IP Library › Patent Application 11680843

Patent Application

App. No. 11/680,843

COMPOUNDS AND THERAPEUTICAL USE THEREOF

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Patent No.: US None
App. No.: 11/680,843

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Abstract

Disclosed are 4-arylamino-quinazolines and analogs thereof effective as activators of caspases and inducers of apoptosis. The compounds of this invention are useful in the treatment of a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

Claims (258)

1 . A method of inhibiting tubulin in a mammal in need of such treatment, said method comprises treating the mammal with an effective amount of a compound according to Formula Ia or a pharmaceutically acceptable salt or solvate thereof:

wherein:

A ring is a 6-membered aryl, heteroaryl or carbocycle;

L is [C(R L1 )(R L2 )] n or —N(R L1 )C(O)—, wherein R L1 and R L2 independently are H or C 1-6 alkyl, n is 0, 1 or 2;

R 1 is methyl or ethyl;

Ar is aryl or heteroaryl, each of which is optionally substituted by one or more substituents wherein each substituent is independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R 3 )(R k ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;

R 2 -R 6 , and R 12 -R 17 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, with the proviso that when A ring is aryl or heteroaryl, then there are no substituents R 14 -R 17 ; and

B, D, Q, T, U and V, are independently C or N, wherein at least one of B and D is nitrogen; wherein when B or D is N, then there is no substituent at the N; and wherein when A ring is heteroaryl and Q, T, U or V is N, then there is no substituent at the N.

2 . The method of claim 1 , wherein said treating step comprises administering to the mammal a pharmaceutical composition comprising said effective amount of said compound.

3 . The method of claim 1 , wherein B and D are both nitrogen in Formula Ia.

4 . The method of claim 1 , wherein said compound is according to Formula Ib or a pharmaceutically acceptable salt or solvate thereof:

wherein:

R 1 is methyl or ethyl;

R 5 is H or F; and

R 2 , R 3 , R 4 , R 6 -R 11 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein optionally two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered aryl, heteroaryl, carbocycle, or heterocycle.

5 . The method of claim 1 , wherein said compound is according to Formula Ic or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

R 5 is H or F; and

6 . The method of claim 1 , wherein said compound is according to Formula II or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

Ar is aryl or heteroaryl, each of which is optionally substituted by one or more substituents wherein each substituent is independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;

R 5 is H or F;

R 2 -R 4 , R 6 , and R 12 and R 13 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl,

C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—

C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; and

B, D, Q, T, U and V, are independently C or N, wherein at least one of B and D is N, wherein when B, D, Q, T, U or V is N, then there is not substituent at the N.

7 . The method of claim 1 , wherein said compound is according to Formula III or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

R 2 -R 6 and R 12 -R 17 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; and

B and D are independently C or N, wherein at least one of B and D is N, and when B or D is N, then there is no substituent at the N.

8 . The method of claim 1 , wherein said compound is according to Formula IV or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

A ring is a 6-membered carbocycle, aryl or heteroaryl;

R 2 -R 17 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle, with the proviso that when A ring is aryl or heteroaryl, then there are no substituents R 14 -R 17 ; and

B, D, Q, T, U, V, W, X, Y, and Z are independently C or N, wherein at least one of B and D is N; wherein when B, D, W, X, Y, or Z is N, then there is no substituent at the N; and wherein when A is heteroaryl and Q, T, U or V is N, then there is no substituent at the N.

9 . The method of claim 1 , wherein said compound is according to Formula IVa or a pharmaceutically acceptable salt or solvate thereof:

wherein:

R 1 is methyl or ethyl;

B, D, W, X, Y, and Z are independently C or N, provided that at least one of B and D is N, at least one of W, X, Y and Z is N, and when B, D, W, X, Y or Z is N then there is no substituent at the N.

10 . The method of claim 1 , wherein said compound is according to Formula IVb or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

R 2 -R 17 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, (C 2-6 alkenyl)O—, (C 2-6 alkynyl)O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

B and D are independently C or N, provided that at least one of B and D is N, and when B or D is N then there is no substituent at the N.

11 . The method of claim 1 , wherein said compound is according to Formula V or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 1 is methyl or ethyl;

R 5 is H, F, Cl, N 3 , methoxy or NH 2 ;

R 2 -R 4 , and R 6 -R 13 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

B, D, Q, T, U, V, W, X, Y and Z are independently C or N, provided that at least one of B and D is N, and at least one of W, X, Y and Z is N, and wherein when B, D, Q, T, U, V, W, X, Y or Z is N, then there is no substituent at the N.

12 . The method of claim 1 , wherein said compound is according to Formula VI or a pharmaceutically acceptable salt or solvate thereof:

wherein:

R 1 is methyl or ethyl;

R 5 is H or F;

R 2 -R 4 , R 6 -R 13 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

B, D, Q, T, U and V are independently C or N, provided that at least one of B and D is N; wherein when B, D, Q, T, U or V is N, then there is no substituent at the N.

13 . The method of claim 1 , wherein said compound is according to Formula VIb or a pharmaceutically acceptable salt or solvate thereof:

wherein:

R 1 is methyl or ethyl;

R 5 is H or F; and

R 2 -R 4 , R 6 -R 11 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle.

14 . The method of claim 13 , wherein said treating step comprises administering to the mammal a pharmaceutical composition comprising said effective amount of said compound.

15 . A method of treating fungi infection in a mammal in need of such treatment, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

16 . A method of inhibiting topoisomerase II in a mammal in need of such treatment, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

17 . A method of activating caspase-3 in a mammal in need of such treatment, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

18 . A method of treating a neoplastic disease in a mammal in need of such treatment, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound of claim 1 according to Formula IV or a pharmaceutically acceptable salt or solvate thereof:

R 1 is methyl or ethyl;

A ring is a carbocycle, aryl or heteroaryl;

B, D, Q, T, U, V, W, X, Y and Z are independently C or N, wherein at least one of B and D is N; wherein when B, D, W, X, Y or Z is N, then there is no substituent at the N; and wherein when A is heteroaryl and Q, T, U or V is N, then there is no substituent at the N; and

with the provisos that: (1) when A is aryl, W, X, Y and Z are all C, and R 9 is H then at least one of R 8 and R 10 is not H or halo; and

(2) when A is heteroaryl, W, X, Y and Z are all C, and R 9 is H, then at least one of R 8 and R 10 is not H, halo or C 1-6 alkyl.

19 . The method of claim 18 , further comprising administering to the mammal another anti-cancer agent selected from the group consisting of alkylating agents, antimitotic agents, topo I inhibitors, topo TI inhibitors, RNA/DNA antimetabolites, EGFR inhibitors, angiogenesis inhibitors, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Gleevec® (Imatinib Mesylate) and alanosine.

20 . A method of treating cancer in a patient who has been treated with and is not responsive to another anti-cancer drug or has developed resistance to such other anti-cancer compound, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound of Formula IV according to claim 18 , or a pharmaceutically acceptable salt or solvate thereof.

21 . A compound represented by Formula IVa:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

B, D, W, X, Y, and Z are independently C or N, provided that at least one of B and D is N, at least one of W, X, Y and Z is N, and when B, D, W, X, Y or Z is N then there is no substituent at the N.

22 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 21 .

23 . A compound of claim 21 represented by Formula IVb:

or pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

R 2 -R 17 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, (C 2-6 alkenyl)O—, (C 2-6 alkynyl)O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R k ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

B and D are independently C or N, provided that at least one of B and D is N, and when B or D is N then there is no substituent at the N; with the proviso that said compound is not 2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline.

24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 23 .

25 . A compound represented by Formula V:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

R 5 is H, F, Cl, N 3 , methyl, methoxy or NH 2 , with the proviso that when R 5 is methoxy, then R 1 is

methyl;

R 2 -R 4 , and R 6 -R 13 are independently H, halo, N 3 , OH, thiol, nitro, CN, NH 2 , C 16 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, halo-C 1-6 alkyl, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle; and

26 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 25 .

27 . The compound of claim 25 , wherein said compound is selected from the group consisting of:

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

N 2 -(2-Hydroxyethyl)-N 4 -(6-methoxypyridin-3-yl)-N 4 -methyl-quinazoline-2,4-diamine;

N 4 -(6-Methoxypyridin-3-yl)-N 4 -methyl-quinazoline-2,4-diamine;

(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine;

(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and

(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

28 . A compound of claim 25 represented by Formula VIa

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

R 5 is H or F;

Q, T, U and V are independently C or N, wherein at least one of Q, T, U and V is N, and when Q, T, U or V is N there is no substituent at the N, provided that when R 9 is H then at least one of R 8 and R 10 is not H or alkyl.

29 . The compound of claim 28 , wherein said compound is selected from the group consisting of:

(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine; and

(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

30 . A compound of claim 25 represented by Formula VIb:

or pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

R 5 is H or F; and

C 1-6 acyloxy, —C 1-6 alkyl-C(O)O—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or heteroaryl, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle; wherein any of the groups is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , OH, thiol, nitro, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyl-O—, C 2-6 alkynyl-O—, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 acyl, C 1-6 acyloxy, C 1-6 alkyl-C(O)O—C 1-6 alkyl-, C 1-6 acylamido, —N(R a )(R b ), —C 1-6 alkyl-C(O)N(R a )(R b ), —C(O)N(R a )(R b ), N(R a )(R b )—C 1-6 alkyl-, wherein R a and R b are independently H, OH (R a and R b are not both OH), C 2-6 hydroxyalkyl, or C 1-6 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any two adjacent R 7 -R 11 groups together form a 3, 4, 5 or 6-membered carbocycle or heterocycle;

provided that R 9 is not —O(C 1-6 alkyl)C(O)O(C 1-6 alkyl), and when R 9 is H, then R 8 and R 10 are not both H, or one H and the other halo.

31 . The compound of claim 30 , wherein when R 9 is H then at least one of R 8 and R 10 is not H or halo or C 1-6 alkyl.

32 . The compound of claim 30 wherein:

R 2 is H; halo; N 3 ; C 1-6 alkyl optionally substituted with 1-4 substituents which are independently OH or halo; —XR 23 where X is S or O, and R 2a is C 1-6 alkyl optionally substituted with OH or halo; —CO 2 —R 2f , where R 2f is C 16 ; or —N(R 2b )(R 2c ) where R 2b and R 2 , are independently H, OH, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 alkyl that is optionally substituted with —N(R 2d )(R 2e ) where R 2d and R 2e are independently H, OH, C 1-3 alkyl, or C 2-3 hydroxyalkyl, and wherein R 2b and R 2c together with the nitrogen atom to which they are both linked may form a 3, 4, 5 or 6-membered heterocycle, and wherein R 2b and R 2c are not both OH, R 2d and R 2e are not both OH;

R 3 is H; halo; C 1-3 alkyl; or C 1-3 alkoxy;

R 4 and R 6 are independently H; halo; N 3 ; C 1-3 alkyl; C 1-3 alkoxy; or —N(R 2b )(R 2c ) wherein R 2b and R 2c are independently H, OH, CH 3 , and optionally R 2b and R 2c together with the nitrogen atom to which they are both linked may form a 3, 4, 5 or 6-membered heterocycle, and where R 2b and R 2c are not both OH;

R 5 is H;

R 7 and R 11 are independently H, halo, CH 3 , or OCH 3 ;

R 8 and R 10 are independently H; halo; C 1-3 alkyl; C 1-3 alkoxy; —XR 9a , where X is O or S, and R 9a is C 1-4 alkyl or C 1-3 haloalkyl; —N(R a )(R b ) where R a and R b are independently C 1-3 alkyl; or —COOR 9b , wherein R 9b is C 1-3 alkyl; and

R 9 is selected from the group consisting of H; hydroxy; Cl; N 3 ; C 1-3 alkyl or C 1-3 haloalkyl; —OR 93 , wherein R 9a is C 1-3 alkyl or C 1-3 haloalkyl; —N(R 2b )(R 2c ) where R 2b and R 2c are independently H, C 1-3 alkyl, or C 1-3 haloalkyl; or —COOR 9b , wherein R 9b is C 1-3 alkyl; and optionally R 9 and one of R 8 and R 10 together form a 3, 4, 5, or 6-membered heterocycle.

33 . The compound of claim 30 wherein:

R 2 is H; halo; N 3 ; C 1-6 alkyl optionally substituted with 1-4 substituents which are OH or halo; —XR 2a where X is S or O, and R 2a is C 1-6 alkyl optionally substituted with OH or halo; or —N(R 2b )(R 2c ) where R 2b and R 2 , are independently H, OH, C 1-6 alkyl, C 1-6 hydroxyalkyl, or R 2b and R 2 , together with the N to which they are both linked form a 3, 4, 5 or 6-membered heterocycle.

34 . The compound of claim 30 , wherein:

R 2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH 2 F, CHF 2 , CF 3 ), C 1-3 hydroxyalkyl, NH 2 , NH 2 OH, NHCH 2 CH 2 OH, NHCH 3 , N(CH 3 ) 2 , N 3 , morpholino, OCH 3 , OC 2 H 5 , or SCH 3 ; and

R 9 is selected from the group consisting of H, OH, N 3 , C 1 , C 1-3 alkyl, C 1-3 haloalkyl, or —OR 9a where R 9a is C 1-3 alkyl or C 1-3 haloalkyl, —N(R 2b )(R 2c ) wherein R 2b and R 2c are independently C 1-3 alkyl, or —COOR 9b where R 9b is C 1-3 alkyl, and optionally R 8 and R 9 together form a 3, 4, 5, or 6-membered heterocycle; provided that when R 9 is H, then at least one of R 8 and R 10 is OCH 3 ; and when R 9 is C 1-3 alkyl or C 1-3 haloalkyl or Cl, then R 2 is Cl or methyl or ethyl.

35 . The compound of claim 30 , wherein R 9 is selected from the group consisting of H, C 1 , N 3 ;

C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C 1-3 alkoxy, (halo)C 1-3 alkoxy, —N(R a )(R b ) where R a and R b are independently H, OH (R a and R b are not both OH), C 2-4 hydroxyalkyl, or C 1-3 alkyl or R a and R b together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle;

—XR c wherein X is S or O and R c is C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents, each substituent being independently OH, halo, C 1-3 alkoxy, or (halo)C 1-3 alkoxy;

—(C 0-3 alkyl)CO 2 R d where R d is C 1-6 alkyl;

—N(R a )(R b ) where R a and R b are independently H, OH (R a and R b are not both OH), C 2-4 hydroxyalkyl, C 1-3 alkyl, or —N(R e )(R f ) where R e and R f are independently H, OH (R e and R f are not both OH), or C 1-3 alkyl; wherein optionally R a and R b together with the N to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, and optionally R e and R f together with the nitrogen atom to which they both are linked form a 3, 4, 5 or 6-membered heterocycle; or

—(C 0-3 alkyl)C(O)N(R a )(R b ) where R a and R b are independently H or C 1-3 alkyl;

and optionally R 9 and one of R 8 and R 10 together form a 3, 4, 5, or 6-membered heterocycle.

36 . The compound of claim 30 , wherein R 9 is H; OH; Cl; N 3 ; C 1-3 alkyl; C 1-3 haloalkyl; —OR 9a where R 9a is C 1-4 alkyl or C 1-3 haloalkyl; —NH(R a ) or —N(R a )(R b ) where R a and R b are independently C 1-3 alkyl; or —COOR 9b where R 9b is C 1-3 alkyl; and optionally R 9 and one of R 8 and R 10 together form a 3, 4, 5, or 6-membered heterocycle.

37 . The compound of claim 30 , wherein R 1 is CH 3 ; R 2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH 2 F, CHF 2 , CF 3 ), CH 2 OH, NH 2 , NHCH 3 , N(CH 3 ) 2 , —NHCH 2 CH 2 OH, OCH 3 , or SCH 3 ; R 3 is H, CH 3 , OCH 3 , F, or Cl; R 4 and R 6 are independently H, CH 3 , NH 2 , F, or Cl; R 5 is H; R 7 and R 11 are independently H, F, or OCH 3 ; R 8 and R 10 are independently H, F, Cl, or OCH 3 ; and R 9 is selected from the group consisting of —OR 12 where R 12 is methyl, ethyl, fluoromethyl or fluoroethyl, —NHCH 3 , N(CH 3 ) 2 , N 3 , and —COOR 13 where R 13 is methyl or ethyl.

38 . The compound of claim 30 , wherein said compound is selected from the group consisting of:

N 2 -Hydroxyl-N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

N 2 -(2-Hydroxylethyl)-N 4-(4-methoxy-phenyl)-N 4-methyl-quinazoline-2,4-diamine;

N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

N 2 -(3,7-Dimethyl-octa-2,6-dienyl)-N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

N 4 -(4-Methoxy-phenyl)-N 4 -methyl-N 2 -(2-morpholin-4-yl-ethyl)-quinazoline-2,4-diamine;

(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;

N 2 -(3,7-Dimethyl-octa-2,6-dienyl)-N 4 -(4-methyl-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

N 2 -[2-(1H-Imidazol-4-yl)-ethyl]-N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

N 2 -(3-Dimethylamino-propyl)-N 4 -(4-methoxy-phenyl)-N 4 -methyl-quinazoline-2,4-diamine;

5-Chloro-N 2 ,N 4 -bis-(4-methoxy-phenyl)-N 2 ,N 4 -dimethyl-quinazoline-2,4-diamine;

6-Chloro-N 2 ,N 4 -bis-(4-methoxy-phenyl)-N 2 N 4 -dimethyl-quinazoline-2,4-diamine;

(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and

(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

39 . The compound of claim 30 , wherein said compound is selected from the group consisting of:

(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine; (2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-carboxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

Ethyl 4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;

(2-hydroxymethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;

(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Methoxy-phenyl-2,3,5,6-d 4 )-(2-methyl-quinazolin-4-yl)-methyl-amine;

(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;

(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(4-Methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine;

(2,4,6-Trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;

(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(3,5-Dibromo-4-methoxyphenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;

(4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and

Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;

or a pharmaceutically acceptable salt or solvate thereof.

40 . The compound of claim 30 , wherein said compound is selected from the group consisting of:

(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;

(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;

(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;

(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;

(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;

(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;

(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;

(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and

(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

41 . The compound of claim 30 , wherein said compound is selected from the group consisting of:

(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine; and

(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

42 . The compound of claim 30 , wherein said compound is selected from the group consisting of:

(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine; and

(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;

or a pharmaceutically acceptable salt or solvate thereof.

43 . The compound of claim 30 , wherein said compound is (2-methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine, or a pharmaceutically acceptable salt or solvate thereof.

44 . The compound of claim 30 , wherein said compound is (2-azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine, or a pharmaceutically acceptable salt or solvate thereof.

45 . The compound of claim 30 , wherein said compound is (4-methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine hydrochloride, or a pharmaceutically acceptable salt or solvate thereof.

46 . The compound of claim 30 , wherein said compound is (2-chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine, or a pharmaceutically acceptable salt or solvate thereof.

47 . The compound of claim 30 , wherein said compound is (isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine, or a pharmaceutically acceptable salt or solvate thereof.

48 . The compound of claim 30 , wherein said compound is (4-methoxy-phenyl)-methyl-(quinolin-4-yl)-amine, or a pharmaceutically acceptable salt or solvate thereof.

49 . The compound of claim 30 , wherein said compound is (4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine, or a pharmaceutically acceptable salt or solvate thereof.

50 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 30 .

51 . The pharmaceutical composition of claim 50 , further comprising at least one known cancer chemotherapeutic agent, or a pharmaceutically acceptable salt of said agent.

52 . The pharmaceutical composition of claim 50 , further comprising at least one compound selected from the group consisting of busulfan, cis-platin, mitomycin C, carboplatin, colchicine, vinblastine, paclitaxel, docetaxel, camptothecin, topotecan, doxorubicin, etoposide, 5-azacytidine, 5-fluorouracil, methotrexate, 5-fluoro-2′-deoxy-uridine, ara-C, hydroxyurea, thioguanine, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, octreotide, retinoic acid, tamoxifen, Herceptin®, Rituxan®, arsenic trioxide, gamcitabine, doxazosin, terazosin, tamsulosin, CB-64D, CB-184, haloperidol, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, BMS-232,632, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, fenretinide, N-4-carboxyphenyl retinamide, lactacystin, MG-132, PS-341, Gleevec®, ZD1839 (Iressa), SH268, genistein, CEP2563, SU6668, SU11248, EMD121974, R15777, SCH66336, L-778,123, BAL9611, TAN-1813, flavopiridol, UCN-01, roscovitine, olomoucine, celecoxib, valecoxib, rofecoxib and alanosine.

53 . A method of inducing apoptosis in a mammal in need of such treatment, said method comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof.

54 . A process for the manufacture of a compound of claim 30 , or a pharmaceutically acceptable salt or solvate thereof, comprising reacting a compound of the following formula

wherein R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 30;

with the following compound

wherein R 1 , R 7 , R 8 , R 9 , R 10 , and R 11 are as defined in claim 30;

to obtain a compound of claim 30.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 24, 2009

From: MYRIAD GENETICS, INC.

To: MYRIAD PHARMACEUTICALS, INC.

Reel/Frame 023138/0115 →