US2017088583A1PendingUtilityA1
Macrocyclic proline derived hcv serine protease inhibitors
Est. expirySep 21, 2030(~4.2 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 37/02A61P 31/04A61P 43/00A61P 31/10A61P 31/12A61P 31/14A61P 1/16A61K 38/00C07K 14/811C07K 5/06034C07K 5/0808A61K 31/00C07D 498/22C07D 498/00A61K 31/495A61K 31/33C07K 5/123A61K 38/215C07K 5/0827C07D 498/18C07K 5/0823C07D 498/12A61K 45/06A61K 31/395A61K 31/4985A61K 39/00A61K 38/12A61K 38/212
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Claims
Abstract
The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
wherein:
A is absent, —(C═O)—, —S(O) 2 —, —C(═N—OR 1 )— or —C(═N—CN)—;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
M 1 and M 2 are each independently selected from O or NR 1 ;
each R 1 is independently selected at each occurrence from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
L 1 and L 2 are each independently selected from —C 1 -C 8 alkylene, —C 2 -C 8 alkenylene, or —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkylene, substituted —C 2 -C 8 alkenylene, or substituted —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkylene, or substituted —C 3 -C 12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkenylene, and substituted —C 3 -C 12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
X and Y taken together with the carbon atoms to which they are attached to form a cyclic moiety which selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocylic, carbocyclic, and substituted carbocyclic;
X′ is N or —C(R 2 )—, where R 2 is selected from the group consisting of:
(i) hydrogen, halogen, CN, CF 3 , NO 2 , OR 3 , SR 3 , —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , NR 4 R 5 , CO 2 R 3 , COR 3 , CONR 4 R 5 , N(R 1 )COR 3 ; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; 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 selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
each R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; and —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, r substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogenor deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
2 . The compound of claim 1 , wherein the compound is of Formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, where X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
hydrogen; halogen; —NO 2 ; —CN; or N 3 ;
(ii) -M-R 3 , wherein M is O, S, NH;
(iii) NR 4 R 5 ;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
(vi) heterocycloalkyl or substituted heterocycloalkyl;
A is absent, —(C═O)—, —S(O) 2 —, —C(═N—OR 1 )— or —C(═N—CN)—;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
M 1 and M 2 are each independently selected from O and NR 1 ;
each R 1 is independently selected at each occurrence from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
L 1 and L 2 are each independently selected from —C 1 -C 8 alkylene, —C 2 -C 8 alkenylene, or —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkylene, substituted —C 2 -C 8 alkenylene, or substituted —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkylene, or substituted —C 3 -C 12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkenylene or substituted —C 3 -C 12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
X′ is N or —C(R 2 )—, where R 2 is selected from the group consisting of:
(i) hydrogen, halogen, CN, CF 3 , NO 2 , OR 3 , SR 3 , —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , NR 4 R 5 , CO 2 R 3 , COR 3 , CONR 4 R 5 , N(R 1 )COR 3 ; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; 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 selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
each R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogen; deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
3 . The compound of claim 1 , wherein the compound is of Formula III or IV:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, where each Y 1 and Y 2 are independently selected from CR 6 , N, and each Y 3 is selected from NR 6 , S and O;
each R 6 is independently selected from:
(i) hydrogen; halogen; —NO 2 ; —CN; or N 3 ;
(ii) -M-R 3 , wherein M is O, S, or NH;
(iii) NR 4 R 5 ;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
(vi) heterocycloalkyl or substituted heterocycloalkyl;
A is absent, —(C═O)—, —S(O) 2 —, —C(═N—OR 1 )— or —C(═N—CN)—;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
M 1 and M 2 are each independently selected from O and NR 1 ;
each R 1 is independently selected at each occurrence from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
L 1 and L 2 are each independently selected from —C 1 -C 8 alkylene, —C 2 -C 8 alkenylene, or —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkylene, substituted —C 2 -C 8 alkenylene, or substituted —C 2 -C 8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkylene, or substituted —C 3 -C 12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkenylene, or substituted —C 3 -C 12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
X′ is N or —C(R 2 )—, where R 2 is selected from the group consisting of:
(i) hydrogen, halogen, CN, CF 3 , NO 2 , OR 3 , SR 3 , —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , NR 4 R 5 , CO 2 R 3 , COR 3 , CONR 4 R 5 , N(R 1 )COR 3 ; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; 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 selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
each R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogen or deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
4 . The compound of claim 1 , wherein the compound is of Formula V:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein
X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
(i) hydrogen; halogen; —NO 2 ; —CN; or N 3 ;
(ii) -M-R 3 , where M is O, S, or NH;
(iii) NR 4 R 5 ;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
(vi) heterocycloalkyl or substituted heterocycloalkyl;
A is absent, —(C═O)—, —S(O) 2 —, —C(═N—OR 1 )— or —C(═N—CN)—;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
M 1 and M 2 are each independently selected from O and NR 1 ;
each R 1 is independently selected at each occurrence from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
X′ is N or —C(R 2 )—, where R 2 is selected from the group consisting of:
(i) hydrogen, halogen, CN, CF 3 , NO 2 , OR 3 , SR 3 , —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , NR 4 R 5 , CO 2 R 3 , COR 3 , CONR 4 R 5 , N(R 1 )COR 3 ; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; 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 selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
each R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
—C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogen; or deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
5 . The compound of claim 1 , wherein the compound is of Formula VI:
or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein
X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
(i) hydrogen; halogen; —NO 2 ; —CN; or N 3 ;
(ii) -M-R 3 , wherein M is O, S, or NH;
(iii) NR 4 R 5 ;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
(vi) heterocycloalkyl or substituted heterocycloalkyl;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
M 1 and M 2 are each independently selected from O and NR 1 ;
each R 1 is independently selected at each occurrence from the group consisting of:
hydrogen;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; cycloalkyl, substituted —C 3 -C 12 cycloalkyl; cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
each R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 —C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogen; or deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 , and NR 4 R 5 ; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
6 . The compounds of claim 1 , wherein the compound is of Formula VII:
wherein:
R 1′ , R 2′ , R 3′ and R 4′ are each independently R 6 , or R 1′ and R 2′ , R 2′ and R 3′ , or R 3′ and R 4′ combined together with the carbons they are attached to form aromatic or heteroaromatic or cyclic or heterocyclic ring;
{circle around (B)} is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted C 3 -C 12 heterocycloalkyl;
or {circle around (B)} is
wherein R 7 and R 5 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
each R 6 is independently selected from:
(i) hydrogen; halogen; —NO 2 ; —CN; or N 3 ;
(ii) -M-R 3 , wherein M is O, S, or NH;
(iii) NR 4 R 5 ;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
(vi) heterocycloalkyl or substituted heterocycloalkyl;
R 3 is independently selected from C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
each R 4 and R 5 are independently selected from H and R 3 , or R 4 and R 5 combined together with the N they are attached to form a heterocyclic ring;
R and R′ are each independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or 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 selected from O, S or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; and
(iv) hydrogen; or deuterium; and
R″ is selected from hydrogen, methyl, ethyl, and allyl.
7 . The compound of claim 6 , wherein {circle around (B)} is C 3 -C 12 cycloalkyl or 4- to 6-membered heterocycloalkyl and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 8 alkyl or C 2 -C 8 alkenyl.
8 . The compound of claim 7 , wherein {circle around (B)} is a non-aromatic C 3 -C 6 cycloalkyl or a non-aromatic 4- to 6-membered heterocycloalkyl and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl or C 2 -C 6 alkenyl.
9 . The compound of claim 8 , wherein {circle around (B)} is saturated C 4 -C 6 cycloalkyl or saturated 4- to 6-membered heterocycloalkyl and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 8 alkyl or C 2 -C 8 alkenyl.
10 . The compound of claim 8 , wherein {circle around (B)} is selected from:
11 . The compound of claim 6 , wherein (a) R 1′ , R 2′ , R 3′ and R 4′ are hydrogen; (b) R 1′ and R 4′ are hydrogen; and one of R 2′ and R 3′ is hydrogen, and the other is selected from halo, methyl optionally substituted with one or more halo, or —O-methyl optionally substituted with one or more halo; (c) R 1′ and R 2′ , or R 2′ and R 3′ , or R 3′ and R 4′ , taken together with carbon atoms to which they are attached, form a 5- or 6-membered carbocycle or heterocycle (e.g., phenyl), and the rest of R 1′ , R 2′ , R 3′ and R 4′ are hydrogen.
12 . The compound of claim 6 , wherein R 3 is
13 . The compound of claim 6 , wherein R′ is
14 . The compound of claim 6 , wherein R is
15 . The compound of claim 6 , wherein:
(a) {circle around (B)} is
R′ is vinyl
or difluoromethyl
R 3 is
and R is
(b) {circle around (B)}
is R′ is vinyl
or difluoromethyl
R 3 is
and R is
R 3′ is —O-methyl optionally substituted with one or more halo, and R 1′ , R 2′ , and R 4′ are hydrogen;
(c) {circle around (B)} is
R′ is vinyl
or difluoromethyl
R 3 is
and R is
and R 1′ , R 2′ , R 3′ and R 4′ are hydrogen;
(d) {circle around (B)} is
R′ is vinyl
or difluoromethyl
R 3 is
and R is
R 3′ is halo, and R″, R 2′ , and R 4′ are hydrogen; or
(e) {circle around (B)} is
R′ is vinyl
or difluoromethyl
R 3 is
and R is
R 3′ and R 4′ taken together with carbon atoms to which they are attached form phenyl, and R 1′ and R 2′ are hydrogen.
16 . A pharmaceutical composition comprising an inhibitory amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
17 . A method of treating a viral infection in a subject, comprising administering to the subject an inhibitory amount of a pharmaceutical composition according to claim 16 .
18 . The method according to claim 17 , wherein the viral infection is hepatitis C virus.
19 . A method of inhibiting the replication of hepatitis C virus, the method comprising supplying a hepatitis C viral NS3 protease inhibitory amount of the pharmaceutical composition of claim 16 .
20 . The method of claim 17 , further comprising administering concurrently an additional anti-hepatitis C virus agent.
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