IP Library › Granted Patent US 7,547,804

Granted Patent B2

US 7,547,804 · App. 11/039,275 · Granted Jun 16, 2009

Compounds, compositions, and methods employing same

Assignee: Myriad Genetics, Inc.

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Quick Facts

Patent No.: US 7,547,804
App. No.: 11/039,275
Granted: Jun 16, 2009
Kind: B2

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Abstract

Compounds and pharmaceutical compositions containing the same are provided, which are useful in therapeutic treatment or prevention of various diseases.

Claims (180)

1. A method for promoting apoptosis in a cell of a mammal, comprising identifying a mammal in need of the promoting of apoptosis, and treating the mammal with a therapeutically effective amount of a compound having a structure according to Formula 2L:

or pharmaceutically acceptable salts thereof, wherein,

R 0 is hydroxyl;

Z is O, N(R z ) (R z is H or C 1-6 alkyl), or S;

R 5 is H or C 1-6 alkyl;

R 11 -R 18 are independently selected from

(a) H, halo, N 3, nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

(d) —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 , or —G 3 C(═G 1 )G 2 R 41 ;

R 4 represents (1) haloalkyl; (2) (C 2-6 alkoxy)C 2-6 alkyl; (3) -Ak-O—R 8 , -Ak-R 8 or -Ak(R 8 R 9 ), wherein Ak is C 1-6 alkylene, R 8 and R 9 are independently selected from cycloalkyl, aryl, heterocycle or heteroaryl; each being optionally substituted by one or more substituents independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbocycle, heterocycle, aryl, heteroaryl, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, heteroaryl, carbocycloxy, heterocycloxy, aryloxy, heteroaryloxy, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, carbocycle, heterocycle, aryl, heteroaryl, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

G 1 is S or N; G 2 and G 3 are independently S or —N(R 50 )—; G 4 is —N(R 52 )—;

R 40 is selected from: H, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy and C 1-6 alkylthiol, wherein R 40 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl;

R 41 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein R 41 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl;

R 42 is selected from: H, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and C 1-6 alkylthiol, wherein R 42 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN and C 1-6 alkyl;

R 43 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein R 43 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN and C 1-6 alkyl;

R 50 , R 51 and R 54 are independently H, OH (R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

R 52 , R 53 and R 55 are independently H, OH (R 52 and R 53 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, or R 52 and R 53 together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein R 52 and R 53 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl.

2. A method for promoting apoptosis in a cell of a mammal comprising identifying a mammal in need of the promoting of apoptosis, and treating the mammal with a therapeutically effective amount of a compound having a structure according to Formula 2n:

or pharmaceutically acceptable salts thereof, wherein,

R 0 is hydroxyl;

Z is O, N(R z ) (R z is H or C 1-6 alkyl), or S;

R 5 is H or C 1-6 alkyl;

R 11 -R 18 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

R 4 represents (1) haloalkyl; (2) (C 2-6 alkoxy)C 2-6 alkyl; (3) -Ak-O—R 8 , -Ak-R 8 or -Ak(R 8 R 9 ), wherein Ak is C 2-6 alkylene, R 8 and R 9 are independently selected from cycloalkyl, aryl, heterocycle or heteroaryl; each being optionally substituted by one or more substituents independently selected from

(a) halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbocycle, heterocycle, aryl, heteroaryl, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O) 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 42 or —G 3 C(═G 1 )G 2 R 41 ,

G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 42 is selected from: H, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and C 1-6 alkylthiol, wherein R 42 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN and C 1-6 alkyl;

3. The method of claim 2 , wherein Ak is is C 2-6 alkylene, and R 8 or R 9 or both are substituted with one or more said substituents defined for R 8 and R 9 .

4. A method for promoting apoptosis in a cell of a mammal, comprising identifying a mammal in need of the promoting of apoptosis, and treating the mammal with a therapeutically effective amount of a compound having a structure according to Formula 2p:

or pharmaceutically acceptable salt thereof, wherein

R 5 is H or C 1-6 alkyl;

R 11 -R 25 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40) , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 40 is selected from: H, —OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy and C 1-6 alkylthiol, wherein R 40 is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl;

R 50 , R 51 and R 54 are independently H, OH (R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 halo alkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

5. The method of claim 4 , wherein at least one of R 19 -R 25 is selected from Cl, Br, I, or C 1-6 haloalkyl.

6. The method of claim 5 , wherein R 21 is Cl, Br, I, or C 1-6 haloalkyl.

7. A compound having a structure according to Formula 2p:

and pharmaceutically acceptable salts thereof, wherein

R 5 is H or C 1-6 alkyl;

R 15 -R 20, and R 22 -R 25 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3, nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

wherein R 11 , R 12 and R 14 are H: R 13 is halo; and R 21 is halo or C 1-6 haloalkyl.

8. The compound of claim 7 , wherein R 11 , R 12 and R 14 are H; R 13 is halo; R 15 -R 18 are independently H, F, Cl, Br, I, or C 1-3 haloalkyl; R 21 is Cl, Br, I, or C 1-3 haloalkyl; and R 19 , R 20 , R 22 -R 25 are independently H, F, Cl, Br, I, C 1-6 alkyl, or C 1-3 haloalkyl.

9. A method for promoting apoptosis in a cell of a mammal, comprising identifying a mammal in need of the promoting of apoptosis, and treating a mammal with a therapeutically effective amount of a compound having a structure according to Formula 2q:

or pharmaceutically acceptable salts thereof, wherein

Z is O, N(R z ) (R z is H or C 1-6 alkyl), or S;

R 4a is C 1-6 alkylene;

R 5 is H or C 1-6 alkyl;

R 11 -R 18 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

R 4 represents C 1-6 haloalkyl; (C 2-6 alkoxy)C 2-6 alkyl; R 8 ; -Ak-O—R 8 ; -Ak-R 8 or -Ak(R 8 R 9 ), wherein Ak is lower alkyl, R 8 and R 9 are independently selected from (1) cycloalkyl, (2) aryl, (3) heterocycle, or (4) heteroaryl; each being optionally substituted by one or more substituents independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 50 , R 51 and R 54 are independently H, OH (R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-40 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

with the proviso that when Z is S, R 4 is not bicyclic heteroaryl.

10. The method of claim 9 , wherein R 13 is not H or nitro.

11. The method of claim 9 , wherein R 13 is halo.

12. The method of claim 9 , wherein

Z is NH or O;

R 4a is —CH 2 — or —CH 2 CH 2 —;

R 4 is aryl, aralkyl or heteroaralkyl, each being optionally substituted with one to three substituents selected from F, Cl, Br, I, C 1-6 alkyl, and C 1-6 lower alkoxy;

R 11 , R 12 , and R 14 -R 18 are H; and

R 13 is halo.

13. A method for promoting apoptosis in a cell of a mammal, comprising identifying a mammal in need of the promoting of apoptosis, and treating a mammal with a therapeutically effective amount of a compound having a structure according to Formula 2r:

or pharmaceutically acceptable salts thereof, wherein

R 0 is hydroxyl;

Z is O, N(R z ) (R z is H or C 1-6 alkyl), or S;

R 5 is H or C 1-6 alkyl;

R 11 -R 18 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

each R A when present is selected from the group consisting of

(a) halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, C 1-6 alkylsulfonyl (i.e., C 1-6 alkyl-SO 2 —), C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, —CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbocycle, heterocycle, aryl, heteroaryl, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, heteroaryl, carbocycloxy, heterocycloxy, aryloxy, heteroaryloxy, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., C 1-6 alkyl-SO 2 —), C 1-6 alkylsulfonamide, carbocycle, heterocycle, aryl, heteroaryl, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

(e) two adjacent R A can be taken together to form a carbocyclic, heterocyclic, aryl, or heteroaryl ring fused to the phenyl ring where the resultant bicyclic ring system is substituted with 1-3 substitutents selected from the group consisting of halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., C 1-6 alkyl-SO 2 —), C 1-10 alkylsulfonamide, carbocycle, heterocycle, aryl, heteroaryl, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 , —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ;

wherein G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 50, R 51 and R 54 are independently H, OH (R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3, nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or −N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

R 52 , R 53 and R 55 are independently H, OH (R 52 and R 53 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, or R 52 and R 53 together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), wherein R 52 and R 53 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl,

with the provision that the compound is not 5-chloro-N-[3-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxy-benzamide or 5-chloro-2-hydroxy-N-[3-(2-naphthalenyloxy)-5-(trifluoromethyl)phenyl]-benzamide.

14. A compound having a structure

and pharmaceutically acceptable salts thereof, wherein

R 13 is a halo;

R 16 is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy; and

each R A is independently selected from the group consisting of halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, carbocycle, heterocycle, aryl, heteroaryl, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 , —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 and —G 3 C(═G 1 )G 2 R 41 ,

wherein G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 50, R 51 and R 54 are independently H, OH (R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3, nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or −N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

R 52 , R 53 and R 55 are independently H, OH (R 52 and R 53 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, or R 52 and R 53 together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), wherein R 52 and R 53 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl.

15. A method for promoting apoptosis in a cell of a mammal, comprising identifying a mammal in need of the promoting of apoptosis, and treating a mammal with a therapeutically effective amount of a compound having a structure according to Formula 2s:

or pharmaceutically acceptable salts thereof, wherein

R 0 is hydroxyl;

Z is O, N(R z ) (R z is H or C 1-6 alkyl), or S;

R 5 is H or C 1-6 alkyl;

R 11 -R 18 are independently selected from

(a) H, halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(c) carbocycle, heterocycle, aryl, and heteroaryl, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, sulfone, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfonyl (i.e., —SO 2 —C 1-6 alkyl), C 1-6 alkylsulfonamide, —N(R 52 )(R 53 ), —N(R 52 )C(═O)R 42 , —N(R 52 )C(═O)N(R 55 )(R 53 ), —C(═O)N(R 52 )(R 53 ), —OC(═O)N(R 52 )(R 53 ), —C(═O)R 42 , —OC(═O)R 42 , —C(═G 1 )R 42 , —G 2 C(═G 1 )R 42 , —(R 52 )G 2 C(═G 1 )R 42 , —C(═G 1 )G 2 R 43 , or —G 4 C(═G 1 )G 2 R 43 ,

(a) halo, N 3 , nitro, hydroxy, thiol, sulfone, and CN,

(b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol, C 2-6 alkenyloxy, C 2-6 alkynyloxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, each of which being optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, carbocycle, heterocycle, aryl, heteroaryl, —N(R 50 )(R 51 ), —N(R 50 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ,

(d) —N(R 50 )(R 51 ), —N(R 51 )C(═O)R 40 , —N(R 50 )C(═O)N(R 54 )(R 51 ), —C(═O)N(R 50 )(R 51 ), —OC(═O)N(R 50 )(R 51 ), —C(═O)R 40 , —OC(═O)R 40 , —C(═G 1 )R 40 , —G 2 C(═G 1 )R 40 , —(R 50 )G 2 C(═G 1 )R 40 , —C(═G 1 )G 2 R 41 or —G 3 C(═G 1 )G 2 R 41 ;

G 1 is S or N; G 2 and G 3 are independently S or N(R 50 ); G 4 is N(R 52 );

R 41 is H, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein R 4 , is optionally substituted with from one to three substituents independently selected from halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl;

R 50 , R 51 and R 54 are independently H, OH(R 50 and R 51 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-10 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, wherein R 50 and R 51 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl; and

R 52 , R 53 and R 55 are independently H, OH(R 52 and R 53 are not both OH), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthiol, C 2-10 alkenyloxy, C 2-10 alkynyloxy, C 1-40 haloalkyl, C 2-6 hydroxyalkyl, C 1-6 alkyl-O—C 1-6 alkyl-, or R 52 and R 53 together with the nitrogen atom to which they are both linked form a 3, 4, 5 or 6-membered heterocycle, wherein R 52 and R 53 each is optionally substituted with 1-3 substituents wherein each substituent is independently halo, N 3 , nitro, hydroxy, thiol, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, —C(═O)N(R 54 )(R 55 ), R 44 C(═O)— or —N(R 54 )(R 55 ), wherein R 54 and R 55 are independently H, OH or C 1-4 alkyl, and wherein R 44 is H or C 1-4 alkyl.

16. The method of claim 15 , wherein R 8 or R 9 or both are substituted with one or more said substituents defined for R 8 and R 9 .

17. The method of claim 1 , wherein said mammal is identified as having head or neck squamous cell carcinoma, and said promoting apoptosis comprises promoting apoptosis in a head or neck squamous cell carcinoma cell, and wherein said compound has the structure:

18. The method of claim 17 , wherein the treating step comprises administering to the mammal said therapeutically effective amount of said compound or the pharmaceutically acceptable salt thereof.

19. A method for promoting apoptosis in a cell of a mammal comprising identifying a mammal in need of promoting apoptosis, and treating the mammal with a therapeutically effective amount of the compound of claim 7 or the pharmaceutically acceptable salt thereof.

20. The method of claim 4 , wherein said compound has the structure:

and wherein said mammal is diagnosed as having cancer selected from leukemia, lymphoma, prostate or ovarian cancer, and said promoting apoptosis comprises promoting apoptosis in a leukemia, lymphoma, prostate or ovarian cancer cell.

21. The method of claim 20 , wherein the treating step comprises administering to the mammal said therapeutically effective amount of said compound or the pharmaceutically acceptable salt thereof.

22. The method of claim 4 , wherein said compound has the structure:

23. The compound of claim 8 , wherein said compound has the structure:

24. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 , and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 23 , and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 14 , and a pharmaceutically acceptable carrier.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 3, 2005

From: BAJJI, ASHOK C.; ARRANZ, ESTHER; SRINIVASAN, JAYASREE M.; DELMAR, ERIC; SLADE, RACHEL; WILLARDSEN, JON ADAM

To: MYRIAD GENETICS, INC.

Reel/Frame 017051/0043 →

Continuity (4)

Continuation In Part PCTUS0302218300 · Jul 15, 2003

Provisional Application 6039677300 · Jul 16, 2002

Provisional Application 6039626600 · Jul 15, 2002

Related Publication 20050187300A1 · Aug 25, 2005