Diterpenoid compounds, compositions thereof and their use as anti-cancer or anti-fungal agents
View Patent ↗The present invention relates to Diterpenoid Compounds, compositions comprising an effective amount of a Diterpenoid Compound, and methods useful for treating or preventing cancer or a neoplastic disorder comprising administering an effective amount of a Diterpenoid Compound. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a cancer cell or neoplastic cell, or for inducing apoptosis in a cancer or neoplastic cell. The compounds, compositions, and methods of the invention are further useful for treating or preventing a fungal infection. The compounds, compositions, and methods of the invention are also useful for inhibiting the growth of a fungus.
1. A compound having the Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Q 1 and Q 2 are independently ═O, ═S, ═NH or ═N—NHR, where R is —H, —C 1 –C 10 alkyl, or -aryl;
Q 3 is —O—, —S—, or —N(H)—;
R 1 and R 2 are independently —H, -halogen, -amino, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, (C 3 –C 7 )cycloalkyl, -aryl, C 1 –C 10 (aryl)alkyl, or three- to seven-membered non-aromatic heterocycle, or R 1 , R 2 and the carbon atom to which they are both attached are taken together to form a (C 3 –C 7 )cycloalkyl group or a three- to seven-membered non-aromatic heterocycle;
A is CR 3 ; B is CR 4 ; D is CR 5 ; E is CR 6 ;
each R 3 , R 4 , R 5 and R 6 is independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 —C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCH 2 OR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —S(O) 2 NHR 11 , —SOR 11 , —S(O) 2 R 11 , —NHC(O)R 11 , —NHSOR 11 , or NHS(O) 2 R 11 ; or
R 3 and R 4 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 5 and R 6 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 4 and R 5 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a non-oxygen-containing five-membered non-aromatic heterocycle, a non-oxygen-containing five-membered aromatic heterocycle, a six- to seven-membered non-aromatic heterocycle or a six- to seven-membered aromatic heterocycle;
R 7 is —H, —C 1 –C 10 alkyl, or —C 1 –C 10 alkoxy;
R 8 and R 9 are each independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —SOR 11 , —S(O) 2 R 11 , —S(O) 2 NHR 11 , —NHSR 11 , —NHSOR 11 , or —NHS(O) 2 R 11 ;
R 10 is —H, —C 1 –C 10 alkyl, —C 3 –C 7 cycloalkyl, —C(O)C 1 –C 10 alkyl, —C 1 –C 10 (oxy)alkyl, —C(O)NH 2 , —C(O)NHR 12 , or -aryl;
R 11 is —H, —C 1 –C 10 alkyl, —(C 3 –C 7 )cycloalkyl, —C 1 –C 10 (halo)alkyl, -aryl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —C 1 –C 10 (aryl)alkyl, —C 2 –C 10 (aryl)alkenyl, —C 2 –C 10 (aryl)alkynyl, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (amino)alkyl,
a —(C 3 –C 7 )cycloalkyl unsubstituted or substituted with one or more —C 1 –C 10 alkyl,
a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, or
a three- to seven-membered aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, or —C 2 –C 10 alkynyl;
R 12 is C 1 –C 10 alkyl; and
each halogen is independently —F, —Cl, —Br or —I;
with the proviso that the compound of Formula (I) is not:
10-Hydroxy-6-methoxy-1,1,4a,7-tetramethyl-1H,4aH-phenanthrene-2,9-dione or
10-Hydroxy-7-hydroxymethyl-6-methoxy-1,1,4a-trimethyl-1H,4aH-phenanthrene-2,9-dione, or a pharmaceutically acceptable salt thereof.
2. A compound of the formula:
or a pharmaceutically acceptable salt thereof, the compound or pharmaceutically acceptable salt thereof being in isolated and purified form.
3. A compound of the formula:
or a pharmaceutically acceptable salt thereof, the compound or pharmaceutically acceptable salt thereof being in isolated and purified form.
4. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein
Q 1 and Q 2 and Q 3 are oxygen;
R 1 and R 2 are C 1 –C 10 alkyl;
R 8 and R 9 are H;
R 7 is C 1 –C 10 alkyl;
R 3 and R 6 are H; and
R 4 and R 5 are independently C 1 –C 10 alkyl, C 1 –C 10 alkoxy, or C 1 –C 10 (hydroxy)alkyl.
5. A compound having the structure:
6. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
7. A compound having the Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
Q 1 and Q 2 are independently ═O, ═S, ═NH or ═N—NHR, where R is —H, —C 1 –C 10 alkyl, or -aryl;
Q 3 is —O—, —S—, or —N(H)—;
R 1 and R 2 are independently —H, -halogen, -amino, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 —C 10 alkenyl, —C 2 –C 10 alkynyl, (C 3 –C 7 )cycloalkyl, -aryl, C 1 –C 10 (aryl)alkyl, or three- to seven-membered non-aromatic heterocycle, or R 1 , R 2 and the carbon atom to which they are both attached are taken together to form a (C 3 –C 7 )cycloalkyl group or a three- to seven-membered non-aromatic heterocycle;
A is CR 3 ; B is CR 4 ; D is CR 5 ; E is CR 6 ;
each R 3 , R 4 , R 5 and R 6 is independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCH 2 OR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —S(O) 2 NHR 11 , —SOR 11 , —S(O) 2 R 11 , —NHC(O)R 11 , —NHSOR 11 , or NHS(O) 2 R 11 ; or
R 3 and R 4 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 5 and R 6 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 4 and R 5 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a non-oxygen-containing five-membered non-aromatic heterocycle, a non-oxygen-containing five-membered aromatic heterocycle, a six- to seven-membered non-aromatic heterocycle or a six- to seven-membered aromatic heterocycle;
R 7 is —H, —C 1 –C 10 alkyl, or —C 1 –C 10 alkoxy;
R 8 and R 9 are each independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —SOR 11 , —S(O) 2 R 11 , —S(O) 2 NHR 11 , —NHSR 11 , —NHSOR 11 , or —NHS(O) 2 R 11 ;
R 10 is —H, —C 1 –C 10 alkyl, —C 3 –C 7 , cycloalkyl, —C(O)C 1 –C 10 alkyl, —C 1 –C 10 (oxy)alkyl, —C(O)NH 2 , —C(O)NHR 12 , or -aryl;
R 11 is —H, —C 1 –C 10 alkyl, —(C 3 –C 7 )cycloalkyl, —C 1 –C 10 (halo)alkyl, -aryl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —C 1 –C 10 (aryl)alkyl, —C 2 –C 10 (aryl)alkenyl, —C 2 –C 10 (aryl)alkynyl, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (amino)alkyl,
a —(C 3 –C 7 )cycloalkyl unsubstituted or substituted with one or more —C 1 –C 10 alkyl,
a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, or
a three- to seven-membered aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, or —C 2 –C 10 alkynyl;
R 12 is C 1 –C 10 alkyl; and
each halogen is independently —F, —Cl, —Br or —I.
8. A compound having the Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
Q 1 , Q 2 and Q 3 are independently ═O, ═S, ═NH or ═N—NHR, where R is —H, —C 1 –C 10 alkyl, or -aryl;
R 1 and R 2 are independently —H, -halogen, -amino, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, (C 3 –C 7 )cycloalkyl, -aryl, C 1 –C 10 (aryl)alkyl, or three- to seven-membered non-aromatic heterocycle, or R 1 , R 2 and the carbon atom to which they are both attached are taken together to form a (C 3 –C 7 )cycloalkyl group or a three- to seven-membered non-aromatic heterocycle;
A is CR 3 ; B is CR 4 ; D is CR 5 ; E is CR 6 ;
each R 3 , R 4 , R 5 and R 6 is independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCH 2 OR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —S(O) 2 NHR 11 , —SOR 11 , —S(O) 2 R 11 , —NHC(O)R 11 , —NHSOR 11 , or NHS(O) 2 R 11 ; or
R 3 and R 4 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 5 and R 6 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 4 and R 5 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a non-oxygen-containing five-membered non-aromatic heterocycle, a non-oxygen-containing five-membered aromatic heterocycle, a six- to seven-membered non-aromatic heterocycle or a six- to seven-membered aromatic heterocycle;
R 7 is —H, —C 1 –C 10 alkyl, or —C 1 –C 10 alkoxy;
R 8 and R 9 are each independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —SOR 11 , —S(O) 2 R 11 , —S(O) 2 NHR 11 , —NHSR 11 , —NHSOR 11 , or —NHS(O) 2 R 11 ;
R 11 is —H, —C 1 –C 10 alkyl, —(C 3 –C 7 )cycloalkyl, —C 1 –C 10 (halo)alkyl, -aryl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —C 1 –C 10 (aryl)alkyl, —C 2 –C 10 (aryl)alkenyl, —C 2 –C 10 (aryl)alkynyl, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (amino)alkyl,
a —(C 3 –C 7 )cycloalkyl unsubstituted or substituted with one or more —C 1 –C 10 alkyl,
a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, or
a three- to seven-membered aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, or —C 2 –C 10 alkynyl;
R 12 is C 1 –C 10 alkyl; and
each halogen is independently —F, —Cl, —Br or —I.
9. The compound of claim 8 having the formula:
or a pharmaceutically acceptable salt thereof.
10. A compound having the Formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
Q 1 , Q 2 and Q 3 are independently ═O, ═S, ═NH or ═N—NHR, where R is —H, —C 1 –C 10 alkyl, or -aryl;
R 1 and R 2 are independently —H, -halogen, -amino, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, (C 3 –C 7 )cycloalkyl, -aryl, C 1 –C 10 (aryl)alkyl, or three- to seven-membered non-aromatic heterocycle, or R 1 , R 2 and the carbon atom to which they are both attached are taken together to form a (C 3 –C 7 )cycloalkyl group or a three- to seven-membered non-aromatic heterocycle;
A is CR 3 ; B is CR 4 ; D is CR 5 ; E is CR 6 ;
each R 3 , R 4 , R 5 and R 6 is independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COCH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCH 2 OR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —S(O) 2 NHR 11 , —SOR 11 , —S(O) 2 R 11 , —NHC(O)R 11 , —NHSOR 11 , or NHS(O) 2 R 11 ; or
R 3 and R 4 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 5 and R 6 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a five- to seven-membered non-aromatic heterocycle, or a five- to seven-membered aromatic heterocycle; or
R 4 and R 5 and the carbon atoms to which they are attached are taken together to form a (C 3 –C 7 )cycloalkenyl group, a non-oxygen-containing five-membered non-aromatic heterocycle, a non-oxygen-containing five-membered aromatic heterocycle, a six- to seven-membered non-aromatic heterocycle or a six- to seven-membered aromatic heterocycle;
R 7 is —H, —C 1 –C 10 alkyl, or —C 1 –C 10 alkoxy;
R 8 and R 9 are each independently —H, -halogen, —CN, —NH 2 , —NO 2 , —COOH, —C(O)NH 2 , —SH, —S(O)NH 2 , —S(O) 2 NH 2 , —C 1 –C 10 (oxy)alkyl, —C 1 –C 10 alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 (amino)alkyl, —C 1 –C 10 (halo)alkyl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —(C 3 –C 7 )cycloalkyl, -aryl, —C 1 –C 10 (aryl)alkyl, three- to seven-membered non-aromatic heterocycle, five- to seven-membered aromatic heterocycle, —CH 2 OR 11 , —OCR 11 , —OC(O)R 11 , —C(O)R 11 , —OC(O)OR 11 , —OC(O)NR 11 , —C(O)OR 11 , —C(O)NR 11 , —OP(O)(OR 11 ) 2 , —SR 11 , —SOR 11 , —S(O) 2 R 11 , —S(O) 2 NHR 11 , —NHSR 11 , —NHSOR 11 , or —NHS(O) 2 R 11 ;
R 11 is —H, —C 1 –C 10 alkyl, —(C 3 –C 7 )cycloalkyl, —C 1 –C 10 (halo)alkyl, -aryl, —C 2 –C 10 alkenyl, —C 2 –C 10 alkynyl, —C 1 –C 10 (aryl)alkyl, —C 2 –C 10 (aryl)alkenyl, —C 2 –C 10 (aryl)alkynyl, —C 1 –C 10 (hydroxy)alkyl, —C 1 –C 10 alkoxy, —C 1 –C 10 (amino)alkyl,
a —(C 3 –C 7 )cycloalkyl unsubstituted or substituted with one or more —C 1 –C 10 alkyl,
a three- to seven-membered non-aromatic heterocycle unsubstituted or substituted with one or more —C 1 —C 10 alkyl, or
a three- to seven-membered aromatic heterocycle unsubstituted or substituted with one or more —C 1 –C 10 alkyl, —C 2 –C 10 alkenyl, or —C 2 –C 10 alkynyl;
R 12 is C 1 –C 10 alkyl; and
each halogen is independently —F, —Cl, —Br or —I.
11. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier.
12. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 2 and a pharmaceutically acceptable carrier.
13. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 3 and a pharmaceutically acceptable carrier.
14. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 7 and a pharmaceutically acceptable carrier.
15. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 8 and a pharmaceutically acceptable carrier.
16. A composition comprising an effective amount of the compound or pharmaceutically acceptable salt of the compound of claim 10 and a pharmaceutically acceptable carrier.