl,

(4) —C(O)NR a R b , wherein:

R b is alkyl, or, alternatively,

(5) R 1p , wherein R 1p is heterocycle;

R 2 is alkyl;

R 7 is selected from the group consisting of:

(1) formyl,

(2) —OR a , wherein R a , is selected from the group consisting of hydrogen and alkyl, wherein: the alkyl is substituted with one substituent selected from the group consisting of cyano and —C(O)NR c R d , wherein R c is hydrogen and R d is hydrogen,

(3) —OP(═O)(R e )(OR e ), wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl,

(4) —NR a R b , wherein R a is selected from the group consisting of hydrogen and alkyl substituted with one cyano and R b is hydrogen,

(5) —N(R e )C(═NH)R e , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl,

(6) —N(R e )C(O)R a , wherein:

R a is alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2, or 3 independently selected halo, and

R e is selected from the group consisting of hydrogen and alkyl,

(7) —N(R e )C(O)NR a R b , wherein R a is hydrogen, R b is hydrogen, and R e is selected from the group consisting of hydrogen and alkyl,

(8) —N(R e )C(═S)NR a R b , wherein R a is hydrogen, R b is hydrogen, and R e is selected from the group consisting of hydrogen and alkyl,

(9) —N(R e )C(═S)N(R e )C(O)R a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is R p , wherein R p is aryl,

(10) —N(R e )C(O)OR a , wherein R a is alkyl and R e is selected from the group consisting of hydrogen and alkyl,

(11) —N(R e )SOR a , wherein R a is alkyl, and R e is selected from the group consisting of hydrogen and alkyl,

(12) —N(R e )SO 2 R a , wherein:

R e is selected from the group consisting of hydrogen and alkyl,

R a is selected from the group consisting of alkyl, alkenyl, and R q , wherein:

R q is selected from the group consisting of heteroaryl and aryl, and

the alkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

(a) halo,

(b) —C(O)OR c , wherein R c is selected from the group consisting of hydrogen and alkyl,

(d) —C(O)NR c R d , wherein R c is hydrogen and R d is hydrogen,

(13) —N(R e )SO 2 NR a R b , wherein:

R e is selected from the group consisting of hydrogen and alkyl, and

as to R a and R b :

R b is hydrogen, and

R a is selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of:

(a) —OR c , wherein R c is hydrogen,

(b) —NR c R d , wherein R c and R d are hydrogen, and

(c) —OC(O)NR c R d , wherein R c and R d , together with the nitrogen atom to which they are attached, form a heterocycle ring; or, alternatively,

R a and R b , together with the nitrogen atom to which they are attached, form a heterocycle ring;

(14) —N(R e )SO 2 N(R e )C(O)R a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl,

(15) —N(R e )SO 2 N(R e )C(O)OR a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl substituted with one R q , wherein R q is aryl, and

(16) alkyl substituted with one substituent selected from the group consisting of

(a) N 3 ,

(b) —OR a , wherein R a is selected from the group consisting of hydrogen and alkyl substituted with one —OR c , wherein R c is alkyl,

(d) —N(R e )SOR a , wherein R a is alkyl and R e is selected from the group consisting of hydrogen and alkyl,

(e) —N(R e )SO 2 R a , wherein R b is selected from the group consisting of hydrogen and alkyl, and R a is alkyl, wherein the alkyl is unsubstituted or substituted with one substituent selected from the group consisting of halo and 1R, wherein; is heterocycle;

(f) —N(R e )SO 2 NR a R b , wherein R a and R b are hydrogen, and R e is selected from the group consisting of hydrogen and alkyl,

(g) —N(R e )SO 2 N(R e )C(O)OR a , wherein R e at each occurrence is independently selected from the group consisting of hydrogen and alkyl, and R a is alkyl substituted with R q , wherein R q is aryl,

(h) C(O)NR a R b , wherein R a is hydrogen and R b is hydrogen, and

(i) R 7q , wherein R 7q is heterocycle;

R 8 is selected from the group consisting of halo and —OR a , wherein R a is selected from the group consisting of hydrogen and alkyl;

m is selected from the group consisting of 0 and 1; and

n is selected from the group consisting of 0 and 1.

11. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 6 wherein the compound is selected from the group consisting of:

1,1-dibutyl-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-2(1H)-naphthalenone;

1,1-dibutyl-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-2(1H)-naphthalenone;

(1R)-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;

(1R)-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;

(1R)-3-[7-(azidomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-4-hydroxy-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;

(1R)-3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-4-hydroxy-1-methyl-1-(3-methylbutyl)naphthalen-2(1H)-one;

N-({3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide;

N-({3-[(4R)-1-hydroxy-4-methyl-4-(3-methylbutyl)-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)-2-morpholin-4-ylethanesulfonamide;

(1R)-1-(3,3-dimethylbutyl)-4-hydroxy-3-{7-[(methoxymethoxy)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-1-methylnaphthalen-2(1H)-one;

(1R)-1-(3,3-dimethylbutyl)-4-hydroxy-3-[7-(hydroxymethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-methylnaphthalen-2(1H)-one;

(1R)-3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-(3,3-dimethyl-butyl)-4-hydroxy-1-methylnaphthalen-2(1H)-one;

N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)-N-methylmethanesulfonamide;

N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-4-methyl-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)-N-methylmethanesulfonamide;

benzyl[({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)amino]sulfonylcarbamate;

3-chloro-N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)propane-1-sulfonamide; and

(1R)-1-(3,3-dimethylbutyl)-3-{7-[(1,1-dioxidoisothiazolidin-2-yl)methyl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl}-4-hydroxy-1-methylnaphthalen-2(1H)-one.

12. A compound, a stereoisomer of the compound, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, stereoisomer, or tautomer, or a combination thereof, wherein the compound is selected from the group consisting of:

N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)methanesulfonamide; and

N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)sulfamide.

13. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 12 , wherein the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, calcium, and magnesium salt.

14. A pharmaceutical composition comprising:

a therapeutically effective amount of one or more compounds, stereoisomers, tautomers, or salts of claim 1 or a combination thereof, and

a pharmaceutically acceptable carrier.

15. A method of treating infection caused by a a hepatitis C virus, wherein the method comprises administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds, stereoisomers, tautomers, or salts of claim 1 , or a combination thereof.

16. A pharmaceutical composition comprising:

a therapeutically effective amount of one or more compounds, stereoisomers, tautomers, or salts of claim 12 or a combination thereof, and

a pharmaceutically acceptable carrier.

17. A method of treating infection caused by a a hepatitis C virus, wherein the method comprises administering to a patient in need of such treatment a therapeutically effective amount of one or more compounds, stereoisomers, tautomers, or salts of claim 12 , or a combination thereof.

18. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 12 , wherein the compound is N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)methane-sulfonamide.

19. The compound, stereoisomer, tautomer, salt, or combination thereof of claim 12 , wherein the compound is N-({3-[(4R)-4-(3,3-dimethylbutyl)-1-hydroxy-4-methyl-3-oxo-3,4-dihydronaphthalen-2-yl]-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl}methyl)sulfamide.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 9, 2013

From: ABBOTT LABORATORIES

To: ABBVIE INC.

Reel/Frame 030182/0547 →