METHODS FOR TREATING BRAIN TUMORS

1 . A method for treating a brain tumor, comprising administering to a human in need thereof an effective amount of a compound having Formula (I):

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 5 alkoxy optionally substituted with aryl;

A is CH or N;

B is CH or N, with the proviso that at least one of A or B is N, and that when A is N, Bis CH;

R 1 is hydroxyl; C 1 to C 8 alkyl optionally substituted with alkylthio, 5 to 10 membered heteroaryl, or aryl optionally substituted with one or more independently selected R o substituents; C 2 to C 8 alkyenyl; C 2 to C 8 alkynyl; 3 to 12 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio; 5 to 12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, amino, alkylamino, acetamino, thio, or alkylthio; or aryl, optionally substituted with one or more independently selected R 0 substituents;

R o is a halogen; cyano; nitro; sulfonyl optionally substituted with C 1 to C 6 alkyl or 3 to 10 membered heterocycle; amino optionally substituted with C 1 to C 6 alkyl, —C(O)—R b , —C(O)O—R b , sulfonyl, alkylsulfonyl, 3 to 10 membered heterocycle optionally substituted with —C(O)O—R n ; —C(O)—NH—R b ; 5 to 6 membered heterocycle; 5 to 6 membered heteroaryl; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, amino, or 3 to 12 membered heterocycle wherein amino and 3 to 12 membered heterocycle are optionally substituted with one or more C 1 to C 4 alkyl substituents optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, amino, alkylamino, or 5 to 10 membered heterocycle; —C(O)—R n ; or —OR a ;

R a is hydrogen; C 2 to C 8 alkylene; —C(O)—R n ; —C(O)O—R b ; —C(O)—NH—R b ; C 3 -C 14 cycloalkyl; aryl; heteroaryl; heterocyclyl; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen, C 1 to C 4 alkoxy, amino, alkylamino, acetamide, —C(O)—R b , —C(O)O—R b , aryl, 3 to 12 membered heterocycle, or 5 to 12 membered heteroaryl, further wherein the alkylamino is optionally substituted with hydroxyl, C 1 to C 4 alkoxy, or 5 to 12 membered heteroaryl optionally substituted with C 1 to C 4 alkyl, further wherein the acetamide is optionally substituted with C 1 to C 4 alkoxy, sulfonyl, or alkylsulfonyl, further wherein the 3 to 12 membered heterocycle is optionally substituted with C 1 to C 4 alkyl optionally substituted with hydroxyl, —C(O)—R n , —C(O)O—R n , or oxo, further wherein the 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;

R b is hydroxyl; amino; alkylamino optionally substituted with hydroxyl, amino, alkylamino, C 1 to C 4 alkoxy, 3 to 12 membered heterocycle optionally substituted with one or more independently selected C 1 to C 6 alkyl, oxo, —C(O)O—R n , or 5 to 12 membered heteroaryl optionally substituted with C 1 to C 4 alkyl; C 1 to C 4 alkoxy; C 2 to C 8 alkenyl; C 2 to C 8 alkynyl; aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from halogen or C 1 to C 4 alkoxy; 5 to 12 membered heteroaryl; 3 to 12 membered heterocycle optionally substituted with one or more substituents independently selected from acetamide, —C(O)O—R n , 5 to 6 membered heterocycle, or C 1 to C 6 alkyl optionally substituted with hydroxyl, C 1 to C 4 alkoxy, amino, or alkylamino; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from C 1 to C 4 alkoxy, aryl, amino, or 3 to 12 membered heterocycle, wherein the amino and 3 to 12 membered heterocycle are optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl, oxo, or —C(O)O—R n ;

R 2 is hydrogen; hydroxyl; 5 to 10 membered heteroaryl; C 1 to C 8 alkyl optionally substituted with hydroxyl, C 1 to C 4 alkoxy, 3 to 10 membered heterocycle, 5 to 10 membered heteroaryl, or aryl; —C(O)—R c ; —C(O)O—R d ; —C(O)—N(R d R d ); —C(S)—N(R d R d ); —C(S)—O—R c ; —S(O 2 )—R e ; —C(NR e )—S—R e ; or —C(S)—S—R f ;

R c is hydrogen; amino optionally substituted with one or more substituents independently selected from C 1 to C 6 alkyl or aryl; aryl optionally substituted with one or more substituents independently selected from halogen, haloalkyl, hydroxyl, C 1 to C 4 alkoxy, or C 1 to C 6 alkyl; —C(O)—R n ; 5 to 6 membered heterocycle optionally substituted with —C(O)—R n ; 5 to 6 membered heteroaryl; thiazoleamino; C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from halogen, C 1 to C 4 alkoxy, phenyloxy, aryl, —C(O)—R n , —O—C(O)—R n , hydroxyl, or amino optionally substituted with —C(O)O—R n ;

R d is independently hydrogen; C 2 to C 8 alkenyl; C 2 to C 8 alkynyl; aryl optionally substituted with one or more substituents independently selected from halogen, nitro, C 1 to C 6 alkyl, —C(O)O—R e , or —OR e ; or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from halogen, C 1 to C 4 alkyl, C 1 to C 4 alkoxy, phenyloxy, aryl, 5 to 6 membered heteroaryl, —C(O)—R n , —C(O)O—R n , or hydroxyl, wherein the aryl is optionally substituted with one or more substituents independently selected from halogen or haloalkyl;

R e is hydrogen; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halogen or alkoxy; or aryl optionally substituted with one or more substituents independently selected from halogen or alkoxy;

R f is C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1 to C 4 alkoxy, cyano, aryl, or —C(O)—R n , wherein the alkoxy is optionally substituted with one or more C 1 to C 4 alkoxy substituents and the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1 to C 4 alkoxy, cyano, or C 1 to C 6 alkyl;

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

R 3 is hydrogen or —C(O)—R g ; and

R g is hydroxyl; amino optionally substituted with cycloalkyl or 5 to 10 membered heteroaryl; or 5 to 10 membered heterocycle, wherein the 5 to 10 membered heterocycle is optionally substituted with —C(O)—R n .

2 . The method of claim 1 , wherein the brain tumor is a malignant primary brain tumor, a malignant non-primary brain tumor, a benign primary brain tumor or a benign non-primary brain tumor.

3 . The method of claim 2 , wherein the primary brain tumor is a glioma or non-glioma, wherein the glioma is selected from an astrocytoma, an oligodendroglioma, a mixture of oligodendroglioma and astrocytoma elements or an ependymoma, and wherein the non-glioma is selected from a non-malignant meningioma or pituitary adenoma or a malignant primitive neuroectodermal tumor, medullblastoma, primary Central Nervous System (CNS) lymphoma or CNS germ cell tumor.

4 . The method of claim 2 , wherein the brain tumor is an acoustic neuroma, an anaplastic astrocytoma, glioblastoma multiforme, a meningioma, a brain stem glioma, a craniopharyngioma, an ependyoma, a juvenile pilocytic astrocytoma, a medulloblastoma, an optic nerve glioma, a primitive neuroectodermal tumor or a rhabdoid tumor.

5 . The method of claim 4 , wherein the brain tumor is glioblastoma multiforme.

6 . The method of claim 1 , wherein the brain tumor is in a human adult.

7 . The method of claim 1 , wherein the brain tumor is in a human child.

8 . The method of claim 1 , wherein the effective amount of the compound is administered based on body weight.

9 . 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.

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

11 . 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.

12 . The method of claim 11 , wherein the effective amount of the compound is administered two times per day at a time interval of about 12 hours between doses.

13 . 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.

14 . The method of claim 13 , wherein the effective amount of the compound is administered three times per day at a time interval of about 8 hours between doses.

15 . The method of claim 1 , wherein the compound has the 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 5 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 , —C(O)O—R b , alkylsulfonyl, morpholinyl or tetrahydropyranyl; C 1 to C 6 alkyl optionally substituted with one or more substituents independently selected from hydroxyl, halogen or 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 hydroxyl, halogen, C 1 to C 4 alkoxy, C 1 to C 4 alkoxy C 1 to C 4 alkoxy, 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 or 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 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 C 1 to C 4 alkoxy, aryl, amino, morpholinyl, piperidinyl or piperazinyl;

R d is aryl optionally substituted with one or more substituents independently selected from 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 halogen and alkoxy; or phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and alkoxy; and

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

16 . 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, substituted or unsubstituted C 1 to C 8 alkyl or OR a ;

R a is H, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

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

17 . 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, substituted or unsubstituted C 1 to C 8 alkyl or OR a ;

R a is H, or C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

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

18 . 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 H, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

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

19 . 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 H, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

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

20 . 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 H, C 1 to C 8 alkyl optionally substituted with one or more substituents independently selected from hydroxyl and halogen; and

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