Macrocyclic hepatitis c serine protease inhibitors

Abstract

The present invention relates to novel fluorinated macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.

1 . A compound of formula I or formula I′; 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, or prodrugs thereof, 
       
       wherein:
 X is an optionally substituted carbocyclic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 Z is O, S(O) m , NR x , OC(O), C(O), C(O)O, NR x C(O), or C(O)NR x ;
 each R, is independently H or alkyl; 
 
 J is —C(O)—, —O—C(O)—, —C(O)O—, —N(R 3 )—C(O)—, —C(S)—, —C(═NR 4 )—, —N(R 3 )—, —S(O)—, or —S(O 2 )— or absent; 
 A is selected from the group consisting of the following:
 (i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (ii) heterocyclyl or substituted heterocyclyl; and 
 (iii) —C 1 -C 8  alkyl, C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl or substituted —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12  carbocyclic, substituted —C 3 -C 12  carbocyclic; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 
 E is -G-R 5 ;
 wherein G is absent; optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; 
 or —O—, —S—, —N(R 3 )—, —N(R 3 )S(O p ), —N(R 3 )C(O), —N(R 3 )C(O)S(O p )—, —OS(O p )—, —C(O)S(O p )—, or —C(O)N(R 3 )S(O p )—; 
 each p is independently 0, 1, or 2; 
 R 5  is H; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; 
 
    denotes a carbon-carbon single or double bond (i.e., 
 
       
         
           
           
               
               
           
         
       
       means 
       
         
           
           
               
               
           
         
         each of R a , R b , R c , and R d  are each independently H or halo, wherein at least two of R a , R b , R c , and R d  are halo; and R b  and R d  are absent if   is a double bond 
         each R 3  and R 4  is independently selected at each occurrence from the following: H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; and optionally substituted carbocyclic; 
         L is absent or a C 2 -C 5  saturated or unsaturated chain, optionally containing one to three heteroatoms independently selected from O, N and S(O) q  wherein L is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein each C 2 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, group is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl and cyano; 
         j=independently 0, 1, 2, 3, or 4; 
         k=independently 0, 1, 2, or 3; 
         each m is independently 0, 1, or 2; and 
         q is independently 0, 1, or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein Z is O or OC(O); and ring X is cyciopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, phenyl, naphtliyi, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H 1,5,2 dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H indazolyl, indolenyl, indolinyl indozinyl, indolyl, 3H indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3 oxadiazolyl, 1,2,4 oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4 oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazdlyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H 1,2,5 thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4 thiadiazolyl, 1,2,5 thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3 triazolyl, 1,2,4 triazolyl, 1,2,5 triazolyl, 1,3,4 triazolyl, or xanthenyl; each of which may be optionally substituted. 
     
     
         3 . The compound of  claim 2 , wherein ring X is phenanthridinyl, quinoxalinyl, quinolinyl, or isoindolinyl. 
     
     
         4 . The compound of  claim 2 , wherein ring X is 
       
         
           
           
               
               
           
         
       
       wherein
 Y is N or —C(R″)—; 
 wherein if Y is —C(R″)—, then R′ and R″ taken together with the carbon atoms to which they are attached form a ring, which is optionally substituted; 
 R′ is H, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; 
 each R 1  is independently selected from halogen, hydroxy, amino, —CN, —CF 3 , —N 3 , —NO 2 , —OR 4 , —SR 4 , —SOR 4 , —SO 2 R 4 , N(R 3 )S(O) 2 R 4 , —N(R 3 )(SO 2 )NR 3 R 4 , —NR 3 R 4 , —C(O)—OR 4 , —C(O)R 4 , —C(O)NR 3 R 4 , —N(R 3 )C(O)R 4 ; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; 
 each n is independently 0, 1, 2, 3, or 4; 
 each R 3  and R 4  are independently selected at each occurrence from the following: optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen; and 
 k is 0, 1, or 2. 
 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1  wherein J is —C(O)—, or —O—C(O)—. 
     
     
         7 . The compound of  claim 1 , wherein A is methyl, ethyl, propyl, iso-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, furanyl, thiophenyl, pyrrolyl, isoxazolyl, or pyrazolyl; each of which may be optionally substituted. 
     
     
         8 . The compound of  claim 1 , wherein G is —N(R 3 )S(O) p — and R 5  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each of which is optionally substituted. 
     
     
         9 . The compound of  claim 5 , wherein R a  and R b  are F. 
     
     
         10 . The compound of  claim 5 , wherein R c  and R d  are F. 
     
     
         11 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient. 
     
     
         19 . A method of treating a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or prodrug thereof. 
     
     
         20 . A method of producing a compound of formula I, comprising the step of reacting a compound of formula I-a: 
       
         
           
           
               
               
           
         
       
       with a compound of formula I-b: 
       
         
           
           
               
               
           
         
       
       to arrive at a compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is an optionally substituted carbocyclic, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 Z is O, S(O)m, NRx, OC(O), C(O), C(O)O, NRxC(O), or C(O)NRx;
 each Rx is independently H or alkyl; 
 
 Nuc is a nucleophile; 
 LG is a leaving group; 
 J is —C(O)—, —O—C(O)—, —C(O)O—, —N(R 3 )—C(O)—, —C(S)—, —C(═NR 4 )—, —N(R 3 )—, —S(O)—, or —S(O 2 )- or absent; 
 A is selected from the group consisting of the following:
 (i) H, aryl; substituted aryl; heteroaryl; substituted heteroaryl; 
 (ii) heterocyclyl or substituted beterocyclyl; and 
 —C 1 -C 8  alkyl, —C 2 -C 8  alkenyl or —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S, and N; substituted —C 1 -C 8  alkyl, substituted —C 2 -C 8  alkenyl or substituted —C 2 -C 8  alkynyl, each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; —C 3 -C 12  carbocyclic, substituted —C 3 -C 12  carbocyclic; —C 3 -C 12  cycloalkenyl, or substituted —C 3 -C 12  cycloalkenyl; 
 
 E is -G-R 5 ;
 wherein G is absent; optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; 
 or —O—, —S—, —N(R 3 )S(O p )—, —N(R 3 )C(O)—, —N(R 3 ) C(O)S(O p )—, —OS(O p )—, —C(O)S(O)—, or —C(O)N(R 3 )S(O p )—; 
 each p is independently 0, 1, or 2; 
 R 5  is H; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl; 
 
    denotes a carbon-carbon single or double bond (i.e., 
 
       
         
           
           
               
               
           
         
       
       means or); 
       
         
           
           
               
               
           
         
         each of R a , R b , R c , and R d  are each independently H or halo, wherein at least two of R a , R b , R c , and R d  are halo; and R b  and R d  are absent if   is a double bond 
         each R 3  and R 4  is independently selected at each occurrence from the following; H, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; 
         optionally substituted heteroaryl; optionally substituted heterocyclic; and optionally substituted carbocyclic; 
         L is absent or a C 2 -C 5  saturated or unsaturated chain, optionally containing one to three heteroatoms independently selected from O, N and S(O) q , wherein L is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, wherein each C 2 -C 6 alkenyl and C 2 -C 6 alkynyl, group is optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl and cyano; 
         j=independently 0, 1, 2, 3, or 4; 
         k=independently 0, 1, 2, or 3; 
         each m is independently 0, 1, or 2; and 
         q is independently 0, 1, or 2.