INHIBITORS OF MTOR KINASE AS ANTI -VIRAL AGENT
The present invention provides methods for treating or preventing viral infections using modulators of host cell enzymes relating to mTOR. The invention also provides methods for treating or preventing viral infections using modulators of host cell enzymes relating to mTOR and modulators of the unfolded protein response.
1 . A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula VIII
wherein:
X is O or S;
R 1 is selected from H, F, Cl, Br, I, CN, —CR 14 R 15 —NR 16 R 17 , —CR 14 R 15 —NHR 10 , —(CR 14 R 15 ) t NR 10 R 11 , —C(R 14 R 15 ) n NR 12 C(═Y)R 10 , —(CR 14 R 15 ) n NR 12 S(O) 2 R 10 , —(CR 14 R 15 ) m OR 10 , —(CR 14 R 15 ) n S(O) 2 R 10 , —(CR 14 R 15 ) n S(O) 2 NR 10 R 11 , —C(OR 10 )R 11 R 14 , —C(R 14 )═CR 18 R 19 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —C(═Y)NR 12 OR 10 , —C(═O)NR 12 S(O) 2 R 10 , —C(═O)NR 12 (CR 14 R 15 ) m NR 10 R 11 , —NO 2 , —NHR 12 , —NR 12 C(═Y)R 11 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 S(O) 2 R 10 , —NR 12 SO 2 NR 10 R 11 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —SC(═Y)R 10 , —SC(═Y)OR 10 , C 2 -C 12 alkyl, C 2 -C 12 alkyl-R 10 , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or C 1 -C 20 heteroaryl;
R 2 is selected from H, F, Cl, Br, I, CN, CF 3 , —NO 2 , —C(═Y)R 10 , —C(—Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) m NR 10 R 11 , —(CR 14 R 15 ) n OR 10 , —(CR 14 R 15 ) t —NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 10 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, and C 1 -C 20 heteroaryl;
R 3 is a C 2 -C 5 heterocyclyl, a C 2 -C 5 heteroaryl, a fused bicyclic C 4 -C 20 heterocyclyl or a fused bicyclic C 3 -C 20 heteroaryl, each of which are unsubstituted or are optionally substituted;
R 10 , R 11 and R 12 are independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or C 1 -C 20 heteroaryl,
or R 10 and R 11 together with the nitrogen to which they are attached optionally form a saturated, partially unsaturated or fully unsaturated C 3 -C 20 heterocyclic ring optionally containing one or more additional ring atoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, (CH 2 ) m OR 10 NR 10 R 11 , CF 3 , F, Cl, Br, I, SO 2 R 10 , C(═O)R 10 , NR 12 C(═Y)R 11 , NR 12 S(O) 2 R 11 , C(═Y)NR 10 R 11 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl and C 1 -C 20 heteroaryl;
R 14 and R 15 are independently selected from H, C 1 -C 12 alkyl, or —(CH 2 )-aryl,
or R 14 and R 15 together with the atoms to which they are attached form a saturated or partially unsaturated C 3 -C 12 carbocyclic ring,
R 16 and R 17 are independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, or C 6 -C 20 aryl,
R 18 and R 19 together with the carbon to which they are attached form a C 3 -C 20 heterocyclic ring,
where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, CF 3 , —NO 2 , oxo, R 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) n NR 10 R 11 , —(CR 14 R 15 ) n OR 10 , —NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , ═NR 12 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 optionally substituted alkyl, C 2 -C 8 optionally substituted alkenyl, C 2 -C 8 optionally substituted alkynyl, C 3 -C 12 optionally substituted carbocyclyl, C 2 -C 20 optionally substituted heterocyclyl, C 6 -C 20 optionally substituted aryl, C 1 -C 20 optionally substituted heteroaryl, —(CR 14 R 15 ) t —NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , and (CR 14 R 15 ) t NR 10 R 11 ;
Y is O, S, or NR 12 ;
m is 0, 1, 2, 3, 4, 5 or 6;
n is 1, 2, 3, 4, 5 or 6; and
t is 1, 2, 3, 4, 5 or 6, and
wherein the substituent groups that are alkyls, alkenyls, alkynyls, carbocyclyls, heterocyclyls, aryls, heteroaryls, fused bicyclic heterocyclyls, and fused bicyclic heteroaryls are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, CN, CF 3 , —NO 2 , —NH 2 , oxo, R 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) n NR 10 R 11 , —(CR 14 R 15 ) n OR 10 , —NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , ═NR 12 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 optionally substituted alkyl, C 2 -C 8 optionally substituted alkenyl, C 2 -C 8 optionally substituted alkynyl, C 3 -C 12 optionally substituted carbocyclyl, C 2 -C 20 optionally substituted heterocyclyl, C 6 -C 20 optionally substituted aryl, C 1 -C 20 optionally substituted heteroaryl, —(CR 14 R 15 ) t —NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , and (CR 14 R 15 ) t —NR 10 R 11 .
2 . The method of claim 1 , wherein the compound of formula VIII is GNE-493.
3 . The method of claim 1 , wherein the compound of formula VIII is GNE-0941.
4 . The method of claim 1 , wherein the compound is an inhibitor of mTORC1.
5 . The method of claim 1 , wherein the compound is an inhibitor of mTORC2.
6 . The method of claim 1 , wherein the viral infection is by a herpesvirus.
7 . The method of claim 1 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
8 . The method of claim 1 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
9 . The method of claim 8 wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
10 . The method of claim 8 wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
11 . A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula VIII:
wherein:
X is O or S;
R 1 is selected from H, F, Cl, Br, I, CN, —CR 14 R 15 —NR 16 R 17 , —CR 14 R 15 —NHR 10 , —(CR 14 R 15 ) t NR 10 R 11 , —C(R 14 R 15 ) n NR 12 C(═Y)R 10 , —(CR 14 R 15 )NR 12 S(O) 2 R 10 , —(CR 14 R 15 ) m OR 10 , —(CR 14 R 15 )S(O) 2 R 10 , —(CR 14 R 15 ) n S(O) 2 NR 10 R 11 , —C(OR 10 )R 11 R 14 , —C(R 14 )═CR 18 R 19 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —C(═Y)NR 12 OR 10 , —C(═O)NR 12 S(O) 2 R 10 , —C(═O)NR 12 (CR 14 R 15 ) m NR 10 R 11 , —NO 2 , —NHR 12 , —NR 12 C(═Y)R 11 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 S(O) 2 R 10 , —NR 12 SO 2 NR 10 R 11 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —SC(═Y)R 10 , —SC(═Y)OR 10 , C 2 -C 12 alkyl, C 2 -C 12 alkyl-R 10 , C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or C 1 -C 20 heteroaryl;
R 2 is selected from H, F, Cl, Br, I, CN, CF 3 , —NO 2 , —C(═Y)R 10 , —C(—Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) m NR 10 R 11 , —(CR 14 R 15 ) n OR 10 , —(CR 14 R 15 ) t NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 10 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, and C 1 -C 20 heteroaryl;
R 3 is a C 2 -C 5 heterocyclyl, a C 2 -C 5 heteroaryl, a fused bicyclic C 4 -C 20 heterocyclyl or a fused bicyclic C 3 -C 20 heteroaryl, each of which are unsubstituted or are optionally substituted;
R 10 , R 11 and R 12 are independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl, or C 1 -C 20 heteroaryl,
or R 10 and R 11 together with the nitrogen to which they are attached optionally form a saturated, partially unsaturated or fully unsaturated C 3 -C 20 heterocyclic ring optionally containing one or more additional ring atoms selected from N, O or S, wherein said heterocyclic ring is optionally substituted with one or more groups independently selected from oxo, (CH 2 ) m OR 10 NR 10 R 11 , CF 3 , F, Cl, Br, I, SO 2 R 10 , C(═O)R 10 , NR 12 C(═Y)R 11 , NR 12 S(O) 2 R 11 , C(═Y)NR 10 R 11 , C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 6 -C 20 aryl and C 1 -C 20 heteroaryl;
R 14 and R 15 are independently selected from H, C 1 -C 12 alkyl, or —(CH 2 ) n -aryl,
or R 14 and R 15 together with the atoms to which they are attached form a saturated or partially unsaturated C 3 -C 12 carbocyclic ring,
R 16 and R 17 are independently H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 carbocyclyl, or C 6 -C 20 aryl,
R 18 and R 19 together with the carbon to which they are attached form a C 3 -C 20 heterocyclic ring,
where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, CF 3 , —NO 2 , oxo, R 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) n NR 10 R 11 , —(CR 14 R 15 ) n OR 10 , —NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , ═NR 12 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 optionally substituted alkyl, C 2 -C 8 optionally substituted alkenyl, C 2 -C 8 optionally substituted alkynyl, C 3 -C 12 optionally substituted carbocyclyl, C 2 -C 20 optionally substituted heterocyclyl, C 6 -C 20 optionally substituted aryl, C 1 -C 20 optionally substituted heteroaryl, —(CR 14 R 15 ) t —NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , and (CR 14 R 15 )NR 10 R 11 ;
Y is O, S, or NR 12 ;
m is 0, 1, 2, 3, 4, 5 or 6;
n is 1, 2, 3, 4, 5 or 6; and
t is 1, 2, 3, 4, 5 or 6, and
wherein the substituent groups that are alkyls, alkenyls, alkynyls, carbocyclyls, heterocyclyls, aryls, heteroaryls, fused bicyclic heterocyclyls, and fused bicyclic heteroaryls are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, CN, CF 3 , —NO 2 , —NH 2 , oxo, R 10 , —C(═Y)R 10 , —C(═Y)OR 10 , —C(═Y)NR 10 R 11 , —(CR 14 R 15 ) n NR 10 R 11 , —(CR 14 R 15 )OR 10 , —NR 10 R 11 , —NR 12 C(═Y)R 10 , —NR 12 C(═Y)OR 11 , —NR 12 C(═Y)NR 10 R 11 , —NR 12 SO 2 R 10 , ═NR 12 , OR 10 , —OC(═Y)R 10 , —OC(═Y)OR 10 , —OC(═Y)NR 10 R 11 , —OS(O) 2 (OR 10 ), —OP(═Y)(OR 10 )(OR 11 ), —OP(OR 10 )(OR 11 ), SR 10 , —S(O)R 10 , —S(O) 2 R 10 , —S(O) 2 NR 10 R 11 , —S(O)(OR 10 ), —S(O) 2 (OR 10 ), —SC(═Y)R 10 , —SC(═Y)OR 10 , —SC(═Y)NR 10 R 11 , C 1 -C 12 optionally substituted alkyl, C 2 -C 8 optionally substituted alkenyl, C 2 -C 8 optionally substituted alkynyl, C 3 -C 12 optionally substituted carbocyclyl, C 2 -C 20 optionally substituted heterocyclyl, C 6 -C 20 optionally substituted aryl, C 1 -C 20 optionally substituted heteroaryl, —(CR 14 R 15 ) t —NR 12 C(═O)(CR 14 R 15 )NR 10 R 11 , and (CR 14 R 15 ) t —NR 10 R 11 .
12 . The pharmaceutical composition of claim 11 , wherein the compound of formula VIII is GNE-493.
13 . The pharmaceutical composition of claim 11 , wherein the compound of formula VIII is GNE-0941.
14 . The pharmaceutical composition of claim 11 , wherein the compound is an inhibitor of mTORC1.
15 . The pharmaceutical composition of claim 11 , wherein the compound is an inhibitor of mTORC2.
16 . The pharmaceutical composition of claim 11 , wherein the viral infection is by a herpesvirus.
17 . The pharmaceutical composition of claim 11 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
18 . The pharmaceutical composition of claim 11 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
19 . The pharmaceutical composition of claim 18 wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
20 . The pharmaceutical composition of claim 18 wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
21 - 40 . (canceled)
41 . A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula IX
wherein,
Het1 and Het2 are independently selected from (i) a 5 to 7 membered heterocyclic group having 1-3 heteroatoms selected from O, N, and S, and (ii) a 6 to 10 membered bicyclic heterocyclic group having 1-3 heteroatoms selected from O, N, and S; wherein each of (i) or (ii) may by unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 4 alkyl, NH 2 , —O—R 0 , CN, and halo;
X and Z are independently selected from N and CH;
R 1 is selected from the group consisting of:
(i) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, and C 3 to C 10 cycloalkyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , —O—(C 2 -C 10 alkyl), aryl, heteroaryl, and heterocyclyl;
(ii) aryl, heteroaryl and heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, heterocyclyl, —O—R 0 , —(C 1 -C 10 alkyl)-OR 0 , —O—(C 1 -C 10 alkyl)-OR 0 , —(C 1 -C 10 alkyl)-N(R 0 ) 2 , —O—(C 2 -C 10 alkyl)-N(R 0 ) 2 , —O—(C 2 -C 10 alkyl)-C(═O)—N(R 0 ) 2 , —C(═O)—(C 2 -C 10 alkyl)-N(R 0 ) 2 , —C(═O)N(R 0 )—(C 2 -C 10 alkyl)-N(R 0 ) 2 , and —(C 1 -C 6 alkyl)-aryl;
(iii) -aryl-C(═O)-aryl, -aryl-C(═O)-heteroaryl, and -aryl-C(═O)-heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and —OR 0 ; and
(iv) -aryl-aryl, -aryl-heteroaryl, and -aryl-heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —O—R 0 ; and
each R 0 is independently selected from H and C 1 -C 6 alkyl; or alternatively two adjacent R 0 attached to a nitrogen atom may be taken together to form a 5 or 6-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from N, O, and S, and which may be unsubstituted or substituted by 1 to 3 substituents selected form the group consisting of C 1 -C 4 alkyl, NH 2 , —OH, CN, and halo.
42 . The method of claim 41 , wherein the compound of Formula IX is Wyeth BMCL 20102644-13.
43 . The method of claim 41 , wherein the compound of Formula IX is Wyeth BMCL 20102648-27.
44 . The method of claim 41 , wherein the compound is an inhibitor of mTORC1.
45 . The method of claim 41 , wherein the compound is an inhibitor of mTORC2.
46 . The method of claim 41 , wherein the viral infection is by a herpesvirus.
47 . The method of claim 41 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
48 . The method of claim 41 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
49 . The method of claim 48 , wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
50 . The method of claim 48 , wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
51 . A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula IX
wherein,
Het1 and Het2 are independently selected from (i) a 5 to 7 membered heterocyclic group having 1-3 heteroatoms selected from O, N, and S, and (ii) a 6 to 10 membered bicyclic heterocyclic group having 1-3 heteroatoms selected from O, N, and S; wherein each of (i) or (ii) may by unsubstituted or substituted with 1 to 3 substituents selected from C 1 -C 4 alkyl, NH 2 , —O—R 0 , CN, and halo;
X and Z are independently selected from N and CH;
R 1 is selected from the group consisting of:
(i) C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, and C 3 to C 10 cycloalkyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , —O—(C 2 -C 10 alkyl), aryl, heteroaryl, and heterocyclyl;
(ii) aryl, heteroaryl and heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, heterocyclyl, —O—R 0 , —(C 1 -C 10 alkyl)-OR 0 , —O—(C 1 -C 10 alkyl)-OR 0 , —(C 1 -C 10 alkyl)-N(R 0 ) 2 , —O—(C 2 -C 10 alkyl)-N(R 0 ) 2 , —O—(C 2 -C 10 alkyl)-C(═O)—N(R 0 ) 2 , —C(═O)—(C 2 -C 10 alkyl)-N(R 0 ) 2 , —C(═O)N(R 0 )—(C 2 -C 10 alkyl)-N(R 0 ) 2 , and —(C 1 -C 6 alkyl)-aryl;
(iii) -aryl-C(═O)-aryl, -aryl-C(═O)-heteroaryl, and -aryl-C(═O)-heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and —O—R 0 ;
(iv) -aryl-aryl, -aryl-heteroaryl, and -aryl-heterocyclyl; each of which is unsubstituted or is substituted by 1 to 3 substituents selected from the group consisting of halo, —N(R 0 ) 2 , CN, NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —O—R 0 ; and
each R 0 is independently selected from H and C 1 -C 6 alkyl; or alternatively two adjacent R 0 attached to a nitrogen atom may be taken together to form a 5 or 6-membered heterocyclic ring having 0 to 2 additional ring heteroatoms selected from N, O, and S, and which may be unsubstituted or substituted by 1 to 3 substituents selected form the group consisting of C 1 -C 4 alkyl, NH 2 , —OH, CN, and halo.
52 . The pharmaceutical composition of claim 50 , wherein the compound of Formula IX is Wyeth BMCL 20102644-13.
53 . The pharmaceutical composition of claim 50 , wherein the compound of Formula IX is Wyeth BMCL 20102648-27.
54 . The pharmaceutical composition of claim 50 , wherein the compound is an inhibitor of mTORC1.
55 . The pharmaceutical composition of claim 50 , wherein the compound is an inhibitor of mTORC2.
56 . The pharmaceutical composition of claim 50 , wherein the viral infection is by a herpesvirus.
57 . The pharmaceutical composition of claim 50 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
58 . The pharmaceutical composition of claim 50 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
59 . The pharmaceutical composition of claim 58 , wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
60 . The pharmaceutical composition of claim 58 , wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
61 - 80 . (canceled)
81 . A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula X:
wherein
R 1 is selected from naphthyl or phenyl, which is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of (i) halogen; (ii) lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; (iii) cycloalkyl; (iv) amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; (v) piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; (vi) 2-oxo-pyrrolidinyl; (vii) lower alkoxy lower alkyl; (viii) imidazolyl; (ix) pyrazolyl; and (x) triazolyl;
R 2 is O or S;
R 3 is lower alkyl;
R 4 is selected from (i) pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; (ii) pyrimidinyl unsubstituted or substituted by lower alkoxy; (iii) quinolinyl unsubstituted or substituted by halogen; or (iv) quinoxalinyl;
R 5 is hydrogen or halogen;
n is 0 or 1;
R 6 is oxido; with the proviso that if n=1, the N-atom bearing the radical R 6 has a positive charge; and
R 7 is hydrogen or amino.
82 . The method of claim 81 , wherein the compound of Formula X is NVP-BEZ235.
83 . The method of claim 81 , wherein the compound is an inhibitor of mTORC1.
84 . The method of claim 81 , wherein the compound is an inhibitor of mTORC2.
85 . The method of claim 81 , wherein the viral infection is by a herpesvirus.
86 . The method of claim 81 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
87 . The method of claim 81 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
88 . The method of claim 87 , wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
89 . The method of claim 87 , wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
90 . A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is a compound of Formula X:
wherein
R 1 is selected from naphthyl or phenyl, which is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of (i) halogen; (ii) lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; (iii) cycloalkyl; (iv) amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; (v) piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; (vi) 2-oxo-pyrrolidinyl; (vii) lower alkoxy lower alkyl; (viii) imidazolyl; (ix) pyrazolyl; and (x) triazolyl;
R 2 is O or S;
R 3 is lower alkyl;
R 4 is selected from (i) pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; (ii) pyrimidinyl unsubstituted or substituted by lower alkoxy; (iii) quinolinyl unsubstituted or substituted by halogen; or (iv) quinoxalinyl;
R 5 is hydrogen or halogen;
n is 0 or 1;
R 6 is oxido; with the proviso that if n=1, the N-atom bearing the radical R 6 has a positive charge; and
R 7 is hydrogen or amino.
91 . The pharmaceutical composition of claim 90 , wherein the compound of Formula X is NVP-BEZ235.
92 . The pharmaceutical composition of claim 90 , wherein the compound is an inhibitor of mTORC1.
93 . The pharmaceutical composition of claim 90 , wherein the compound is an inhibitor of mTORC2.
94 . The pharmaceutical composition of claim 90 , wherein the viral infection is by a herpesvirus.
95 . The pharmaceutical composition of claim 90 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
96 . The pharmaceutical composition of claim 90 , further comprising administering to the mammalian subject an inhibitor of the unfolded protein response.
97 . The pharmaceutical composition of claim 96 , wherein the inhibitor of the unfolded protein response is 4-phenylbutyrate.
98 . The pharmaceutical composition of claim 96 , wherein the inhibitor of the unfolded protein response is tauroursodeoxycholic acid.
99 - 116 . (canceled)
117 . A method of treating or preventing viral infection in a mammal, comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is selected from AZD2014, CC-223 (TORKi), SB-2015, NVP-BGT-226, LY294002, GSK2126458, XL147, XL765, PF-04691502, P-2281, GDC-0980, ETP-45658, WJD008, PKI-179, PKI-402, PKI-587, OXA-01, Compound 401, ZSTK-474, PI-103, and Palomid-529.
118 . The method of claim 117 , wherein the viral infection is by a herpesvirus.
119 . The method of claim 117 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
120 . A pharmaceutical composition for treatment or prevention of a viral infection comprising a therapeutically effective amount of a composition comprising (i) a compound or prodrug thereof, or pharmaceutically acceptable salt of said compound or prodrug; and (ii) a pharmaceutically acceptable carrier, wherein the compound is an inhibitor of a rapamycin-resistant function of mTOR and wherein the compound is selected from AZD2014, CC-223 (TORKi), SB-2015, NVP-BGT-226, LY294002, GSK2126458, XL147, XL765, PF-04691502, P-2281, GDC-0980, ETP-45658, WJD008, PKI-179, PKI-402, PKI-587, OXA-01, Compound 401, ZSTK-474, PI-103, and Palomid-529.
121 . The pharmaceutical composition of claim 120 , wherein the viral infection is by a herpesvirus.
122 . The pharmaceutical composition of claim 120 , wherein the viral infection is by a herpesvirus selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 variant A, human herpesvirus 6 variant B, human herpesvirus 7, human herpesvirus 8, and cercopithecine herpesvirus 1.
123 - 128 . (canceled)