MACROCYCLIC HEPATITIS C SERINE PROTEASE INHIBITORS

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.