Details for Patent: 9,220,748

Title:	Macrocyclic proline derived HCV serine protease inhibitors
Abstract:	The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: ##STR00001## 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.
Inventor(s):	Or; Yat Sun (Watertown, MA), Ma; Jun (Belmont, MA), Wang; Guoqiang (Belmont, MA), Long; Jiang (Wayland, MA), Wang; Bin (Brighton, MA)
Assignee:	Enanta Pharmaceuticals, Inc. (Watertown, MA)
Filing Date:	Jan 02, 2014
Application Number:	14/146,161
Claims:	1. A compound of Formula I: ##STR01638## or a pharmaceutically acceptable salt thereof, wherein A is absent, --(C.dbd.O)--, --S(O).sub.2-, --C(.dbd.N--OR.sub.1)-- or --C(.dbd.N--CN)--; {circle around (B )} is ##STR01639## wherein R.sub.7 and R.sub.8 are each independently C.sub.1-C.sub.8 alkyl or C.sub.2-C.sub.8 alkenyl and are each independently optionally substituted with one or more halo; M.sub.1 and M.sub.2 are each independently O or NR.sub.1; each R.sub.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.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; L.sub.1 and L.sub.2 are each independently selected from --C.sub.1-C.sub.8 alkylene, --C.sub.2-C.sub.8alkenylene, or --C.sub.2-C.sub.8alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkylene, substituted --C.sub.2-C.sub.8alkenylene, or substituted --C.sub.2-C.sub.8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12cycloalkylene, or substituted --C.sub.3-C.sub.12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12cycloalkenylene, and substituted --C.sub.3-C.sub.12cycloalkenylene 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.sub.2)--, where R.sub.2 is selected from the group consisting of: (i) hydrogen, halogen, CN, CF.sub.3, NO.sub.2, OR.sub.3, SR.sub.3, --NHS(O).sub.2--R.sub.3,--NH(SO.sub.2)NR.sub.4R.sub.5, NR.sub.4R.sub.5, CO.sub.2R.sub.3, COR.sub.3, CONR.sub.4R.sub.5, N(R.sub.1)COR.sub.3; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; (ii) heterocycloalkyl or substituted heterocycloalkyl; and (iii) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; each R.sub.3 is independently selected from C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl; each R.sub.4 and R.sub.5 are independently selected from H and R.sub.3, or R.sub.4 and R.sub.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.sub.1-C.sub.8alkyl, --C.sub.2-C.sub.8alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, r substituted --C.sub.3-C.sub.12cycloalkyl; --C.sub.4-C.sub.12 alkylcycloalkyl, substituted --C.sub.4-C.sub.12 alkylcycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, substituted --C.sub.3-C.sub.12 cycloalkenyl; --C.sub.4-C.sub.12 alkylcycloalkenyl, or substituted --C.sub.4-C.sub.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).sub.2--R.sub.3, --NH(SO.sub.2)NR.sub.4R.sub.5, and NR.sub.4R.sub.5; and R'' is selected from hydrogen, methyl, ethyl, and allyl. 2. The compound of claim 1, wherein the compound is of Formula II: ##STR01640## or a pharmaceutically acceptable salt thereof, where X.sub.1-X.sub.4 are independently selected from --CR.sub.6 and N, wherein each R.sub.6 is independently selected from: (i) hydrogen; halogen; --NO.sub.2; --CN; or N.sub.3; (ii) -M-R.sub.3, wherein M is O, S, NH; (iii) NR.sub.4R.sub.5; (iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; X', L.sub.1, W, L.sub.2, {circle around (B)} , M.sub.2, A, R, R', R'', R.sub.3 R.sub.4 R.sub.5 and G are as defined in claim 1. 3. The compound of claim 1, wherein the compound is of Formula III or IV: ##STR01641## or a pharmaceutically acceptable salt thereof, where each Y.sub.1 and Y.sub.2 are independently selected from CR.sub.6, N, and each Y.sub.3 is selected from NR.sub.6, S and O; each R.sub.6 is independently selected from: (i) hydrogen; halogen; --NO.sub.2; --CN; or N.sub.3; (ii) -M-R.sub.3, wherein M is O, S, or NH; (iii) NR.sub.4R.sub.5; (iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3--C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; X', L.sub.1, W, L.sub.2, M.sub.1, {circle around (B)} , M.sub.2, A, R, R', R'', R.sub.3 R.sub.4 R.sub.5 and G are as defined in claim 1. 4. The compound of claim 1, wherein the compound is of Formula V: ##STR01642## or a pharmaceutically acceptable salt thereof, wherein X.sub.1-X.sub.4 are independently selected from --CR.sub.6 and N, wherein each R.sub.6 is independently selected from: (i) hydrogen; halogen; --NO.sub.2; --CN; or N.sub.3; (ii) -M-R.sub.3, where M is O, S, or NH; (iii) NR.sub.4R.sub.5; (iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; X', L.sub.1, W, L.sub.2, M.sub.1, {circle around (B)} , M.sub.2, A, R, R', R'', R.sub.3R.sub.4, R.sub.5 and G are as defined in claim 1. 5. The compound of claim 1, wherein the compound is of Formula VI: ##STR01643## or a pharmaceutically acceptable salt thereof, wherein X.sub.1-X.sub.4 are independently selected from --CR.sub.6 and N, wherein each R.sub.6 is independently selected from: (i) hydrogen; halogen; --NO.sub.2; --CN; or N.sub.3; (ii) -M-R.sub.3, wherein M is O, S, or NH; (iii) NR.sub.4R.sub.5; (iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; L.sub.1, W, L.sub.2, M.sub.1, {circle around (B)} , M.sub.2, A, R, R', R'', R.sub.3, R.sub.4, R.sub.5 and G are as defined in claim 1. 6. The compound of claim 1, wherein the compound is of Formula VII: ##STR01644## or a pharmaceutically acceptable salt thereof, wherein R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are each independently R.sub.6, or R.sup.1' and R.sup.2', R.sup.2' and R.sup.3', or R.sup.3' and R.sup.4' are taken together with the carbon atoms to which they are attached to form an aromatic or heteroaromatic or cyclic or heterocyclic ring; each R.sub.6 is independently selected from: (i) hydrogen; halogen; --NO.sub.2; --CN; or N.sub.3; (ii) -M-R.sub.3, wherein M is O, S, or NH; (iii) NR.sub.4R.sub.5; (iv) --C.sub.1-C.sub.8 alkyl, --C.sub.2-C.sub.8 alkenyl, or --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted --C.sub.1-C.sub.8 alkyl, substituted --C.sub.2-C.sub.8 alkenyl, or substituted --C.sub.2-C.sub.8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; --C.sub.3-C.sub.12 cycloalkyl, substituted --C.sub.3-C.sub.12 cycloalkyl; --C.sub.3-C.sub.12 cycloalkenyl, or substituted --C.sub.3-C.sub.12 cycloalkenyl; (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and (vi) heterocycloalkyl or substituted heterocycloalkyl; L.sub.1, W, L.sub.2, M.sub.1, {circle around (B)} , M.sub.2, A, R, R', R'', R.sub.3, R.sub.4, R.sub.5and G are as defined in claim 1. 7. The compound of claim 6, wherein (a) R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are hydrogen; (b) R.sup.4' and R.sup.4' are hydrogen; and one of R.sup.2' and R.sup.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; or (c) R.sup.1' and R.sup.2', or R.sup.2' and R.sup.3', or R.sup.3' and R.sup.4', taken together with carbon atoms to which they are attached, form a 5- or 6- membered carbocycle or heterocycle, and the rest of R.sup.1', R.sup.2', R.sup.3' and R.sup.4' are hydrogen. 8. The compound of claim 6, wherein R.sub.3 is ##STR01645## 9. The compound of claim 6, wherein R' is ##STR01646## 10. The compound of claim 6, wherein R is ##STR01647## 11. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or excipient. 12. A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 11. 13. A method of inhibiting the replication of hepatitis C virus, the method comprising contacting the virus with a hepatitis C viral NS3 protease inhibitory amount of the compound of claim 1. 14. The method of claim 12, further comprising administering concurrently an additional anti-hepatitis C virus agent. 15. The compound of claim 1, represented by Formula XI, ##STR01648## or a pharmaceutically acceptable salt thereof, wherein R, ##STR01649## R' and G are delineated for each compound in the table below: TABLE-US-00005 Compound R ##STR01650## ##STR01651## R' G 1. ##STR01652## ##STR01653## ##STR01654## ##STR01655## ##STR01656## 2. ##STR01657## ##STR01658## ##STR01659## ##STR01660## ##STR01661##