Substituted gemcitabine bicyclic amide analogs and treatment methods using same
In one aspect, the invention relates to substituted gemcitabine aryl amide analogs, derivatives thereof, and related compounds; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating viral disorders and disorders of uncontrolled cellular proliferation using the compounds and compositions. In certain aspects, the compounds have the following structure:
1. A compound having a structure represented by a formula:
wherein Ar 1 is a bicyclic fused ring system having an aryl ring fused to a 5-, 6-, or 7-membered heterocycloalkyl;
wherein the aryl ring is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl;
wherein the aryl ring is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 monohaloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkylamino, and C 1 -C 6 dialkylamino;
wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —OH, —CN, —NH 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 monohaloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, —(C═O)OR 5 , and —(C═O)NR 6a R 6b ;
wherein each R 5 is independently selected from hydrogen, C 1 -C 8 alkyl, and a hydroxyl protecting group;
wherein each of R 6a and R 6b is independently selected from hydrogen, C 1 -C 4 alkyl, and an amine protecting group;
wherein R 2 is selected from hydrogen, C 1 -C 4 alkyl, and an amine protecting group;
wherein R 3 is selected from hydrogen and a hydroxyl protecting group; and
wherein R 4 is selected from hydrogen, C 1 -C 8 alkyl, and a hydroxyl protecting group, or wherein R 3 and R 4 together comprise a divalent moiety having a structure represented by a formula:
wherein each of R 7a , R 7b , R 7c , and R 7d is independently selected from methyl, ethyl, propyl, and butyl;
or a pharmaceutically acceptable salt, or polymorph thereof.
2. The compound of claim 1 , wherein Ar 1 is a bicyclic fused ring system having a phenyl ring fused to a 5-, 6-, or 7-membered heterocycloalkyl.
3. The compound of claim 1 , wherein the heterocycloalkyl is substituted with 0, 1, or 2 groups independently selected from —F, —CN, —NH 2 , methyl, —CH 2 F, —CHF 2 , —CF 3 , —OCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 OH, —CH 2 NH 2 , —(C═O)OH, —(C═O)OCH 3 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .
4. The compound of claim 1 , wherein the heterocycloalkyl is unsubstituted.
5. The compound of claim 1 , wherein each of R 2 , R 3 , and R 4 are hydrogen.
6. The compound of claim 1 selected from the group consisting of:
7. A method of making a compound of claim 1 , comprising the steps of:
(a) providing a first compound having a structure represented by a formula:
wherein R 2 is an amine protecting group;
wherein R 3 is a hydroxyl protecting group; and
wherein R 4 is a hydroxyl protecting group, or wherein R 3 and R 4 together comprise a hydroxyl protecting group; and
(b) reacting with a second compound having a structure represented by a formula:
wherein X is halogen or pseudohalogen;
wherein Ar 1 is a bicyclic fused ring system having an aryl ring fused to a 5-, 6-, or 7-membered heterocycloalkyl;
wherein the aryl ring is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl;
wherein the aryl ring is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 monohaloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkylamino, and C 1 -C 6 dialkylamino;
wherein the heterocycloalkyl is substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —OH, —CN, —NH 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 monohaloalkyl, C 1 -C 6 polyhaloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 aminoalkyl, C 1 -C 6 hydroxyalkyl, —(C═O)OR 5 , and —(C═O)NR 6a R 6b ;
wherein each R 5 is independently selected from hydrogen, C 1 -C 8 alkyl, and a hydroxyl protecting group;
wherein each of R 6a and R 6b is independently selected from hydrogen, C 1 -C 4 alkyl, and an amine protecting group;
thereby forming an amide bond.
8. The method of claim 7 , wherein providing the first compound further comprises converting a compound having the structure:
wherein R 2 is hydrogen, to the first compound wherein R 2 is an amine protecting group.
9. The method of claim 7 , wherein providing the first compound further comprises converting a compound having the structure:
wherein R 3 is hydrogen, to the first compound wherein R 3 is a hydroxyl protecting group.
10. The method of claim 7 , wherein providing the first compound further comprises converting a compound having the structure:
wherein R 4 is hydrogen, to the first compound wherein R 4 is a hydroxyl protecting group.
11. The method of claim 7 , wherein R 3 and R 4 together are a divalent moiety having a structure represented by a formula:
wherein each of R 7a , R 7b , R 7c , and R 7d is independently selected from methyl, ethyl, propyl, and butyl.
12. The method of claim 7 , further comprising deprotecting R 2 .
13. The method of claim 7 , further comprising deprotecting R 3 .
14. The method of claim 7 , further comprising deprotecting R 4 .
15. A method for treating a subject for a viral infection comprising a hepatitis C virus, comprising administering to a subject in need thereof an effective amount of the compound of claim 6 .
16. The method of claim 15 , wherein the compound is: