Tricyclic compounds and their use in the treatment of cancer

Abstract

There is provided compounds of formula (I), or pharmaceutically-acceptable salts thereof, wherein X, Y, Z, R.sup.1 and R.sup.2 have meanings provided in the description, which compounds are useful in the treatment of cancers. ##STR00001##

Claims

1. A compound of formula I ##STR00084## or a pharmaceutically acceptable salt thereof, wherein: X represents C.sub.1-12 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-12 alkenyl optionally substituted by one or more groups independently selected from G.sup.1a, C.sub.2-12 alkynyl optionally substituted by one or more groups independently selected from G.sup.1a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.1b, aryl optionally substituted by one or more groups independently selected from G.sup.1c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.1d; Y represents C.sub.1-12 alkyl optionally substituted by one or more groups independently selected from G.sup.2a; C.sub.2-12 alkenyl optionally substituted by one or more groups independently selected from G.sup.2a, C.sub.2-12 alkynyl optionally substituted by one or more groups independently selected from G.sup.2a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.2b, aryl optionally substituted by one or more groups independently selected from G.sup.2c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.2d; Z represents O, S, NR.sup.a or N(OR.sup.b); R.sup.1 and R.sup.2 independently represents H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are optionally substituted by one or more groups independently selected from halo, OC.sub.1-6 alkyl optionally substituted by one or more halo, OC.sub.2-6 alkenyl optionally substituted by one or more halo, and OC.sub.2-6 alkynyl optionally substituted by one or more halo; each G.sup.1a, G.sup.1b, G.sup.1c and G.sup.1d independently represents halo, R.sup.a1, CN, -A.sup.a1C(Q.sup.a1)R.sup.b1, -A.sup.b1C(Q.sup.b1)N(R.sup.c1)R.sup.d1, -A.sub.c1C(Q.sub.c1)OR.sub.e1, -A.sup.d1S(O).sub.nR.sup.f1, -A.sup.e1-S(O).sub.nC(O)R.sup.g1, -A.sup.f1S(O).sub.nN(R.sup.h1)R.sup.i1, -A.sub.g1S(O).sub.nOR.sup.j1, N.sub.3, N(R.sup.k1)R.sup.l1, N(H)CN, NO.sub.2, OR.sup.m1, SR.sup.n1 or Q.sup.d1; each A.sup.a1 to A.sup.g1 independently represents a single bond, N(R.sup.o1), C(Q.sup.e1)N(R.sup.p1) or O; each Q.sup.a1 to Q.sup.e1 independently represents O, S, NR.sup.q1 or N(OR.sup.r1); R.sup.a and R.sup.b each independently represent H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl are optionally substituted by one or more groups independently selected from halo, OC.sub.1-6 alkyl optionally substituted by one or more halo, OC.sub.2-6 alkynyl optionally substituted by one or more halo; each R.sup.a1 and R.sup.f1 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.3a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.3a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.3a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.3b, aryl optionally substituted by one or more groups independently selected from G.sup.3c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.3d; each R.sup.b1, R.sup.c1, R.sup.d1, R.sup.e1, R.sup.g1, R.sup.h1, R.sup.i1, R.sup.j1, R.sup.k1, R.sup.l1, R.sup.m1, R.sup.n1, R.sup.q1 and R.sup.r1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.3a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.3a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.3a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.3b, aryl optionally substituted by one or more groups independently selected from G.sup.3c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.3d; or any two R.sup.c1 and R.sup.d1, R.sup.h1 and R.sup.j1 and/or R.sup.k1 and R.sup.l1 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.o1 and R.sup.p1 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, or C.sub.2-3 alkynyl optionally substituted by one or more halo; each G.sup.2a, G.sup.2b, G.sup.2c and G.sup.2d independently represents halo, R.sup.a2, CN, -A.sup.a2-(Q.sup.a2)R.sup.b2, -A.sup.b2C(Q.sup.b2)N(R.sup.c2)R.sup.d2, -A.sup.c2C(Q.sup.c2)OR.sup.e1, -A.sup.d2S(O).sub.pR.sup.f2, -A.sup.e2S(O).sub.pC(O)R.sup.g2, -A.sup.f2S(O).sub.pN(R.sup.h2)R.sup.i2, -A.sup.g2S(O).sub.pOR.sup.j2, N.sub.3, N(R.sup.k2)R.sup.l2, N(H)CN, NO.sub.2, OR.sup.m2, SR.sup.n2 or Q.sup.d2; each A.sup.a2 to A.sup.g2 independently represents a single bond, N(R.sup.o2), C(Q.sup.e2)N(R.sup.p2) or O; each Q.sup.a2 to Q.sup.e3 independently represents O, S, NR.sup.q2 or N(OR.sup.r2); each R.sup.a2 independently represents heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.4b, aryl optionally substituted by one or more groups independently selected from G.sup.4c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.4d; each R.sup.f2 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.4a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.4a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.4a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.4b, aryl optionally substituted by one or more groups independently selected from G.sup.4c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.4d; each R.sup.b2, R.sup.c2, R.sup.d2, R.sup.e2, R.sup.g2, R.sup.h2, R.sup.i2, R.sup.j2, R.sup.k2, R.sup.l2, R.sup.m2, R.sup.n2, R.sup.q2 and R.sup.r2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.4a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.4a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.4a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.4b, aryl optionally substituted by one or more groups independently selected from G.sup.4c, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.4d; or any two R.sup.c2 and R.sup.d2, R.sup.h2 and R.sup.i2 and/or R.sup.k2 and R.sup.l2 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.o2 and R.sup.p2 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more halo, C.sub.2-6 alkenyl optionally substituted by one or more halo, or C.sub.2-6 alkynyl optionally substituted by one or more halo; each G.sup.3a independently represents halo, CN, -A.sup.a3C(Q.sup.a3)R.sup.b3, -A.sup.b3C(Q.sup.b3)N(R.sup.c3)R.sup.d3, -A.sup.c3C(Q.sup.c3)OR.sup.e3, -A.sup.d3S(O).sub.qR.sup.f3, -A.sup.e3-S(O).sub.qC(O)R.sup.g3, -A.sup.f3S(O).sub.qN(R.sup.h3)R.sup.i3, -A.sup.g3S(O).sub.qOR.sup.j3, N.sub.3, N(R.sup.k3)R.sup.l3, N(H)CN, NO.sub.2, OR.sup.m3, SR.sup.n3 or Q.sup.d3; each G.sup.3b, G.sup.3c and G.sup.3d independently represents halo, R.sup.a3, CN, -A.sup.3C(Q.sup.a3)R.sup.b3, -A.sup.b3C(Q.sup.b3)N(R.sup.c3) R.sup.d3, -A.sup.c3C(Q.sup.c3)OR.sup.e3, -A.sup.d3S(O).sub.qR.sup.f3, -A.sup.e3S(O).sub.qC(O) R.sup.g3, -A.sup.f3S(O)N(R.sup.h3)R.sup.i3, -A.sup.g3S(O).sub.qOR.sup.j3, N.sub.3, N(R.sup.k3)R.sup.l3, N(H)CN, NO.sub.2, OR.sup.m3, SR.sup.n3 or Q.sup.d3; each A.sup.a3 to A.sup.g3 independently represents a single bond, N(R.sup.o3), C(Q.sup.e3)N(R.sup.p3) or O; each Q.sup.a3 to Q.sup.e3 independently represents O, S, NR.sup.q3 or N(OR.sup.r3); each R.sup.a3 and R.sup.f3 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.5a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.5a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.5a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.5b; each R.sup.b3, R.sup.c3, R.sup.d3, R.sup.e3, R.sup.g3, R.sup.h3, R.sup.i3, R.sup.j3, R.sup.k3, R.sup.l3, R.sup.m3, R, R.sup.q3 and R.sup.r3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.5a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.5a, C.sub.2-6 alkynyl optionally substituted by one or moree groups independently selected from G.sup.5a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.5b; or any two R.sup.c3 and R.sup.d3, R.sup.h3 and R.sup.i3 and/or R.sup.k3 and R.sup.l3 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, C.sub.2-3 alkynyl optionally substituted by one or more halo, and O; each R.sup.o3 and R.sup.p3 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more halo, C.sub.2-6 alkenyl optionally substituted by one or more halo, or C.sub.2-6 alkynyl optionally substituted by one or more halo; each G.sup.4a independently represents halogen, CN, -A.sup.a4C(Q.sup.a4)R.sup.b4, -A.sup.b4C(Q.sup.b4)N(R.sup.c4)R.sup.d4, -A.sup.c4C(Q.sup.c4)OR.sup.e4, -A.sup.d4S(O).sub.rR.sup.f4, -A.sup.e4S(O).sub.rC(O)R.sup.g4, -A.sup.f4S(O).sub.rN(R.sup.h4) R.sup.i4, -A.sup.g4S(O)OR.sup.j4, N.sub.3, N(R.sup.k4)R.sup.l4, N(H)CN, NO.sub.2, OR.sup.m4, SR.sup.n4 or Q.sup.d4; each G.sup.4b, G.sup.4c and G.sup.4d independently represents halo, R.sup.a4, CN, -A.sup.a4C(Q.sup.a4)R.sup.b4-A.sup.b4C(Q.sup.b4)N(R.sup.c4) R.sup.d4, -A.sup.c4C(Q.sup.c4)OR.sup.e4, -A.sup.d4-S(O).sub.rR.sup.f4, -A.sup.e4S(O).sub.rC(O)R.sup.g4, -A.sup.f4S(O).sub.rN(R.sup.h4)R.sup.i4, -A.sup.g4S(O).sub.rOR.sup.j4, N.sub.3, N(R.sup.k4)R.sup.l4, N(H)CN, NO.sub.2, OR.sup.m4, SR.sup.n4 or Q.sup.d4; each A.sup.a4 to A.sup.g4 independently represents a single bond, N(R.sup.o4), C(Q.sup.e4)N(R.sup.p4) or O; each Q.sup.a4 to Q.sup.e4 independently represents O, S, NR.sup.q4 or N(OR.sup.r4); each R.sup.a4 and R.sup.f4 independently represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.6a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.6a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.6a, heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.6b, or aryl optionally substituted by one or more groups independently selected from G.sup.6c; each R.sup.b4, R.sup.c4, R.sup.d4, R.sup.e4, R.sup.g4, R.sup.h4, R.sup.i4, R.sup.j4, R.sup.k4, R.sup.l4, R.sup.m4, R.sup.n4, R.sup.q4 and R.sup.r4 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.6a, C.sub.2-6 alkenyl optionally substituted by one or more groups independently selected from G.sup.6a, C.sub.2-6 alkynyl optionally substituted by one or more groups independently selected from G.sup.6a, or heterocycloalkyl optionally substituted by one or more groups independently selected from G.sup.6b; or any two R.sup.c4 and R.sup.d4, R.sup.h4 and R.sup.i4 and/or R.sup.k4 and R.sup.l4 are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, C.sub.2-3 alkenyl optionally substituted by one or more halo, C.sub.2-3 alkynyl optionally substituted by one or more halo and O; each R.sup.o4 and R.sup.p4 independently represents H, C.sub.1-6 alkyl optionally substituted by one or more halo, C.sub.2-6 alkenyl optionally substituted by one or more halo, or C.sub.2-6 alkynyl optionally substituted by one or more halo; each G.sup.5a and G.sup.6a independently represents halo or OC.sub.1-6 alkyl optionally substituted by one or more halo, OC.sub.2-6 alkenyl optionally substituted by one or more halo, and OC.sub.2-6 alkynyl optionally substituted by one or more halo; each G.sup.5b, G.sup.6b and G.sup.6c represents halo, C.sub.1-6 alkyl optionally substituted by one or more halo, C.sub.2-6 alkenyl optionally substituted by one or more halo, or C.sub.2-6 alkynyl optionally substituted by one or more halo, OC.sub.1-6 alkyl optionally substituted by one or more halo, OC.sub.2-6 alkenyl optionally substituted by one or more halo, or OC.sub.2-6 alkynyl optionally substituted by one or more halo; each n independently represents 1 or 2; each p independently represents 1 or 2; each q independently represents 1 or 2; and each r independently represents 1 or 2, with the proviso that the compound of formula I is not a compound selected from: exo-11-methyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; 11-methyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-methyl 3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-8-en-11-carboxylate; exo-methyl 3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-8-en-11-carboxylate; exo-4,11-diphenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4,11-diphenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; diphenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; 11-(4-bromobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-phenyl-11-(4-pyridyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-phenyl-11-(2-pyridyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(2-iodobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(2-iodobenzyl)-4-methyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; 11-benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-4-methyl-11-(2-vinylphenyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-methyl-11-(2-vinylphenyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-4-phenyl-11-(2-pyridyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(3-oxocyclohex-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-(3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-8-en-11-yl)pyridine-1-oxide; exo-4-phenyl-11-styryl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(6,6-dimethyl-3-oxocyclohex-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; 11-(4-tert-butylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(2-iodobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(4,6-dimethylpyrimidin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(4,6-dimethylpyrimidin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(4,4-dimethyl-3-oxopent-1-ene-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-4-(4-ethylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(6-chloropyridazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(6-chloropyridazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(2-pyridylmethyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(2,4-dinitrophenyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-phenyl-11-(6-phenylpyridazin-3-yl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(4,6-diphenyl-1,3,5-triazin-2-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-4-(2,6-diisopropylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-4-(2,6-diisopropylphenyl)-11-(2-iodobenzyl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-((E)-3-(4-bromophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-((E)-3-(4-chlorophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo-[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-((E)-3-(2,4-dinitrophenyl)-3-oxoprop-1-en-1-yl)-4-phenyl-4,11-diazatricyclo-[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo,exo-1,2-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione-11-yl)-ethane; endo,exo-1,2-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione-11-yl)-ethane; exo,exo-1,3-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione-11-yl)-propane; endo,exo-1,3-bis-(4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione-11-yl)-propane; 4-phenyl-11-(3-phenyl-1,2,4-thiadiazol-5-yl)-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; exo-11-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; endo-11-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione; and endo-11-(1,2-bis(3-nitrophenyl)vinyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.sup.2,6]undec-9-ene-3,5,8-trione.

2. A compound as claimed in claim 1, wherein R.sup.1 represents H or C.sub.1 alkyl optionally substituted by one or more halo.

3. A compound as claimed in claim 1, wherein R.sup.2 represents H or C.sub.1-3 alkyl, the latter of which is optionally substituted by one or more groups independently selected from halo and OC.sub.1-6 alkyl optionally substituted by one or more halo.

4. A compound as claimed in claim 1, wherein: R.sup.1 represents H; and/or R.sup.2 represents H or C.sub.1 alkyl optionally substituted by one or more halo.

5. A compound as claimed in claim 1, wherein X represents C.sub.1-12 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, or aryl optionally substituted by one or more groups independently selected from G.sup.1c.

6. A compound as claimed in claim 1, wherein X represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.1a, or phenyl optionally substituted by one or more groups independently selected from G.sup.1c.

7. A compound as claimed in claim 1, wherein: G.sup.1a represents halo or R.sup.a1; and/or R.sup.a1 represents aryl optionally substituted by one or more groups independently selected from G.sup.3c.

8. A compound as claimed in claim 1, wherein G.sup.1c represents halo, R.sup.a1, N(R.sup.o1)C(O)R.sup.b1 or OR.sup.m1.

9. A compound as claimed in claim 1, wherein Y represents C.sub.1-6 alkyl optionally substituted by one or more groups independently selected from G.sup.2a.

10. A compound as claimed in claim 1, wherein G.sup.2a represents halo or R.sup.a2.

11. A compound as claimed in claim 1, wherein Z represents O.

12. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1 but without the proviso.

13. The method of claim 12, wherein the cancer is selected from the group consisting of: soft tissue cancers, sarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma; lung cancers, bronchogenic carcinoma, alveolar or bronchiolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal cancers: esophageal cancers, stomach cancers, pancreatic cancers, small bowel cancers, large bowel cancers; genitourinary tract cancers, cancer of the kidney, bladder and urethra, prostate, testis; liver cancers, such as hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone cancers, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; cancers of the head and/or nervous system, cancer of the skull, meninges, brain, spinal cord; gynecological cancers, cancers of the uterus, cervix, ovaries, cancers of the vulva, vagina, fallopian tubes; haematologic cancers, cancers of the blood and bone marrow, Hodgkin's disease, non- Hodgkin's lymphoma; skin cancers, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and adrenal glands; and neuroblastomas.

14. The method of claim 12, wherein the cancer is a solid tumor cancer.

15. A pharmaceutical composition comprising a compound as defined in claim 1 and optionally one or more pharmaceutically acceptable adjuvant, diluent and/or carrier.

16. A combination product comprising: (A) a compound as defined in claim 1; and (B) one or more other therapeutic agent that is useful in the in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable adjuvant, diluent or carrier.

17. A kit-of-parts comprising: (a) a pharmaceutical formulation as defined in claim 15; and (b) one or more other therapeutic agent that is useful in the treatment of cancer, optionally in admixture with one or more pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

18. A process for the preparation of a compound as defined in claim 1, which process comprises: (i) reaction of a compound of formula II ##STR00085## wherein X is as defined with claim 1 with a compound of formula IIIA ##STR00086## wherein R.sup.1, R.sup.2 and Y are as defined claim 1, in the presence of a suitable solvent and in the presence of a suitable base; (ii) reaction of a compound of formula II with a compound of formula IIIB ##STR00087## wherein R.sup.1, R.sup.2 and Y are as defined claim 1 in the presence of a suitable solvent; (iii) reaction of a compound of formula II with a compound of formula IV ##STR00088## wherein R.sup.1, R.sup.2 and Y are as defined claim 1, PG.sup.1 is a suitable protecting group and LM is a suitable metal complex, in the presence of a suitable catalyst and a suitable solvent, followed by treatment with a suitable oxidizing agent in a suitable solvent; (iv) where Z represents NR.sup.a, reaction of a compound of formula I wherein Z represents O with a compound of formula VA
HNR.sup.a(VA) where R.sup.a is as defined claim 1, in the presence of a suitable solvent and optionally under conditions suitable for the removal of water; (v) where Z represents NOR.sup.b, reaction of a compound of formula I wherein Z represents O with a compound of formula VB
HNOR.sup.b(VB) or a suitable salt thereof, where R.sup.b is as defined claim 1, in the presence of a suitable solvent and in the presence of a suitable base; (vi) where Z represents S, reaction of a compound of formula I wherein Z represents O with a suitable reagent in the presence of a suitable solvent; or (vii) reaction of a compound corresponding to a compound of formula I as defined claim 1 but wherein Y represents H with a compound of formula VC
Y-LG.sup.2(VC) wherein Y is as defined in claim 1 and LG.sup.2 is a suitable leaving group, in the presence of a suitable solvent and a suitable base.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows results obtained from the experiment described in Biological Example 1 for the compound of Example 1.

(2) FIG. 2 shows results obtained from the experiment described in Biological Example 2 (using the compound of Example 1).

(3) FIG. 3 shows results obtained from the experiment described in Biological Example 3 (using the compound of Example 1).

EXAMPLES

(4) The invention is illustrated by way of the following examples, in which the following abbreviations may be employed.

(5) aq aqueous

(6) BSA bovine serum albumin

(7) DMA N,N-dimethylacetamide

(8) DMSO dimethyl sulphoxide

(9) DTNB 5,5-dithio-bis-(2-nitrobenzoic acid)

(10) EDTA ethylenediaminetetraacetic acid

(11) GSSG glutathione disulfide

(12) HPLC high performance liquid chromatography

(13) HRMS high resolution mass spectrometry

(14) NADPH nicotinamide adenine dinucleotide phosphate

(15) NMR nuclear magnetic resonance

(16) PBS phosphate buffered saline

(17) rt room temperature

(18) Starting materials and chemical reagents specified in the syntheses described below are commercially available from a number of suppliers, such as Sigma Aldrich.

(19) In the event that there is a discrepancy between nomenclature and the structure of compounds as depicted graphically, it is the latter that presides (unless contradicted by any experimental details that may be given and/or unless it is clear from the context). Final compounds are named according to the IUPAC system as used in e.g. Fielding, M. R. et al., Tetrahedron 57, 7737 (2001). Conversion of the names to chemical structures using e.g. using ChemBioDraw Ultra 14 gives the correct structures but not necessarily with the assigned configuration.

Example 1: exo-11-Benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(20) ##STR00012##

(a) 1-Benzyl-3-hydroxypyridin-1-ium Bromide

(21) ##STR00013##

(22) A mixture of 3-hydroxypyridine (0.20 g, 2.10 mmol), benzyl bromide (0.25 mL, 2.10 mmol) and trifluoroacetic acid (10 mL) was heated in a sealed tube for 18 h at 70 C. The mixture was allowed to cool to room temperature and concentrated to give the sub-title compound, which was used in the next step without further purification or characterization. LC-MS retention time (Method 1): 1.32 min.

(b) exo-11-Benzyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(23) ##STR00014##

(24) A mixture of 1-benzyl-3-hydroxypyridin-1-ium bromide (0.21 g, 0.79 mmol), N-phenylmaleimide (0.14 g, 0.79 mmol), triethylamine (0.28 ml, 1.97 mmol) and toluene (4.0 mL) was heated at reflux overnight, cooled and concentrated. The residue was purified using prep-HPLC (gradient 10-100% acetonitrile w/0.1% trifluoroacetic acid in water w/0.1% trifluoroacetic acid) to give the title compound.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.56-7.39 (m, 3H), 7.37-7.21 (m, 5H), 7.19-7.04 (m, 3H), 6.24 (dd, J=1.5, and 9.9 Hz, 1H), 4.17 (d, J=4.8 Hz, 1H), 3.99 (dt, J=0.7, and 1.4 Hz, 1H), 3.90-3.77 (m, 2H), 3.45 (d, J=7.3 Hz, 1H), and 3.30-3.23 (m, 1H).

(26) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.19N.sub.2O.sub.3 359.1390) found, 359.1405.

Example 2: exo-11-([1,1-Biphenyl]-4-ylmethyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(27) ##STR00015##

(28) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-phenylbenzyl bromide and N-phenylmaleimide.

(29) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (ddd, J=1.98, 8.14, and 18.47 Hz, 6H), 7.48-7.28 (m, 7H), 7.23 (d, J=7.94 Hz, 2H), 7.12 (dd, J=4.83, and 9.85 Hz, 1H), 6.27 (dd, J=1.52, and 9.94 Hz, 1H), 4.23 (d, J=4.86 Hz, 1H), 4.04 (s, 1H), 3.97-3.74 (m, 2H), 3.48 (d, J=7.35 Hz, 1H), and 3.30 (d, J=7.35 Hz, 1H).

(30) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.28H.sub.23N.sub.2O.sub.3 435.1703) found, 435.1691.

Example 3: exo-11-Methyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(31) ##STR00016##

(32) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, methyl iodide and N-phenylmaleimide.

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.54-7.35 (m, 3H), 7.27-7.14 (m, 3H), 6.10 (dd, J=1.54, and 9.89 Hz, 1H), 4.08 (d, J=4.80 Hz, 1H), 3.63 (dt, J=0.68, and 1.48 Hz, 1H), 3.56 (d, J=7.39 Hz, 1H), 3.30 (dd, J=0.52, and 7.50 Hz, 1H), and 2.37 (s, 3H).

(34) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.1-6H.sub.15N.sub.2O.sub.3 283.1077) found, 283.1089.

Example 4: exo-11-Methylbenzyl-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(35) ##STR00017##

(36) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-methylbenzyl bromide and N-phenylmaleimide.

(37) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.57-7.38 (m, 3H), 7.34-7.23 (m, 2H), 7.20-7.00 (m, 6H), 6.24 (dd, J=1.51, and 9.88 Hz, 1H), 4.16 (d, J=4.86 Hz, 1H), 3.98 (d, J=1.55 Hz, 1H), 3.86-3.73 (m, 2H), 3.45 (d, J=7.33 Hz, 1H), 3.27 (d, J=7.35 Hz, 1H), and 2.32 (s, 3H).

(38) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1560.

Example 5: 4-Phenyl-11-(1-phenylethyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(39) ##STR00018##

(40) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 1-(bromoethyl)benzene and N-phenylmaleimide. The isomers were not separated.

(41) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.59-7.18 (m, 12H), 7.22-6.88 (m, 4H), 6.24 (ddd, J=1.51, 2.58, and 9.88 Hz, 1H), 4.41-4.27 (m, 1H), 3.96-3.84 (m, 1H), 3.81-3.64 (m, 1H), 3.39-3.29 (m, 1H), and 1.31 (dd, J=6.48, and 14.62 Hz, 3H).

(42) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1545.

Example 6: 11-(4-Bromobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(43) ##STR00019##

(44) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-bromobenzyl bromide and N-phenylmaleimide. The isomers were not separated.

(45) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55-7.29 (m, 5H), 7.19-7.00 (m, 6H), 6.36-6.19 (m, 1H), 4.26-4.15 (m, 1H), 4.13-3.95 (m, 3H), 3.75 (d, J=1.99 Hz, 2H); .sup.1H NMR (400 MHz, Chloroform-d) 7.57-7.21 (m, 8H), 7.19-6.99 (m, 4H), 6.27 (ddd, J=1.30, 9.85, and 19.87 Hz, 1H), 4.26-4.13 (m, 1H), 3.97 (dt, J=0.68, 1.50 Hz, 1H), 3.77 (dd, J=2.03, and 17.74 Hz, 2H), 3.47 (d, J=7.41 Hz, 1H), and 3.28 (dt, J=0.41, and 7.30 Hz, 1H).

(46) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18BrN.sub.2O.sub.3 437.0495) found, 437.0487.

Example 7: exo-4-Phenyl-11-(2-phenylethyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(47) ##STR00020##

(48) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-phenethyl bromide and N-phenylmaleimide.

(49) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.57-7.35 (m, 4H), 7.25 (dd, J=4.85, and 9.89 Hz, 1H), 7.20-7.03 (m, 5H), 7.03-6.85 (m, 2H), 6.11 (dd, J=1.54, and 9.88 Hz, 1H), 4.30-4.14 (m, 1H), 3.72 (dt, J=0.63, and 1.40 Hz, 1H), 3.53 (d, J=7.36 Hz, 1H), 3.27 (d, J=0.56 Hz, 1H), 3.00-2.75 (m, 2H), and 2.66 (t, J=6.81 Hz, 2H).

(50) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1529.

Example 8: 11-(4-Fluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(51) ##STR00021##

(52) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-fluorobenzyl bromide and N-phenylmaleimide. The isomers were not separated.

(53) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50-6.99 (m, 10H), 6.18 (ddd, J=1.48, 2.48, and 9.70 Hz, 1H), 4.36-4.14 (m, 3H), 3.91 (dt, J=1.37, and 8.27 Hz, 1H), and 3.66 (s, 2H).

(54) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18FN.sub.2O.sub.3 377.1296) found, 377.1306.

Example 9: exo-11-Benzyl-4-cyclohexyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(55) ##STR00022##

(56) and

Example 10: endo-11-Benzyl-4-cyclohexyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(57) ##STR00023##

(58) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-cyclohexylmaleimide and were separated by HPLC.

Example 9

(59) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37-7.21 (m, 5H), 7.13 (dd, J=5.54, and 9.74 Hz, 1H), 6.00 (dd, J=1.37, and 9.73 Hz, 1H), 4.16-4.02 (m, 2H), 3.97 (dd, J=7.11, and 8.63 Hz, 1H), 3.78 (dt, J=1.37, and 8.24 Hz, 1H), 3.69-3.56 (m, 3H), 1.85 (pd, J=3.66, and 12.73 Hz, 2H), 1.69 (d, J=13.24 Hz, 3H), 1.55 (d, J=13.17 Hz, 2H), 1.36 (d, J=11.33 Hz, 2H), and 1.25-0.95 (m, 3H).

(60) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.25N.sub.2O.sub.3 365.1860) found, 365.1865.

Example 10

(61) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.33-7.17 (m, 4H), 7.10-7.01 (m, 2H), 6.13 (dd, J=1.5, and 9.9 Hz, 1H), 3.96 (d, J=4.8 Hz, 1H), 3.85 (tt, J=3.9, and 12.2 Hz, 1H), 3.76 (d, J=13.8 Hz, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.46 (d, J=1.5 Hz, 1H), 3.35 (t, J=6.7 Hz, 2H), 3.19-3.07 (m, 1H), 2.03 (qdd, J=3.5, 8.5, and 12.4 Hz, 2H), 1.78 (dt, J=3.4, and 13.0 Hz, 2H), 1.65-1.51 (m, 3H), 1.40-1.20 (m, 2H), and 1.20-1.04 (m, 1H).

(62) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.25N.sub.2O.sub.3 365.1860) found, 365.1866.

Example 11: exo-4,11-Dibenzyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(63) ##STR00024##

(64) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-benzylmaleimide.

(65) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.47-7.10 (m, 9H), 6.95-6.87 (m, 1H), 6.16 (dd, J=1.52, and 9.89 Hz, 1H), 4.61 (s, 2H), 4.06-3.93 (m, 1H), 3.78-3.55 (m, 2H), 3.56-3.45 (m, 2H), and 3.28-3.17 (m, 1H).

(66) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1558.

Example 12: 9-Benzyl-7-methyl-2-phenyl-3a,4,8,8a-tetrahydro-4,8-epiminocyclohepta[c]-pyrrole-1,3,5(2H)-trione Trifluoroacetate

(67) ##STR00025##

(68) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxy-5-methylpyridine, benzyl bromide and N-phenylmaleimide. The isomers were not separated.

(69) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.50 (m, 2H), 7.50-7.37 (m, 2H), 7.35-7.21 (m, 7H), 7.18-7.11 (m, 2H), 7.06-6.97 (m, 1H), 6.01 (dtd, J=0.60, 1.48, and 7.94 Hz, 1H), 4.40-4.01 (m, 1H), 3.88-3.64 (m, 4H), 3.57 (d, J=7.20 Hz, 2H), 3.30 (d, J=7.32 Hz, 1H), 2.04 (d, J=1.50 Hz, 3H), and 1.95 (d, J=1.46 Hz, 1H).

(70) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1536.

Example 13: endo-11-Benzyl-4-cyclohexyl-10-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec -9-ene-3,5,8-trione Trifluoroacetate

(71) ##STR00026##

(72) and

Example 14: exo-11-Benzyl-4-cyclohexyl-10-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(73) ##STR00027##

(74) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxy-5-methylpyridine, benzyl bromide and N-cyclohexylmaleimide and were separated by HPLC.

Example 13

(75) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37-7.17 (m, 5H), 5.83 (p, J=1.34 Hz, 1H), 4.08-3.91 (m, 3H), 3.71-3.55 (m, 4H), 1.97-1.77 (m, 5H), 1.70 (d, J=13.11 Hz, 2H), 1.55 (d, J=12.79 Hz, 1H), 1.36 (s, 2H), and 1.27-0.96 (m, 3H).

(76) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.27N.sub.2O.sub.3 379.2016) found, 379.2010.

Example 14

(77) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36-7.17 (m, 3H), 7.10-7.02 (m, 2H), 5.93 (tt, J=0.90, and 1.75 Hz, 1H), 3.85 (tt, J=3.86, and 12.24 Hz, 1H), 3.78-3.58 (m, 3H), 3.41 (d, J=1.38 Hz, 1H), 3.33 (d, J=7.27 Hz, 1H), 3.07 (d, J=7.21 Hz, 1H), 2.11-1.95 (m, 5H), 1.78 (dt, J=3.41, and 13.49 Hz, 2H), 1.65-1.51 (m, 3H), 1.36-1.21 (m, 2H), and 1.12 (dddd, J=3.93, 8.50, 13.98, and 17.50 Hz, 1H.

(78) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.27N.sub.2O.sub.3 379.2016) found, 379.2007.

Example 15: 4,11-Dibenzyl-10-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(79) ##STR00028##

(80) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxy-5-methylpyridine, benzyl bromide and N-benzylxylmaleimide. The isomers were not separated.

(81) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.40-7.08 (m, 14H), 6.94-6.84 (m, 2H), 5.95 (tt, J=0.88, 1.77 Hz, 1H), 4.59 (s, 2H), 4.39 (q, J=14.49 Hz, 1H), 4.16 (t, J=8.34 Hz, 0H), 4.07 (dd, J=7.12, 8.59 Hz, 0H), 3.96-3.92 (m, OH), 3.76-3.53 (m, 6H), 3.50-3.41 (m, 2H), 3.24-3.13 (m, 1H), 1.99 (d, J=1.51 Hz, 3H), and 1.67 (d, J=1.49 Hz, 1H).

(82) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.24H.sub.23N.sub.2O.sub.3 387.1703) found, 387.1705.

Example 16: endo 11-Benzyl-4-(tert-butyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(83) ##STR00029##
and

Example 17: exo-11-Benzyl-4-(tert-butyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(84) ##STR00030##

(85) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-tert-butylmaleimide and were separated by HPLC.

Example 16

(86) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36-7.21 (m, 5H), 7.17 (dd, J=5.56, and 9.72 Hz, 1H), 6.04 (dd, J=1.37, and 9.69 Hz, 1H), 4.10 (ddd, J=1.44, 5.58, and 7.05 Hz, 1H), 3.97 (dd, J=8.20, and 8.94 Hz, 1H), 3.87 (dd, J=7.09, and 8.93 Hz, 1H), 3.77 (dt, J=1.42, and 8.24 Hz, 1H), 3.60 (s, 2H), and 1.35 (s, 9H).

(87) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.20H.sub.23N.sub.2O.sub.3 339.1703) found, 339.1698.

Example 17

(88) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.33-7.17 (m, 4H), 7.13-7.03 (m, 2H), 6.12 (dd, J=1.55, and 9.87 Hz, 1H), 3.99-3.93 (m, 1H), 3.77 (d, J=13.85 Hz, 1H), 3.67 (d, J=13.86 Hz, 1H), 3.47 (dt, J=0.65, and 1.50 Hz, 1H), 3.29 (d, J=7.65 Hz, 1H), 3.07-3.00 (m, 1H), and 1.52 (s, 9H).

(89) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.20H.sub.23N.sub.2O.sub.3 339.1703) found, 339.1710.

Example 18: exo-11-(2-Chloro-4-fluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(90) ##STR00031##

(91) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-chloro-4-fluorobenzyl bromide and N-phenylmaleimide.

(92) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.56-7.12 (m, 11H), 6.22-6.18 (m, 1H), 4.38-4.27 (m, OH), 4.07 (d, J=4.80 Hz, 1H), 3.93-3.77 (m, 2H), 3.62 (dt, J=0.59, and 1.39 Hz, 1H), 3.59 (d, J=7.29 Hz, 1H), and 3.35 (dd, J=0.61, and 7.43 Hz, 1H).

(93) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17ClFN.sub.2O.sub.3 411.0906) found, 411.0900.

Example 19: exo-11-(2-Methylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(94) ##STR00032##

(95) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-methylbenzyl bromide and N-phenylmaleimide.

(96) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.56-7.48 (m, 2H), 7.47-7.39 (m, 1H), 7.30 (dd, J=4.84, and 9.89 Hz, 1H), 7.20-7.07 (m, 6H), 7.00-6.94 (m, 1H), 6.21 (dd, J=1.49, and 9.87 Hz, 1H), 4.00 (d, J=4.80 Hz, 1H), 3.85-3.68 (m, 2H), 3.63-3.49 (m, 2H), 3.33 (d, J=7.38 Hz, 1H), and 2.16 (s, 3H).

(97) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1556.

Example 20: 11-(2-Bromobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(98) ##STR00033##

(99) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-bromobenzyl bromide and N-phenylmaleimide. The isomers were not separated.

(100) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.60 (ddd, J=1.15, 6.94, and 8.27 Hz, 1H), 7.56-7.26 (m, 6H), 7.28-7.13 (m, 4H), 7.12-6.96 (m, 1H), 6.20 (ddd, J=1.46, 6.58, and 9.76 Hz, 1H), 4.42-4.27 (m, 1H), 3.93-3.69 (m, 2H), 3.67-3.52 (m, 2H), and 3.35 (dd, J=0.58, and 7.39 Hz, 1H).

(101) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18BrN.sub.2O.sub.3 437.0495) found, 437.0484.

Example 21: exo-11-(3-Methylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(102) ##STR00034##

(103) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-phenylmaleimide.

(104) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.41 (m, 3H), 7.34-7.01 (m, 5H), 7.00-6.90 (m, 2H), 6.18 (dd, J=1.52, and 9.87 Hz, 1H), 4.08 (d, J=4.86 Hz, 1H), 3.79 (d, J=13.71 Hz, 1H), 3.71 (d, J=13.69 Hz, 1H), 3.65-3.54 (m, 2H), 3.38-3.29 (m, 2H), and 2.22 (d, J=0.79 Hz, 3H).

(105) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.3 373.1547) found, 373.1551.

Example 22: exo-11-(3-Methoxybenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(106) ##STR00035##

(107) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methoxybenzyl bromide and N-phenylmaleimide.

(108) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.58-7.38 (m, 3H), 7.35-7.14 (m, 4H), 6.83-6.68 (m, 3H), 6.18 (dd, J=1.49, and 9.88 Hz, 1H), 4.09 (d, J=4.85 Hz, 1H), 3.85-3.69 (m, 2H), 3.67-3.53 (m, 5H), and 3.39-3.21 (m, 1H).

(109) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.4 389.1496) found, 389.1487.

Example 23: exo-11-(4-(Methylsulfonyl)benzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(110) ##STR00036##

(111) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-(methylsulfonyl)benzyl bromide and N-phenylmaleimide.

(112) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.92-7.80 (m, 3H), 7.62-7.51 (m, 2H), 7.53-7.35 (m, 4H), 7.35-7.20 (m, 4H), 6.20 (dd, J=1.51, and 9.90 Hz, 1H), 4.10 (d, J=4.87 Hz, 1H), 4.00-3.86 (m, 2H), 3.68-3.58 (m, 2H), 3.38 (d, J=7.37 Hz, 1H), and 3.22 (d, J=17.30 Hz, 3H).

(113) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.5S 437.1166) found, 437.1153.

Example 24: exo-11-(2-Chlorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(114) ##STR00037##

(115) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-chlorobenzyl bromide and N-phenylmaleimide.

(116) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.57-7.48 (m, 2H), 7.46-7.25 (m, 5H), 7.25-7.14 (m, 3H), 6.21 (dd, J=1.51, and 9.89 Hz, 1H), 4.09 (d, J=4.80 Hz, 1H), 3.97-3.75 (m, 2H), 3.66-3.52 (m, 2H), and 3.35 (dd, J=0.59, and 7.35 Hz, 1H).

(117) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18ClN.sub.2O.sub.3 393.1000) found, 393.0991.

Example 25: exo-11-(Cyclopropylmethyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(118) ##STR00038##

(119) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, cyclopropylmethyl bromide and N-phenylmaleimide.

(120) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.64-7.40 (m, 3H), 7.36-7.12 (m, 3H), 6.09 (dd, J=1.5, and 9.9 Hz, 1H), 4.27 (d, J=4.8 Hz, 1H), 3.84 (d, J=1.5 Hz, 1H), 3.59 (d, J=7.3 Hz, 1H), 3.33 (s, 2H), 2.45 (dd, J=6.7, 12.5 Hz, 1H), 0.91-0.66 (m, 1H), 0.63-0.21 (m, 2H), and 0.16-0.01 (m, 2H).

(121) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.19H.sub.19N.sub.2O.sub.3 323.1390) found, 323.1385.

Example 26: endo 11-(2,5-Difluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(122) ##STR00039##

(123) and

Example 27: exo-11-(2,5-Difluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(124) ##STR00040##

(125) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2,5-difluorobenzyl bromide and N-phenylmaleimide and were separated by HPLC.

Example 26

(126) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50-7.12 (m, 7H), 7.10-7.02 (m, 2H), 6.19 (dd, J=1.35, and 9.75 Hz, 1H), 4.38-4.27 (m, 2H), 4.21 (dd, J=7.14, and 8.62 Hz, 1H), 3.99 (dt, J=1.41, and 8.24 Hz, 1H), and 3.73 (d, J=1.24 Hz, 2H).

(127) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17F.sub.2N.sub.2O.sub.3 395.1202) found, 395.1220.

Example 27

(128) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.57-6.97 (m, 11H), 6.23-6.15 (m, 1H), 4.11 (d, J=4.85 Hz, 1H), 3.85 (q, J=14.23 Hz, 2H), 3.68-3.57 (m, 2H), and 3.36 (d, J=7.33 Hz, 1H).

(129) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17F.sub.2N.sub.2O.sub.3 395.1202) found, 395.1208.

Example 28: endo-1-(3-Fluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(130) ##STR00041##

(131) and

Example 29: exo-11-(3-Fluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(132) ##STR00042##

(133) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2,5-difluorobenzyl bromide and N-phenylmaleimide and were separated by HPLC.

Example 28

(134) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.51-7.27 (m, 5H), 7.19-7.02 (m, 5H), 6.19 (dd, J=1.38, and 9.73 Hz, 1H), 4.38-4.16 (m, 3H), 3.93 (dt, J=1.40, and 8.31 Hz, 1H), and 3.71 (s, 2H).

(135) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18FN.sub.2O.sub.3 377.1296) found, 377.1293.

Example 29

(136) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.60-7.50 (m, 2H), 7.51-7.42 (m, 1H), 7.40-7.21 (m, 4H), 7.12-6.93 (m, 3H), 6.18 (dd, J=1.51, and 9.88 Hz, 1H), 4.09 (d, J=4.86 Hz, 1H), 3.89-3.75 (m, 2H), 3.66-3.55 (m, 2H), and 3.36 (dd, J=0.62, and 7.40 Hz, 1H).

(137) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18FN.sub.2O.sub.3 377.1296) found, 377.1302.

Example 30: endo-11-(2,3-Difluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(138) ##STR00043##

(139) and

Example 31: exo-11-(2,3-Difluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(140) ##STR00044##

(141) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2,3-difluorobenzyl bromide and N-phenylmaleimide and were separated by HPLC.

Example 30

(142) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.49-7.34 (m, 4H), 7.31 (dd, J=5.50, and 9.76 Hz, 1H), 7.28-7.15 (m, 2H), 7.08-7.03 (m, 2H), 6.19 (dd, J=1.36, and 9.76 Hz, 1H), 4.39-4.24 (m, 2H), 4.20 (dd, J=7.16, and 8.64 Hz, 1H), 4.04-3.91 (m, 1H), and 3.83-3.69 (m, 2H).

(143) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17F.sub.2N.sub.2O.sub.3 395.1202) found, 395.1215.

Example 31

(144) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.40 (m, 3H), 7.40-7.26 (m, 2H), 7.23-7.11 (m, 3H), 7.03 (tdt, J=1.55, 6.22, and 7.71 Hz, 1H), 6.20 (dd, J=1.52, and 9.90 Hz, 1H), 4.10 (d, J=4.84 Hz, 1H), 3.98-3.80 (m, 2H), 3.67-3.54 (m, 2H), and 3.35 (dd, J=0.61, and 7.37 Hz, 1H).

(145) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17F.sub.2N.sub.2O.sub.3 395.1202) found, 395.1196.

Example 32: 4-Phenyl-11-(3-trifluorobenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(146) ##STR00045##

(147) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-trifluoromethylbenzyl bromide and N-phenylmaleimide. The isomers were not separated.

(148) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.74-7.38 (m, 12H), 7.32 (dd, J=5.02, and 9.86 Hz, 2H), 7.27-7.19 (m, 2H), 7.11-7.01 (m, 1H), 6.19 (ddd, J=1.43, 2.64, and 9.72 Hz, 2H), 4.31-4.18 (m, 1H), 4.10 (d, J=4.84 Hz, 1H), 3.97-3.82 (m, 3H), 3.78 (s, 1H), 3.69-3.55 (m, 2H), and 3.42-3.34 (m, 6H).

(149) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.18F.sub.3N.sub.2O.sub.3 427.1264) found, 427.1270.

Example 33: exo-11-(3,5-Dimethylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(150) ##STR00046##

(151) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3,5-dimethylbenzyl bromide and N-phenylmaleimide.

(152) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.62-7.50 (m, 2H), 7.50-7.39 (m, 1H), 7.37-7.19 (m, 3H), 6.86 (dq, J=0.90, and 1.74 Hz, 1H), 6.76 (dt, J=0.77, and 1.83 Hz, 2H), 6.17 (dd, J=1.53, and 9.89 Hz, 1H), 4.09 (d, J=4.84 Hz, 1H), 3.81-3.62 (m, 2H), 3.62-3.51 (m, 2H), 3.39-3.31 (m, 1H), and 2.18 (d, J=0.78 Hz, 6H).

(153) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.24H.sub.23N.sub.2O.sub.3 387.1703) found, 387.1720.

Example 34: exo-11-(3-Bromobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(154) ##STR00047##

(155) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-bromobenzyl bromide and N-phenylmaleimide.

(156) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.58-7.50 (m, 2H), 7.50-7.40 (m, 2H), 7.40-7.36 (m, 1H), 7.34-7.23 (m, 4H), 7.16 (ddd, J=0.88, 1.63, and 7.80 Hz, 1H), 6.18 (dd, J=1.47, and 9.86 Hz, 1H), 4.10 (d, J=4.85 Hz, 1H), 3.91-3.69 (m, 2H), 3.65-3.53 (m, 2H), and 3.41-3.33 (m, 1H).

(157) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18BrN.sub.2O.sub.3 439.0478) found, 439.0496.

Example 35: exo-11-(2-Fluoro-3-methylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(158) ##STR00048##

(159) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-fluoro-3-methylbenzyl bromide and N-phenylmaleimide.

(160) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.57-7.40 (m, 3H), 7.33 (dd, J=4.84, and 9.91 Hz, 1H), 7.22-7.13 (m, 3H), 7.08-6.96 (m, 2H), 6.19 (dd, J=1.51, and 9.89 Hz, 1H), 4.08 (dd, J=5.07, and 12.09 Hz, 1H), 3.91-3.83 (m, 1H), 3.77 (dd, J=0.94, and 13.51 Hz, 1H), 3.64-3.55 (m, 2H), 3.37-3.22 (m, 1H), and 2.25-2.17 (m, 3H).

(161) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.20FN.sub.2O.sub.3 391.1452) found, 391.1443.

Example 36: 3-((4-Phenyl-3,5,10-trioxo-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-8-en-11-yl)-methyl)benzonitrile Trifluoroacetate

(162) ##STR00049##

(163) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-(bromomethyl)benzonitrile and N-phenylmaleimide. The isomers were not separated.

(164) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.81-7.70 (m, 1H), 7.75-7.62 (m, 1H), 7.61 (dt, J=0.7, and 1.5 Hz, 1H), 7.59-7.35 (m, 7H), 7.37-7.22 (m, 4H), 7.10-7.02 (m, 1H), 6.19 (dt, J=1.7, and 9.7 Hz, 1H), 4.39-4.18 (m, 1H), 4.09 (d, J=4.8 Hz, 1H), 3.99-3.79 (m, 3H), 3.74 (s, 1H), 3.66-3.55 (m, 2H), and 3.40-3.25 (m, 1H).

(165) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.18N.sub.3O.sub.3 384.1343) 384.1342.

Example 37: exo-11-(4-Fluoro-3-methylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(166) ##STR00050##

(167) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 4-fluoro-3-methylbenzyl bromide and N-phenylmaleimide.

(168) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.41 (m, 3H), 7.34-7.20 (m, 3H), 7.11-6.94 (m, 3H), 6.18 (dd, J=1.52, and 9.88 Hz, 1H), 4.07 (d, J=4.85 Hz, 1H), 3.81-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.35 (d, J=7.29 Hz, 1H), and 2.15 (d, J=1.87 Hz, 3H).

(169) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.20FN.sub.2O.sub.3 391.1452) found, 391.1457.

Example 38: endo-11-(2,6-Difluoro-3-methylbenzyl)-4-phenyl-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(170) ##STR00051##

(171) and

Example 39: exo-11-(2,6-Difluoro-3-methylbenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(172) ##STR00052##

(173) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2,6-difluoro-3-methylbenzyl bromide and N-phenylmaleimide and were separated by HPLC.

Example 38

(174) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.52-7.24 (m, 5H), 7.09-6.97 (m, 3H), 6.17 (dd, J=1.34, and 9.77 Hz, 1H), 4.31-4.22 (m, 2H), 4.15 (dd, J=7.07, and 8.67 Hz, 1H), 3.96 (dt, J=1.35, and 8.31 Hz, 1H), 3.73 (t, J=1.29 Hz, 2H), and 2.24-2.18 (m, 3H).

(175) HRMS: m/z (M+Na).sup.+=(Calculated for C.sub.23H.sub.18F.sub.2N.sub.2NaO.sub.3 431.1178) found, 431.1157.

Example 39

(176) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.55-7.19 (m, 5H), 7.11-6.92 (m, 3H), 6.24-6.13 (m, 1H), 4.08-3.92 (m, 1H), 3.91-3.78 (m, 2H), 3.68-3.52 (m, 2H), 3.38-3.22 (m, 1H), and 2.24-2.09 (m, 3H).

(177) LC-MS retention time (Method 1): 5.686 min.

(178) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.19F.sub.2N.sub.2O.sub.3 409.1358) found, 409.1363.

Example 40: exo-11-(5-Chloro-2-fluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(179) ##STR00053##

(180) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 5-chloro-2-fluorobenzyl bromide and N-phenylmaleimide.

(181) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.57-7.20 (m, 7H), 7.11-6.94 (m, 2H), 6.18 (dd, J=1.34, and 9.75 Hz, 1H), 4.42-4.26 (m, 2H), 4.22 (dd, J=7.12, and 8.63 Hz, 1H), 3.99 (dt, J=1.42, and 8.28 Hz, 1H), and 3.72 (s, 2H).

(182) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17ClFN.sub.2O.sub.3 411.0906) found, 411.0920.

Example 41: endo-11-(3-Chlorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(183) ##STR00054##

(184) and

Example 42: exo-11-(3-Chlorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(185) ##STR00055##

(186) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-chlorobenzyl bromide and N-phenylmaleimide and were separated by HPLC.

Example 41

(187) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50-7.24 (m, 8H), 7.10-7.02 (m, 2H), 6.18 (dd, J=1.36, and 9.75 Hz, 1H), 4.38-4.16 (m, 3H), 3.93 (dt, J=1.37, and 8.30 Hz, 1H), and 3.69 (s, 2H).

(188) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.18ClN.sub.2O.sub.3 393.1000) found, 393.1001.

(189) LC-MS retention time (Method 1): 5.533 min.

(190) HRMS: m/z (M+Na).sup.+=(Calculated for C.sub.23H.sub.18F.sub.2N.sub.2NaO.sub.3 431.1178) found, 431.1157.

Example 42

(191) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.21 (m, 9H), 7.19-7.02 (m, 1H), 6.18 (dd, J=1.52, and 9.87 Hz, 1H), 4.10 (d, J=4.84 Hz, 1H), 3.97-3.73 (m, 2H), 3.73-3.57 (m, 2H), and 3.42-3.32 (m, 1H).

(192) HRMS: m/z (M+Na).sup.+=(Calculated for C.sub.22H.sub.17ClN.sub.2NaO.sub.3 415.0820) found, 415.0804.

Example 43: 11-(3,5-Difluorobenzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(193) ##STR00056##

(194) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3,5-difluorobenzyl bromide and N-phenylmaleimide. The isomers were not separated.

(195) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59-7.22 (m, 10H), 7.19-6.99 (m, 6H), 6.88 (dt, J=1.99, and 7.76 Hz, 2H), 6.19 (ddd, J=1.45, 3.51, and 9.90 Hz, 2H), 4.38-4.16 (m, 3H), 4.14-4.02 (m, 1H), 4.00-3.75 (m, 3H), 3.72 (s, 2H), 3.69-3.58 (m, 2H), and 3.43-3.31 (m, 1H).

(196) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.17F.sub.2N.sub.2O.sub.3 395.1202) found, 395.1204.

Example 44: exo-11-(2-Fluoro-3-(trifluoromethyl)benzyl)-4-phenyl-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(197) ##STR00057##

(198) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 2-fluoro-3-(trifluoromethyl)benzyl bromide and N-phenylmaleimide.

(199) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.82-7.65 (m, 3H), 7.58-7.28 (m, 12H), 7.21-7.11 (m, 2H), 7.10-7.02 (m, 1H), 6.20 (ddd, J=1.45, 4.40, and 9.74 Hz, 2H), 4.39-4.28 (m, 1H), 4.22 (dd, J=7.11, and 8.64 Hz, 1H), 4.10 (d, J=4.81 Hz, 1H), 4.04-3.93 (m, 2H), 3.92-3.80 (m, 2H), 3.69-3.49 (m, 2H), and 3.36 (dd, J=0.58, and 7.38 Hz, 1H).

(200) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.17F.sub.4N.sub.2O.sub.3 445.1170) found, 445.1173.

Example 45: endo-Methyl 3-((3,5,10-trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec -8-en-11-yl)methyl)benzoate

(201) ##STR00058##

(202) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, methyl 3-(bromomethyl)benzoate and N-phenylmaleimide.

(203) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94-7.76 (m, 2H), 7.59-7.35 (m, 5H), 7.35-7.23 (m, 3H), 6.19 (dd, J=1.52, and 9.89 Hz, 1H), 4.13-4.03 (m, 1H), 3.96-3.71 (m, 5H), 3.64-3.56 (m, 2H), and 3.39-3.21 (m, 2H).

(204) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.24H.sub.21N.sub.2O.sub.5 417.1445) found, 417.1437.

Example 46: endo-11-Benzyl-4-ethyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(205) ##STR00059##

(206) and

Example 47: exo-11-Benzyl-4-ethyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(207) ##STR00060##

(208) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-ethylmaleimide and were separated by HPLC.

Example 46

(209) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.37-7.22 (m, 5H), 7.15 (dd, J=5.57, and 9.73 Hz, 1H), 5.98 (dd, J=1.38, and 9.74 Hz, 1H), 4.18-4.08 (m, 2H), 4.02 (dd, J=7.13, and 8.51 Hz, 1H), 3.80 (dt, J=1.36, and 8.30 Hz, 1H), 3.63 (s, 2H), 3.23 (qd, J=1.25, and 7.13 Hz, 2H), and 0.87 (t, J=7.17 Hz, 3H).

(210) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.18H.sub.19N.sub.2O.sub.3 311.1390) found, 311.1395.

Example 47

(211) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.31-7.17 (m, 4H), 7.10-7.02 (m, 2H), 6.13 (dd, J=1.54, and 9.88 Hz, 1H), 3.98 (d, J=4.85 Hz, 1H), 3.81-3.65 (m, 2H), 3.51-3.37 (m, 4H), 3.30-3.13 (m, 1H), and 1.09 (t, J=7.16 Hz, 3H).

(212) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.18H.sub.19N.sub.2O.sub.3 311.1390) found, 311.1387.

Example 48: endo-4-Ethyl-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(213) ##STR00061##

(214) and

Example 49: exo-4-Ethyl-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(215) ##STR00062##

(216) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-ethylmaleimide and were separated by HPLC.

Example 48

(217) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.26-7.01 (m, 6H), 5.98 (dd, J=1.37, and 9.74 Hz, 1H), 4.17-4.08 (m, 2H), 4.02 (dd, J=7.13, and 8.52 Hz, 1H), 3.80 (dt, J=1.37, and 8.29 Hz, 1H), 3.58 (s, 2H), 3.23 (qd, J=1.25, and 7.22 Hz, 2H), 2.28 (s, 3H), and 0.92-0.83 (m, 3H).

(218) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.19H.sub.21N.sub.2O.sub.3 325.1547) found, 325.1537.

Example 49

(219) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.24 (dd, J=4.88, and 9.88 Hz, 1H), 7.14 (t, J=7.51 Hz, 1H), 7.07-6.99 (m, 1H), 6.91-6.81 (m, 2H), 6.13 (dd, J=1.54, and 9.84 Hz, 1H), 3.98 (d, J=4.84 Hz, 1H), 3.73 (d, J=13.79 Hz, 1H), 3.64 (d, J=13.79 Hz, 1H), 3.51-3.31 (m, 4H), 3.16 (d, J=7.17 Hz, 1H), 2.21 (s, 3H), and 1.10 (t, J=7.16 Hz, 3H).

(220) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.19H.sub.21N.sub.2O.sub.3 325.1547 found, 325.1555.

Example 50: endo-11-Benzyl-4-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(221) ##STR00063##

(222) and

Example 51: exo-11-Benzyl-4-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(223) ##STR00064##

(224) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-methylmaleimide and were separated by HPLC.

Example 50

(225) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.39-7.23 (m, 27H), 7.15 (dd, J=5.49, and 9.77 Hz, 1H), 6.00 (dd, J=1.39, and 9.76 Hz, 1H), 4.22-4.02 (m, 3H), 3.81 (dt, J=1.40, and 8.27 Hz, 1H), 3.64 (s, 2H), and 2.69 (s, 3H).

(226) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.17H.sub.17N.sub.2O.sub.3 297.1234 found, 297.1235.

Example 51

(227) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.32-7.16 (m, 4H), 7.05 (ddt, J=0.68, 1.40, and 7.26 Hz, 2H), 6.13 (dd, J=1.55, and 9.87 Hz, 1H), 3.96 (dd, J=0.75, and 4.85 Hz, 1H), 3.82-3.65 (m, 2H), 3.50 (dt, J=0.63, and 1.43 Hz, 1H), 3.43 (d, J=7.23 Hz, 1H), 3.19 (d, J=7.20 Hz, 1H), and 2.90 (s, 3H).

(228) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.17H.sub.17N.sub.2O.sub.3 297.1234 found, 297.1226.

Example 52: endo-4-Methyl-1-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(229) ##STR00065##

(230) and

Example 53: exo-4-Methyl-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene -3,5,8-trione Trifluoroacetate

(231) ##STR00066##

(232) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-methylmaleimide and were separated by HPLC.

Example 52

(233) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.26-6.96 (m, 6H), 5.98 (dd, J=1.40, and 9.75 Hz, 1H), 4.20-4.00 (m, 3H), 3.79 (dt, J=1.39, and 8.28 Hz, 1H), 3.58 (s, 2H), 2.68 (s, 3H), and 2.28 (s, 3H).

(234) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.18H.sub.19N.sub.2O.sub.3 311.1390) found, 311.1397.

Example 53

(235) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.28-7.10 (m, 2H), 7.07-6.96 (m, 1H), 6.89-6.76 (m, 2H), 6.13 (dd, J=1.52, and 9.87 Hz, 1H), 3.96 (d, J=4.88 Hz, 1H), 3.78-3.61 (m, 2H), 3.50 (dt, J=0.64, and 1.43 Hz, 1H), 3.43 (d, J=7.20 Hz, 1H), 3.26-3.12 (m, 1H), 2.91 (s, 3H), and 2.23 (d, J=0.81 Hz, 3H).

(236) LC-MS retention time (Method 1): 5.047 min.

(237) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.18H.sub.19N.sub.2O.sub.3 311.1390) found, 311.1399.

Example 54: exo-11-Benzyl-4-(4-hydroxyphenyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(238) ##STR00067##

(239) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, benzyl bromide and N-(4-hydroxyphenyl)maleimide.

(240) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.34-7.19 (m, 5H), 7.18-7.08 (m, 2H), 7.05-6.96 (m, 2H), 6.91-6.84 (m, 2H), 6.17 (dd, J=1.54, and 9.87 Hz, 1H), 4.05 (d, J=4.87 Hz, 1H), 3.78 (d, J=15.44 Hz, 2H), 3.64-3.47 (m, 2H), and 3.32-3.25 (m, 1H).

(241) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.19N.sub.2O.sub.4 375.1339) found, 375.1356.

Example 55: exo-4-(4-Hydroxyphenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(242) ##STR00068##

(243) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(4-hydroxyphenyl)maleimide.

(244) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.79 (s, 1H), 7.35-7.08 (m, 2H), 7.10-6.80 (m, 7H), 6.17 (dd, J=1.55, and 9.90 Hz, 1H), 4.06 (d, J=4.88 Hz, 1H), 3.84-3.64 (m, 2H), 3.60-3.49 (m, 2H), 3.31-3.25 (m, 2H), and 2.23 (s, 3H).

(245) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.4 389.1496) found, 389.1505.

Example 56: exo-4-(2-Hydroxyphenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(246) ##STR00069##

(247) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(2-hydroxyphenyl)maleimide.

(248) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.83 (s, 1H), 7.43 (s, 1H), 7.28 (dt, J=4.70, and 9.90 Hz, 2H), 7.18 (t, J=7.40 Hz, 1H), 7.08-6.89 (m, 7H), 6.17 (d, J=9.82 Hz, 1H), 4.07 (d, J=4.82 Hz, 1H), 3.80 (d, J=13.80 Hz, 1H), 3.71 (d, J=13.89 Hz, 1H), 3.59 (d, J=1.48 Hz, 2H), 3.41 (s, 1H), and 2.23 (s, 3H).

(249) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.4 389.1496) found, 389.1507.

Example 57: N-(4-(11-(3-Methylbenzyl)-3,5,10-trioxo-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec -8-en-4-yl)phenyl)acetamide Trifluoroacetate

(250) ##STR00070##

(251) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(4-acetylamino)phenyl)maleimide.

(252) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.12 (s, 1H), 7.79-7.54 (m, 2H), 7.29 (dd, J=4.86, and 9.90 Hz, 1H), 7.23-7.09 (m, 3H), 7.05 (ddd, J=0.93, 1.84, and 8.31 Hz, 1H), 7.02-6.86 (m, 2H), 6.17 (dd, J=1.50, and 9.89 Hz, 1H), 4.07 (d, J=4.83 Hz, 1H), 3.86-3.65 (m, 2H), 3.65-3.50 (m, 2H), 3.33 (s, 1H), 2.23 (s, 3H), and 2.06 (s, 3H).

(253) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.25H.sub.24N.sub.3O.sub.4 430.1761) found, 430.1764.

Example 58: exo-4-(3-Hydroxyphenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(254) ##STR00071##

(255) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(3-hydroxyphenyl)maleimide.

(256) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.79 (s, 1H), 7.34-7.24 (m, 2H), 7.18 (t, J=7.53 Hz, 1H), 7.08-7.01 (m, 1H), 6.96 (t, J=1.71 Hz, 1H), 6.92 (d, J=7.51 Hz, 1H), 6.84 (ddd, J=1.12, 2.28, and 8.25 Hz, 1H), 6.69-6.61 (m, 2H), 6.17 (dd, J=1.53, and 9.88 Hz, 1H), 4.07 (d, J=4.86 Hz, 1H), 3.84-3.63 (m, 2H), 3.62-3.46 (m, 2H), and 2.23 (s, 3H).

(257) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.4 389.1496) found, 389.1501.

Example 59: exo-4-(4-Ethylphenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(258) ##STR00072##

(259) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-ethylmaleimide.

(260) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41-7.25 (m, 3H), 7.22-7.08 (m, 3H), 7.09-7.01 (m, 1H), 7.00-6.89 (m, 2H), 6.17 (dd, J=1.53, and 9.88 Hz, 1H), 4.11-4.05 (m, 1H), 3.79 (d, J=13.73 Hz, 1H), 3.70 (d, J=13.75 Hz, 1H), 3.62-3.54 (m, 2H), 3.32 (dd, J=0.59, and 7.30 Hz, 1H), 2.66 (q, J=7.59 Hz, 2H), 2.23 (d, J=0.78 Hz, 3H), and 1.20 (t, J=7.58 Hz, 3H).

(261) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.25H.sub.25N.sub.2O.sub.3 401.1860) found, 401.1849.

Example 60: exo-4,11-Dimethyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(262) ##STR00073##

(263) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, methyl iodide and N-methylmaleimide.

(264) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.17 (ddd, J=1.25, 4.84, and 9.92 Hz, 1H), 6.05 (dt, J=1.40, and 9.90 Hz, 1H), 3.96 (d, J=4.86 Hz, 1H), 3.48 (d, J=1.52 Hz, 1H), 3.39 (d, J=7.28 Hz, 1H), 3.19-3.05 (m, 1H), 2.85 (d, J=1.14 Hz, 3H), and 2.29 (d, J=1.12 Hz, 3H).

(265) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.11H.sub.13N.sub.2O.sub.3 221.0921) found, 221.0924.

Example 61: exo-4-Ethyl-11-methyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(266) ##STR00074##

(267) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, methyl iodide and N-ethylmaleimide.

(268) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.17 (dd, J=4.84, and 9.91 Hz, 1H), 6.05 (dd, J=1.56, and 9.88 Hz, 1H), 3.99-3.91 (m, 1H), 3.53-3.32 (m, 4H), 3.17-3.10 (m, 1H), 2.29 (s, 3H), and 1.03 (t, J=7.17 Hz, 3H).

(269) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.1-2H.sub.15N.sub.2O.sub.3 235.1077) found, 235.1085.

Example 62: exo-4-(3-Bromophenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(270) ##STR00075##

(271) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(3-bromophenyl)maleimide.

(272) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.69 (ddd, J=0.98, 1.98, and 8.11 Hz, 1H), 7.53 (t, J=8.03 Hz, 1H), 7.45 (t, J=1.90 Hz, 1H), 7.36-7.24 (m, 2H), 7.17 (t, J=7.52 Hz, 1H), 7.11-7.02 (m, 1H), 7.00-6.84 (m, 2H), 6.18 (dd, J=1.50, and 9.88 Hz, 1H), 4.08 (d, J=4.83 Hz, 1H), 3.87-3.64 (m, 2H), 3.64-3.54 (m, 2H), 3.36 (d, J=7.28 Hz, 1H), and 2.23 (s, 3H).

(273) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.20BrN.sub.2O.sub.3 453.0634) found, 453.0644.

Example 63: exo-11-(3-Methylbenzyl)-4-(3-(piperidin-1-yl)phenyl)-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(274) ##STR00076##

(275) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(3-(piperidin-1-yl)phenyl)maleimide.

(276) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.35-7.26 (m, 2H), 7.19-7.11 (m, 1H), 7.08-6.91 (m, 4H), 6.69 (t, J=2.13 Hz, 1H), 6.57 (ddd, J=0.85, 1.84, and 7.73 Hz, 1H), 6.17 (dd, J=1.52, and 9.87 Hz, 1H), 4.08 (d, J=4.86 Hz, 1H), 3.85-3.65 (m, 2H), 3.62-3.48 (m, 2H), 3.32 (d, J=0.59 Hz, 1H), 3.17-3.11 (m, 4H), 2.23 (s, 3H), and 1.65-1.48 (m, 6H).

(277) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.28H.sub.30N.sub.3O.sub.3 456.2282) found, 456.2280.

Example 64: exo-11-(3-Methylbenzyl)-4-(4-(4-morpholino)phenyl)-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(278) ##STR00077##

(279) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(4-morpholinophenyl)maleimide.

(280) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.29 (dd, J=4.87, and 9.89 Hz, 1H), 7.17 (t, J=7.54 Hz, 1H), 7.11-7.02 (m, 5H), 7.00-6.85 (m, 2H), 6.17 (dd, J=1.54, and 9.87 Hz, 1H), 4.07 (d, J=4.85 Hz, 1H), 3.83-3.69 (m, 6H), 3.61-3.49 (m, 2H), 3.30 (d, J=0.61 Hz, 1H), 3.19-3.07 (m, 4H), and 2.23 (s, 3H).

(281) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.27H.sub.28N.sub.3O.sub.4 458.2074) found, 458.2064.

Example 65: exo 4-(2,6-Dimethylphenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(282) ##STR00078##

(283) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(2,6-dimethylphenyl)maleimide.

(284) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41 (dd, J=5.7, and 9.7 Hz, 1H), 7.27-7.03 (m, 7H), 6.17 (dd, J=1.4, and 9.7 Hz, 1H), 4.54 (dd, J=8.2, and 9.2 Hz, 1H), 4.44 (dd, J=7.1, and 9.1 Hz, 1H), 4.23 (ddd, J=1.4, 5.7, and 7.1 Hz, 1H), 3.90 (dt, J=1.4, and 8.2 Hz, 1H), 3.64 (s, 2H), 2.30 (s, 3H), 2.00 (s, 3H), and 1.88 (s, 3H).

(285) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.25H.sub.25N.sub.2O.sub.3 401.1860) found, 401.1869.

Example 66: exo-4-(4-Bromophenyl)-11-(3-methylbenzyl)-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(286) ##STR00079##

(287) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(4-bromophenyl)maleimide.

(288) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.82-7.73 (m, 2H), 7.34-7.14 (m, 4H), 7.08-6.88 (m, 3H), 6.18 (dd, J=1.48, and 9.88 Hz, 1H), 4.08 (d, J=4.88 Hz, 1H), 3.83-3.65 (m, 2H), 3.59 (d, J=7.26 Hz, 2H), 3.35 (d, J=7.27 Hz, 1H), and 2.22 (s, 3H) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.20BrN.sub.2O.sub.3 451.0652) found, 451.0655.

Example 67: exo-3-((3,5,10-Trioxo-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]undec-8-en-11-yl)methyl)benzenesulfonamide Trifluoroacetate

(289) ##STR00080##

(290) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-(bromomethyl)benzenesulfonamide and N-phenylmaleimide.

(291) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73 (dt, J=1.36, and 7.95 Hz, 1H), 7.66 (s, 1H), 7.54-7.41 (m, 5H), 7.39-7.24 (m, 7H), 6.20 (dd, J=1.50, and 9.88 Hz, 1H), 4.19-4.02 (m, 1H), 3.98-3.71 (m, 2H), 3.66-3.52 (m, 2H), and 3.36 (d, J=7.48 Hz, 1H).

(292) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.22H.sub.19N.sub.3NaO.sub.5S 460.0938) found, 460.0917.

Example 68: exo-11-(3-(Methylsulfonyl)benzyl)-4-phenyl-4,11-diazatricyclo[5.3.1.0.SUP.2,6.]-undec-9-ene-3,5,8-trione Trifluoroacetate

(293) ##STR00081##

(294) The title compound was prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-(methylsulfonyl)benzyl bromide and N-phenylmaleimide.

(295) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.81 (dt, J=1.50, and 7.79 Hz, 1H), 7.77 (t, J=1.74 Hz, 1H), 7.60 (t, J=7.69 Hz, 1H), 7.53 (ddt, J=1.52, 6.12, and 7.80 Hz, 3H), 7.49-7.42 (m, 1H), 7.37-7.21 (m, 3H), 6.21 (dd, J=1.55, and 9.91 Hz, 1H), 4.10 (d, J=4.88 Hz, 1H), 4.00-3.82 (m, 2H), 3.70-3.51 (m, 2H), 3.44-3.32 (m, 1H), and 3.11 (s, 3H).

(296) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.23H.sub.21N.sub.2O.sub.5S 437.1166) found, 437.1155.

Example 69: endo-11-(3-Methylbenzyl)-4-(3-(4-morpholino)phenyl)-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(297) ##STR00082##

(298) and

Example 70: exo-11-(3-Methylbenzyl)-4-(3-(4-morpholino)phenyl)-4,11-diazatricyclo-[5.3.1.0.SUP.2,6.]undec-9-ene-3,5,8-trione Trifluoroacetate

(299) ##STR00083##

(300) The title compounds were prepared in accordance with Example 1, Steps (a) and (b) from 3-hydroxypyridine, 3-methylbenzyl bromide and N-(3-morpholinophenyl)maleimide and were separated by HPLC.

Example 69

(301) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.33-7.13 (m, 3H), 7.13-7.04 (m, 3H), 6.95 (dd, J=2.5, and 8.5 Hz, 1H), 6.53 (t, J=2.1 Hz, 1H), 6.47-6.39 (m, 1H), 6.18 (dd, J=1.3, and 9.7 Hz, 1H), 4.32-4.10 (m, 3H), 3.88 (dt, J=1.4, and 8.3 Hz, 1H), 3.61 (s, 2H), 3.30 (s, 4H), 3.11-3.01 (s, 4H), and 2.28 (s, 3H).

(302) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.27H.sub.28N.sub.3O.sub.4 458.2074) found, 458.2055.

Example 70

(303) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36 (t, J=8.1 Hz, 1H), 7.28 (dd, J=4.9, and 9.9 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.07-6.99 (m, 2H), 6.99-6.89 (m, 2H), 6.71 (t, J=2.1 Hz, 1H), 6.63 (dd, J=1.7, and 7.5 Hz, 1H), 6.16 (dd, J=1.5, and 9.9 Hz, 1H), 4.06 (d, J=4.9 Hz, 1H), 3.78 (d, J=13.7 Hz, 1H), 3.76-3.66 (m, 5H), 3.66-3.51 (m, 2H), 3.09 (dd, J=3.7, and 5.9 Hz, 4H), and 2.21 (s, 3H).

(304) HRMS: m/z (M+H).sup.+=(Calculated for C.sub.27H.sub.28N.sub.3O.sub.4 458.2074) found, 458.2080.

BIOLOGICAL EXAMPLES

Biological Example 1: Inhibition of Recombinant TrxR1 and GR

(305) Small molecule inhibition of recombinant thioredoxin reductase 1 (TrxR1) and gluthathione reductase (GR) was examined in 96-well plate format. 15 nM TrxR1 was incubated in the presence of 250 M NADPH, 0.1 mg/ml BSA, and various concentrations of the compound of Example 1 (1% DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubation period, 2.5 mM DTNB was added to each well and the change in O.D. at 412 nm was followed. Percent activity was determined using DMSO vehicle and no TrxR1 (blank) controls. 2 nM GR was incubated in the presence of 250 M NADPH, 0.1 mg/ml BSA, and various concentrations of compounds (1% DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA buffer for 15 minutes. Following the incubation period, 1 mM GSSG was added to each well and the change in O.D. at 340 nm was followed. Percent activity was determined using DMSO vehicle and no GR (blank) controls.

(306) Using the assays described in Biological Example 1, the following IC.sub.50 values were obtained. Results obtained for the compound of Example 1 are also represented in FIG. 1.

(307) TABLE-US-00001 Example TrxR inhibition (M) GR inhibition (M) 1 2.14 >100 3 3.09 43.97 6 2.12 61.91 7 1.75 >100 9 1.85 >100 10 2.70 >100 15 1.45 >100 18 2.45 70.43 20 3.70 >100 21 7.39 >100 22 1.97 >100 58 0.75 >100 65 4.52 >100 67 1.31 >100 68 1.88 >100 69 7.40 >100 70 2.26 >100

Biological Example 2: Cell Culture

(308) Cell lines were plated 2000 cells/well in 96-well black optical plates in the presence of 10% FBS media containing 25 nM selenite. The following day cells were treated with various concentrations of the compound of Example 1 (0.1% DMSO final) and incubated for 72 hrs. After the incubation Cell-Quanti Blue reagent was added to each well and incubated for additional 3 hrs. Fluorescence was read ex:530 nm/em:590 nm, and percent of viability was determined using DMSO vehicle and no cell (blank) controls.

(309) Various results obtained are shown in FIG. 2 herein, wherein data for the following cell lines is presented.

(310) TABLE-US-00002 Cell line Cell type FaDu pharyngeal squamous cell carcinoma HCT116 colorectal carcinoma HCT116 p53 colorectal carcinoma HCT116 ++ BLC2 colorectal carcinoma A431 epidermoid (skin) carcinoma KPC-Luc pancreatic ductal carcinoma MDA-MB-231 metastatic mammary adenocarcinoma A549 lung carcinoma THP-1 acute monocytic leukemia

(311) Further results obtained in similar experiments were as indicated below (GI50 refers to concentration of compound yielding 50% growth inhibition; E denotes an exponent to the base 10).

(312) TABLE-US-00003 Panel/Cell Line GI50 (M) Leukemia CCRF-CEM 9.42E07 HL-60(TB) 1.17E06 K-562 1.67E06 MOLT-4 1.72E06 RPMI-8226 1.59E06 SR 1.87E06 Non-Small Cell Lung Cancer A549/ATCC 1.49E05 EKVX 7.78E06 HOP-62 1.38E06 HOP-92 3.66E06 NCI-H226 7.26E06 NCI-H23 5.37E06 NCI-H322M 1.02E05 NCI-H460 3.49E06 NCI-H522 2.68E06 Colon Cancer COLO 205 5.47E06 HCC-2998 7.94E06 HCT-116 1.56E06 HCT-15 1.74E06 HT29 1.79E06 KM12 2.56E06 SW-620 1.86E06 CNS Cancer SF-268 3.34E06 SF-295 6.41E06 SF-539 1.66E06 SNB-19 6.04E06 SNB-75 4.19E06 U251 2.29E06 Melanoma LOX IMVI 1.61E06 MALME-3M 4.62E06 M14 2.60E06 MDA-MB-435 2.72E06 MDA-N 3.14E06 SK-MEL-2 4.37E06 SK-MEL-28 3.01E06 SK-MEL-5 3.56E06 UACC-257 3.22E06 UACC-62 2.01E06 Ovarian Cancer IGROV1 4.81E06 OVCAR-3 3.44E06 OVCAR-4 5.53E06 OVCAR-5 6.75E06 OVCAR-8 2.88E06 NCI/ADR-RES 2.55E06 SK-OV-3 1.32E05 Renal Cancer 786-0 1.69E06 A498 8.57E06 ACHN 3.36E06 CAKI-1 4.09E06 RXF 393 2.42E06 SN12C 1.64E06 TK-10 8.07E06 UO-31 3.42E06 Prostate Cancer PC-3 4.68E06 DU-145 9.66E06 Breast Cancer MCF7 3.19E06 MDA-MB-231/ATCC 5.45E06 HS 5781 3.51E06 BT-549 3.45E06 T-47D 4.92E06

Biological Example 3: Mouse Model

(313) Fox Chase male severe combined immunodeficiency (SCID, Charles River, #250) mice were inoculated with 110.sup.6 FaDu cells in PBS at a pre-shaved region located at the anterior lateral thoracic wall. After 13 days of growth, tumors were caliper measured and treatments were initiated. Mice were injected with 15 mg/kg of the compound of Example 1, or vehicle a total of nine times in a five-day span via i.v. tail injection. Upon the final dose, injections were performed subcutaneously (s.c.) due to pronounced hematomas at the tail injection site. Mouse health status was monitored daily, weight was measured, and tumor volume was recorded from caliper measurements. The mice displayed no overt signs of general or systemic toxic effects in normal cells or tissues. Tumor growth was normalized to day 0 caliper measurements, and treatment with the compound of Example 1 (N=6, p<0.01) was compared to vehicle (N=4) using a repeated measures ANOVA with a Dunnett's multiple comparison post test.

Biological Example 4: Inhibition of Recombinant TrxR1 and GR

(314) Using the assays described in Biological Example 1, the following IC.sub.50 values were obtained for example compounds as described herein.

(315) TABLE-US-00004 Example TrxR Inhibition (M) GR Inhibition (M) 1 2.19 >100 2 1.46 65.21 3 1.12 23.00 4 1.18 55.62 5 2.49 >100 6 0.57 31.30 7 1.97 >100 8 2.03 28.53 9 1.85 >100 10 0.79 >100 11 0.90 >100 12 1.25 41.41 13 7.82 >100 14 33.35 >100 15 3.33 >100 16 5.56 >100 17 1.64 >100 18 0.94 22.03 19 1.50 >100 20 0.94 >100 21 1.15 >100 22 1.24 75.21 23 3.83 >100 24 1.30 >100 25 7.06 >100 26 2.50 30.09 27 1.34 >100 28 2.71 29.76 29 1.07 >100 30 1.87 25.19 31 1.06 >100 32 1.44 35.79 33 1.33 >100 34 1.23 >100 35 1.06 >100 36 1.47 68.46 37 0.93 >100 38 1.36 12.31 39 1.29 >100 40 0.77 31.57 41 2.35 49.49 42 0.76 76.38 43 1.59 91.74 44 2.33 177.10 45 1.40 >100 46 5.10 >100 47 4.15 >100 48 3.63 >100 49 2.53 >100 50 3.08 >100 51 4.61 >100 52 1.81 >100 53 3.26 >100 54 1.80 >100 55 1.64 >100 56 1.44 >100 57 3.04 >100 58 1.30 >100 59 1.63 >100 60 15.37 >100 61 23.36 >100 62 1.23 >100 63 1.58 >100 65 5.30 >100 66 1.43 >100 67 1.99 >100 68 2.24 >100 69 4.15 >100 70 2.62 >100