IP Library › Patent Application 11779086

Patent Application

App. No. 11/779,086

COMPOUNDS AND THERAPEUTICAL USE THEREOF

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Patent No.: US None
App. No.: 11/779,086

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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 (149)

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 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 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;

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 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;

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 is heteroaryl and Q, T, U or V is N, then there is no substituent at the N.

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 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;

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 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;

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 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 II inhibitors, RNA/DNA antimetabolites, EGFR inhibitors, angiogenesis inhibitors, melphalan, chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium, fludarabine, ocreotide, 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 . The compound of claim 21 , wherein said compound is represented by

or pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is methyl or ethyl;

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;

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 . The compound of claim 25 , wherein said compound is 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 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 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;

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 24, 2009

From: MYRIAD GENETICS, INC.

To: MYRIAD PHARMACEUTICALS, INC.

Reel/Frame 023137/0639 →