Methods for treating Kaposi sarcoma

1. A method for treating a Kaposi sarcoma (KS), comprising administering to a human having the KS an effective amount of a compound having Formula (II):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more halogen substituents; hydroxyl; halogen; or C 1 to C 6 alkoxy optionally substituted with phenyl;

R o is halogen; cyano; nitro; sulfonyl substituted with C 1 to C 6 alkyl or morpholinyl; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —(O)O—R b , alkylsulfonyl, morpholinyl or tetrahydropyranyl; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen and amino; —C(O)R n ; or —OR a ;

R a is hydrogen; C 2 to C 8 alkenyl; —C(O)—R n ; —C(O)O—R b ; —C(O)—NH—R b ; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen, C 1 to C 4 alkoxy, (C 1 to C 4 )alkyl-O—(C 1 to C 4 )alkyl-O—, amino, alkylamino, dialkylamino, acetamide, —C(O)—R b , —C(O)O—R b , aryl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxolan-2-one, oxiranyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3-triazole, 1,2,4-triazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, thiazole, thiophene and tetrazole;

wherein amino is optionally substituted with C 1 to C 4 alkoxycarbonyl, imidazole, isothiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, thiazole or sulfonyl substituted with C 1 to C 6 alkyl, wherein pyridine and thiazole are each optionally substituted with C 1 to C 4 alkyl;

wherein alkylamino and dialkylamino are each optionally substituted on alkyl with hydroxyl, C 1 to C 4 alkoxy, imidazole, pyrazole, pyrrole or tetrazole; and,

wherein morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl and oxiranyl are each optionally substituted with —C(O)—R n , —C(O)O—R n or C 1 to C 4 alkyl, wherein C 1 to C 4 alkyl is optionally substituted with hydroxyl;

R b is hydroxyl; amino; alkylamino, optionally substituted on alkyl with hydroxyl, amino, alkylamino or C 1 to C 4 alkoxy; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; C 2 to C 8 alkynyl; aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen and C 1 to C 4 alkoxy; furan; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of C 1 to C 4 alkoxy, aryl, amino, morpholinyl, piperidinyl and piperazinyl;

R d is aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, nitro, C 1 to C 6 alkyl, —C(O)O—R e , and —OR e ;

R e is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkoxy; or phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkoxy; and

R n is hydroxyl, C 1 to C 4 alkoxy, amino or C 1 to C 6 alkyl;

wherein administering the compound to the human produces one or more of the results selected from the group consisting of:

(i) decrease in the number of previously existing KS lesions in the human relative to the number of KS lesions observed prior to administration of the compound;

(ii) decrease in the number of raised KS lesions in the human relative to the number of raised KS lesions observed prior to administration of the compound;

(iii) complete flattening of one or more previously raised KS lesions in the human; and

(iv) decrease in the sum of perpendicular diameters of a KS lesion in the human, relative to the sum of perpendicular diameters in the KS lesion observed prior to administration of the compound.

2. The method of claim 1 , wherein the KS is classic Kaposi sarcoma.

3. The method of claim 1 , wherein the KS is endemic Kaposi sarcoma.

4. The method of claim 1 , wherein the KS is AIDS-related Kaposi sarcoma.

5. The method of claim 1 , wherein the KS is iatrogenic Kaposi sarcoma.

6. The method of claim 1 , wherein the effective amount is in a range of from about 0.001 mg per kg per day to about 1500 mg per kg per day.

7. The method of claim 1 , wherein the compound is administered during or within about 30 minutes after a meal.

8. The method of claim 1 , wherein the effective amount of the compound is administered two times per day at a time interval of from about 12 hours to about 18 hours between doses.

9. The method of claim 8 , wherein the effective amount of the compound is administered two times per day at a time interval of about 12 hours between doses.

10. The method of claim 1 , wherein the effective amount of the compound is administered three times per day at a time interval of from about 8 hours to about 12 hours between doses.

11. The method of claim 10 , wherein the effective amount of the compound is administered three times per day at a time interval of about 8 hours between doses.

12. The method of claim 1 , wherein the compound has the Formula (II):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R o is halogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen and amino, or —OR a ;

R a is hydrogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and halogen; and

R d is phenyl optionally substituted with one or more —O(C 1 -C 6 alkyl) or halogen substituents.

13. The method of claim 1 , wherein the compound has the Formula (II):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R o is halogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl, halogen and amino, or —OR a ;

R a is hydrogen, or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and halogen; and

R d is phenyl optionally substituted with one or more halogen substituents.

14. The method of claim 1 , wherein the compound has the Formula (III):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R a is hydrogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and halogen; and

R d is phenyl substituted with one or more halogen substituents.

15. The method of claim 1 , wherein the compound has the Formula (IV):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R a is hydrogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and halogen; and

R d is phenyl substituted with one or more halogen substituents.

16. The method of claim 1 , wherein the compound has the Formula (IV):

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof, wherein,

X is halogen;

R a is hydrogen, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxyl and halogen; and

R d is phenyl substituted on a para position with a halogen substituent.

17. A method for treating a Kaposi sarcoma (KS), comprising administering to a human having the KS an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt, racemate or stereoisomer thereof;

wherein administering the compound to the human produces one or more of the results selected from the group consisting of:

(i) decrease in the number of previously existing KS lesions in the human relative to the number of KS lesions observed prior to administration of the compound;

(ii) decrease in the number of raised KS lesions in the human relative to the number of raised KS lesions observed prior to administration of the compound;

(iii) complete flattening of one or more previously raised KS lesions in the human; and

(iv) decrease in the sum of perpendicular diameters of a KS lesion in the human, relative to the sum of perpendicular diameters in the KS lesion observed prior to administration of the compound.

18. The method of any one of claims 1 and 12 - 17 , wherein said compound is a stereoisomer having a chiral carbon atom at the substituted carbon atom in the beta-position to the nitrogen atom of the five-membered ring of the tricyclic core, and said compound is an (S) stereoisomer at said chiral carbon atom.