U.S. patent application number 11/779086 was filed with the patent office on 2008-02-07 for compounds and therapeutical use thereof.
This patent application is currently assigned to Myriad Genetics, Incorporated. Invention is credited to Vijay Baichwal, Leena Bhoite, Sui Xiong Cai, John A. Drewe, Songchun Jiang, Shailaja Kasibhatla, John Manfredi, Azra Pervin, Chris Pleiman, Nilantha Sudath Sirisoma, Hong Zhang.
Application Number | 20080032974 11/779086 |
Document ID | / |
Family ID | 33568832 |
Filed Date | 2008-02-07 |
United States Patent
Application |
20080032974 |
Kind Code |
A1 |
Cai; Sui Xiong ; et
al. |
February 7, 2008 |
COMPOUNDS AND THERAPEUTICAL USE THEREOF
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.
Inventors: |
Cai; Sui Xiong; (San Diego,
CA) ; Sirisoma; Nilantha Sudath; (San Diego, CA)
; Pervin; Azra; (Escondido, CA) ; Drewe; John
A.; (Carlsbad, CA) ; Kasibhatla; Shailaja;
(San Diego, CA) ; Jiang; Songchun; (San Diego,
CA) ; Zhang; Hong; (San Diego, CA) ; Pleiman;
Chris; (Holladay, UT) ; Baichwal; Vijay; (Salt
Lake City, UT) ; Manfredi; John; (Salt Lake City,
UT) ; Bhoite; Leena; (Salt Lake City, UT) |
Correspondence
Address: |
MYRIAD GENETICS INC.;INTELLECUTAL PROPERTY DEPARTMENT
320 WAKARA WAY
SALT LAKE CITY
UT
84108
US
|
Assignee: |
Myriad Genetics,
Incorporated
Salt Lake City
UT
84108
Cytovia, Inc.
San Diego
CA
92121
|
Family ID: |
33568832 |
Appl. No.: |
11/779086 |
Filed: |
July 17, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10885903 |
Jul 6, 2004 |
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11779086 |
Jul 17, 2007 |
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60484325 |
Jul 3, 2003 |
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60493006 |
Aug 7, 2003 |
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60557556 |
Mar 29, 2004 |
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60571288 |
May 14, 2004 |
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Current U.S.
Class: |
514/234.5 ;
514/263.4; 514/266.21; 514/266.4; 544/119; 544/277; 544/284;
544/293 |
Current CPC
Class: |
C07D 403/12 20130101;
A61P 31/10 20180101; C07D 405/12 20130101; A61P 31/00 20180101;
C07D 471/04 20130101; C07D 401/12 20130101; A61P 37/00 20180101;
A61P 37/02 20180101; C07D 473/34 20130101; A61P 37/06 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; C07D 487/04 20130101;
C07D 403/04 20130101; A61P 35/00 20180101; A61P 31/12 20180101;
C07D 239/95 20130101; C07D 239/94 20130101 |
Class at
Publication: |
514/234.5 ;
514/263.4; 514/266.21; 514/266.4; 544/119; 544/277; 544/284;
544/293 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 31/52 20060101 A61K031/52; A61K 31/5377 20060101
A61K031/5377; A61P 31/10 20060101 A61P031/10; A61P 35/00 20060101
A61P035/00; C07D 239/94 20060101 C07D239/94; C07D 401/12 20060101
C07D401/12; C07D 413/12 20060101 C07D413/12; C07D 473/16 20060101
C07D473/16 |
Claims
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: ##STR206##
wherein: A ring is a 6-membered aryl, heteroaryl or carbocycle; L
is [C(R.sub.L1)(R.sub.L2)].sub.n or --N(R.sub.L1)C(O)--, wherein
R.sub.L1 and R.sub.L2 independently are H or C.sub.1-6 alkyl, n is
0, 1 or 2; R.sub.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.sub.3, OH,
thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; R.sub.2-R.sub.6, and
R.sub.12-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.14-R.sub.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: ##STR207## wherein: R.sub.1 is methyl or ethyl; R.sub.5 is
H or F; and R.sub.2, R.sub.3, R.sub.4, R.sub.6-R.sub.11 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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: ##STR208## wherein, R.sub.1 is methyl or ethyl; R.sub.5 is
H or F; and R.sub.2, R.sub.3, R.sub.4, R.sub.6-R.sub.11 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11
groups together form a 3, 4, 5 or 6-membered aryl, heteroaryl,
carbocycle, or heterocycle.
6. The method of claim 1, wherein said compound is according to
Formula II or a pharmaceutically acceptable salt or solvate
thereof: ##STR209## wherein, R.sub.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.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; R.sub.5 is H or F;
R.sub.2-R.sub.4, R.sub.6, and R.sub.12 and R.sub.13 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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: ##STR210## wherein, R.sub.1 is methyl or ethyl;
R.sub.2-R.sub.6 and R.sub.12-R.sub.17 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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: ##STR211## wherein, R.sub.1 is methyl or ethyl; A ring is
a 6-membered carbocycle, aryl or heteroaryl; R.sub.2-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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.sub.14-R.sub.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: ##STR212## wherein: R.sub.1 is methyl or ethyl;
R.sub.2-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and 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: ##STR213## wherein, R.sub.1 is methyl or ethyl;
R.sub.2-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, (C.sub.2-6 alkenyl)O--, (C.sub.2-6 alkynyl)O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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:
##STR214## wherein, R.sub.1 is methyl or ethyl; R.sub.5 is H, F,
Cl, N.sub.3, methoxy or NH.sub.2; R.sub.2-R.sub.4, and
R.sub.6-R.sub.13 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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: ##STR215## wherein: R.sub.1 is methyl or ethyl; R.sub.5 is
H or F; R.sub.2-R.sub.4, R.sub.6-R.sub.13 are independently H,
halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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: ##STR216## wherein: R.sub.1 is methyl or ethyl; R.sub.5 is
H or F; and R.sub.2-R.sub.4, R.sub.6-R.sub.11 are independently H,
halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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: ##STR217## wherein: A ring is a 6-membered
aryl, heteroaryl or carbocycle; L is [C(R.sub.L1)(R.sub.L2)].sub.n
or --N(R.sub.L1)C(O)--, wherein R.sub.L1 and R.sub.L2 independently
are H or C.sub.1-6 alkyl, n is 0, 1 or 2; R.sub.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.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; R.sub.2-R.sub.6, and R.sub.12-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.14-R.sub.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 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: ##STR218## wherein: A ring is a 6-membered
aryl, heteroaryl or carbocycle; L is [C(R.sub.L1)(R.sub.L2)].sub.n
or --N(R.sub.L1)C(O)--, wherein R.sub.L1 and R.sub.L2 independently
are H or C.sub.1-6 alkyl, n is 0, 1 or 2; R.sub.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.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; R.sub.2-R.sub.6, and R.sub.12-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.14-R.sub.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 is heteroaryl and Q, T, U
or V is N, then there is no substituent at the N.
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: ##STR219## wherein: A ring is a 6-membered
aryl, heteroaryl or carbocycle; L is [C(R.sub.L1)(R.sub.L2)].sub.n
or --N(R.sub.L1)C(O)--, wherein R.sub.L1 and R.sub.L2 independently
are H or C.sub.1-6 alkyl, n is 0, 1 or 2; R.sub.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.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; R.sub.2-R.sub.6, and R.sub.12-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.14-R.sub.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 is heteroaryl and Q, T, U
or V is N, then there is no substituent at the N.
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: ##STR220## R.sub.1 is methyl or
ethyl; A ring is a carbocycle, aryl or heteroaryl; R.sub.2-R.sub.17
are independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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.sub.14-R.sub.17;
wherein when A ring is aryl or heteroaryl then R.sub.5 is H or F;
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; and with the provisos that: (1) when A is aryl, W, X, Y
and Z are all C, and R.sub.9 is H then at least one of R.sub.8 and
R.sub.10 is not H or halo; and (2) when A is heteroaryl, W, X, Y
and Z are all C, and R.sub.9 is H, then at least one of R.sub.8 and
R.sub.10 is not H, halo or C.sub.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.RTM.(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: ##STR221## or a
pharmaceutically acceptable salt or solvate thereof, wherein:
R.sub.1 is methyl or ethyl; R.sub.2-R.sub.17 are independently H,
halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and 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 ##STR222## or pharmaceutically acceptable salt or solvate
thereof, wherein: R.sub.1 is methyl or ethyl; R.sub.2-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, (C.sub.2-6
alkenyl)O--, (C.sub.2-6 alkynyl)O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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: ##STR223## or a
pharmaceutically acceptable salt or solvate thereof, wherein:
R.sub.1 is methyl or ethyl; R.sub.5 is H, F, Cl, N.sub.3, methyl,
methoxy or NH.sub.2, with the proviso that when R.sub.5 is methoxy,
then R.sub.1 is methyl; R.sub.2-R.sub.4, and R.sub.6-R.sub.13 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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.
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.sup.2-(2-Hydroxyethyl)-N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-q-
uinazoline-2,4-diamine;
N.sup.4-(6-Methoxypyridin-3-yl)-N.sup.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 ##STR224## or a pharmaceutically acceptable salt or
solvate thereof, wherein: R.sub.1 is methyl or ethyl; R.sub.5 is H
or F; R.sub.2-R.sub.4, R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.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.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and 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.sub.9 is H then at least one of R.sub.8 and
R.sub.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: ##STR225## wherein: A ring is a 6-membered
aryl, heteroaryl or carbocycle; L is [C(R.sub.L1)(R.sub.L2)].sub.n
or --N(R.sub.L1)C(O)--, wherein R.sub.L1 and R.sub.L2 independently
are H or C.sub.1-6 alkyl, n is 0, 1 or 2; R.sub.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.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; R.sub.2-R.sub.6, and R.sub.12-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.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.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.14-R.sub.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 is heteroaryl and Q, T, U
or V is N, then there is no substituent at the N.
Description
RELATED U.S. APPLICATIONS
[0001] This application is a divisional of Ser. No. 10/885,903
filed Jul. 6, 2004, and claims benefit (under 35 U.S.C. .sctn. 120)
on the earlier filing date of prior U.S. Provisional Application
Ser. No. 60/484,325 filed Jul. 3, 2003, U.S. Provisional
Application Ser. No. 60/493,006 filed Aug. 7, 2003, U.S.
Provisional Application Ser. No. 60/557,556, filed Mar. 29, 2004,
and U.S. Provisional Application Ser. No. 60/571,288, filed May 14,
2004, the contents of each of which are incorporated herein by
reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention is in the field of medicinal chemistry. In
particular, the invention relates to compounds that are activators
of caspases and inducers of apoptosis. The invention also relates
to the use of these compounds as therapeutically effective
anti-cancer agents.
TECHNICAL BACKGROUND
[0003] Organisms eliminate unwanted cells by a process variously
known as regulated cell death, programmed cell death or apoptosis.
Such cell death occurs as a normal aspect of animal development, as
well as in tissue homeostasis and aging (Glucksmann, A., Biol. Rev.
Cambridge Philos. Soc. 26:59-86 (1951); Glucksmann, A., Archives de
Biologie 76:419-437 (1965); Ellis, et al., Dev. 112:591-603 (1991);
Vaux, et al., Cell 76:777-779 (1994)). Apoptosis regulates cell
number, facilitates morphogenesis, removes harmful or otherwise
abnormal cells and eliminates cells that have already performed
their function. Additionally, apoptosis occurs in response to
various physiological stresses, such as hypoxia or ischemia (PCT
published application WO96/20721).
[0004] There are a number of morphological changes shared by cells
experiencing regulated cell death, including plasma and nuclear
membrane blebbing, cell shrinkage (condensation of nucleoplasm and
cytoplasm), organelle relocalization and compaction, chromatin
condensation and production of apoptotic bodies (membrane enclosed
particles containing intracellular material) (Orrenius, S., J.
Internal Medicine 237:529-536 (1995)).
[0005] Apoptosis is achieved through an endogenous mechanism of
cellular suicide (Wyllie, A. H., in Cell Death in Biology and
Pathology, Bowen and Lockshin, eds., Chapman and Hall (1981), pp.
9-34). A cell activates its internally encoded suicide program as a
result of either internal or external signals. The suicide program
is executed through the activation of a carefully regulated genetic
program (Wyllie, et al., Int. Rev. Cyt. 68:251 (1980); Ellis, et
al., Ann. Rev. Cell Bio. 7:663 (1991)). Apoptotic cells and bodies
are usually recognized and cleared by neighboring cells or
macrophages before lysis. Because of this clearance mechanism,
inflammation is not induced despite the clearance of great numbers
of cells (Orrenius, S., J. Internal Medicine 237:529-536
(1995)).
[0006] It has been found that a group of proteases are a key
element in apoptosis (see, e.g., Thornberry, Chemistry and Biology
5:R97-R103 (1998); Thornberry, British Med. Bull. 53:478-490
(1996)). Genetic studies in the nematode Caenorhabditis elegans
revealed that apoptotic cell death involves at least 14 genes, 2 of
which are the pro-apoptotic (death-promoting) ced (for cell death
abnormal) genes, ced-3 and ced-4. CED-3 is homologous to
interleukin 1 beta-converting enzyme, a cysteine protease, which is
now called caspase-1. When these data were ultimately applied to
mammals, and upon further extensive investigation, it was found
that the mammalian apoptosis system appears to involve a cascade of
caspases, or a system that behaves like a cascade of caspases. At
present, the caspase family of cysteine proteases comprises 14
different members, and more may be discovered in the future. All
known caspases are synthesized as zymogens that require cleavage at
an aspartyl residue prior to forming the active enzyme. Thus,
caspases are capable of activating other caspases, in the manner of
an amplifying cascade.
[0007] Apoptosis and caspases are thought to be crucial in the
development of cancer (Apoptosis and Cancer Chemotherapy, Hickman
and Dive, eds., Humana Press (1999)). There is mounting evidence
that cancer cells, while containing caspases, lack parts of the
molecular machinery that activates the caspase cascade. This makes
the cancer cells lose their capacity to undergo cellular suicide
and the cells become cancerous. In the case of the apoptosis
process, Control points are known to exist that represent points
for intervention leading to activation. These control points
include the CED-9-BCL-like and CED-3-ICE-like gene family products,
which are intrinsic proteins regulating the decision of a cell to
survive or die and executing part of the cell death process itself,
respectively (see, Schmitt, et al., Biochem. Cell. Biol. 75:301-314
(1997)). BCL-like proteins include BCL-xL and BAX-alpha, which
appear to function upstream of caspase activation. BCL-xL appears
to prevent activation of the apoptotic protease cascade, whereas
BAX-alpha accelerates activation of the apoptotic protease
cascade.
[0008] It has been shown that chemotherapeutic (anti-cancer) drugs
can trigger cancer cells to undergo suicide by activating the
dormant caspase cascade. This may be a crucial aspect of the mode
of action of most, if not all, known anticancer drugs (Los, et al.,
Blood 90:3118-3129 (1997); Friesen, et al., Nat. Med. 2:574
(1996)). The mechanism of action of current antineoplastic drugs
frequently involves an attack at specific phases of the cell cycle.
In brief, the cell cycle refers to the stages through which cells
normally progress during their lifetime. Normally, cells exist in a
resting phase termed G.sub.o. During multiplication, cells progress
to a stage in which DNA synthesis occurs, termed S. Later, cell
division, or mitosis occurs, in a phase called M. Antineoplastic
drugs, such as cytosine arabinoside, hydroxyurea, 6-mercaptopurine,
and methotrexate are S phase specific, whereas antineoplastic
drugs, such as vincristine, vinblastine, and paclitaxel are M phase
specific. M phase specific antineoplastic drugs, such as
vinblastine and paclitaxel, are known to affect tubulin
polymerization. The ability of cells to appropriately polymerize
and depolymerize tubulin is thought to be an important activity for
M phase cell division.
[0009] Many slow growing tumors, e.g. colon cancers, exist
primarily in the G.sub.o phase, whereas rapidly proliferating
normal tissues, for example bone marrow, exist primarily in the S
or M phase. Thus, a drug like 6-mercaptopurine can cause bone
marrow toxicity while remaining ineffective for a slow growing
tumor. Further aspects of the chemotherapy of neoplastic diseases
are known to those skilled in the art (see, e.g., Hardman, et al.,
eds., Goodman and Gilman's The Pharmacological Basis of
Therapeutics, Ninth Edition, McGraw-Hill, New York (1996), pp.
1225-1287). Thus, it is clear that the possibility exists for the
activation of the caspase cascade, although the exact mechanisms
for doing so are not clear at this point. It is equally clear that
insufficient activity of the caspase cascade and consequent
apoptotic events are implicated in various types of cancer. The
development of caspase cascade activators and inducers of apoptosis
is a highly desirable goal in the development of therapeutically
effective antineoplastic agents. Moreover, since autoimmune disease
and certain degenerative diseases also involve the proliferation of
abnormal cells, therapeutic treatment for these diseases could also
involve the enhancement of the apoptotic process through the
administration of appropriate caspase cascade activators and
inducers of apoptosis.
[0010] EP520722 discloses derivatives of 4-anilino-quinazolines as
inhibitors of the EGFR tyrosine kinase with antitumor activity:
##STR1## wherein, for example, R.sup.a is hydrogen,
trifluoromethyl, or nitro, n is 1; and R.sup.b is halogen,
trifluoromethyl or nitro.
[0011] EP602851 discloses quinazolines as inhibitors of the EGFR
tyrosine kinase: ##STR2## wherein, for example R.sup.a is hydroxy,
amino, ureido, or trifluoromethoxy, m is 1, 2 or 3; Q is a 9 or
10-membered bicyclic heterocyclic moiety.
[0012] EP635498 discloses 4-anilino-quinazolines as inhibitors of
the EGFR tyrosine kinase: ##STR3## wherein, for example R.sub.1
includes hydroxy, amino or C.sub.1-4 alkoxy, R.sub.2 is hydrogen,
hydroxy, or halogen, R.sub.3 is halogen, n is 1, 2 or 3.
[0013] EP635507 discloses tricyclic derivatives as inhibitors of
the EGFR tyrosine kinase: ##STR4## wherein, R.sub.1 and R.sub.2
together form an optionally substituted 5 or 6 membered ring
containing at least one heteroatom; R.sub.3 includes hydrogen,
hydroxy, or halogen, m is 1, 2 or 3.
[0014] WO9609294 discloses substituted heteroaromatic compounds as
inhibitors of protein tyrosine kinase: ##STR5## wherein, for
example X is N or CH; Y is O, S, or NR.sup.a wherein R.sup.a is H
or C.sub.1-8 alkyl; R.sub.1, R.sub.2, R.sub.3 and R.sub.3' includes
amino, hydrogen, hydroxy, or halogen; R.sub.4 includes amino,
hydrogen, hydroxy, or halogen; n is 1, 2 or 3; R.sub.5 is selected
from the group comprising hydrogen, halogen, trifluoromethyl,
C.sub.1-4 alkyl and C.sub.1-4 alkoxy; R.sub.6 is a group ZR.sub.7
wherein Z includes O, S or NH and R.sub.7 is an optionally
substituted C.sub.3-6 cycloalkyl, or an optionally substituted
5,6,7,8,9,10-membered carbocyclic or heterocyclic moiety.
[0015] WO9713771 discloses substituted heteroaromatic compounds as
inhibitors of protein tyrosine kinase: ##STR6## wherein, for
example X is N or CH; U represents a fused 5,6,7-membered
heterocyclic ring; Y is O, S, or NR.sup.a wherein R.sup.a is H or
C.sub.1-8 alkyl; R.sub.1 included 5,6-membered heterocyclic ring,
or amino, hydrogen, hydroxy, or halogen; n is 0, 1, 2 or 3. R.sub.2
is selected from the group comprising hydrogen, halogen,
trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4 alkoxy; R.sub.3 is a
group ZR.sub.4 wherein Z includes O, S or NH and R.sub.4 is an
optionally substituted C.sub.3-6 cycloalkyl, or an optionally
substituted 5,6,7,8,9,10-membered carbocyclic or heterocyclic
moiety. R.sub.5 includes hydrogen, hydroxy, or halogen; n is 1, 2
or 3.
[0016] WO9802438 discloses bicyclic heteroaromatic compounds as
inhibitors of protein tyrosine kinase: ##STR7## wherein, for
example X is N or CH; Y is O, S, or NR.sup.a wherein R.sup.a is H
or C.sub.1-8 alkyl; R'' represents a phenyl group or a 5- or
6-membered heterocyclic ring, or amino, hydrogen, hydroxy, or
halogen; n is 0 or 1. R.sub.1 includes amino, hydrogen, hydroxy, or
halogen; p is 0 to 3. R.sub.2 is selected from the group comprising
hydrogen, halogen, trifluoromethyl, C.sub.1-4 alkyl and C.sub.1-4
alkoxy; U represents a 5 to 10-membered mono or bicyclic ring
system; A represents a fused 5, 6, or 7-membered heterocyclic
ring.
[0017] Myers et al. (Bioorg. Med. Chem. Lett. 7:421-424 (1997))
reported 4-(N-methyl-N-phenyl)amino-6,7-dimethoxyquinazoline as
inhibitor of CSF-1R tyrosine kinase. It was reported that
substitutions on the phenyl ring resulted in reduced activity.
Replacement of the 6,7-dimethoxy groups by hydrogen resulted in
more than 40-fold reduction in potency. Substitution in the
2-position of quinazoline by a Cl or methoxy group resulted in
inactive compounds (IC.sub.50>50 .mu.M). ##STR8##
[0018] Rewcastle et al. (J. Med. Chem. 38:3482-3487 (1995))
reported 4-(phenylamino)-quinazolines as inhibitors of tyrosine
kinase of Epidermal Growth Factor Receptor. It was reported that
N-methylation of the amino group (R.sub.1=Me,
R.sub.2=R.sub.3=R.sub.4=H) completely abolished activity
(IC.sub.50>100,000 nM). The 6,7-dimethoxy compound (R.sub.1=H,
R.sub.2=R.sub.3=OMe, R.sub.4=Br, IC.sub.50=0.029 nM) was almost
1000-fold more potent than the corresponding non-substituted analog
(R.sub.1=H, R.sub.2=R.sub.3=H, R.sub.4=Br, IC.sub.50=27 nM).
##STR9##
[0019] Bridges et al. (J. Med. Chem. 39:267-276 (1996)) reported
analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline as
inhibitors of tyrosine kinase of Epidermal Growth Factor Receptor.
It was reported that introduction of a methyl group to the
2-position (R.sub.1=Me, R.sub.2=3'-Br, R.sub.3=H) resulted in at
least 400,000-fold loss of potency (IC.sub.50>10,000 nM) vs the
hydrogen analog. Introduction of an amino group to the 2-position
(R.sub.1=NH.sub.2, R.sub.2=3'-Br, R.sub.3=H) also resulted in over
18,000-fold loss of potency (IC.sub.50>10,000 nM). Methylation
of the anilino nitrogen (R.sub.3=Me) led to 6,000-fold drop in
activity. The 4'-Br analog (IC.sub.50=0.96 nM) was almost 40-fold
less active than the 3'-Br analog (IC.sub.50=0.025 nM), and the
2'-Br analog (IC.sub.50=128 nM) was at least 5,000-fold less active
than the 3'-Br analog. ##STR10##
SUMMARY OF THE INVENTION
[0020] The present invention is related to the discovery that
4-arylamino-quinazolines and analogs, as represented in Formula
I-VIb below, are potent tubulin inhibitors and active in inhibiting
topoisomerase, particularly topoisomerase II. They are activators
of the caspase cascade leading to the activation of caspase-3 and
inducers or promoters of apoptosis. Thus, they are useful in
treating or delaying the onset of diseases and disorders that are
responsive to the inhibition of tubulin or topoisomerase, or to the
induction of apoptosis.
[0021] Accordingly, one aspect of the present invention is directed
to the use of compounds of the present invention in inhibiting
tubulin, in inducing caspase activities, particularly caspase-3
activities, in inhibiting topoisomerase I or II, and inducing or
promoting apoptosis, by administering the compounds to cells in
vitro or in vivo in warm-blood animals, particularly mammals.
[0022] Another aspect of the present invention is to provide a
method for treating or delaying the onset of diseases and disorders
that are responsive to inhibition of tubulin or topoisomerase II,
including but not limited to neoplastic diseases (such as cancer),
psoriasis, autoimmune diseases, and fungi infection. The method
comprises administering to a subject mammal in need of the
treatment a therapeutically effective amount of a compound of the
present invention.
[0023] Many of the compounds as represented by Formula I-VIb below
are novel compounds. Therefore, another aspect of the present
invention is to provide novel compounds, and to also provide for
the use of these novel compounds for treating, preventing or
ameliorating neoplasia and cancer.
[0024] Yet another aspect of the present invention is to provide a
pharmaceutical composition useful for treating disorders responsive
to the inhibition of tubulin or topoisomerase II, and the induction
of apoptosis, containing an effective amount of a compound of the
present invention, preferably in admixture with one or more
pharmaceutically acceptable carriers or diluents.
[0025] In yet another aspect of the present invention, methods are
provided for the preparation of the novel compounds of the present
invention.
[0026] The foregoing and other advantages and features of the
invention, and the manner in which the same are accomplished, will
become more readily apparent upon consideration of the following
detailed description of the invention taken in conjunction with the
accompanying examples, which illustrate preferred and exemplary
embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 depicts the results of a Topoisomerase II activity
assay testing Example 1 compound;
[0028] FIG. 2 shows the results of a Topoisomere I activity assay
testing Example 1 compound;
[0029] FIG. 3 depicts the binding of radiolabeled Example 102
compound to Topoisomerase II.
DETAILED DESCRIPTION OF THE INVENTION
[0030] It has been discovered that compounds of the present
invention are potent inhibitors of tubulin. It is also discovered
that the compounds can also inhibit topoisomerase activities, such
as topoisomerase II-dependent conversion of supercoiled DNA to
topoisomers. The compounds are potent and highly efficacious
activators of the caspase cascade particularly caspase-3, and
inducers of apoptosis. Therefore, the compounds are useful for
treating diseases and disorders responsive to induction of
apoptosis, inhibition of tubulin and/or inhibition of topoisomerase
II.
[0031] Thus, the present invention provides a method of inhibiting
tubulin in cells in vitro or in warm-blood animals, particularly
mammals, more particularly humans. As used herein, the term
"inhibiting tubulin" means inhibiting the polymerization (or
assembly) of tubulin monomers or promoting depolymerization of
microtubules (i.e., tubulin disassembly). Inhibition of tubulin can
be assayed, e.g., by the method described in Example 145 below. The
present invention also provides a method for inhibiting
topoisomerase II in cells in vitro or in warm-blood animals,
particularly mammals, more particularly humans. As used herein, the
term "inhibiting topoisomerase II" means inhibiting the activities
of the enzyme topoisomerase II in topoisomerase II-dependent
conversion of supercoiled DNA to topoisomers. Inhibition of
topoisomerase II activities can be assayed by, e.g., a method
described in Example 151. In addition, the present invention also
provides a method of activating caspase, particularly caspase-3 and
inducing apoptosis in cells in vitro or in warm-blood animals,
particularly mammals, more particularly humans. The term
"activating caspase" as used herein means activating or enhancing
the enzymatic (protease) activity of a caspase (e.g., caspase-3),
which, if occurring inside cells, results in promoted apoptosis or
cell death. The ability of a compound in activating caspase,
particularly caspase-3, can be assayed in a method as provided in
Example 143 below. The term "inducing apoptosis" as used herein
means inducing apoptosis in cells so as to cause cell death. The
ability of a compound to induce apoptosis can be tested in a method
as described in Example 147 below. Also provided are methods for
treating or delaying the onset of diseases and disorders responsive
to inhibiting tubulin, inhibiting topoisomerase II, activating
caspase-3, or inducing apoptosis. Specific examples of such
diseases and disorders are provided in details below.
[0032] The above various methods of the present invention can be
practiced by or comprise treating cells in vitro or a warm-blood
animal, particularly mammal, more particularly a human with an
effective amount of a compound according to the present invention.
As used herein, the phrase "treating . . . with . . . a compound"
means either administering the compound to cells or an animal, or
administering to cells or an animal the compound or another agent
to cause the presence or formation of the compound inside the cells
or the animal. Preferably, the methods of the present invention
comprise administering to cells in vitro or to a warm-blood animal,
particularly mammal, more particularly a human a pharmaceutical
composition comprising an effective amount of a compound according
to the present invention.
[0033] Specifically, the methods of the present invention comprise
treating cells in vitro or a warm-blood animal, particularly
mammal, more particularly a human with an effective amount of a
compound according to Formula I: ##STR11## or pharmaceutically
acceptable salts or solvates thereof, wherein: Ar is aryl or
heteroaryl; each of which is optionally substituted by one or more
substituents wherein each substituent is independently halo,
hydroxy, hydroxy-C.sub.1-6 alkyl-, C.sub.1-6 alkyl-C(O)O--, amino,
nitro, cyano, C.sub.1-6 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, C.sub.1-6 acylamino, C.sub.1-6 acyloxy, C.sub.1-6 alkoxy,
or C.sub.1-6 alkylthiol-; R.sub.1 is C.sub.1-6 alkyl, preferably
methyl or ethyl, more preferably methyl; A is an aromatic,
heteroaromatic, heterocyclic, or carbocyclic ring; each of which is
optionally substituted by one or more substituents wherein each
substituent is as defined for Ar; R.sub.2 is H, halo, nitro, cyano,
azido, hydroxy, thiol, or a member of the group consisting of:
amino, alkoxy, C.sub.1-6 alkyl, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, hydroxyalkyl, amino-C.sub.1-6 alkyl,
carboxy-C.sub.1-6 alkyl, nitro, cyano, acylamido, acyloxy, carboxy,
carbonylamido, alkylthiol; each of which is optionally substituted
by one or more substituents wherein each substituent is as defined
for Ar; L is (CR.sub.11R.sub.12)n or NR.sub.11CO wherein R.sub.11
and R.sub.12 independently are hydrogen or alkyl optionally
substituted by R.sub.1a, R.sub.1b, or R.sub.1c; wherein R.sub.1a,
R.sub.1b, and R.sub.1c are as defined for Ar; n is 0, 1 or 2; B and
D are independently nitrogen or CR.sub.13, wherein R.sub.13 is
hydrogen, halo, nitro, cyano, azido, hydroxy, thiol, or a member of
the group consisting of amino, alkoxy, C.sub.1-6 alkyl,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
hydroxyalkyl, amino-C.sub.1-6 alkyl, carboxy-C.sub.1-6 alkyl,
nitro, cyano, acylamido, acyloxy, carboxy, carbonylamido,
alkylthiol; each of which is optionally substituted by one or more
substituents wherein each substituent is as defined for Ar; and
with the proviso that at least one of B and D is nitrogen.
[0034] Preferred compounds of Formula I include compounds wherein D
is nitrogen, and B is CR.sub.13. Other preferred compounds of
Formula I include those having Formula Ia: ##STR12## or
pharmaceutically acceptable salts or solvates thereof, wherein:
[0035] A ring is a 6-membered aryl, heteroaryl or carbocycle;
[0036] L is [C(R.sub.L1)(R.sub.L2)].sub.n or --N(R.sub.L1)C(O)--,
wherein R.sub.L1 and R.sub.L2 independently are H or C.sub.1-6
alkyl, n is 0, 1 or 2; [0037] R.sub.1 is methyl or ethyl; [0038] Ar
is aryl or heteroaryl, each of which is optionally substituted by
one or more substituents wherein each substituent is independently
H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(Ra)(Rb)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b are
independently H, OH(R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0039] R.sub.2-R.sub.6, and
R.sub.12-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H,
OH(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH(R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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
is aryl or heteroaryl, then there are no substituents
R.sub.14-R.sub.17; and [0040] B, D, Q, T, U and V, are
independently carbon or nitrogen, wherein at least one of B and D
is nitrogen; wherein when B or D is nitrogen, then there is no
substituent at the nitrogen; and wherein when A is heteroaryl and
Q, T, U or V is nitrogen, then there is no substituent at the
nitrogen.
[0041] Preferably, when the A ring is aryl or heteroaryl and U is
carbon, then R.sub.5 is hydrogen or flourine, preferably
hydrogen.
[0042] Other preferred compounds include compounds wherein ring A
is benzo or fused cyclohexyl. Another group of preferred compounds
include compounds wherein Ar is phenyl, naphthyl, pyridyl,
pyridazyl, pyrimidyl, pyrazyl, quinolyl, isoquinolyl, isoxazolyl,
pyrazolyl, imidazolyl, thienyl, furyl or pyrrolyl; each of which is
optionally substituted by one or more substituents wherein each
substituent is independently halo, hydroxy, hydroxyC.sub.1-6
alkyl-, C.sub.1-6 alkyl-C(O)O--, amino, nitro, cyano,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, C.sub.1-C.sub.6 acylamino, C.sub.1-C.sub.6 acyloxy,
C.sub.1-C.sub.6 alkoxy, or C.sub.1-6 alkylthiol-. More preferably,
Ar is phenyl, pyridyl, pyridazyl, pyrimidyl or pyrazyl, each of
which is optionally substituted by one or more substituents wherein
each substituent is as defined immediately above.
[0043] Another group of preferred compounds of Formula Ia include
compounds wherein R.sub.2 is H, halo, or a member of the group
consisting of N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol,
hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkyl and --N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; each of the member is optionally substituted by 1-4
substituents wherein each substituent is independently halo, OH, or
C.sub.1-4 alkyl.
[0044] In preferred embodiments of the compounds of Formula Ia, one
or two of Q, T, U and V are nitrogen, and both B and D are
nitrogen.
[0045] Other compounds of Formula I for use in the methods of the
present invention include those having Formula Ib: ##STR13## or
pharmaceutically acceptable salts or solvates thereof, wherein:
R.sub.1 is C.sub.1-4 alkyl, preferably methyl or ethyl, more
preferably methyl; R.sub.2-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.e),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH(R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups may together form a 3, 4, 5 or
6-membered aryl, heteroaryl, carbocycle, or heterocycle.
[0046] Preferably, R.sub.5 is H or F, more preferably H. Also
preferably R.sub.2 is R.sub.2 is H, halo, or a member of the group
consisting of: N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl and --N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered heterocycle
(e.g., morpholino); each of the member is optionally substituted by
1-4 substituents wherein each substituent is independently halo,
OH, or C.sub.1-4 alkyl.
[0047] Other preferred compounds of Formula I for the methods of
the invention include those having Formula Ic: ##STR14## or
pharmaceutically acceptable salts or solvates thereof, wherein:
R.sub.1 is C.sub.1-4 alkyl, preferably methyl or ethyl, more
preferably methyl; R.sub.2-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups may together form a 3, 4, 5 or
6-membered aryl, heteroaryl, carbocycle, or heterocycle.
[0048] Preferably, R.sub.5 is H or F, more preferably H. Also
preferably R.sub.2 is H, halo, or a member of the group consisting
of: N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol,
hydroxy-C.sub.1-4 alkyl, C.sub.1-4 alkyl and --N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered heterocycle
(e.g., morpholino); each of the member is optionally substituted by
1-4 substituents wherein each substituent is independently halo,
OH, or C.sub.1-4 alkyl.
[0049] Another group of compounds useful in the various methods of
the present invention are those represented by Formula II:
##STR15## or pharmaceutically acceptable salts or solvates thereof,
wherein: [0050] Ar is as defined in Formula Ia above; [0051]
R.sub.1 is a C.sub.1-3 alkyl, preferably methyl or ethyl; [0052]
R.sub.2-R.sub.6, R.sub.12 and R.sub.13 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; preferably, when U is C,
R.sub.5 is H or F, preferably H; and [0053] B, D, Q, T, U and V are
independently C or N, wherein at least one of B and D is nitrogen.
In some embodiments, at least one of Q, T, U and V is N. In one
embodiment, D is N and B is C. In another embodiment, B is N and D
is C. In another specific embodiment, both B and D are N. In all
embodiments, preferably when B, D, Q, T, U or V is N, there is no
substituent at the N.
[0054] Other preferred compounds include compounds wherein Ar is
phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, quinolyl,
isoquinolyl, isoxazolyl, pyrazolyl, imidazolyl, thienyl, furyl or
pyrrolyl; each of which is optionally substituted by one or more
substituents wherein each substituent is as defined immediately
above. More preferably, Ar is phenyl, pyridyl or pyridazyl,
pyrimidyl, pyrazyl, each of which is optionally substituted by one
or more substituents wherein each substituent is as defined
immediately above. Another group of preferred compounds of Formula
II include compounds wherein R.sub.2 is a member of the group
consisting of H, halo, N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4
alkylthiol, hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkyl, and
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-4
hydroxyalkyl, or C.sub.1-4 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; each of the member being optionally
substituted by 1-4 substituents wherein each substituent is
independently halo, OH, or C.sub.1-4 alkyl.
[0055] In preferred embodiments of the compounds of Formula II, one
or two of Q, T, U and V are N, and both B and D are N.
[0056] Another group of preferred compounds that may be employed in
the methods of the present invention are represented by Formula
III: ##STR16## or pharmaceutically acceptable salts or solvates
thereof, wherein: [0057] Ar is as defined above in Formula Ia and
II; [0058] R.sub.1 is a C.sub.1-3 alkyl, preferably methyl or
ethyl, more preferably methyl; [0059] R.sub.2-R.sub.6 and
R.sub.12-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; and [0060] 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 nitrogen
atom.
[0061] Other preferred compounds according to Formula III include
compounds wherein Ar is phenyl, naphthyl, pyridyl, pyridazyl,
pyrimidyl, pyrazyl, quinolyl, isoquinolyl, isoxazolyl, pyrazolyl,
imidazolyl, thienyl, furyl or pyrrolyl; each of which is optionally
substituted by one or more substituents wherein each substituent is
as defined immediately above. More preferably, Ar is phenyl,
pyridyl pyridazyl, pyrimidyl, or pyrazyl, each of which is
optionally substituted by one or more substituents wherein each
substituent is as defined immediately above. In one embodiment, Ar
is pyridyl pyridazyl, pyrimidyl, or pyrazyl, each of which is
optionally substituted by one or more substituents as defined above
for Ar. Also preferably R.sub.2 is a member of the group consisting
of H, halo, N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol,
hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkyl, and --N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4
alkyl or R.sup.a and R.sup.b together with the nitrogen atom to
which they are both linked form a 3, 4, 5 or 6-membered
heterocycle; each of the member being optionally substituted by 1-4
substituents wherein each substituent is independently halo, OH, or
C.sub.1-4 alkyl. In preferred embodiments of the compounds of
Formula III, both B and D are N.
[0062] Preferably a compound according to Formula III is other than
(5,6,7,8-tetrahydro-quinazolin-4-yl)-phenyl-ethyl-amine.
[0063] More preferably, the methods of inhibiting tubulin,
inhibiting topoisomerase II, activating caspase-3, inducing
apoptosis and treating or delaying the onset of diseases and
disorders responsive to the inhibition of tubulin or topoisomerase
II or to the activation of caspase-3 or induction of apoptosis
comprise administering an effective amount of a compound or a
pharmaceutical composition containing an effective amount of the
compound, which compound is represented by any one of Formulae IV,
IVa, IVb, V, Va, Vb, Vc, VI, VIa and VIb, and each and all
embodiments thereof and salts or solvates thereof, as provided
below.
[0064] Additional compounds useful in such methods, particularly
the methods of inhibiting tubulin, inhibiting topoisomerase II,
activating caspase-3 and inducing apoptosis, and treating diseases
and disorders responsive to the inhibition of tubulin or
topoisomerase II, or activating caspase-3 and inducing apoptosis
include compounds according to Formula IV: ##STR17## and
pharmaceutically acceptable salts and solvates thereof, wherein:
[0065] R.sub.1 is methyl or ethyl, preferably methyl; [0066] A ring
is a carbocycle, aryl or heteroaryl; [0067] R.sub.2-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.b 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 any of the groups is
optionally substituted with 1-3 substituents wherein each
substituent is independently halo, N.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11
groups together form a 3, 4, 5 or 6-membered carbocycle or
heterocycle, with the proviso that when A is aryl or heteroaryl,
then there are no substituents R.sub.14-R.sub.17; and [0068] 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.
[0069] Preferably when the A ring is aryl or heteroaryl and U is C,
R.sub.5 is not alkoxy. More preferably, when the A ring is aryl or
heteroaryl and U is C, then R.sub.5 is H or F, preferably H.
[0070] In some embodiments of the compounds of Formula IV, one of
W, X, Y and Z is N. In other embodiments of the compounds of
Formula IV, two of W, X, Y and Z are N. In any of the embodiments,
preferably one or two of Q, T, U and V are N. In preferred
embodiments, B and D both are N.
[0071] Further additional compounds in addition to the compounds
represented by Formulae IV, IVa, IVb, V, Va, Vb, Vc, VI, VIa and
VIb, and all embodiments thereof, which are useful in the methods
of the present invention, particularly the methods of inhibiting
tubulin, inhibiting topoisomerase II, activating caspase-3 and
inducing apoptosis, and treating diseases and disorders responsive
to the inhibition of tubulin or topoisomerase II, activating
caspase-3 and inducing apoptosis, include compounds according to
Formula VI: ##STR18## or pharmaceutically acceptable salts or
solvates thereof, wherein: [0072] R.sub.1 is methyl or ethyl,
preferably methyl; [0073] R.sub.5 is H or F, preferably H; [0074]
R.sub.2-R.sub.4, R.sub.6-R.sub.13 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0075] 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.
[0076] In some embodiments of the compounds according to Formula
VI, one or two of Q, T, U and V are N. In preferred embodiments,
both B and D are N.
[0077] Further additional compounds useful in such methods,
particularly the methods of inhibiting tubulin, inhibiting
topoisomerase II, activating caspase-3 and inducing apoptosis, and
treating diseases and disorders responsive to the inhibition of
tubulin or topoisomerase II, activating caspase-3 and inducing
apoptosis, include compounds according to Formula VIa: ##STR19## or
pharmaceutically acceptable salts or solvates thereof, wherein:
[0078] R.sub.1 is methyl or ethyl, preferably methyl; [0079]
R.sub.5 is H or F, preferably H; [0080] R.sub.2-R.sub.4,
R.sub.6-R.sub.11 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0081] Q, T, U and V are
independently C or N, wherein when Q, T, U or V is N, then there is
no substituent at the N.
[0082] In some embodiments of the compounds according to Formula
VIa, one or two of Q, T, U and V are N.
[0083] Still further additional compounds useful in such methods,
particularly the methods of inhibiting tubulin or topoisomerase II,
activating caspase-3 and inducing apoptosis, and treating diseases
and disorders responsive to the inhibition of tubulin or
topoisomerase II, activating caspase-3 and inducing apoptosis,
include compounds according to Formula VIb: ##STR20## or
pharmaceutically acceptable salts or solvates thereof, wherein:
[0084] R.sub.1 is methyl or ethyl, more preferably methyl; [0085]
R.sub.5 is H or F, preferably H; [0086] R.sub.2-R.sub.4,
R.sub.6-R.sub.11 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle.
[0087] In the various embodiments of the above methods of the
present invention, preferably the compounds administered in the
methods of the invention are able to induce caspase activation as
determined by the method and under conditions (measurement at 24
hours) described in Example 143, preferably at an EC.sub.50 no
greater than 1,000 nM, more preferably at an EC.sub.50 no greater
than about 500 nM, more preferably at an EC.sub.50 no greater than
about 200 nM, more preferably at an EC.sub.50 no greater than about
100 nM, even more preferably at an EC.sub.50 no greater than about
50 nM, and most preferably at an EC.sub.50 no greater than about 10
nM. Also preferred in the above methods of the invention are
compounds of Formula I-VIb, and pharmaceutically acceptable salts
or solvates thereof, that are able to inhibit tubulin at an
IC.sub.50 of no greater than about 2,000 nM, more preferably no
greater than about 1,000 nM, most preferably less than about 500
nM, as determined by the method and under conditions described in
Example 145.
[0088] Exemplary compounds useful in the methods of the invention
include, but are not limited to, compounds in Examples 1-142; and
pharmaceutically acceptable salts or solvates thereof, and: [0089]
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; [0090]
(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine; [0091]
(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine; [0092]
(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [0093]
(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
[0094] (2-Chloro-quinazolin-4-yl)-phenyl-methyl-amine; [0095]
N.sup.2-Hydroxyl-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,-
4-diamine; [0096]
N.sup.2-(2-Hydroxylethyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quina-
zoline-2,4-diamine; [0097]
N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[0098]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methoxy-phenyl)-
-N.sup.4-methyl-quinazoline-2,4-diamine; [0099]
N.sup.4-(4-Methoxy-phenyl)-N.sup.4-methyl-N.sup.2-(2-morpholin-4-yl-ethyl-
)-quinazoline-2,4-diamine; [0100]
(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
[0101]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methyl-phenyl)--
N.sup.4-methyl-quinazoline-2,4-diamine; [0102]
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0103]
(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-am-
ine; [0104]
(2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine; [0105]
(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine; [0106]
(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine; [0107]
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0108]
(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
[0109]
(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
[0110]
(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;
[0111] (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;
[0112]
(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;
[0113]
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;
[0114] (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
[0115] (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
[0116] 4-Chloro-benzoic acid
N'-methyl-N'-(2-methylthio-quinazolin-4-yl)-hydrazide; [0117]
Benzoic acid N'-methyl-N'-(2-methylthio-quinazolin-4-yl)-hydrazide;
[0118] Thiophene-2-carboxylic acid
N'-methyl-N'-(2-methylthio-quinazolin-4-yl)-hydrazide;
[0119]
N.sup.2-[2-(1H-Imidazol-4-yl)-ethyl]-N.sup.4-(4-methoxy-phenyl)-N.-
sup.4-methyl-quinazoline-2,4-diamine; [0120]
N.sup.2-(3-Dimethylamino-propyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methy-
l-quinazoline-2,4-diamine; [0121]
N.sup.2-(2-Hydroxyethyl)-N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-q-
uinazoline-2,4-diamine; [0122]
N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[0123]
(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
[0124] (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;
[0125] (2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;
[0126]
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0127]
(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [0128]
(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0129]
(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [0130]
(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0131]
(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0132]
(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0133]
(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-
-amine; [0134] (Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine;
[0135] (4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine; [0136]
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;
[0137]
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;
[0138] (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;
[0139] (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;
[0140] (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;
[0141] 4-Methoxy-benzoic acid
N'-methyl-N'-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide; [0142]
3-Methyl-benzoic acid
N'-methyl-N'-(2-methylthio-quinazolin-4-yl)-hydrazide; [0143]
4-Fluoro-benzoic acid
N'-methyl-N'-(2-methylthio-quinazolin-4-yl)-hydrazide; and [0144]
2-Fluoro-benzoic acid
N'-methyl-N'-(2-trifluoromethyl-quinazolin-4-yl)-hydrazide; [0145]
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine; [0146]
5-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl--
quinazoline-2,4-diamine; [0147]
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0148] (2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0149]
(2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;
[0150]
(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0151] (4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine;
[0152]
(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amin-
e; [0153]
(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0154]
(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0155] (4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0156]
(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine;
[0157]
(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0158]
(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0159]
(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-am-
ine; [0160]
(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;
[0161] (4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0162] (2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;
[0163]
(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0164]
(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-ami-
ne; [0165]
(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [0166]
(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [0167]
(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [0168]
(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0169]
(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0170]
(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine- ;
[0171] (4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0172]
(4-Methoxy-phenyl-2,3,5,6-d.sub.4)-(2-methyl-quinazolin-4-yl)-met-
hyl-amine; [0173]
(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
[0174]
(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [0175]
(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0176]
(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [0177]
(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0178] Ethyl
4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
[0179] Succinimidyl
4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid Ester;
[0180]
(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0181] (2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0182]
(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0183]
(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0184] (4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0185]
(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amin-
e; [0186]
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0187]
(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0188]
(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl--
amine; [0189]
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0190]
Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;
[0191] (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;
[0192]
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0193] and pharmaceutically acceptable salts or solvates
thereof.
[0194] The present invention also provides novel compounds, which
are potent tubulin inhibitors, topoisomerase II inhibitors,
caspase-3 activators and/or apoptosis inducers/promoters.
Specifically, the novel compounds of the present invention are
represented by Formula IV and pharmaceutically acceptable salts or
solvates thereof: ##STR21## wherein [0195] R.sub.1 is methyl or
ethyl, and preferably methyl; [0196] A ring is a carbocycle, aryl
or heteroaryl; [0197] R.sub.2-R.sub.17 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.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.sub.14-R.sub.17; and with the proviso that when A ring is aryl or
heteroaryl and U is C, then R.sub.5 is H or F, preferably H; and
[0198] 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 [0199] wherein when A is carbocycle and W, X, Y and Z
are all carbon atoms, then the compound is not
2-amino-4-(N-ethylanilino)-5,6,7,8-tetrahydro-quinazoline; and
[0200] wherein when A is benzo and W, X, Y and Z are all C, then
(1) R.sub.9 is not (C.sub.1-3 alkyl)OC(O)alkoxy-; and (2) when
R.sub.9 is H, then at least one of R.sub.8 and R.sub.10 are not H
or C.sub.1-6 alkyl, or halo; and [0201] wherein when A is
heteroaryl and W, X, Y and Z are all C, when R.sub.9 is H, then at
least one of R.sub.8 and R.sub.10 is not H or alkyl, provided that
R.sub.8 and R.sub.10 may be both alkyl.
[0202] Preferably when R.sub.9 is H then R.sub.8 or R.sub.10 or
both are independently selected from the group OH; N.sub.3;
--XR.sub.2a wherein X is S or O and R.sub.2a is C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo; --NH(R.sub.2b) or
N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and R.sub.2c are
independently C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, and wherein optionally R.sub.2b and R.sub.2c may
together form a 3-6 membered heterocycle; and --C(O)OR.sub.2d
wherein R.sub.2d is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl);
and more preferably R.sub.9 is not H.
[0203] In some embodiments of the compounds of Formula IV, one of
W, X, Y and Z is N. In other embodiments of the compounds of
Formula IV, two of W, X, Y and Z are N. In any of the embodiments,
preferably one or two of Q, T, U and V are N. In preferred
embodiments, B and D both are N.
[0204] One group of the compounds of the present invention are
represented by Formula IVa: ##STR22## or a pharmaceutically
acceptable salt or solvate thereof, wherein: [0205] R.sub.1 is
methyl, ethyl, preferably methyl; [0206] R.sub.2-R.sub.17 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.b 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 any of the groups is
optionally substituted with 1-3 substituents wherein each
substituent is independently halo, N.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11
groups together form a 3, 4, 5 or 6-membered carbocycle or
heterocycle; and [0207] 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.
[0208] In some embodiments, one of X, Y, W and Z is N. In other
embodiments, two of X, Y, W and Z are N. Preferably D is nitrogen,
and more preferably both B and D are N.
[0209] In a preferred embodiment, compounds of the present
invention have Formula IVa, or a pharmaceutically acceptable salt
or solvate thereof, wherein: [0210] R.sub.1 is methyl or ethyl,
preferably methyl; [0211] R.sub.2 is a member of the group
consisting of H, halo, N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4
alkylthiol, hydroxyC.sub.1-4 alkyl, C.sub.1-4 alkyl, and
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-4
hydroxyalkyl, or C.sub.1-4 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; each of the member being optionally
substituted by 1-4 substituents wherein each substituent is
independently halo, OH, or C.sub.1-4 alkyl; [0212] R.sub.7 and
R.sub.11 are independently H, halo (preferably F), CH.sub.3, or
OCH.sub.3; [0213] R.sub.8 and R.sub.10 are independently H, halo
(preferably F or Cl), C.sub.1-3 alkyl (preferably CH.sub.3)
optionally substituted with halo (preferably 1-3 F), C.sub.1-3
alkoxy (preferably OCH.sub.3), or C.sub.1-3 alkylthiol (preferably
--S--CH.sub.3); [0214] R.sub.9 is H, OH, Cl, N.sub.3, C.sub.1-4
alkoxy, C.sub.1-4 alkylthiol, hydroxyC.sub.1-4 alkyl, C.sub.1-4
alkyl, [0215] --COOR.sup.c wherein R.sup.c is C.sub.1-3 alkyl, or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-4
hydroxyalkyl, or C.sub.1-4 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; each of the member being optionally
substituted by 1-4 substituents wherein each substituent is
independently halo, OH, or C.sub.1-4 alkyl; and optionally two
adjacent R.sub.8, R.sub.9, and R.sub.10 groups may together form a
3, 4, 5, or 6-membered carbocycle, heterocycle, preferably
heterocyle; and [0216] B, D, W, X, Y, and Z are independently C or
N, and 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. Preferably D is N. In some embodiments, both
B and D are N.
[0217] In specific embodiments, only one of W, X, Y and Z is N. In
other specific embodiments, two of W, X, Y and Z are N.
[0218] In preferred embodiments of the compound of Formula IVa,
R.sub.9 is selected from the group:
[0219] --OR.sub.9a, wherein R.sub.9a is methyl, ethyl, fluoromethyl
(CH.sub.2F, CHF.sub.2, CF.sub.3), or fluoroethyl;
[0220] --N.sub.3;
[0221] --N(CH.sub.3).sub.2;
[0222] --NHCH.sub.3; and
[0223] --COOR.sub.9b, wherein R.sub.9b is H or C.sub.1-2 alkyl.
[0224] Another group of compounds of the present invention are
represented by Formula IVb: ##STR23## or pharmaceutically
acceptable salts or solvates thereof, wherein: [0225]
R.sub.2-R.sub.17 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0226] 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.
[0227] Preferably, in the compounds of Formula IVb, D is N, and
more preferably both B and D are N.
[0228] In preferred embodiments, when R.sub.1 is ethyl then at
least one of R.sub.8, R.sub.9, and R.sub.10 is not H; preferably
R.sub.9 is not H. Also preferably, when R.sub.9 is H then R.sub.8
or R.sub.10 or both are independently selected from the group OH;
N.sub.3; amido; N-dimethylamido; --XR.sub.9a wherein X is S or O
and R.sub.9a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo;
C.sub.1-3 alkyl optionally substituted with halo (preferably F);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), or C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo (preferably F, and wherein optionally
R.sub.2b and R.sub.2c may together form a 3-6 membered heterocycle;
and --C(O)OR.sup.c wherein R.sup.c is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl).
[0229] In a preferred embodiment of the compound of Formula IVb:
[0230] R.sub.1 is methyl or ethyl, preferably methyl; [0231]
R.sub.3-R.sub.6, R.sub.12-R.sub.17 are as defined above; [0232]
R.sub.2 is a member of the group consisting of H, halo, N.sub.3,
C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol, hydroxyC.sub.1-4 alkyl,
C.sub.1-4 alkyl, and --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle; each of the member
being optionally substituted by 1-4 substituents wherein each
substituent is independently halo, OH, or C.sub.1-4 alkyl; [0233]
R.sub.7 and R.sub.11 are independently H, halo (preferably F),
CH.sub.3, or OCH.sub.3; [0234] R.sub.8 and R.sub.10 are
independently H, halo (preferably F or Cl), C.sub.1-3 alkyl
(preferably CH.sub.3) optionally substituted with halo (preferably
1-3 F), C.sub.1-3 alkoxy (preferably OCH.sub.3), or C.sub.1-3
alkylthiol (preferably --S--CH.sub.3); [0235] R.sub.9 is OH, Cl,
N.sub.3, C.sub.1-4 alkoxy, C.sub.1-4 alkylthiol, hydroxyC.sub.1-4
alkyl, C.sub.1-4 alkyl, [0236] --COOR.sup.c wherein R.sup.c is
C.sub.1-3 alkyl, or --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-4 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle; each of the member
being optionally substituted by 1-4 substituents wherein each
substituent is independently halo, OH, or C.sub.1-4 alkyl; and
optionally two adjacent R.sub.8, R.sub.9, and R.sub.10 groups may
together form a 3, 4, 5, or 6-membered carbocycle, heterocycle,
preferably heterocyle; and [0237] B and D are independently C or N,
and at least one of B and D is N.
[0238] In more preferred embodiments of the compound of Formula
IVa, R.sub.9 is selected from the group:
[0239] --OR.sub.9a, wherein R.sub.9a is methyl, ethyl, fluoromethyl
(e.g., CH.sub.2F, CHF.sub.2, CF.sub.3), fluoroethyl;
[0240] --N.sub.3;
[0241] --N(CH.sub.3).sub.2;
[0242] --NHCH.sub.3; and
[0243] --COOR.sub.9b, wherein R.sub.9b is H or C.sub.1-2 alkyl.
[0244] Other novel compounds of the present invention are those
represented by Formula V: ##STR24## or a pharmaceutically
acceptable salt or solvate thereof, wherein: [0245] R.sub.1 is
methyl or ethyl, preferably methyl; [0246] R.sub.5 is H, F, Cl,
N.sub.3, methyl, methoxy or NH.sub.2, with the proviso that when
R.sub.5 is methoxy, R.sub.1 is methyl; Preferably R.sub.5 is H, F
or N.sub.3, more preferably H or F, and most preferably H; [0247]
R.sub.2-R.sub.4, and R.sub.6-R.sub.13 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R1 are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0248] 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.
[0249] In a specific embodiment, preferably when R.sub.9 is H, at
least one of R.sub.8 and R.sub.10 is not H, more preferably R.sub.9
is other than H.
[0250] In some specific embodiments, B is C and D is N. In other
specific embodiments, B is N and D is C. In preferred embodiments,
both B and D are N.
[0251] In one embodiment of the compounds of Formula V,
R.sub.2 is H; halo; N.sub.3;
[0252] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro);
[0253] --XR.sub.2a wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted);
[0254] --CO.sub.2R.sup.d, wherein R.sup.d is C.sub.1-3 alkyl,
preferably methyl or ethyl; or
[0255] --N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-6 hydroxyalkyl
(preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH.sub.2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3
alkyl, more preferably CH.sub.3) that is optionally substituted
with --N(R.sup.e)(R.sup.f) wherein R.sup.e and R.sup.f are
independently H, OH (R.sup.e and R.sup.f are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.2-3 hydroxyalkyl
(preferably --CH.sub.2CH2OH), and wherein optionally R.sup.a and
R.sup.b together may form a 3, 4, 5 or 6-membered heterocycle
(e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
[0256] In another embodiment of the compound of Formula V, R.sub.2
is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0257] In preferred embodiment, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0258] In one embodiment, R.sub.9 is selected from the group
consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl (preferably
methyl or ethyl) or C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle.
[0259] In another embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0260] In yet another embodiment, when R.sub.9 is H, at least one
of R.sub.8 and R.sub.10 is not H. In another embodiment, when
R.sub.9 is alkyl, R.sub.2 is not H.
[0261] In a specific embodiment, compounds of the invention include
compounds of Formula V or pharmaceutically acceptable salts or
solvates thereof, wherein: [0262] R.sub.1 is C.sub.1-2 alkyl, and
preferably R.sub.1 is methyl; [0263] R.sub.5 is H or F, preferably
H; [0264] R.sub.2-R.sub.4, R.sub.6, R.sub.8-R.sub.10, R.sub.12 and
R.sub.13 are independently H; halo; N.sub.3; [0265] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with 1, 2 or 3 substituents, each substituent being
independently OH, halo, C.sub.1-3 alkoxy, (halo) C.sub.1-3 alkoxy,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0266] --XR.sup.c wherein X is S or O
and R.sup.c is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0267] --(C.sub.0-3
alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably methyl or ethyl)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), [0268] --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle; or [0269]
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H; OH (R.sup.a and R.sup.b are not both OH); C.sub.2-6
hydroxyalkyl; C.sub.1-6 alkyl; or C.sub.1-6 alkyl substituted with
--N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f are independently
H, OH (R.sup.e and R.sup.f are not both OH), or C.sub.1-3 alkyl;
[0270] wherein optionally R.sup.a and R.sup.b together, and/or
R.sup.e and R.sup.f together, with the nitrogen atom to which they
are linked form a 3, 4, 5 or 6-membered heterocycle; preferably
when R.sub.9 is H, at least one of R.sub.8 and R.sub.10 is not H,
more preferably R.sub.9 is other than H. [0271] R.sub.7 and
R.sub.11 are independently H, halo (preferably F or Cl, more
preferably F), C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.1-4
alkoxy (preferably OCH3); and [0272] B, D, Q, T, U, V, W, X, Y, and
Z are as defined above, provided that when B, D, Q, T, U, V, W, X,
Y or Z is N there is no substituent at the N.
[0273] In another preferred embodiment of the compounds of Formula
V, [0274] R.sub.1 is methyl or ethyl, more preferably methyl;
[0275] R.sub.2 is H; halo; N.sub.3; [0276] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo (preferably F, e.g., monofluoro,
difluoro, or trifluoro); [0277] --XR.sub.2a wherein X is S or O,
and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0278] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0279]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b with N together may form a 3, 4, 5
or 6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0280] R.sub.3 and R.sub.12 are independently H;
halo; C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0281] R.sub.4,
R.sub.6, and R.sub.13 are independently H; halo (preferably F or
Cl); N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3
alkoxy (preferably OCH.sub.3); or --N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are independently H, OH, C.sub.1-3 alkyl,
(hydroxy)C.sub.1-3 alkyl, and optionally R.sup.a and R.sup.b
together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and [0282] wherein
R.sup.a and R.sup.b are not both OH; [0283] R.sub.5 is H; [0284]
R.sub.7 and R.sub.11 are independently H, halo (preferably F),
CH.sub.3, or OCH.sub.3; [0285] R.sub.8 and R.sub.10 are
independently H; halo (preferably F or Cl, more preferably F);
C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); and [0286] R.sub.9 is selected from the group: H; OH;
Cl; N.sub.3; C.sub.1-3 alkyl (preferably methyl or ethyl) or
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); [0287] --OR.sub.9a, wherein R.sub.9a is C.sub.1-3
alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); [0288] --N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently H or C.sub.1-3 alkyl;
or --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl); and optionally R.sub.9 and one of R.sub.8 and
R.sub.10 together form a 3, 4, 5, or 6-membered heterocycle;
preferably when R.sub.9 is H, at least one of R.sub.8 and R.sub.10
is not H, more preferably R.sub.9 is other than H; and [0289] 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, wherein when B, D, Q, T, U, V, W, X, Y, or Z is nitrogen, then
there is no substituent at the N.
[0290] In more preferred embodiment, compounds of the invention
include compounds of Formula V or pharmaceutically acceptable salts
or solvates thereof, wherein: [0291] R.sub.1 is methyl or ethyl,
preferably methyl; [0292] R.sub.2 is H, methyl, ethyl, Cl, F,
fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; [0293] R.sub.3 and R.sub.12 are independently H,
CH.sub.3, OCH.sub.3, F, or Cl; [0294] R.sub.4, R.sub.6, and
R.sub.13 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; [0295] R.sub.5 is H; [0296] R.sub.7 and R.sub.11 are
independently H, F, or OCH.sub.3; [0297] R.sub.8 and R.sub.10 are
independently H, F, Cl, or OCH.sub.3; [0298] R.sub.9 is selected
from the group of consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl
(preferably methyl or ethyl); C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a
where R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; and --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl), and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; preferably when R.sub.9 is H, at least one
of R.sub.8 and R.sub.10 is not H, more preferably R.sub.9 is other
than H; and [0299] B, D, Q, T, U, V, W, X, Y and Z are as defined
above, provided that when B, D, Q, T, U, V, W, X, Y or Z is N, then
there is no substituent at the N. Preferably in this embodiment,
when R.sub.9 is alkyl, R.sub.2 not H.
[0300] In a even more preferred embodiment, compounds of the
invention include compounds of Formula V or pharmaceutically
acceptable salts or solvates thereof, wherein R.sub.1 is methyl;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or --CH.sub.2F;
R.sub.3 and R.sub.12 are independently H, methyl, --OCH.sub.3, or
Cl; R.sub.4 is H, methyl, or NH.sub.2; R.sub.5 is H; R.sub.6 and
R.sub.13 are independently H or methyl; R.sub.7 and R.sub.11 are
independently H or F; R.sub.8 and R.sub.10 are independently H, or
F or OCH.sub.3; and R.sub.9 is --OCH.sub.3, --OC.sub.2H.sub.5,
--N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3;
and B, D, Q, T, U, V, W, X, Y, and Z are as defined above, provided
that when B, D, Q, T, U, V, W, X, Y, or Z is N, then there is no
substituent at the N.
[0301] In all embodiments of the compounds of Formula V, it is
preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z
are N. In any of the embodiments, preferably one or two of Q, T, U
and V are N. For example, Q and V can be both N and T and U are
C.
[0302] Other preferred compounds of the present invention are those
represented by Formula V, with the proviso that Q, T, U, and V are
all carbon. Specifically, such compounds are represented by Formula
Va: ##STR25## or pharmaceutically acceptable salts or solvates
thereof, wherein: [0303] R.sub.1 is methyl or ethyl, preferably
methyl; [0304] R.sub.5 is H, F, Cl, N.sub.3, methyl, methoxy or
NH.sub.2, with the proviso that when R.sub.5 is methoxy, R.sub.1 is
methyl; Preferably R.sub.5 is H, F or N.sub.3, more preferably H or
F, and most preferably H; [0305] R.sub.2-R.sub.4, and
R.sub.6-R.sub.13 are independently H, halo, N.sub.3, OH, thiol,
nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6
alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0306] B, D, 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, W, X, Y or Z is N, then there is no substituent at the N.
[0307] In a specific embodiment, preferably when R.sub.9 is H, then
at least one of R.sub.8 and R.sub.10 is not H, more preferably
R.sub.9 is other than H.
[0308] In some specific embodiments, B is C and D is N. In other
specific embodiments, B is N and D is C. In preferred embodiments,
both B and D are N.
[0309] In one embodiment of the compounds of Formula Va,
R.sub.2 is H; halo; N.sub.3;
[0310] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro);
[0311] --XR.sub.2a wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted);
[0312] --CO.sub.2R.sup.d, wherein R.sup.d is C.sub.1-3 alkyl,
preferably methyl or ethyl; or
[0313] --N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-6 hydroxyalkyl
(preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH.sub.2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3
alkyl, more preferably CH.sub.3) that is optionally substituted
with --N(R.sup.e)(R.sup.f) wherein R.sup.e and R.sup.f are
independently H, OH (R.sup.e and R.sup.f are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.2-3 hydroxyalkyl
(preferably --CH.sub.2CH2OH), and wherein optionally R.sup.a and
R.sup.b together may form a 3, 4, 5 or 6-membered heterocycle
(e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
[0314] In another embodiment of the compound of Formula Va, R.sub.2
is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0315] In preferred embodiment, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0316] In one embodiment, R.sub.9 is selected from the group
consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl (preferably
methyl or ethyl) or C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle.
[0317] In another embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0318] In yet another embodiment, when R.sub.9 is H, then at least
one of R.sub.8 and R.sub.10 is not H. In another embodiment, when
R.sub.9 is alkyl, then R.sub.2 is not H.
[0319] In a specific embodiment, compounds of the invention include
compounds of Formula Va or pharmaceutically acceptable salts or
solvates thereof, wherein: [0320] R.sub.1 is C.sub.1-2 alkyl, and
preferably R.sub.1 is methyl; [0321] R.sub.5 is H or F, preferably
H; [0322] R.sub.2-R.sub.4, R.sub.6, R.sub.8-R.sub.10, R.sub.12 and
R.sub.13 are independently H; halo; N.sub.3; [0323] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with 1, 2 or 3 substituents, each substituent being
independently OH, halo, C.sub.1-3 alkoxy, (halo) C.sub.1-3 alkoxy,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0324] --XR.sup.c wherein X is S or O
and R.sup.c is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle;
[0325] --(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably methyl
or ethyl) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; or
[0326] --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H; OH (R.sup.a and R.sup.b are not both OH);
C.sub.2-6 hydroxyalkyl; C.sub.1-6 alkyl; or C.sub.1-6 alkyl
substituted with --N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f
are independently H, OH (R.sup.e and R.sup.f are not both OH), or
C.sub.1-3 alkyl; wherein optionally R.sup.a and R.sup.b together,
and/or R.sup.e and R.sup.f together, with the nitrogen atom to
which they are linked form a 3, 4, 5 or 6-membered heterocycle;
preferably when R.sub.9 is H, at least one of R.sub.8 and R.sub.10
is not H, more preferably R.sub.9 is other than H. [0327] R.sub.7
and R.sub.11 are independently H, halo (preferably F or Cl, more
preferably F), C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.1-4
alkoxy (preferably OCH3); and [0328] B, D, W, X, Y, and Z are as
defined above, provided that when B, D, W, X, Y or Z is N there is
no substituent at the N.
[0329] In another preferred embodiment of the compounds of Formula
Va, [0330] R.sub.1 is methyl or ethyl, more preferably methyl;
[0331] R.sub.2 is H; halo; N.sub.3; [0332] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo (preferably F, e.g., monofluoro,
difluoro, or trifluoro); [0333] --XR.sub.2a wherein X is S or O,
and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0334] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0335]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0336] R.sub.3 and R.sub.12 are independently H;
halo; C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0337] R.sub.4,
R.sub.6, and R.sub.13 are independently H; halo (preferably F or
Cl); N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3
alkoxy (preferably OCH.sub.3); or --N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are independently H, OH, C.sub.1-3 alkyl,
hydroxy-C.sub.1-3 alkyl, and optionally R.sup.a and R.sup.b
together may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R.sup.a
and R.sup.b are not both OH; [0338] R.sub.5 is H; [0339] R.sub.7
and R.sub.11 are independently H, halo (preferably F), CH.sub.3, or
OCH.sub.3; [0340] R.sub.8 and R.sub.10 are independently H; halo
(preferably F or Cl, more preferably F); C.sub.1-3 alkyl
(preferably CH.sub.3); C.sub.1-3 alkoxy (preferably OCH.sub.3); and
[0341] R.sub.9 is selected from the group: H; OH; Cl; N.sub.3;
C.sub.1-3 alkyl (preferably methyl or ethyl) or C.sub.1-3 haloalkyl
(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
--OR.sub.9a, wherein R.sub.9a is C.sub.1-3 alkyl (i.e., methyl,
ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are
independently H or C.sub.1-3 alkyl; or --COOR.sub.9b, wherein
R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl); and
optionally R.sub.9 and one of R.sub.8 and R.sub.10 together form a
3, 4, 5, or 6-membered heterocycle; preferably when R.sub.9 is H,
at least one of R.sub.8 and R.sub.10 is not H, more preferably
R.sub.9 is other than H; and [0342] B, D, 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, wherein when B, D, W, X,
Y, or Z is nitrogen, then there is no substituent at the N.
[0343] In more preferred embodiment, compounds of the invention
include compounds of Formula Va or pharmaceutically acceptable
salts or solvates thereof, wherein: [0344] R.sub.1 is methyl or
ethyl, preferably methyl; [0345] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; [0346] R.sub.3 and R.sub.12 are independently H,
CH.sub.3, OCH.sub.3, F, or Cl; [0347] R.sub.4, R.sub.6, and
R.sub.13 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; [0348] R.sub.5 is H; [0349] R.sub.7 and R.sub.11 are
independently H, F, or OCH.sub.3; [0350] R.sub.8 and R.sub.10 are
independently H, F, Cl, or OCH.sub.3; [0351] R.sub.9 is selected
from the group of consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl
(preferably methyl or ethyl); C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a
where R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; and --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl), and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; preferably when R.sub.9 is H, at least one
of R.sub.8 and R.sub.10 is not H, more preferably R.sub.9 is other
than H; and [0352] B, D, W, X, Y and Z are as defined above,
provided that when B, D, W, X, Y or Z is N, then there is no
substituent at the N. Preferably in this embodiment, when R.sub.9
is alkyl, R.sub.2 not H.
[0353] In a even more preferred embodiment, compounds of the
invention include compounds of Formula Va or pharmaceutically
acceptable salts or solvates thereof, wherein R.sub.1 is methyl;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or --CH.sub.2F;
R.sub.3 and R.sub.12 are independently H, methyl, --OCH.sub.3, or
Cl; R.sub.4 is H, methyl, or NH.sub.2; R.sub.5 is H; R.sub.6 and
R.sub.13 are independently H or methyl; R.sub.7 and R.sub.11 are
independently H or F; R.sub.8 and R.sub.10 are independently H, or
F or OCH.sub.3; and R.sub.9 is --OCH.sub.3, --OC.sub.2H.sub.5,
--N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3;
and B, D, W, X, Y, and Z are as defined above, provided that when
B, D, W, X, Y, or Z is N, then there is no substituent at the
N.
[0354] In all embodiments of the compounds of Formula Va, it is
preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z
are N.
[0355] Another group of preferred compounds of the present
invention are those represented by Formula V with the proviso that
both B and D are nitrogen. Specifically such compounds are
represented by Formula Vb: ##STR26## or pharmaceutically acceptable
salts or solvates thereof, wherein: [0356] R.sub.1 is methyl or
ethyl, preferably methyl; [0357] R.sub.5 is H, F, Cl, N.sub.3,
methyl, methoxy or NH.sub.2, with the proviso that when R.sub.5 is
methoxy, R.sub.1 is methyl; Preferably R.sub.5 is H, F or N.sub.3,
more preferably H or F, and most preferably H; [0358]
R.sub.2-R.sub.4, and R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0359] Q, T, U, V, W, X,
Y and Z are independently C or N, provided that at least one of W,
X, Y and Z is N, and wherein when Q, T, U, V, W, X, Y or Z is N,
then there is no substituent at the N.
[0360] In a specific embodiment, preferably when R.sub.9 is H, then
at least one of R.sub.8 and R.sub.10 is not H, more preferably
R.sub.9 is other than H.
[0361] In one embodiment of the compounds of Formula Vb,
R.sub.2 is H; halo; N.sub.3;
[0362] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro);
[0363] --XR.sub.2a wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted);
[0364] --CO.sub.2R.sup.d, wherein R.sup.d is C.sub.1-3 alkyl,
preferably methyl or ethyl; or --N(R.sup.a)(R.sup.b) wherein
R.sup.a and R.sup.b are independently H, OH (R.sup.a and R.sup.b
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-6
hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH.sub.2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3
alkyl, more preferably CH.sub.3) that is optionally substituted
with --N(R.sup.e)(R.sup.f) wherein R.sup.e and R.sup.f are
independently H, OH (R.sup.e and R.sup.f are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.2-3 hydroxyalkyl
(preferably --CH.sub.2CH2OH), and wherein optionally R.sup.a and
R.sup.b together may form a 3, 4, 5 or 6-membered heterocycle
(e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
[0365] In another embodiment of the compound of Formula V, R.sub.2
is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0366] In preferred embodiment, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0367] In one embodiment, R.sub.9 is selected from the group
consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl (preferably
methyl or ethyl) or C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle.
[0368] In another embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0369] In yet another embodiment, when R.sub.9 is H, then at least
one of R.sub.8 and R.sub.10 is not H. In another embodiment, when
R.sub.9 is alkyl, then R.sub.2 is not H.
[0370] In a specific embodiment, compounds of the invention include
compounds of Formula Vb or pharmaceutically acceptable salts or
solvates thereof, wherein: [0371] R.sub.1 is C.sub.1-2 alkyl, and
preferably R.sub.1 is methyl; [0372] R.sub.5 is H or F, preferably
H; [0373] R.sub.2-R.sub.4, R.sub.6, R.sub.8-R.sub.10 are
independently H; halo; N.sub.3; [0374] C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with 1, 2 or 3 substituents, each substituent being independently
OH, halo, C.sub.1-3 alkoxy, (halo) C.sub.1-3 alkoxy,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0375] --XR.sup.c wherein X is S or O
and R.sup.c is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0376] --(C.sub.0-3
alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably methyl or ethyl)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; or [0377]
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H; OH (R.sup.a and R.sup.b are not both OH); C.sub.2-6
hydroxyalkyl; C.sub.1-6 alkyl; or C.sub.1-6 alkyl substituted with
--N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f are independently
H, OH (R.sup.e and R.sup.f are not both OH), or C.sub.1-3 alkyl;
wherein optionally R.sup.a and R.sup.b together, and/or R.sup.e and
R.sup.f together, with the nitrogen atom to which they are linked
to form a 3, 4, 5 or 6-membered heterocycle; preferably when
R.sub.9 is H, at least one of R.sub.8 and R.sub.10 is not H, more
preferably R.sub.9 is other than H. [0378] R.sub.7 and R.sub.11 are
independently H, halo (preferably F or Cl, more preferably F),
C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.1-4 alkoxy
(preferably OCH.sub.3); and [0379] Q, T, U, V, W, X, Y, and Z are
as defined above, provided that when Q, T, U, V, W, X, Y or Z is N
there is no substituent at the N.
[0380] In another preferred embodiment of the compounds of Formula
Vb, [0381] R.sub.1 is methyl or ethyl, more preferably methyl;
[0382] R.sub.2 is H; halo; N.sub.3; [0383] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo (preferably F, e.g., monofluoro,
difluoro, or trifluoro); [0384] --XR.sub.2a wherein X is S or O,
and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0385] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0386]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0387] R.sub.3 is H; halo; C.sub.1-3 alkyl; or
C.sub.1-3 alkoxy; [0388] R.sub.4, and R.sub.6 are independently H;
halo (preferably F or Cl); N.sub.3; C.sub.1-3 alkyl (preferably
CH.sub.3); C.sub.1-3 alkoxy (preferably OCH.sub.3); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH, C.sub.1-3 alkyl, hydroxy-C.sub.1-3 alkyl, and optionally
R.sup.a and R.sup.b together may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sup.a and R.sup.b are not both OH; [0389] R.sub.5 is H;
[0390] R.sub.7 and R.sub.11 are independently H, halo (preferably
F), CH.sub.3, or OCH.sub.3; [0391] R.sub.8 and R.sub.10 are
independently H; halo (preferably F or Cl, more preferably F);
C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); and [0392] R.sub.9 is selected from the group: H; OH;
Cl; N.sub.3; C.sub.1-3 alkyl (preferably methyl or ethyl) or
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --OR.sub.9a, wherein R.sub.9a is C.sub.1-3 alkyl
(i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl
(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F,
CHF.sub.2, CF.sub.3); --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl);
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle; preferably when R.sub.9
is H, at least one of R.sub.8 and R.sub.10 is not H, more
preferably R.sub.9 is other than H; and [0393] Q, T, U, V, W, X, Y,
and Z are independently C or N, provided that at least one of W, X,
Y, and Z is N, wherein when Q, T, U, V, W, X, Y, or Z is nitrogen,
then there is no substituent at the N.
[0394] In more preferred embodiment, compounds of the invention
include compounds of Formula Vb or pharmaceutically acceptable
salts or solvates thereof, wherein: [0395] R.sub.1 is methyl or
ethyl, preferably methyl; [0396] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; [0397] R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl;
[0398] R.sub.4, and R.sub.6 are independently H, CH.sub.3,
NH.sub.2, N.sub.3, F, or Cl; [0399] R.sub.5 is H; [0400] R.sub.7
and R.sub.11 are independently H, F, or OCH.sub.3; [0401] R.sub.8
and R.sub.10 are independently H, F, Cl, or OCH.sub.3; [0402]
R.sub.9 is selected from the group of consisting of H; OH; Cl;
N.sub.3; C.sub.1-3 alkyl (preferably methyl or ethyl); C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --OR.sub.9a where R.sub.9a is C.sub.1-3 alkyl
(i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl
(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F,
CHF.sub.2, CF.sub.3); --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; and --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl),
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle; preferably when R.sub.9
is H, at least one of R.sub.8 and R.sub.10 is not H, more
preferably R.sub.9 is other than H; and [0403] Q, T, U, V, W, X, Y
and Z are as defined above, provided that when Q, T, U, V, W, X, Y
or Z is N, then there is no substituent at the N. Preferably in
this embodiment, when R.sub.9 is alkyl, then R.sub.2 is not H.
[0404] In an even more preferred embodiment, compounds of the
invention include compounds of Formula Vb or pharmaceutically
acceptable salts or solvates thereof, wherein R.sub.1 is methyl;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or --CH.sub.2F;
R.sub.3 is H, methyl, --OCH.sub.3, or Cl; R.sub.4 is H, methyl, or
NH.sub.2; R.sub.5 is H; R.sub.6 is H or methyl; R.sub.7 and
R.sub.11 are independently H or F; R.sub.5 and R.sub.10 are
independently H, or F or OCH.sub.3; and R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3; and Q, T, U, V, W, X, Y, and Z are as
defined above, provided that when Q, T, U, V, W, X, Y, or Z is N,
then there is no substituent at the N.
[0405] In all embodiments of the compounds of Formula Vb, it is
preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z
are N. In any of the embodiments, preferably one or two of Q, T, U
and V are N. For example, Q and V can be both N, and T and U are
C.
[0406] Another specific group of compounds of Formula V include
those represented by Formula Vc: ##STR27## or pharmaceutically
acceptable salts or solvates thereof, wherein: [0407] R.sub.1 is
methyl or ethyl, preferably methyl; [0408] R.sub.5 is H, F, Cl,
N.sub.3, methyl, methoxy or NH.sub.2, with the proviso that when
R.sub.5 is methoxy, R.sub.1 is methyl; preferably R.sub.5 is H, F
or N.sub.3, more preferably H or F, and most preferably H; [0409]
R.sub.2-R.sub.4, and R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0410] W, X, Y and Z are
independently C or N, provided that at least one of W, X, Y and Z
is N, and wherein when W, X, Y or Z is N, then there is no
substituent at the N.
[0411] In a specific embodiment, preferably when R.sub.9 is H, then
at least one of R.sub.8 and R.sub.10 is not H, more preferably
R.sub.9 is other than H.
[0412] In one embodiment of the compounds of Formula Vc,
R.sub.2 is H; halo; N.sub.3;
[0413] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro);
[0414] --XR.sub.2a wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted);
[0415] --CO.sub.2R.sup.d, wherein R.sup.d is C.sub.1-3 alkyl,
preferably methyl or ethyl; or
[0416] --N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-6 hydroxyalkyl
(preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH.sub.2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3
alkyl, more preferably CH.sub.3) that is optionally substituted
with --N(R.sup.e)(R.sup.f) wherein R.sup.e and R.sup.f are
independently H, OH (R.sup.e and R.sup.f are not both OH),
C.sub.1-3 alkyl (preferably CH.sub.3), or C.sub.2-3 hydroxyalkyl
(preferably --CH.sub.2CH2OH), and wherein optionally R.sup.a and
R.sup.b together may form a 3, 4, 5 or 6-membered heterocycle
(e.g., piperidinyl, pyrrolidinyl, and morpholinyl).
[0417] In another embodiment of the compound of Formula Vc, R.sub.2
is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0418] In preferred embodiment, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0419] In one embodiment, R.sub.9 is selected from the group
consisting of H; OH; Cl; N.sub.3; C.sub.1-3 alkyl (preferably
methyl or ethyl) or C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H or C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle.
[0420] In another embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0421] In yet another embodiment, when R.sub.9 is H, then at least
one of R.sub.8 and R.sub.10 is not H. In another embodiment, when
R.sub.9 is alkyl, then R.sub.2 is not H.
[0422] In a specific embodiment, compounds of the invention include
compounds of Formula Vc or pharmaceutically acceptable salts or
solvates thereof, wherein: [0423] R.sub.1 is C.sub.1-2 alkyl, and
preferably R.sub.1 is methyl; [0424] R.sub.5 is H or F, preferably
H; [0425] R.sub.2-R.sub.4, R.sub.6, R.sub.8-R.sub.10 are
independently H; halo; N.sub.3; [0426] C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with 1, 2 or 3 substituents, each substituent being independently
OH, halo, C.sub.1-3 alkoxy, (halo) C.sub.1-3 alkoxy,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0427] --XR.sup.c wherein X is S or O
and R.sup.c is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-6
hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0428] --(C.sub.0-3
alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably methyl or ethyl)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked form
a 3, 4, 5 or 6-membered heterocycle; or [0429]
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H; OH (R.sup.a and R.sup.b are not both OH); C.sub.2-6
hydroxyalkyl; C.sub.1-6 alkyl; or C.sub.1-6 alkyl substituted with
--N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f are independently
H, OH (R.sup.e and R.sup.f are not both OH), or C.sub.1-3 alkyl;
wherein optionally R.sup.a and R.sup.b together, and/or R.sup.e and
R.sup.f together, with the nitrogen atom to which they are linked
form a 3, 4, 5 or 6-membered heterocycle; [0430] --(C.sub.0-3
alkyl)C(O)N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl, C.sub.2-3 hydroxyalkyl or C.sub.1-3
haloalkyl; preferably when R.sub.9 is H, then at least one of
R.sub.8 and R.sub.10 is not H, more preferably R.sub.9 is other
than H; [0431] R.sub.7 and R.sub.11 are independently H, halo
(preferably F or Cl, more preferably F), C.sub.1-3 alkyl
(preferably CH.sub.3), or C.sub.1-4 alkoxy (preferably OCH3); and
[0432] W, X, Y, and Z are as defined above, provided that when W,
X, Y or Z is N there is no substituent at the N.
[0433] In another preferred embodiment of the compounds of Formula
Vc, [0434] R.sub.1 is methyl or ethyl, more preferably methyl;
[0435] R.sub.2 is H; halo; N.sub.3; [0436] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with OH or halo (preferably F, e.g., monofluoro,
difluoro, or trifluoro); [0437] --XR.sub.2a wherein X is S or O,
and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0438] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0439]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0440] R.sub.3 is H; halo; C.sub.1-3 alkyl; or
C.sub.1-3 alkoxy; [0441] R.sub.4, R.sub.6 are independently H; halo
(preferably F or Cl); N.sub.3; C.sub.1-3 alkyl (preferably
CH.sub.3); C.sub.1-3 alkoxy (preferably OCH.sub.3); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH, C.sub.1-3 alkyl, (hydroxy)C.sub.1-3 alkyl, and optionally
R.sup.a and R.sup.b together may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sup.a and R.sup.b are not both OH; [0442] R.sub.5 is H;
[0443] R.sub.7 and R.sub.11 are independently H, halo (preferably
F), CH.sub.3, or OCH.sub.3; [0444] R.sub.8 and R.sub.10 are
independently H; halo (preferably F or Cl, more preferably F);
C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); and [0445] R.sub.9 is selected from the group: H; OH;
Cl; N.sub.3; C.sub.1-3 alkyl (preferably methyl or ethyl) or
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --OR.sub.9a, wherein R.sub.9a is C.sub.1-3 alkyl
(i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl
(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F,
CHF.sub.2, CF.sub.3); --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; --(C.sub.0-3
alkyl)COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl); or --(C.sub.0-3 alkyl)C(O)N(R.sup.a)(R.sup.b)
wherein R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; and
optionally R.sub.9 and one of R.sub.8 and R.sub.10 together form a
3, 4, 5, or 6-membered heterocycle; preferably when R.sub.9 is H,
then at least one of R.sub.8 and R.sub.10 is not H, more preferably
R.sub.9 is other than H; and [0446] W, X, Y, and Z are
independently C or N, provided that at least one of W, X, Y, and Z
is N, wherein when W, X, Y, or Z is nitrogen, then there is no
substituent at the N.
[0447] In more preferred embodiment, compounds of the invention
include compounds of Formula Vc or pharmaceutically acceptable
salts or solvates thereof, wherein: [0448] R.sub.1 is methyl or
ethyl, preferably methyl; [0449] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; [0450] R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl;
[0451] R.sub.4 and R.sub.6 are independently H, CH.sub.3, NH.sub.2,
N.sub.3, F, or Cl; [0452] R.sub.5 is H; [0453] R.sub.7 and R.sub.11
are independently H, F, or OCH.sub.3; [0454] R.sub.8 and R.sub.10
are independently H, F, Cl, or OCH.sub.3;
[0455] R.sub.9 is selected from the group of consisting of H; OH;
Cl; N.sub.3; C.sub.1-3 alkyl (preferably methyl or ethyl);
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --OR.sub.9a where R.sub.9a is C.sub.1-3 alkyl
(i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl
(e.g., fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F,
CHF.sub.2, CF.sub.3); --N(R.sup.a)(R.sup.b) wherein R.sup.a and
R.sup.b are independently H or C.sub.1-13 alkyl; and --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl),
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle; preferably when R.sub.9
is H, then at least one of R.sub.8 and R.sub.10 is not H, more
preferably R.sub.9 is other than H; and [0456] W, X, Y and Z are as
defined above, provided that when W, X, Y or Z is N, then there is
no substituent at the N. Preferably in this embodiment, when
R.sub.9 is alkyl, R.sub.2 not H.
[0457] In a even more preferred embodiment, compounds of the
invention include compounds of Formula Vc or pharmaceutically
acceptable salts or solvates thereof, wherein R.sub.1 is methyl;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or --CH.sub.2F;
R.sub.3 and R.sub.12 are independently H, methyl, --OCH.sub.3, or
Cl; R.sub.4 is H, methyl, or NH.sub.2; R.sub.5 is H; R.sub.6 and
R.sub.13 are independently H or methyl; R.sub.7 and R.sub.11 are
independently H or F; R.sub.8 and R.sub.10 are independently H, or
F or OCH.sub.3; and R.sub.9 is --OCH.sub.3, --OC.sub.2H.sub.5,
--N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3;
and W, X, Y, and Z are as defined above, provided that when W, X,
Y, or Z is N, then there is no substituent at the N.
[0458] In all embodiments of the compounds of Formula Vc, it is
preferred that one of W, X, Y and Z is N, or two of W, X, Y and Z
are N.
[0459] Other preferred compounds of the present invention are those
represented by Formula VI: ##STR28## or pharmaceutically acceptable
salts or solvates thereof, wherein: [0460] R.sub.1 is methyl or
ethyl, preferably methyl; [0461] R.sub.5 is H or F, preferably H;
[0462] R.sub.2-R.sub.4, and R.sub.6-R.sub.13 are independently H,
halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they are both linked to
form a 3, 4, 5 or 6-membered heterocycle, wherein optionally any
two adjacent R.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; and [0463] B, D, Q, T, U and
V are independently C or N, provided that at least one of B and D
is N, and when B, D, Q, T, U or V is N, then there is no
substituent at the N; [0464] wherein when Q, T, U and V are all C,
then R.sub.9 is not carboxyalkoxy or an ester thereof (preferably
R.sub.9 is not --O(C.sub.1-6 alkyl)C(O)O(C.sub.1-6 alkyl); wherein
when R.sub.9 is H then at least one of R.sub.8 and R.sub.10 is not
H or halo or alkyl; and [0465] wherein when R.sub.9 is alkyl, then
R.sub.2 is not aryl.
[0466] In one embodiment, compounds of the invention include
compounds of Formula VI or pharmaceutically acceptable salts or
solvates thereof, wherein: [0467] R.sub.1 is methyl or ethyl,
preferably methyl; [0468] R.sub.5 is H or F, preferably H; [0469]
R.sub.2-R.sub.4, R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b together with the nitrogen
atom to which they are both linked to form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl);
wherein any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-16 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; [0470] exactly one of B and D
is N; and [0471] 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.sub.9 is H then
R.sub.2 is not optionally substituted aryl or heteroaryl.
Preferably, R.sub.8 and R.sub.10 are not both H, or one H and the
other alkyl. Preferably when R.sub.9 is H then at least one of
R.sub.8 and R.sub.10 is not H or alkyl. More preferably, when
R.sub.9 is H then at least one of R.sub.8 and R.sub.10 is not H,
alkyl, or halo.
[0472] In one embodiment, R.sub.9 is selected from the group
consisting of H, OH, Cl, N.sub.3;
[0473] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy,
(halo)C.sub.1-3 alkoxy, --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked to form a 3, 4, 5 or 6-membered heterocycle;
[0474] --XR.sup.c wherein X is S or O and R.sup.c is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy, or
(halo)C.sub.1-3 alkoxy; --(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein
R.sup.d is an C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably methyl or ethyl) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy (e.g., fluoroalkoxy), --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently H, OH (R.sup.a and R.sup.b
are not both OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or
R.sup.a and R.sup.b together with the nitrogen atom to which they
both are linked form a 3, 4, 5 or 6-membered heterocycle;
[0475] --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or C.sub.1-3 alkyl
substituted with --N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f
are independently H, OH (R.sup.e and R.sup.f are not both OH), or
C.sub.1-3 alkyl; wherein optionally R.sup.a and R.sup.b together
with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally
R.sup.e and R.sup.f together with the nitrogen atom to which they
both are linked form a 3, 4, 5 or 6-membered heterocycle; or
[0476] --(C.sub.0-3 alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; preferably R.sub.9 is selected from the
group outlined above except R.sub.9 is not H and
C.sub.1-6alkyl.
[0477] In another embodiment, R.sub.9 is H; OH; Cl; N.sub.3;
C.sub.1-3 alkyl (preferably methyl; C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a); --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl);
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle; preferably R.sub.9 is
selected from the group outlined above except R.sub.9 is not H or
C.sub.1-3alkyl.
[0478] In a preferred embodiment, R.sub.9 is N.sub.3, --OR.sub.9a
wherein R.sub.9a is C.sub.1-3 alkyl optionally substituted with 1-7
F, --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl, --COOR.sub.9b where R.sub.9b is
C.sub.1-3 alkyl.
[0479] In a more preferred embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0480] In the various embodiments of the compounds according to
Formula VI preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or
both are independently OH; Cl; N.sub.3; --XR.sub.9a, where X is O
or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl; --N(R.sup.a)(R.sup.b) where R.sup.a
and R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
Even more preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are C.sub.1-3 alkoxy or C.sub.1-3 haloalkoxy.
[0481] Also preferably in the various embodiments, when R.sub.9 is
H then R.sub.2 is not H, and preferably R.sub.2 is halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl. More preferably
R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH
or CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH,
--NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3,
morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0482] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H, and preferably is methyl,
ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3),
C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0483] In one embodiment, R.sub.2 is H; halo; N.sub.3; C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O, and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); --CO.sub.2R.sup.d, wherein R.sup.d is
C.sub.1-3 alkyl, preferably methyl or ethyl; or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle.
[0484] In a preferred embodiment, R.sub.2 is H; halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl.
[0485] In preferred embodiments, R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0486] In more preferred embodiments, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0487] In all embodiments of the compound of Formula VI, it is
preferred that one or two of Q, T, U and V are N. For example Q and
V are N and T and U are C.
[0488] In one embodiment, compounds of the invention include
compounds of Formula VI or pharmaceutically acceptable salts or
solvates thereof, wherein: [0489] R.sub.1 is methyl or ethyl,
preferably methyl; [0490] R.sub.2 is H; halo; N.sub.3; [0491]
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0492] --XR.sub.2a
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0493] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0494]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl); [0495] R.sub.3 is H;
halo; C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0496] R.sub.4 and
R.sub.6 are independently H; halo (preferably F or Cl); N.sub.3;
C.sub.1-6 alkyl (preferably C.sub.1-3, more preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); or --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, OH, C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3) or C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH),
wherein R.sub.2b and R.sub.2c together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R.sub.2b
and R.sub.2c are not both OH, R.sub.2d and R.sub.2e are not both
OH; [0497] R.sub.5 is H or F, preferably H; [0498] R.sub.7 and
R.sub.11 are independently H; halo (preferably F or Cl, more
preferably F); CH.sub.3; or OCH.sub.3; [0499] R.sub.8 and R.sub.10
are independently H; halo (preferably F or Cl, more preferably Cl);
OH; N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3
alkoxy (preferably OCH.sub.3); C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --XR.sub.9a,
where X is O or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); --NH(R.sup.a) or
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3
alkyl (preferably methyl or ethyl); [0500] R.sub.9 is selected from
the group consisting of H, OH, Cl, N.sub.3; [0501] C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with 1, 2 or 3 substituents, each substituent being
independently OH, halo, C.sub.1-3 alkoxy, (halo)C.sub.1-3 alkoxy,
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.2-4
hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and R.sup.b together
with the nitrogen atom to which they are both linked form a 3, 4, 5
or 6-membered heterocycle; [0502] --XR.sup.c wherein X is S or O
and R.sup.c is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with 1, 2 or 3
substituents, each substituent being independently OH, halo,
C.sub.1-3 alkoxy, or (halo)C.sub.1-3 alkoxy; [0503] --(C.sub.0-3
alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an C.sub.1-6 alkyl
(preferably C.sub.1-3 alkyl, more preferably methyl or ethyl)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they both are linked form
a 3, 4, 5 or 6-membered heterocycle; [0504] --N(R.sup.a)(R.sup.b)
where R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl,
or C.sub.1-3 alkyl substituted with --N(R.sup.e)(R.sup.f) where
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), or C.sub.1-3 alkyl; wherein optionally R.sup.a
and R.sup.b together with the N form a 3, 4, 5 or 6-membered
heterocycle, and optionally R.sup.e and R.sup.f together with the
nitrogen atom to which they both are linked form a 3, 4, 5 or
6-membered heterocycle; or [0505] --(C.sub.0-3
alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H or C.sub.1-3 alkyl; and optionally R.sub.9 and one
of R.sub.8 and R.sub.10 together form a 3, 4, 5, or 6-membered
heterocycle; provided that when R.sub.9 is H, at least one of
R.sub.8 and R.sub.10 is not hydrogen or alkyl; [0506] exactly one
of B and D is N; and [0507] Q, T, U and V are independently C or N,
provided that at least one of Q, T, U and V is N, wherein when Q,
T, U or V is N, then there is no substituent at the N. In some
specific embodiments, one or two of Q, T, U and V are N.
[0508] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; Cl; N.sub.3; --XR.sub.9a, where X is O or S,
and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3
haloalkoxy.
[0509] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl
(CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl
(preferably CH.sub.2OH or CH.sub.2CH.sub.2OH), NH.sub.2,
NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2,
N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0510] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein: [0511] R.sub.1 is methyl or
ethyl, and preferably methyl; [0512] R.sub.2 is H; halo; N.sub.3;
[0513] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0514] --XR.sub.23
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0515] --CO.sub.2--R.sub.2f, wherein
R.sub.2f is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably methyl or ethyl); or [0516] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, OH, C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3), or C.sub.2-3 hydroxyalkyl (preferably
--CH.sub.2CH.sub.2OH), and wherein optionally R.sub.2b and R.sub.2c
together with the N they are both linked to may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl), and wherein R.sub.2b and R.sub.2c are not both OH,
R.sub.2d and R.sub.2e are not both OH; [0517] R.sub.3 is H; halo;
C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0518] R.sub.4 and R.sub.6
are independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, CH.sub.3, or ethyl, and
optionally R.sub.2b and R.sub.2c together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R.sub.2b
and R.sub.2c are not both OH; [0519] R.sub.5 is H; [0520] R.sub.7
and R.sub.11 are independently H, halo (preferably F), CH.sub.3, or
OCH.sub.3; [0521] R.sub.8 and R.sub.10 are independently H; halo
(preferably F or Cl, more preferably F); C.sub.1-3 alkyl
(preferably CH.sub.3); C.sub.1-3 alkoxy (preferably OCH.sub.3); and
[0522] R.sub.9 is selected from the group: [0523] hydrogen;
hydroxy; Cl; N.sub.3; [0524] C.sub.1-3 alkyl (preferably methyl or
ethyl) or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0525] --OR.sub.9a, wherein
R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--N(R.sup.a)(R.sup.b), wherein R.sup.a and R.sup.b are
independently H, C.sub.1-3 alkyl, or haloC.sub.1-3alkyl; or [0526]
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl); and optionally R.sub.9 and one of R.sub.8 and
R.sub.10 together form a 3, 4, 5, or 6-membered carbocycle or
heterocycle; [0527] exactly one of B and D is N; and [0528] Q, T, U
and V are independently C or N, wherein at least one of Q, T, U and
V are N, wherein when Q, T, U or V is N, then the there is no
substituent at the N; with the proviso that when R.sub.9 is H then
R.sub.8 and R.sub.10 are not both H or one H and the other alkyl.
Preferably when R.sub.9 is H then at least one of R.sub.8 or
R.sub.10 is not H or alkyl. More preferably when R.sub.9 is H then
at least one of R.sub.8 or R.sub.10 is not H, alkyl, or halo.
[0529] In some specific embodiments, one or two of Q, T, U and V
are N.
[0530] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently OH; Cl; N.sub.3; C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --XR.sub.9, where X is O or S, and R.sub.9a is
C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g., fluoroalkyl,
preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b
are independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein
R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl). More
preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0531] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H and preferably R.sub.2 is
halo; C.sub.1-3 alkyl optionally substituted with OH or halo
(preferably F, e.g., monofluoro, difluoro, or trifluoro);
--XR.sub.2a wherein X is S or O and R.sub.2a is C.sub.1-3 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with halo (preferably F, e.g., monofluoro-, difluoro-,
or trifluoro-substituted); or --N(R.sup.a)(R.sup.b) wherein R.sup.a
and R.sup.b are independently H, OH (R.sup.a and R.sup.b are not
both OH), C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.2-3
hydroxyalkyl. More preferably R.sub.2 is methyl, ethyl, Cl, F,
fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0532] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0533] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein: [0534] R.sub.1 is methyl or
ethyl, preferably methyl; [0535] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4
and R.sub.6 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; R.sub.5 is H; R.sub.7 and R.sub.11 are independently H, F, or
OCH.sub.3; R.sub.8 and R.sub.10 are independently H, F, Cl, or
OCH.sub.3; and [0536] R.sub.9 is selected from the group: [0537]
hydrogen; hydroxy; Cl; [0538] C.sub.1-3 alkyl (preferably methyl or
ethyl) or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0539] --OR.sub.9a, wherein
R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3); [0540]
C.sub.1-3 alkyl substituted amino (preferably --NHCH.sub.3 or
--N(CH.sub.3).sub.2); [0541] --N.sub.3; or [0542] --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl),
and optionally R.sub.8 and R.sub.9 together form a 3, 4, 5, or
6-membered carbocycle or heterocycle; exactly one of B and D is N;
and [0543] Q, T, U and V are independently C or N, and at least one
of Q, T, U and V is N, wherein when Q, T, U or V is N, then there
is no substituent at the N. In some specific embodiments, one or
two of Q, T, U and V are nitrogen.
[0544] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently OH; Cl; N.sub.3; C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --XR.sub.9a, where X is O or S, and R.sub.9a is
C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g., fluoroalkyl,
preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b
are independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein
R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl). More
preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0545] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H and preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0546] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0547] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is methyl;
[0548] R.sub.2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), CH.sub.2OH, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.2OH, OCH.sub.3, or SCH.sub.3;
R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4 and R.sub.6
are independently H, CH.sub.3, NH.sub.2, F, or Cl; R.sub.5 is H;
R.sub.7 and R.sub.11 are independently H, F, or OCH.sub.3; R.sub.8
and R.sub.10 are independently H, F, Cl, or OCH.sub.3; and
R.sub.9 is selected from the group:
[0549] --OR.sub.9a, wherein R.sub.9a is selected from the group of
methyl, ethyl, fluoromethyl (e.g., CH.sub.2F, CHF.sub.2, CF.sub.3),
and fluoroethyl;
[0550] --NHCH.sub.3;
[0551] --N(CH.sub.3).sub.2;
[0552] --N.sub.3; and
[0553] --COOR.sub.9b, wherein R.sub.9b is H or methyl or ethyl;
exactly one of B and D is N; and
Q, T, U and V are independently C or N, and at least one of Q, T, U
and V is N, wherein when Q, T, U or V is N, then there is no
substituent at the N. In some specific embodiments, one or two of
Q, T, U and V are nitrogen.
[0554] In a more preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or
--CH.sub.2F;
R.sub.3 is H, --CH.sub.3, --OCH.sub.3, or Cl;
R.sub.4 is H, CH.sub.3, or NH.sub.2;
R.sub.5 is H;
R.sub.6 is H, or CH.sub.3;
R.sub.7 and R.sub.11 are independently H, or F;
R.sub.8 and R.sub.10 are independently H, or F or OCH.sub.3;
R.sub.9 is --OCH.sub.3 or --OC.sub.2H.sub.5, --N(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3;
exactly one of B and D is N; and
Q, T, U and V are independently C or N, and at least one of Q, T, U
and V is N, wherein when Q, T, U or V is N, then there is no
substituent at the N. In some specific embodiments, one or two of
Q, T, U and V are nitrogen.
[0555] In a more preferred embodiment, the present invention
provides compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein R.sub.1 is CH.sub.3; R.sub.2 is
Cl, methyl, or CH.sub.2F; R.sub.3 is H, CH.sub.3, F, or Cl;
R.sub.4, R.sub.5 and R.sub.6 are H; R.sub.7, R.sub.8, R.sub.10 and
R.sub.11 are independently H or F; R.sub.9 is --OCH.sub.3 or
--N(CH.sub.3).sub.2; and Q, T, U and V are independently C or N,
and at least one of Q, T, U and V is N, wherein when Q, T, U or V
is N, then there is no substituent at the N. In some specific
embodiments, one or two of Q, T, U and V are nitrogen.
[0556] In another embodiment, compounds of the invention include
compounds of Formula VI or pharmaceutically acceptable salts or
solvates thereof, wherein: [0557] R.sub.1 is methyl or ethyl,
preferably methyl; [0558] R.sub.5 is H or F, preferably H; and
[0559] R.sub.2-R.sub.4, R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6
acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; [0560] exactly one of B and D
is N provided that when B or D is N there is no substituent at the
N; and [0561] all of Q, T, U, and V are C; [0562] provided that:
(1) when R.sub.9 is H then R.sub.8 and R.sub.10 are not both H or
one H and the other halo; and (2) when R.sub.9 is alkyl then
R.sub.2 is not optionally substituted aryl or heteroaryl.
Preferably when R.sub.9 is H then R.sub.8 and R.sub.10 are not both
H or one H and the other halo or alkyl or haloalkyl.
[0563] In one embodiment, R.sub.9 is selected from the group
consisting of H, C.sub.1, N.sub.3;
[0564] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy,
(halo)C.sub.1-3 alkoxy, --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle;
[0565] --XR.sup.c wherein X is S or O and R.sup.c is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy, or
(halo)C.sub.1-3 alkoxy;
[0566] --(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an
C.sub.1-6 alkyl, preferably C.sub.1-3 alkyl;
[0567] --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or --N(R.sup.e)(R.sup.f)
where R.sup.e and R.sup.f are independently H, OH (R.sup.e and
R.sup.f are not both OH), or C.sub.1-3 alkyl; wherein optionally
R.sup.a and R.sup.b together with the N form a 3, 4, 5 or
6-membered heterocycle, and optionally R.sup.e and R.sup.f together
with the nitrogen atom to which they both are linked form a 3, 4, 5
or 6-membered heterocycle; or
[0568] --(C.sub.0-3 alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle. Preferably R.sub.9 is selected from such
groups except R.sub.9 is not H or chloro.
[0569] In another embodiment, R.sub.9 is H; OH; Cl; N.sub.3;
C.sub.1-3 alkyl (preferably methyl; C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl);
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle. Preferably R.sub.9 is
selected from such groups except R.sub.9 is not H or chloro.
[0570] In a preferred embodiment, R.sub.9 is N.sub.3; --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl optionally substituted with 1-7
F; --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b where R.sub.9b is
C.sub.1-3 alkyl.
[0571] In more preferred embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0572] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; N.sub.3; --XR.sub.9a, where X is O or S, and
R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0573] Also preferably in the various embodiments, when R.sub.9 is
H, R.sub.8 and R10 are not H or one H and the other halo, and
R.sub.2 is not H, and preferably R.sub.2 is halo; N.sub.3,
C.sub.1-3 alkyl optionally substituted with OH or halo (preferably
F, e.g., monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X
is S or O and R.sub.2a is C.sub.1-3 alkyl (more preferably
CH.sub.3) optionally substituted with halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl. More preferably
R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH
or CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH,
--NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3,
morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0574] Also preferably, when R.sub.9 is C.sub.1-6 alkyl, halo, or
C.sub.1-6 haloalkyl, R.sub.2 is not H, and preferably R.sub.2 is
halo; N.sub.3, C.sub.1-3 alkyl optionally substituted with OH or
halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
--XR.sub.2a wherein X is S or O and R.sub.2a is C.sub.1-3 alkyl
(more preferably CH.sub.3) optionally substituted with halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); or --N(R.sup.a)(R.sup.b) wherein R.sup.a
and R.sup.b are independently H, OH (R.sup.a and R.sup.b are not
both OH), C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.2-3
hydroxyalkyl. More preferably R.sub.2 is methyl, ethyl, Cl, F,
fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0575] In one embodiment, R.sub.2 is H; halo; N.sub.3; C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O, and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); --CO.sub.2R.sup.d, wherein R.sup.d is
C.sub.1-3 alkyl, preferably methyl or ethyl; or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the nitrogen they both
are linked to may form a 3, 4, 5 or 6-membered heterocycle.
[0576] In a preferred embodiment, R.sub.2 is H; halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl.
[0577] In preferred embodiments, R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3
[0578] In more preferred embodiments, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0579] In one embodiment, compounds of the invention include
compounds of Formula VI or pharmaceutically acceptable salts or
solvates thereof, wherein: [0580] R.sub.1 is methyl or ethyl,
preferably methyl; [0581] R.sub.2 is H; halo; N.sub.3; [0582]
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0583] --XR.sub.2a
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0584] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0585]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0586] R.sub.3 is H; halo; C.sub.1-3 alkyl; or
C.sub.1-3 alkoxy; [0587] R.sub.4 and R.sub.6 are independently H;
halo (preferably F or Cl); N.sub.3; C.sub.1-6 alkyl (preferably
C.sub.1-3, more preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3), C.sub.1-6 hydroxyalkyl
(preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) that is optionally substituted with
--N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and R.sub.2e are
independently H, OH, C.sub.1-3 alkyl (preferably CH.sub.3) or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), wherein
R.sub.2b and R.sub.2c together may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; [0588] R.sub.5 is H or F, preferably H;
[0589] R.sub.7 and R.sub.11 are independently H; halo (preferably F
or Cl, more preferably F); CH.sub.3; or OCH.sub.3; [0590] R.sub.8
and R.sub.10 are independently H; halo (preferably F or Cl, more
preferably Cl); OH; N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); C.sub.1-3 haloalkyl
(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
--XR.sub.9a, where X is O or S, and R.sub.9a is C.sub.1-4 alkyl or
C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl,
i.e., CH.sub.2F, CHF.sub.2, CF.sub.3); --NH(R.sup.a) or
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3
alkyl (preferably methyl or ethyl). and [0591] R.sub.9 is H; OH;
N.sub.3; halo; [0592] C.sub.1-3 alkyl (preferably methyl or ethyl)
or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0593] --(C.sub.0-3
alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or
C.sub.1-3 alkyl optionally substituted with --N(R.sup.e)(R.sup.f)
where R.sup.e and R.sup.f are independently H, OH (R.sup.a and
R.sup.b are not both OH), or C.sub.1-3 alkyl; wherein optionally
R.sup.a and R.sup.b together with the N form a 3, 4, 5 or
6-membered heterocycle, and optionally R.sup.e and R.sup.f together
with the nitrogen atom to which they both are linked form a 3, 4, 5
or 6-membered heterocycle; [0594] --CO.sub.2--R.sub.2f, wherein
R.sub.2f is an optionally substituted C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably methyl or ethyl), the alkyl may be
optionally substituted with OH, halo, C.sub.1-3 alkoxy, amino, and
C.sub.1-3 alkylamino; [0595] --XR.sub.23 wherein X is S or O and
R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with a moiety selected
from the group OH, halo, C.sub.1-3 alkoxy, amino, and C.sub.1-3
alkylamino; or [0596] --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3), C.sub.1-6 haloalkyl,
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3) or C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH),
wherein optionally R.sub.2b and R.sub.2c together with the nitrogen
they both are linked to may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; optionally, R.sub.9 and one of R.sub.8
and R.sub.10 together form a 3, 4, 5 or 6-membered carbocycle or
heterocycle; [0597] exactly one of B and D is N provided that when
B or D is N there is no substituent at the N; and [0598] all of Q,
T, U, and V are C; [0599] provided that when R.sub.9 is H then
R.sub.8 and R.sub.10 are not both H or one H and the other
halo.
[0600] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; N.sub.3; --XR.sub.9a, where X is O or S, and
R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.3) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0601] Also preferably, when R.sub.9 is C.sub.1-6 alkyl, halo, or
C.sub.1-6 haloalkyl, then R.sub.2 is not H and preferably R.sub.2
is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0602] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein: [0603] R.sub.1 is methyl or
ethyl, and preferably methyl; [0604] R.sub.2 is H; halo; N.sub.3;
[0605] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1-4 substituents which are
independently OH or halo (preferably F, e.g., monofluoro, difluoro,
or trifluoro); [0606] --XR.sub.23 wherein X is S or O, and R.sub.2a
is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro-, difluoro-, or trifluoro-substituted); [0607]
--CO.sub.2--R.sub.2f, wherein R.sub.2f is C.sub.1-6 (preferably
C.sub.1-3, more preferably methyl or ethyl); or
--N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and R.sub.2c are
independently H, OH, C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably
C.sub.2-3 hydroxyalkyl, more preferably --CH.sub.2CH2OH), or
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) that is optionally substituted with
--N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and R.sub.2e are
independently H, OH, C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH.sub.2OH), and
wherein optionally R.sub.2b and R.sub.2c together with the nitrogen
they both are linked to may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; [0608] R.sub.3 is H; halo; C.sub.1-3
alkyl; or C.sub.1-3 alkoxy; [0609] R.sub.4 and R.sub.6 are
independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, CH.sub.3, and optionally R.sub.2b
and R.sub.2c together with the nitrogen they both are linked to may
form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,
pyrrolidinyl, and morpholinyl), and wherein R.sub.2b and R.sub.2c
are not both OH; [0610] R.sub.5 is H; [0611] R.sub.7 and R.sub.11
are independently H, halo (preferably F), CH.sub.3, or OCH.sub.3;
[0612] R.sub.8 and R.sub.10 are independently H; halo (preferably F
or Cl, more preferably F); C.sub.1-3 alkyl (preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); --XR.sub.9a, where X is O
or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sup.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl); and [0613] R.sup.9
is selected from the group: [0614] hydrogen; hydroxy; N.sub.3;
[0615] C.sub.1-3 alkyl (preferably methyl or ethyl) or C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); [0616] --OR.sub.9a, wherein R.sub.9a is C.sub.1-3
alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); [0617] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, C.sub.1-3 alkyl,
or C.sub.1-3 halo alkyl; or [0618] --COOR.sub.9b, wherein R.sub.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; [0619] exactly one of B and D is N provided
that when B or D is N there is no substituent at the N; and [0620]
all of Q, T, U, and V are C; [0621] provided that when R.sub.9 is H
at least one of R.sub.8 and R.sub.10 is not H or halo, preferably
at least one of R.sub.8 and R.sub.10 is not H or halo or C.sub.1-3
alkyl.
[0622] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently --XR.sub.9a, where X is O or S,
and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl). More preferably,
when R.sub.9 is H, R.sub.8 or R.sub.10 or both are independently
N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4 alkyl or
C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
Even more preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are C.sub.1-3 alkoxy or C.sub.1-3 halo alkoxy.
[0623] Also preferably in this embodiment, when R.sub.9 is H then
R.sub.8 and R.sub.10 are not both H or one H and the other halo,
and R.sub.2 is not H.
[0624] Also preferably, in this embodiment, when R.sub.9 is
C.sub.1-6 alkyl, halo, or C.sub.1-6 haloalkyl, then R.sub.2 is not
H and preferably R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl
(CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl
(preferably CH.sub.2OH or CH.sub.2CH.sub.2OH), NH.sub.2,
NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2,
N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0625] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0626] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein: [0627] R.sub.1 is methyl or
ethyl, and preferably methyl; [0628] R.sub.2 is H; halo; N.sub.3;
[0629] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1-4 substituents which are OH
or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
[0630] --XR.sub.23 wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted); or [0631]
--N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and R.sub.2c are
independently H, OH, C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or R.sub.2b and R.sub.2c together form
a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,
pyrrolidinyl, and morpholinyl); [0632] R.sub.3 is H; halo;
C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0633] R.sub.4 and R.sub.6
are independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH(R.sub.2b and R.sub.2c are not both
OH), CH.sub.3, or R.sub.2b and R.sub.2c together form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0634] R.sub.5 is H or F, preferably H; [0635]
R.sub.7 and R.sub.11 are independently H, halo (preferably F),
C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-3 alkoxy (preferably
OCH.sub.3), or C.sub.1-3 alkylthiol; Preferably R.sub.7 and
R.sub.11 are independently H, halo or methoxy; [0636] R.sub.8 and
R.sub.10 are independently H; halo (preferably F or Cl); C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol; and [0637] R.sub.9 is selected
from the group: [0638] hydrogen; hydroxy; Cl; N.sub.3; [0639]
C.sub.1-3 alkyl (preferably methyl or ethyl) or C.sub.1-3 haloalkyl
(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
[0640] --OR.sub.9a, wherein R.sub.12 is C.sub.1-3 alkyl (i.e.,
methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); [0641] --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently C.sub.1-3 alkyl; or [0642]
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl); and optionally R.sub.9 and one of R.sub.8 and
R.sub.10 together form a 3, 4, 5, or 6-membered heterocycle; [0643]
exactly one of B and D is N provided that when B or D is N there is
no substituent at the N; and [0644] all of Q, T, U, and V are C;
[0645] provided that when R.sub.9 is H at least one of R.sub.8 and
R.sub.10 is not H or halo, preferably at least one of R.sub.8 and
R.sub.10 is not H or halo or C.sub.1-3 alkyl.
[0646] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol, each being optionally
substituted with 1-4 F. Even more preferably when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are methoxy or ethoxy. Also preferably
R.sub.2 is not H.
[0647] Also preferably, when R.sub.9 is C.sub.1-3 alkyl, halo, or
C.sub.1-3 haloalkyl, then R.sub.2 is not H, preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0648] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0649] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein: [0650] R.sub.1 is methyl or
ethyl, preferably methyl; [0651] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4
and R.sub.6 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; R.sub.5 is H; R.sub.7 and R.sub.11 are independently H, F, or
OCH.sub.3; R.sub.8 and R.sub.10 are independently H, F, Cl, or
OCH.sub.3; and [0652] R.sub.9 is selected from the group: [0653] H;
OH; N.sub.3; [0654] C.sub.1-3 alkyl (preferably methyl or ethyl) or
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); [0655] --OR.sub.9a, wherein R.sub.9a is C.sub.1-3
alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); [0656] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently C.sub.1-3 alkyl; or
[0657] --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl
(preferably methyl or ethyl), and optionally R.sub.8 and R.sub.9
together form a 3, 4, 5, or 6-membered heterocycle; [0658] exactly
one of B and D is N provided that when B or D is N there is no
substituent at the N; and [0659] all of Q, T, U, and V are C;
[0660] provided that when R.sub.9 is H, at least one of R.sub.8 and
R.sub.10 is OCH.sub.3, and when R.sub.9 is C.sub.1-3 alkyl or
C.sub.1-3 haloalkyl or Cl then R.sub.2 is Cl or methyl or
ethyl.
[0661] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol, each being optionally
substituted with 1-4 F. Even more preferably when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are methoxy or ethoxy. Also preferably
R.sub.2 is not H.
[0662] Also preferably, when R.sub.9 is C.sub.1-3 alkyl, halo, or
C.sub.1-3 haloalkyl, then R.sub.2 is not H, preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0663] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0664] In another preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
[0665] R.sub.2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), CH.sub.2OH, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.2OH, OCH.sub.3, or SCH.sub.3;
R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4 and R.sub.6
are independently H, CH.sub.3, NH.sub.2, F, or Cl; R.sub.5 is H;
R.sub.7 and R.sub.11 are independently H, F, or OCH.sub.3; R.sub.8
and R.sub.10 are independently H, F, Cl, or OCH.sub.3; and
R.sub.9 is selected from the group:
[0666] --OR.sub.12, wherein R.sub.12 is selected from the group of
methyl, ethyl, fluoromethyl (e.g., CH.sub.2F, CHF.sub.2, CF.sub.3),
and fluoroethyl;
[0667] --NHCH.sub.3;
[0668] --N(CH.sub.3).sub.2;
[0669] N.sub.3; and
[0670] --COOR.sub.13, wherein R.sub.13 is methyl or ethyl;
exactly one of B and D is N provided that when B or D is N there is
no substituent at the N; and
all of Q, T, U, and V are C.
[0671] In a more preferred embodiment, compounds of the invention
include compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or
--CH.sub.2F;
R.sub.3 is H, --CH.sub.3, --OCH.sub.3, or Cl;
R.sub.4 is H, CH.sub.3, or NH.sub.2;
R.sub.5 is H;
R.sub.6 is H, or CH.sub.3;
R.sub.7 and R.sub.11 are independently H, or F;
R.sub.8 and R.sub.10 are independently H, or F or OCH.sub.3;
and
R.sub.9 is --OCH.sub.3 or --OC.sub.2H.sub.5, --N(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3;
exactly one of B and D is N provided that when B or D is N there is
no substituent at the N; and
all of Q, T, U, and V are C.
[0672] In a more preferred embodiment, the present invention
provides compounds of Formula VI or pharmaceutically acceptable
salts or solvates thereof, wherein R.sub.1 is CH.sub.3; R.sub.2 is
Cl, methyl, or CH.sub.2F; R.sub.3 is H, CH.sub.3, F, or Cl;
R.sub.4, R.sub.5 and R.sub.6 are H; R.sub.7, R.sub.8, R.sub.10 and
R.sub.11 are independently H or F; and R.sub.9 is --OCH.sub.3 or
--N(CH.sub.3).sub.2; exactly one of B and D is N provided that when
B or D is N there is no substituent at the N; and all of Q, T, U,
and V are C.
[0673] Specifically, one group of the compounds of Formula VI are
those represented by Formula VIa: ##STR29## or pharmaceutically
acceptable salts or solvates thereof, wherein: [0674] R.sub.1 is
methyl or ethyl, preferably methyl; [0675] R.sub.5 is H or F,
preferably H; [0676] R.sub.2-R.sub.4, R.sub.6-R.sub.11 are
independently H, halo, N.sub.3, OH, thiol, nitro, CN, NH.sub.2,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, halo-C.sub.1-6 alkyl, C.sub.2-6
alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6 alkyl,
C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, --C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-,
C.sub.1-6 acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, 3, 4, 5, or 6-membered
carbocycle, heterocycle, aryl, or heteroaryl, wherein R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl, or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked to form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl); wherein any of the
groups is optionally substituted with 1-3 substituents wherein each
substituent is independently halo, N.sub.3, OH, thiol, nitro, CN,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
alkoxy, C.sub.1-6 alkylthiol, C.sub.2-6 alkenyl-O--, C.sub.2-6
alkynyl-O--, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6
alkyl, C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
--C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-,
wherein R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or C.sub.1-6
alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11
groups together form a 3, 4, 5 or 6-membered carbocycle or
heterocycle; and [0677] 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.sub.9
is H then R.sub.8 and R.sub.10 are not both H, or one H and the
other alkyl. Preferably when R.sub.9 is H then at least one of
R.sub.8 and R.sub.10 is not H or alkyl. More preferably, when
R.sub.9 is H then at least one of R.sub.8 and R.sub.10 is not H,
alkyl, or halo.
[0678] In one embodiment, R.sub.9 is selected from the group
consisting of H, OH, C.sub.1, N.sub.3;
[0679] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy,
(halo)C.sub.1-3 alkoxy, --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked to form a 3, 4, 5 or 6-membered heterocycle;
[0680] --XR.sup.c wherein X is S or O and R.sup.c is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy, or
(halo)C.sub.1-3 alkoxy;
[0681] --(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably methyl
or ethyl) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they both are linked form
a 3, 4, 5 or 6-membered heterocycle;
[0682] --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or C.sub.1-3 alkyl
substituted with --N(R.sup.e)(R.sup.f) where R.sup.e and R.sup.f
are independently H, OH (R.sup.e and R.sup.f are not both OH), or
C.sub.1-3 alkyl; wherein optionally R.sup.a and R.sup.b together
with the N form a 3, 4, 5 or 6-membered heterocycle, and optionally
R.sup.e and R.sup.f together with the nitrogen atom to which they
both are linked form a 3, 4, 5 or 6-membered heterocycle; or
[0683] --(C.sub.0-3 alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; preferably R.sub.9 is selected from the
group outlined above except R.sub.9 is not H and
C.sub.1-6alkyl.
[0684] In another embodiment, R.sub.9 is H; OH; Cl; N.sub.3;
C.sub.1-3 alkyl (preferably methyl; C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a); --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl);
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle; preferably R.sub.9 is
selected from the group outlined above except R.sub.9 is not H or
C.sub.1-3alkyl.
[0685] In a preferred embodiment, R.sub.9 is N.sub.3, --OR.sub.9a
wherein R.sub.9a is C.sub.1-3 alkyl optionally substituted with 1-7
F, --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl, --COOR.sub.9b where R.sub.9b is
C.sub.1-3 alkyl.
[0686] In a more preferred embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0687] In the various embodiments of the compounds according to
Formula VIa preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or
both are independently OH; Cl; N.sub.3; --XR.sub.9a, where X is O
or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl; --N(R.sup.a)(R.sup.b) where R.sup.a
and R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
Even more preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are C.sub.1-3 alkoxy or C.sub.1-3 haloalkoxy.
[0688] Also preferably in the various embodiments, when R.sub.9 is
H then R.sub.2 is not H, and preferably R.sub.2 is halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl. More preferably
R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH
or CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH,
--NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3,
morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0689] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H, and preferably is methyl,
ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3),
C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0690] In one embodiment, R.sub.2 is H; halo; N.sub.3; C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O, and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); --CO.sub.2R.sup.d, wherein R.sup.d is
C.sub.1-3 alkyl, preferably methyl or ethyl; or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle.
[0691] In a preferred embodiment, R.sub.2 is H; halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl.
[0692] In preferred embodiments, R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0693] In more preferred embodiments, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0694] In all embodiments of the compound of Formula VIa, it is
preferred that one or two of Q, T, U and V are N. For example Q and
V are N and T and U are C.
[0695] In one embodiment, compounds of the invention include
compounds of Formula VIa or pharmaceutically acceptable salts or
solvates thereof, wherein: [0696] R.sub.1 is methyl or ethyl,
preferably methyl; [0697] R.sub.2 is H; halo; N.sub.3; [0698]
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0699] --XR.sub.2a
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0700] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0701]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl); [0702] R.sub.3 is H;
halo; C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0703] R.sub.4 and
R.sub.6 are independently H; halo (preferably F or Cl); N.sub.3;
C.sub.1-6 alkyl (preferably C.sub.1-3, more preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); or --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, OH, C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3) or C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH),
wherein R.sub.2b and R.sub.2c together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R.sub.2b
and R.sub.2c are not both OH, R.sub.2d and R.sub.2e are not both
OH; [0704] R.sub.5 is H or F, preferably H; [0705] R.sub.7 and
R.sub.11 are independently H; halo (preferably F or Cl, more
preferably F); CH.sub.3; or OCH.sub.3; [0706] R.sub.8 and R.sub.10
are independently H; halo (preferably F or Cl, more preferably Cl);
OH; N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3); C.sub.1-3
alkoxy (preferably OCH.sub.3); C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --XR.sub.9a,
where X is O or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); --NH(R.sup.a) or
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3
alkyl (preferably methyl or ethyl); [0707] R.sub.9 is selected from
the group consisting of H, OH, C.sub.1, N.sub.3; [0708] C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy,
(halo)C.sub.1-3 alkoxy, --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle; [0709] --XR.sup.c
wherein X is S or O and R.sup.c is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with 1, 2 or 3 substituents, each substituent being independently
OH, halo, C.sub.1-3 alkoxy, or (halo)C.sub.1-3 alkoxy; [0710]
--(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably methyl or ethyl)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy (e.g.,
fluoroalkoxy), --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and R.sup.b
together with the nitrogen atom to which they both are linked form
a 3, 4, 5 or 6-membered heterocycle; [0711] --N(R.sup.a)(R.sup.b)
where R.sup.a and R.sup.b are independently H, OH (R.sup.a and
R.sup.b are not both OH), C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl,
or C.sub.1-3 alkyl substituted with --N(R.sup.e)(R.sup.f) where
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), or C.sub.1-3 alkyl; wherein optionally R.sup.a
and R.sup.b together with the N form a 3, 4, 5 or 6-membered
heterocycle, and optionally R.sup.e and R.sup.f together with the
nitrogen atom to which they both are linked form a 3, 4, 5 or
6-membered heterocycle; or [0712] --(C.sub.0-3
alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H or C.sub.1-3 alkyl; and optionally R.sub.9 and one
of R.sub.8 and R.sub.10 together form a 3, 4, 5, or 6-membered
heterocycle; provided that when R.sub.9 is H, at least one of
R.sub.8 and R.sub.10 is not hydrogen or alkyl; and [0713] Q, T, U
and V are independently C or N, provided that at least one of Q, T,
U and V is N, wherein when Q, T, U or V is N, then there is no
substituent at the N. In some specific embodiments, one or two of
Q, T, U and V are N.
[0714] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; Cl; N.sub.3; --XR.sub.9a, where X is O or S,
and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3
haloalkoxy.
[0715] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl
(CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl
(preferably CH.sub.2OH or CH.sub.2CH.sub.2OH), NH.sub.2,
NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2,
N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0716] In another preferred embodiment, compounds of the invention
include compounds of Formula VIa or pharmaceutically acceptable
salts or solvates thereof, wherein: [0717] R.sub.1 is methyl or
ethyl, and preferably methyl; [0718] R.sub.2 is H; halo; N.sub.3;
[0719] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0720] --XR.sub.23
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0721] --CO.sub.2--R.sub.2f, wherein
R.sub.2f is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably methyl or ethyl); or [0722] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, OH, C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3), or C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH),
and wherein optionally R.sub.2b and R.sub.2c together with the N
they are both linked to may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; [0723] R.sub.3 is H; halo; C.sub.1-3
alkyl; or C.sub.1-3 alkoxy; [0724] R.sub.4 and R.sub.6 are
independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, CH.sub.3, or ethyl, and
optionally R.sub.2b and R.sub.2c together with the N they are both
linked to may form a 3, 4, 5 or 6-membered heterocycle (e.g.,
piperidinyl, pyrrolidinyl, and morpholinyl), and wherein R.sub.2b
and R.sub.2c are not both OH; [0725] R.sub.5 is H; [0726] R.sub.7
and R.sub.11 are independently H, halo (preferably F), CH.sub.3, or
OCH.sub.3; [0727] R.sub.8 and R.sub.10 are independently H; halo
(preferably F or Cl, more preferably F); C.sub.1-3 alkyl
(preferably CH.sub.3); C.sub.1-3 alkoxy (preferably OCH.sub.3); and
[0728] R.sup.9 is selected from the group: [0729] hydrogen;
hydroxy; Cl; N.sub.3; [0730] C.sub.1-3 alkyl (preferably methyl or
ethyl) or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0731] --OR.sub.9a, wherein
R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3); --N(Ra)(Rb),
wherein Ra and Rb are independently H, C1-3 alkyl, or
haloC1-3alkyl; or [0732] --COOR.sub.9b, wherein R.sub.9b is
C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered carbocycle or heterocycle; [0733] Q, T, U and V are
independently C or N, wherein at least one of, T, U and V are N,
wherein when Q, T, U or V is nitrogen, then the there is no
substituent at the N; with the proviso that when R.sub.9 is H then
R.sub.8 and R.sub.9 are not both H or one H and the other alkyl.
Preferably when R.sub.9 is H then at least one of R.sub.8 or
R.sub.10 is not H or alkyl. More preferably when R.sub.9 is H then
at least one of R.sub.8 or R.sub.10 is not H, alkyl, or halo.
[0734] In some specific embodiments, one or two of Q, T, U and V
are N.
[0735] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently OH; Cl; N.sub.3; C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --XR.sub.9a, where X is O or S, and R.sub.9, is
C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g., fluoroalkyl,
preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b
are independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein
R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl). More
preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0736] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H and preferably R.sub.2 is
halo; C.sub.1-3 alkyl optionally substituted with OH or halo
(preferably F, e.g., monofluoro, difluoro, or trifluoro);
--XR.sub.2a wherein X is S or O and R.sub.2a is C.sub.1-3 alkyl
(preferably C.sub.1-3 alkyl, more preferably CH.sub.3) optionally
substituted with halo (preferably F, e.g., monofluoro-, difluoro-,
or trifluoro-substituted); or --N(R.sup.a)(R.sup.b) wherein R.sup.a
and R.sup.b are independently H, OH (R.sup.a and R.sup.b are not
both OH), C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.2-3
hydroxyalkyl. More preferably R.sub.2 is methyl, ethyl, Cl, F,
fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0737] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0738] In another preferred embodiment, compounds of the invention
include compounds of Formula VIa or pharmaceutically acceptable
salts or solvates thereof, wherein: [0739] R.sub.1 is methyl or
ethyl, preferably methyl; [0740] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4
and R.sub.6 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; R.sub.5 is H; R.sub.7 and R.sub.11 are independently H, F, or
OCH.sub.3; R.sub.8 and R.sub.10 are independently H, F, Cl, or
OCH.sub.3; and [0741] R.sub.9 is selected from the group: [0742]
hydrogen; hydroxy; Cl; [0743] C.sub.1-3 alkyl (preferably methyl or
ethyl) or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0744] --OR.sub.9a, wherein
R.sub.9a is C.sub.1-3 alkyl (i.e., methyl, ethyl, propyl,
isopropyl) or C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably
fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3); [0745]
C.sub.1-3 alkyl substituted amino (preferably --NHCH.sub.3 or
--N(CH.sub.3).sub.2); [0746] --N.sub.3; or [0747] --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl),
and optionally R.sub.8 and R.sub.9 together form a 3, 4, 5, or
6-membered carbocycle or heterocycle; and [0748] Q, T, U and V are
independently C or N, and at least one of Q, T, U and V is N,
wherein when Q, T, U or V is N, then there is no substituent at the
N. In some specific embodiments, one or two of Q, T, U and V are
nitrogen.
[0749] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently OH; Cl; N.sub.3; C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); --XR.sub.9a, where X is O or S, and R.sub.9a is
C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g., fluoroalkyl,
preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2, CF.sub.3);
--NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b
are independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein
R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl). More
preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0750] Also preferably, when R.sub.9 is C.sub.1-6 alkyl or
C.sub.1-6 haloalkyl, R.sub.2 is not H and preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0751] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0752] In another preferred embodiment, compounds of the invention
include compounds of Formula VIa or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is methyl;
[0753] R.sub.2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), CH.sub.2OH, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.2OH, OCH.sub.3, or SCH.sub.3;
R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4 and R.sub.6
are independently H, CH.sub.3, NH.sub.2, F, or Cl; R.sub.5 is H;
R.sub.7 and R.sub.11 are independently H, F, or OCH.sub.3; R.sub.8
and R.sub.10 are independently H, F, Cl, or OCH.sub.3; and
R.sub.9 is selected from the group:
[0754] --OR.sub.9a, wherein R.sub.9a is selected from the group of
methyl, ethyl, fluoromethyl (e.g., CH.sub.2F, CHF.sub.2, CF.sub.3),
and fluoroethyl;
[0755] --NHCH.sub.3;
[0756] --N(CH.sub.3).sub.2;
[0757] --N.sub.3; and
[0758] --COOR.sub.9b, wherein R.sub.9b is H or methyl or ethyl; and
[0759] Q, T, U and V are independently C or N, and at least one of
Q, T, U and V is N, wherein when Q, T, U or V is N, then there is
no substituent at the N. In some specific embodiments, one or two
of Q, T, U and V are nitrogen.
[0760] In a more preferred embodiment, compounds of the invention
include compounds of Formula VIa or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or
--CH.sub.2F;
R.sub.3 is H, --CH.sub.3, --OCH.sub.3, or Cl;
R.sub.4 is H, CH.sub.3, or NH.sub.2;
R.sub.5 is H;
R.sub.6 is H, or CH.sub.3;
R.sub.7 and R.sub.11 are independently H, or F;
R.sub.8 and R.sub.10 are independently H, or F or OCH.sub.3;
R.sub.9 is --OCH.sub.3 or --OC.sub.2H.sub.5, --N(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3; and
Q, T, U and V are independently C or N, and at least one of Q, T, U
and V is N, wherein when Q, T, U or V is N, then there is no
substituent at the N. In some specific embodiments, one or two of
Q, T, U and V are nitrogen.
[0761] In a more preferred embodiment, the present invention
provides compounds of Formula VIa or pharmaceutically acceptable
salts or solvates thereof, wherein R.sub.1 is CH.sub.3; R.sub.2 is
Cl, methyl, or CH.sub.2F; R.sub.3 is H, CH.sub.3, F, or Cl;
R.sub.4, R.sub.5 and R.sub.6 are H; R.sub.7, R.sub.5, R.sub.10 and
R.sub.11 are independently H or F; R.sub.9 is --OCH.sub.3 or
--N(CH.sub.3).sub.2; and Q, T, U and V are independently C or N,
and at least one of Q, T, U and V is N, wherein when Q, T, U or V
is N, then there is no substituent at the N. In some specific
embodiments, one or two of Q, T, U and V are nitrogen.
[0762] Other compounds of the invention include those of Formula
VIb: ##STR30## or pharmaceutically acceptable salts, or solvates
thereof, wherein: [0763] R.sub.1 is methyl or ethyl, preferably
methyl; [0764] R.sub.5 is H or F, preferably H; and [0765]
R.sub.2-R.sub.4, R.sub.6-R.sub.11 are independently H, halo,
N.sub.3, OH, thiol, nitro, CN, NH.sub.2, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
halo-C.sub.1-6 alkyl, C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--,
hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl,
C.sub.1-6 acyl, C.sub.1-6 acyloxy, --C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, C.sub.1-6
alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6 acylamido,
--N(R.sup.a)(R.sup.b), --C.sub.1-6 alkyl-C(O)N(R.sup.a)(R.sup.b),
[0766] --C(O)N(R.sup.a)(R.sup.b), N(R.sup.a)(R.sup.b)--C.sub.1-6
alkyl-, 3, 4, 5, or 6-membered carbocycle, heterocycle, aryl, or
heteroaryl, wherein R.sup.a and R.sup.b are independently H, OH
(R.sup.a and R.sup.b are not both OH), C.sub.2-6 hydroxyalkyl, or
C.sub.1-6 alkyl, or R.sup.a and R.sup.b 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 any of the groups is optionally substituted with 1-3
substituents wherein each substituent is independently halo,
N.sub.3, OH, thiol, nitro, CN, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthiol,
C.sub.2-6 alkenyl-O--, C.sub.2-6 alkynyl-O--, hydroxy-C.sub.1-6
alkyl, C.sub.1-6 alkoxy-C.sub.1-6 alkyl, C.sub.1-6 acyl, C.sub.1-6
acyloxy, C.sub.1-6 alkyl-C(O)O--C.sub.1-6 alkyl-, C.sub.1-6
acylamido, --N(R.sup.a)(R.sup.b), --C.sub.1-6
alkyl-C(O)N(R.sup.a)(R.sup.b), --C(O)N(R.sup.a)(R.sup.b),
N(R.sup.a)(R.sup.b)--C.sub.1-6 alkyl-, wherein R.sup.a and R.sup.b
are independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-6 hydroxyalkyl, or C.sub.1-6 alkyl or R.sup.a and R.sup.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.sub.7-R.sub.11 groups together form a 3, 4, 5 or
6-membered carbocycle or heterocycle; [0767] provided that R.sub.9
is not --O(C.sub.1-6 alkyl)C(O)O(C.sub.1-6 alkyl), and when R.sub.9
is H then R.sub.8 and R.sub.10 are not both H or one H and the
other halo. Preferably when R.sub.9 is H then R.sub.8 and R.sub.10
are not both H or one H and the other halo or alkyl or
haloalkyl.
[0768] In one embodiment, R.sub.9 is selected from the group
consisting of H, C.sub.1, N.sub.3;
[0769] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy,
(halo)C.sub.1-3 alkoxy, --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H, OH (R.sup.a and R.sup.b are not both
OH), C.sub.2-4 hydroxyalkyl, or C.sub.1-3 alkyl or R.sup.a and
R.sup.b together with the nitrogen atom to which they are both
linked form a 3, 4, 5 or 6-membered heterocycle;
[0770] --XR.sup.c wherein X is S or O and R.sup.c is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with 1, 2 or 3 substituents, each
substituent being independently OH, halo, C.sub.1-3 alkoxy, or
(halo)C.sub.1-3 alkoxy;
[0771] --(C.sub.0-3 alkyl)CO.sub.2R.sup.d, wherein R.sup.d is an
C.sub.1-6 alkyl, preferably C.sub.1-3 alkyl;
[0772] --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, OH (R.sup.a and R.sup.b are not both OH),
C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or --N(R.sup.e)(R.sup.f)
where R.sup.e and R.sup.f are independently H, OH (R.sup.e and
R.sup.f are not both OH), or C.sub.1-3 alkyl; wherein optionally
R.sup.a and R.sup.b together with the N form a 3, 4, 5 or
6-membered heterocycle, and optionally R.sup.e and R.sup.f together
with the nitrogen atom to which they both are linked form a 3, 4, 5
or 6-membered heterocycle; or
[0773] --(C.sub.0-3 alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently H or C.sub.1-3 alkyl; and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle. Preferably R.sub.9 is selected from such
groups except R.sub.9 is not H or chloro.
[0774] In another embodiment, R.sub.9 is H; OH; Cl; N.sub.3;
C.sub.1-3 alkyl (preferably methyl; C.sub.1-3 haloalkyl (preferably
monofluoromethyl, difluoromethyl, trifluoromethyl); --OR.sub.9a,
wherein R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl);
and optionally R.sub.9 and one of R.sub.8 and R.sub.10 together
form a 3, 4, 5, or 6-membered heterocycle. Preferably R.sub.9 is
selected from such groups except R.sub.9 is not H or chloro.
[0775] In a preferred embodiment, R.sub.9 is N.sub.3; --OR.sub.9a,
wherein R.sub.9a is C.sub.1-3 alkyl optionally substituted with 1-7
F; --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b where R.sub.9b is
C.sub.1-3 alkyl.
[0776] In more preferred embodiment, R.sub.9 is --OCH.sub.3,
--OC.sub.2H.sub.5, --N(CH.sub.3).sub.2, --CO.sub.2CH.sub.3,
--OCHF.sub.2, or N.sub.3.
[0777] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; N.sub.3; --XR.sub.9a, where X is O or S, and
R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0778] Also preferably in the various embodiments, when R.sub.9 is
H, R.sub.8 and R.sub.10 are not H or one H and the other halo, and
R.sub.2 is not H, and preferably R.sub.2 is halo; N.sub.3,
C.sub.1-3 alkyl optionally substituted with OH or halo (preferably
F, e.g., monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X
is S or O and R.sub.2a is C.sub.1-3 alkyl (more preferably
CH.sub.3) optionally substituted with halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl. More preferably
R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH
or CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH,
--NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3,
morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0779] Also preferably, when R.sub.9 is C.sub.1-6 alkyl, halo, or
C.sub.1-6 haloalkyl, R.sub.2 is not H, and preferably R.sub.2 is
halo; N.sub.3, C.sub.1-3 alkyl optionally substituted with OH or
halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
--XR.sub.2a wherein X is S or O and R.sub.2a is C.sub.1-3 alkyl
(more preferably CH.sub.3) optionally substituted with halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); or --N(R.sup.a)(R.sup.b) wherein R.sup.a
and R.sup.b are independently H, OH (R.sup.a and R.sup.b are not
both OH), C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.2-3
hydroxyalkyl. More preferably R.sub.2 is methyl, ethyl, Cl, F,
fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0780] In one embodiment, R.sub.2 is H; halo; N.sub.3; C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O, and R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) optionally substituted with OH or halo
(preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); --CO.sub.2R.sup.d, wherein R.sup.d is
C.sub.1-3 alkyl, preferably methyl or ethyl; or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together with the nitrogen they both
are linked to may form a 3, 4, 5 or 6-membered heterocycle.
[0781] In a preferred embodiment, R.sub.2 is H; halo; C.sub.1-3
alkyl optionally substituted with OH or halo (preferably F, e.g.,
monofluoro, difluoro, or trifluoro); --XR.sub.2a wherein X is S or
O and R.sub.2a is C.sub.1-3 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with halo (preferably
F, e.g., monofluoro-, difluoro-, or trifluoro-substituted); or
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.2-3 hydroxyalkyl.
[0782] In preferred embodiments, R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3.
[0783] In more preferred embodiments, R.sub.2 is H, methyl, Cl,
--CH.sub.2OH, --NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.2OH,
--OCH.sub.3, --SCH.sub.3, or --CH.sub.2F.
[0784] In one embodiment, compounds of the invention include
compounds of Formula VIb or pharmaceutically acceptable salts or
solvates thereof, wherein: [0785] R.sub.1 is methyl or ethyl,
preferably methyl; [0786] R.sub.2 is H; halo; N.sub.3; [0787]
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro, difluoro, or trifluoro); [0788] --XR.sub.2a
wherein X is S or O, and R.sub.2a is C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) optionally substituted
with OH or halo (preferably F, e.g., monofluoro-, difluoro-, or
trifluoro-substituted); [0789] --CO.sub.2R.sup.d, wherein R.sup.d
is C.sub.1-3 alkyl, preferably methyl or ethyl; or [0790]
--N(R.sup.a)(R.sup.b) wherein R.sup.a and R.sup.b are independently
H, OH (R.sup.a and R.sup.b are not both OH), C.sub.1-3 alkyl
(preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3
hydroxyalkyl, more preferably --CH.sub.2CH.sub.2OH), or C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3) that
is optionally substituted with --N(R.sup.e)(R.sup.f) wherein
R.sup.e and R.sup.f are independently H, OH (R.sup.e and R.sup.f
are not both OH), C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), and wherein
optionally R.sup.a and R.sup.b together may form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0791] R.sub.3 is H; halo; C.sub.1-3 alkyl; or
C.sub.1-3 alkoxy; [0792] R.sub.4 and R.sub.6 are independently H;
halo (preferably F or Cl); N.sub.3; C.sub.1-6 alkyl (preferably
C.sub.1-3, more preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3), C.sub.1-6 hydroxyalkyl
(preferably C.sub.2-3 hydroxyalkyl, more preferably
--CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3) that is optionally substituted with
--N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and R.sub.2e are
independently H, OH, C.sub.1-3 alkyl (preferably CH.sub.3) or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH), wherein
R.sub.2b and R.sub.2c together may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; [0793] R.sub.5 is H or F, preferably H;
[0794] R.sub.7 and R.sub.11 are independently H; halo (preferably F
or Cl, more preferably F); CH.sub.3; or OCH.sub.3; [0795] R.sub.8
and R.sub.10 are independently H; halo (preferably F or Cl, more
preferably Cl); OH; N.sub.3; C.sub.1-3 alkyl (preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); C.sub.1-3 haloalkyl
(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
--XR.sub.9a, where X is O or S, and R.sub.9a is C.sub.1-4 alkyl or
C.sub.1-3 haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl,
i.e., CH.sub.2F, CHF.sub.2, CF.sub.3); --NH(R.sup.a) or
--N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are independently
C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sup.9b is C.sub.1-3
alkyl (preferably methyl or ethyl). and [0796] R.sub.9 is H; OH;
N.sub.3; halo; [0797] C.sub.1-3 alkyl (preferably methyl or ethyl)
or C.sub.1-3 haloalkyl (preferably monofluoromethyl,
difluoromethyl, trifluoromethyl); [0798] --(C.sub.0-3
alkyl)C(O)N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently H, C.sub.2-4 hydroxyalkyl, C.sub.1-3 alkyl, or
C.sub.1-3 alkyl optionally substituted with --N(R.sup.e)(R.sup.f)
where R.sup.e and R.sup.f are independently H, OH (R.sup.a and
R.sup.b are not both OH), or C.sub.1-3 alkyl; wherein optionally
R.sup.a and R.sup.b together with the N form a 3, 4, 5 or
6-membered heterocycle, and optionally R.sup.e and R.sup.f together
with the nitrogen atom to which they both are linked form a 3, 4, 5
or 6-membered heterocycle; [0799] --CO.sub.2--R.sub.2f, wherein
R.sub.2f is an optionally substituted C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably methyl or ethyl), the alkyl may be
optionally substituted with OH, halo, C.sub.1-3 alkoxy, amino, and
C.sub.1-3 alkylamino; [0800] --XR.sub.2a wherein X is S or O and
R.sub.2a is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more
preferably CH.sub.3) optionally substituted with a moiety selected
from the group OH, halo, C.sub.1-3 alkoxy, amino, and C.sub.1-3
alkylamino; or [0801] --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3), C.sub.1-6 haloalkyl,
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or C.sub.1-6 alkyl (preferably
C.sub.1-3 alkyl, more preferably CH.sub.3) that is optionally
substituted with --N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and
R.sub.2e are independently H, OH, C.sub.1-3 alkyl (preferably
CH.sub.3) or C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH2OH),
wherein optionally R.sub.2b and R.sub.2c together with the nitrogen
they both are linked to may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; optionally, R.sub.9 and one of R.sub.8
and R.sub.10 together form a 3, 4, 5 or 6-membered carbocycle or
heterocycle; [0802] provided that when R.sub.9 is H then R.sub.8
and R.sub.10 are not both H or one H and the other halo.
[0803] Preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are independently OH; N.sub.3; --XR.sub.9a, where X is O or S, and
R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --NH(R.sup.a) or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
More preferably, when R.sub.9 is H, R.sub.8 or R.sub.10 or both are
independently N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4
alkyl or C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where
R.sup.a and R.sup.b are independently C.sub.1-3 alkyl; or
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl). Even more preferably when R.sub.9 is H, R.sub.8
or R.sub.10 or both are C.sub.1-3 alkoxy or C.sub.1-3 halo
alkoxy.
[0804] Also preferably, when R.sub.9 is C.sub.1-6 alkyl, halo, or
C.sub.1-6 haloalkyl, then R.sub.2 is not H and preferably R.sub.2
is methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0805] In another preferred embodiment, compounds of the invention
include compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein: [0806] R.sub.1 is methyl or
ethyl, and preferably methyl; [0807] R.sub.2 is H; halo; N.sub.3;
[0808] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1-4 substituents which are
independently OH or halo (preferably F, e.g., monofluoro, difluoro,
or trifluoro); [0809] --XR.sub.23 wherein X is S or O, and R.sub.2a
is C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with OH or halo (preferably F,
e.g., monofluoro-, difluoro-, or trifluoro-substituted); [0810]
--CO.sub.2--R.sub.2f, wherein R.sub.2f is C.sub.1-6 (preferably
C.sub.1-3, more preferably methyl or ethyl); or [0811]
--N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and R.sub.2c are
independently H, OH, C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl,
more preferably CH.sub.3), C.sub.1-6 hydroxyalkyl (preferably
C.sub.2-3 hydroxyalkyl, more preferably --CH.sub.2CH2OH), or
C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) that is optionally substituted with
--N(R.sub.2d)(R.sub.2e) wherein R.sub.2d and R.sub.2e are
independently H, OH, C.sub.1-3 alkyl (preferably CH.sub.3), or
C.sub.2-3 hydroxyalkyl (preferably --CH.sub.2CH.sub.2OH), and
wherein optionally R.sub.2b and R.sub.2c together with the nitrogen
they both are linked to may form a 3, 4, 5 or 6-membered
heterocycle (e.g., piperidinyl, pyrrolidinyl, and morpholinyl), and
wherein R.sub.2b and R.sub.2c are not both OH, R.sub.2d and
R.sub.2e are not both OH; [0812] R.sub.3 is H; halo; C.sub.1-3
alkyl; or C.sub.1-3 alkoxy; [0813] R.sub.4 and R.sub.6 are
independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH, CH.sub.3, and optionally R.sub.2b
and R.sub.2c together with the nitrogen they both are linked to may
form a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,
pyrrolidinyl, and morpholinyl), and wherein R.sub.2b and R.sub.2c
are not both OH; [0814] R.sub.5 is H; [0815] R.sub.7 and R.sub.11
are independently H, halo (preferably F), CH.sub.3, or OCH.sub.3;
[0816] R.sub.8 and R.sub.10 are independently H; halo (preferably F
or Cl, more preferably F); C.sub.1-3 alkyl (preferably CH.sub.3);
C.sub.1-3 alkoxy (preferably OCH.sub.3); --XR.sub.9a, where X is O
or S, and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl); and [0817] R.sub.9
is selected from the group: [0818] hydrogen; hydroxy; N.sub.3;
[0819] C.sub.1-3 alkyl (preferably methyl or ethyl) or C.sub.1-3
haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); [0820] --OR.sub.9a, wherein R.sub.9a is C.sub.1-3
alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); [0821] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently H, C.sub.1-3 alkyl,
or C.sub.1-3 halo alkyl; or [0822] --COOR.sub.9b, wherein R.sub.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl); and optionally
R.sub.9 and one of R.sub.8 and R.sub.10 together form a 3, 4, 5, or
6-membered heterocycle; [0823] provided that when R.sub.9 is H at
least one of R.sub.8 and R.sub.10 is not H or halo, preferably at
least one of R.sub.8 and R.sub.10 is not H or halo or C.sub.1-3
alkyl.
[0824] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently --XR.sub.9a, where X is O or S,
and R.sub.9a is C.sub.1-4 alkyl or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); --N(R.sup.a)(R.sup.b) where R.sup.a and R.sup.b are
independently C.sub.1-3 alkyl; or --COOR.sub.9b, wherein R.sub.9b
is C.sub.1-3 alkyl (preferably methyl or ethyl). More preferably,
when R.sub.9 is H, R.sub.8 or R.sub.10 or both are independently
N.sub.3, --OR.sub.9a, wherein R.sub.9a is C.sub.1-4 alkyl or
C.sub.1-3 haloalkyl, or --N(R.sup.a)(R.sup.b) where R.sup.a and
R.sup.b are independently C.sub.1-3 alkyl; or --COOR.sub.9b,
wherein R.sub.9b is C.sub.1-3 alkyl (preferably methyl or ethyl).
Even more preferably when R.sub.9 is H, R.sub.8 or R.sub.10 or both
are C.sub.1-3 alkoxy or C.sub.1-3 halo alkoxy.
[0825] Also preferably in this embodiment, when R.sub.9 is H then
R.sub.8 and R.sub.10 are not both H or one H and the other halo,
and R.sub.2 is not H.
[0826] Also preferably, in this embodiment, when R.sub.9 is
C.sub.1-6 alkyl, halo, or C.sub.1-6 haloalkyl, then R.sub.2 is not
H and preferably R.sub.2 is methyl, ethyl, Cl, F, fluoromethyl
(CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3 hydroxyalkyl
(preferably CH.sub.2OH or CH.sub.2CH.sub.2OH), NH.sub.2,
NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3, N(CH.sub.3).sub.2,
N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5, or SCH.sub.3.
[0827] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0828] In another preferred embodiment, compounds of the invention
include compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein: [0829] R.sub.1 is methyl or
ethyl, and preferably methyl; [0830] R.sub.2 is H; halo; N.sub.3;
[0831] C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl, more preferably
CH.sub.3) optionally substituted with 1-4 substituents which are OH
or halo (preferably F, e.g., monofluoro, difluoro, or trifluoro);
[0832] --XR.sub.2a wherein X is S or O, and R.sub.2a is C.sub.1-6
alkyl (preferably C.sub.1-3 alkyl, more preferably CH.sub.3)
optionally substituted with OH or halo (preferably F, e.g.,
monofluoro-, difluoro-, or trifluoro-substituted); or [0833]
--N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and R.sub.2c are
independently H, OH, C.sub.1-6 alkyl (preferably C.sub.1-3 alkyl),
C.sub.1-6 hydroxyalkyl (preferably C.sub.2-3 hydroxyalkyl, more
preferably --CH.sub.2CH2OH), or R.sub.2b and R.sub.2c together form
a 3, 4, 5 or 6-membered heterocycle (e.g., piperidinyl,
pyrrolidinyl, and morpholinyl); [0834] R.sub.3 is H; halo;
C.sub.1-3 alkyl; or C.sub.1-3 alkoxy; [0835] R.sub.4 and R.sub.6
are independently H; halo (preferably F or Cl); N.sub.3; C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3); or --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently H, OH(R.sub.2b and R.sub.2c are not both
OH), CH.sub.3, or R.sub.2b and R.sub.2c together form a 3, 4, 5 or
6-membered heterocycle (e.g., piperidinyl, pyrrolidinyl, and
morpholinyl); [0836] R.sub.5 is H or F, preferably H; [0837]
R.sub.7 and R.sub.11 are independently H, halo (preferably F),
C.sub.1-3 alkyl (preferably CH.sub.3), C.sub.1-3 alkoxy (preferably
OCH.sub.3), or C.sub.1-3 alkylthiol; Preferably R.sub.7 and
R.sub.11 are independently H, halo or methoxy; [0838] R.sub.8 and
R.sub.10 are independently H; halo (preferably F or Cl); C.sub.1-3
alkyl (preferably CH.sub.3); C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol; and [0839] R.sub.9 is selected
from the group: [0840] hydrogen; hydroxy; Cl; N.sub.3; [0841]
C.sub.1-3 alkyl (preferably methyl or ethyl) or C.sub.1-3 haloalkyl
(preferably monofluoromethyl, difluoromethyl, trifluoromethyl);
[0842] --OR.sub.9a, wherein R.sub.12 is C.sub.1-3 alkyl (i.e.,
methyl, ethyl, propyl, isopropyl) or C.sub.1-3 haloalkyl (e.g.,
fluoroalkyl, preferably fluoromethyl, i.e., CH.sub.2F, CHF.sub.2,
CF.sub.3); [0843] --N(R.sub.2b)(R.sub.2c) wherein R.sub.2b and
R.sub.2c are independently C.sub.1-3 alkyl; or [0844]
--COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl (preferably
methyl or ethyl); and optionally R.sub.9 and one of R.sub.8 and
R.sub.10 together form a 3, 4, 5, or 6-membered heterocycle; [0845]
provided that when R.sub.9 is H at least one of R.sub.8 and
R.sub.10 is not H or halo, preferably at least one of R.sub.8 and
R.sub.10 is not H or halo or C.sub.1-3 alkyl.
[0846] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol, each being optionally
substituted with 1-4 F. Even more preferably when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are methoxy or ethoxy. Also preferably
R.sub.2 is not H.
[0847] Also preferably, when R.sub.9 is C.sub.1-3 alkyl, halo, or
C.sub.1-3 haloalkyl, then R.sub.2 is not H, preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0848] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0849] In another preferred embodiment, compounds of the invention
include compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein: [0850] R.sub.1 is methyl or
ethyl, preferably methyl; [0851] R.sub.2 is H, methyl, ethyl, Cl,
F, fluoromethyl (CH.sub.2F, CHF.sub.2, CF.sub.3), C.sub.1-3
hydroxyalkyl (preferably CH.sub.2OH or CH.sub.2CH.sub.2OH),
NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH, NHCH.sub.3,
N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3, OC.sub.2H.sub.5,
or SCH.sub.3; R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4
and R.sub.6 are independently H, CH.sub.3, NH.sub.2, N.sub.3, F, or
Cl; R.sub.5 is H; R.sub.7 and R.sub.11 are independently H, F, or
OCH.sub.3; R.sub.8 and R.sub.10 are independently H, F, Cl, or
OCH.sub.3; and [0852] R.sub.9 is selected from the group: [0853] H;
OH; N.sub.3; [0854] C.sub.1-3 alkyl (preferably methyl or ethyl) or
C.sub.1-3 haloalkyl (preferably monofluoromethyl, difluoromethyl,
trifluoromethyl); [0855] --OR.sub.9a, wherein R.sub.9a is C.sub.1-3
alkyl (i.e., methyl, ethyl, propyl, isopropyl) or C.sub.1-3
haloalkyl (e.g., fluoroalkyl, preferably fluoromethyl, i.e.,
CH.sub.2F, CHF.sub.2, CF.sub.3); [0856] --N(R.sub.2b)(R.sub.2c)
wherein R.sub.2b and R.sub.2c are independently C.sub.1-3 alkyl; or
[0857] --COOR.sub.9b, wherein R.sub.9b is C.sub.1-3 alkyl
(preferably methyl or ethyl), and optionally R.sub.8 and R.sub.9
together form a 3, 4, 5, or 6-membered heterocycle; provided that
when R.sub.9 is H, at least one of R.sub.8 and R.sub.10 is
OCH.sub.3, and when R.sub.9 is C.sub.1-3 alkyl or C.sub.1-3
haloalkyl or Cl then R.sub.2 is Cl or methyl or ethyl.
[0858] Preferably in this embodiment, when R.sub.9 is H, R.sub.8 or
R.sub.10 or both are independently C.sub.1-3 alkoxy (preferably
OCH.sub.3) or C.sub.1-3 alkylthiol, each being optionally
substituted with 1-4 F. Even more preferably when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are methoxy or ethoxy. Also preferably
R.sub.2 is not H.
[0859] Also preferably, when R.sub.9 is C.sub.1-3 alkyl, halo, or
C.sub.1-3 haloalkyl, then R.sub.2 is not H, preferably R.sub.2 is
methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F, CHF.sub.2,
CF.sub.3), C.sub.1-3 hydroxyalkyl (preferably CH.sub.2OH or
CH.sub.2CH.sub.2OH), NH.sub.2, NH.sub.2OH, --NHCH.sub.2CH.sub.2OH,
NHCH.sub.3, N(CH.sub.3).sub.2, N.sub.3, morpholino, OCH.sub.3,
OC.sub.2H.sub.5, or SCH.sub.3.
[0860] Also preferably, in this embodiment, when R.sub.9 is H,
R.sub.8 or R.sub.10 or both are OCH.sub.3 and preferably R.sub.7
and R.sub.11 are H, and also preferably R.sub.2 is not hydrogen and
preferably R.sub.2 is methyl or chloro. Also preferably in this
embodiment, when R.sub.9 is alkyl or haloalkyl or chloro, R.sub.2
is not hydrogen and preferably R.sub.2 is methyl or chloro.
[0861] In another preferred embodiment, compounds of the invention
include compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
[0862] R.sub.2 is H, methyl, ethyl, Cl, F, fluoromethyl (CH.sub.2F,
CHF.sub.2, CF.sub.3), CH.sub.2OH, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, --NHCH.sub.2CH.sub.2OH, OCH.sub.3, or SCH.sub.3;
R.sub.3 is H, CH.sub.3, OCH.sub.3, F, or Cl; R.sub.4 and R.sub.6
are independently H, CH.sub.3, NH.sub.2, F, or Cl; R.sub.5 is H;
R.sub.7 and R.sub.11 are independently H, F, or OCH.sub.3; R.sub.8
and R.sub.10 are independently H, F, Cl, or OCH.sub.3; and
R.sub.9 is selected from the group:
[0863] --OR.sub.12, wherein R.sub.12 is selected from the group of
methyl, ethyl, fluoromethyl (e.g., CH.sub.2F, CHF.sub.2, CF.sub.3),
and fluoroethyl;
[0864] --NHCH.sub.3;
[0865] --N(CH.sub.3).sub.2;
[0866] --N.sub.3; and
[0867] --COOR.sub.13, wherein R.sub.13 is methyl or ethyl.
[0868] In a more preferred embodiment, compounds of the invention
include compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein:
R.sub.1 is CH.sub.3;
R.sub.2 is H, methyl, Cl, --CH.sub.2OH, --NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.2OH, --OCH.sub.3, --SCH.sub.3, or
--CH.sub.2F;
R.sub.3 is H, --CH.sub.3, --OCH.sub.3, or Cl;
R.sub.4 is H, CH.sub.3, or NH.sub.2;
R.sub.5 is H;
R.sub.6 is H, or CH.sub.3;
R.sub.7 and R.sub.11 are independently H, or F;
R.sub.8 and R.sub.10 are independently H, or F or OCH.sub.3;
and
R.sub.9 is --OCH.sub.3 or --OC.sub.2H.sub.5, --N(CH.sub.3).sub.2,
--CO.sub.2CH.sub.3, --OCHF.sub.2, or N.sub.3.
[0869] In a more preferred embodiment, the present invention
provides compounds of Formula VIb or pharmaceutically acceptable
salts or solvates thereof, wherein R.sub.1 is CH.sub.3; R.sub.2 is
Cl, methyl, or CH.sub.2F; R.sub.3 is H, CH.sub.3, F, or Cl;
R.sub.4, R.sub.5 and R.sub.6 are H; R.sub.7, R.sub.8, R.sub.10 and
R.sub.11 are independently H or F; and R.sub.9 is --OCH.sub.3 or
--N(CH.sub.3).sub.2.
[0870] In another embodiment, compounds of Formula VIb include
compounds wherein:
R.sub.1 is methyl or ethyl;
R.sub.2 is methyl, ethyl, fluoromethyl, trifluoromethyl, methoxy,
chloro, hydrogen, morpholino, hydroxymethane, methylthiol, or an
amino optionally substituted with hydroxyethyl, or hydroxy;
R.sub.3 is hydrogen, chloro, methyl, or methoxy;
R.sub.4 and R.sub.6 are independently hydrogen, chloro, or
methyl;
R.sub.5 is hydrogen;
R.sub.7, R.sub.8, R.sub.10, and R.sub.11 are independently
hydrogen, fluoro, methyl, or methoxy; and
R.sub.9 is methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy,
trifluoromethoxy, difluoromethoxy, azido, dimethylamino,
methylcarboxy, chloro, hydrogen, or hydroxyl;
or pharmaceutically acceptable salts or solvates thereof.
[0871] Preferably, the compounds of this embodiment are not
selected form the group consisting of: [0872]
6-amino-4-[(N-methyl-N-phenyl)amino]quinazo line; [0873]
1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3-methyltriazene;
[0874]
1-{4-[(N-methyl-N-phenyl)amino]-6-quinazolinyl}-3,3-dimethyltriazene;
[0875] 4-(N-methylanilino)-6-sulfonylquinazoline; [0876]
4-(N-methylanilino)-6-halosulfonylquinazoline; [0877]
8-Chloro-4-(N-methylanilino)quinazoline; [0878]
4-(N-methylanilino)-8-trifluoromethylquinazoline; [0879]
2-butyl-N-methyl-N-phenylquinazolin-4-amine; [0880]
4-(N-methylanilino)-6,8-dimethylquinazoline; [0881]
4-(N-methylanilino)-quinazo line; [0882]
4-(N-methylanilino)-6-methoxyquinazoline; [0883]
4-(N-methylanilino)-6-chloroquinazoline; [0884]
N-(3-chlorophenyl)-N-(quinazolin-4-yl)-N-methyl-amine; [0885]
4-(N-methylanilino)-2-chloroquinazoline; [0886]
4-(N-methylanilino)-2-chloro-8-methoxyquinazoline; [0887]
4-(N-ethylanilino)-2-chloroquinazoline; [0888]
4-(N-methylanilino)-2-chloro-6-methoxyquinazoline; [0889]
4-(N-methylanilino)-2-chloro-8-fluoroquinazoline; [0890]
2-amino-4-(N-methylphenylamino)quinazoline hydrochloride; or [0891]
2-amino-4-(N-methylphenylamino)-8-methoxyquinazoline
hydrochloride.
[0892] In another embodiment, compounds of Formula VIb include
compounds wherein:
R.sub.1 is methyl;
R.sub.2 is methyl, chloro, fluoromethyl, hydroxymethyl, amino,
hydrogen, or hydroxyethylamino;
R.sub.3 is hydrogen, methyl, methoxy, or chloro;
R.sub.4 and R.sub.6 are independently hydrogen or methyl;
R.sub.5 is hydrogen;
R.sub.7 and R.sub.11 are independently hydrogen or fluoro;
R.sub.8 and R.sub.10 are independently hydrogen or fluoro; and
R.sub.9 is methoxy, ethoxy, dimethylamino, methylcarboxy,
difluoromethoxy, or azido;
or pharmaceutically acceptable salts or solvates thereof.
[0893] Among all the compounds of the present invention as
disclosed above, preferred are those that can induce caspase
activation as determined by the method and under conditions
(measurement at 24 hours) described in Example 143, preferably at
an EC.sub.50 of no greater than about 1,000 nM, more preferably at
an EC.sub.50 of no greater than about 500 nM, more preferably at an
EC.sub.50 of no greater than about 200 nM, even more preferably at
an EC.sub.50 of no greater than about 100 nM, and most preferably
at an EC.sub.50 of no greater than about 10 nM. Also preferred
compounds are those of Formula I-VIb, and pharmaceutically
acceptable salts or solvates thereof, that are able to inhibit
tubulin at an IC.sub.50 of no greater than about 2,000 nM,
preferably no greater than about 1,000 nM, more preferably less
than about 500 nM, as determined by the method and under conditions
described in Example 145.
[0894] Exemplary compounds of the present invention are compounds
provided in Examples 1-142; and pharmaceutically acceptable salts
or prodrugs thereof, including but not limited to: [0895]
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; [0896]
(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine; [0897]
(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine; [0898]
(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [0899]
(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
[0900]
N.sup.2-Hydroxyl-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinaz-
oline-2,4-diamine; [0901]
N.sup.2-(2-Hydroxylethyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quina-
zoline-2,4-diamine; [0902]
N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[0903]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methoxy-phenyl)-
-N.sup.4-methyl-quinazoline-2,4-diamine; [0904]
N.sup.4-(4-Methoxy-phenyl)-N.sup.4-methyl-N.sup.2-(2-morpholin-4-yl-ethyl-
)-quinazoline-2,4-diamine; [0905]
(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
[0906]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methyl-phenyl)--
N.sup.4-methyl-quinazoline-2,4-diamine; [0907]
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0908]
(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-am-
ine; [0909]
(2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine; [0910]
(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine; [0911]
(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine; [0912]
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0913]
(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
[0914]
(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
[0915]
(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;
[0916] (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;
[0917]
(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;
[0918]
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;
[0919] (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
[0920] (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
[0921]
N.sup.2-[2-(1H-Imidazol-4-yl)-ethyl]-N.sup.4-(4-methoxy-phenyl)-N.sup.4-m-
ethyl-quinazoline-2,4-diamine; [0922]
N.sup.2-(3-Dimethylamino-propyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methy-
l-quinazoline-2,4-diamine; [0923]
N.sup.2-(2-Hydroxyethyl)-N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-q-
uinazoline-2,4-diamine; [0924]
N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[0925]
(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
[0926] (2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine;
[0927] (2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;
[0928]
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0929]
(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [0930]
(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0931]
(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [0932]
(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0933]
(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0934]
(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0935]
(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-
-amine; [0936] (Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine;
[0937] (4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine; [0938]
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;
[0939]
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;
[0940] (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;
[0941] (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;
and [0942]
(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine; [0943]
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine; [0944]
5-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl--
quinazoline-2,4-diamine; [0945]
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0946] (2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0947]
(2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine;
[0948]
(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0949] (4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine;
[0950]
(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amin-
e; [0951]
(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0952]
(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0953] (4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0954]
(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine;
[0955]
(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0956]
(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0957]
(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-am-
ine; [0958]
(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;
[0959] (4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0960] (2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine;
[0961]
(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0962]
(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-ami-
ne; [0963]
(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [0964]
(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [0965]
(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [0966]
(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0967]
(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0968]
(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine- ;
[0969] (4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0970]
(4-Methoxy-phenyl-2,3,5,6-d.sub.4)-(2-methyl-quinazolin-4-yl)-met-
hyl-amine; [0971]
(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
[0972]
(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [0973]
(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0974]
(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [0975]
(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0976] Ethyl
4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
[0977] Succinimidyl
4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid Ester;
[0978]
(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0979] (2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0980]
(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0981]
(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[0982] (4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0983]
(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amin-
e; [0984]
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0985]
(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0986]
(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl--
amine; [0987]
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0988]
Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;
[0989] (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;
[0990]
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0991] and pharmaceutically acceptable salts or prodrugs
thereof.
[0992] In one embodiment, exemplary compounds of the invention
include: [0993]
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0994]
N.sup.2-(2-Hydroxyethyl)-N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-
-methyl-quinazoline-2,4-diamine; [0995]
N.sup.4-(6-Methoxypyridin-3-yl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[0996]
(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[0997]
(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-ami-
ne; [0998]
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[0999]
(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[1000]
(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl--
amine; [1001]
(2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine; [1002]
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
and [1003]
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1004] or a pharmaceutically acceptable salt or solvate
thereof.
[1005] In another embodiment, exemplary compounds of the invention
include: [1006]
(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine;
and [1007]
(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine;
[1008] or a pharmaceutically acceptable salt or solvate
thereof.
[1009] In another embodiment, exemplary compounds of the invention
include: [1010]
N.sup.2-Hydroxyl-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,-
4-diamine; [1011]
N.sup.2-(2-Hydroxylethyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quina-
zoline-2,4-diamine; [1012]
N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,4-diamine;
[1013]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methoxy-phenyl)-
-N.sup.4-methyl-quinazoline-2,4-diamine; [1014]
N.sup.4-(4-Methoxy-phenyl)-N.sup.4-methyl-N.sup.2-(2-morpholin-4-yl-ethyl-
)-quinazoline-2,4-diamine; [1015]
(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine;
[1016]
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methyl-phenyl)--
N.sup.4-methyl-quinazoline-2,4-diamine; [1017]
N.sup.2-[2-(1H-Imidazol-4-yl)-ethyl]-N.sup.4-(4-methoxy-phenyl)-N.sup.4-m-
ethyl-quinazoline-2,4-diamine; [1018]
N.sup.2-(3-Dimethylamino-propyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methy-
l-quinazoline-2,4-diamine; [1019]
5-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl--
quinazoline-2,4-diamine; [1020]
6-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl--
quinazoline-2,4-diamine; [1021]
(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
and [1022]
(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1023] or a pharmaceutically acceptable salt or solvate
thereof.
[1024] In yet another embodiment, exemplary compounds of the
invention include: [1025]
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1026] (4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine;
[1027]
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1028] (2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1029] (4-carboxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1030] Ethyl
4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate;
[1031]
(2-hydroxymethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine-
; [1032]
(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-meth-
yl-amine; [1033]
(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1034]
(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-ami-
ne; [1035]
(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1036] (4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1037]
(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1038] (4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1039]
(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-ami-
ne; [1040]
(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [1041]
(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [1042]
(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; [1043]
(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1044]
(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1045]
(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine- ;
[1046] (4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1047]
(4-Methoxy-phenyl-2,3,5,6-d.sub.4)-(2-methyl-quinazolin-4-yl)-met-
hyl-amine; [1048]
(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine;
[1049]
(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [1050]
(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1051]
(4-Methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amin-
e; [1052]
(2,4,6-Trimethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine;
[1053]
(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin-
e; [1054]
(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1055]
(3,5-Dibromo-4-methoxyphenyl)-(2-methyl-6-nitro-quinazolin-4-yl)--
methyl-amine; [1056]
(4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine; and
[1057]
Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine;
[1058] or a pharmaceutically acceptable salt or solvate
thereof.
[1059] In another embodiment, exemplary compounds of the invention
include: [1060]
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; [1061]
(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine; [1062]
(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine; [1063]
(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine; [1064]
(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine;
[1065]
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-
-amine; [1066]
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine;
[1067]
(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine;
[1068]
(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine;
[1069]
(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine;
[1070] (2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine;
[1071]
(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine;
[1072]
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine;
[1073] (2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine;
[1074] (2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine;
[1075]
(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine;
[1076] (2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine;
[1077]
(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1078]
(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [1079]
(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1080]
(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-ami-
ne; [1081]
(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1082]
(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1083]
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine;
[1084]
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine;
[1085] (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine;
[1086] (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine;
[1087] (2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine;
[1088]
(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine; and
[1089]
(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1090] or a pharmaceutically acceptable salt or solvate
thereof.
[1091] In yet another embodiment, exemplary compounds of the
invention include: [1092]
(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine; and [1093]
(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine;
[1094] or a pharmaceutically acceptable salt or solvate
thereof.
[1095] In another embodiment, exemplary compounds useful in the
methods of the invention include: [1096]
(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine; and
[1097]
(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine;
[1098] or a pharmaceutically acceptable salt or solvate
thereof.
[1099] The term "alkyl" as employed herein by itself or as part of
another group refers to both straight and branched chain radicals
of up to ten carbons. Useful alkyl groups include straight-chained
and branched C.sub.1-10 alkyl groups, more preferably C.sub.1-6
alkyl groups. Typical C.sub.1-10 alkyl groups include methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl,
hexyl and octyl groups, which may be optionally substituted.
[1100] The term "alkenyl" as employed herein by itself or as part
of another group means a straight or branched chain radical of 2-10
carbon atoms, unless the chain length is limited thereto, including
at least one double bond between two of the carbon atoms in the
chain. Typical alkenyl groups include ethenyl, 1-propenyl,
2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
[1101] The term "alkynyl" is used herein to mean a straight or
branched chain radical of 2-10 carbon atoms, unless the chain
length is limited thereto, wherein there is at least one triple
bond between two of the carbon atoms in the chain. Typical alkynyl
groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl,
2-propynyl, 1-butynyl and 2-butynyl.
[1102] Useful alkoxy groups include oxygen substituted by one of
the C.sub.1-10 alkyl groups mentioned above, which may be
optionally substituted. Alkoxy substituents include, without
limitation, halo, morpholino, amino including alkylamino and
dialkylamino, and carboxy including esters thereof.
[1103] Useful alkylthio groups include sulfur substituted by one of
the C.sub.1-10 alkyl groups mentioned above, which may be
optionally substituted. Also included are the sulfoxides and
sulfones of such alkylthio groups.
[1104] Useful amino groups include --NH.sub.2, --NHR.sub.18 and
--NR.sub.18R.sub.19, wherein R.sub.18 and R.sub.18 are C.sub.1-10
alkyl or cycloalkyl groups, or R.sub.18 and R.sub.19 are combined
with the N to form a ring structure, such as a piperidine, or
R.sub.18 and R.sub.19 are combined with the N and other group to
form a ring, such as a piperazine. The alkyl group may be
optionally substituted.
[1105] Optional substituents on the alkyl, alkenyl, alkynyl,
cycloalkyl, carbocyclic and heterocyclic groups include one or more
halo, hydroxy, carboxyl, amino, nitro, cyano, C.sub.1-C.sub.6
acylamino, C.sub.1-C.sub.6 acyloxy, C.sub.1-C.sub.6 alkoxy,
aryloxy, alkylthio, C.sub.6-C.sub.10 aryl, C.sub.4-C.sub.7
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 aryl(C.sub.2-C.sub.6)alkenyl, C.sub.6-C.sub.10
aryl(C.sub.2-C.sub.6)alkynyl, saturated and unsaturated
heterocyclic or heteroaryl.
[1106] Optional substituents on the aryl, arylalkyl, arylalkenyl,
arylalkynyl and heteroaryl and heteroarylalkyl groups include one
or more halo, C.sub.1-C.sub.6 haloalkyl, C.sub.6-C.sub.10 aryl,
C.sub.4-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
aryl(C.sub.1-C.sub.6)alkyl, C.sub.6-C.sub.10
aryl(C.sub.2-C.sub.6)alkenyl, C.sub.6-C.sub.10
aryl(C.sub.2-C.sub.6)alkynyl, C.sub.1-C.sub.6 hydroxyalkyl, nitro,
amino, ureido, cyano, C.sub.1-C.sub.6 acylamino, hydroxy, thiol,
C.sub.1-C.sub.6 acyloxy, azido, C.sub.1-C.sub.6 alkoxy, carboxy or
C.sub.1-2 alkylenedioxy (e.g., methylenedioxy).
[1107] The term "aryl" as employed herein by itself or as part of
another group refers to monocyclic, bicyclic or tricyclic aromatic
groups containing from 6 to 14 carbons in the ring portion.
[1108] Useful aryl groups include C.sub.6-14 aryl, preferably
C.sub.6-10 aryl. Typical C.sub.6-14 aryl groups include phenyl,
naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl,
biphenylenyl and fluorenyl groups.
[1109] The term "carbocycle" as employed herein include cycloalkyl
and partially saturated carbocyclic groups. Useful cycloalkyl
groups are C.sub.3-8 cycloalkyl. Typical cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[1110] Useful saturated or partially saturated carbocyclic groups
are cycloalkyl groups as described above, as well as cycloalkenyl
groups, such as cyclopentenyl, cycloheptenyl and cyclooctenyl.
[1111] Useful halo or halogen groups include fluorine, chlorine,
bromine and iodine.
[1112] The term "arylalkyl" is used herein to mean any of the
above-mentioned C.sub.1-10 alkyl groups substituted by any of the
above-mentioned C.sub.6-14 aryl groups. Preferably the arylalkyl
group is benzyl, phenethyl or naphthylmethyl.
[1113] The term "arylalkenyl" is used herein to mean any of the
above-mentioned C.sub.2-10 alkenyl groups substituted by any of the
above-mentioned C.sub.6-14 aryl groups.
[1114] The term "arylalkynyl" is used herein to mean any of the
above-mentioned C.sub.2-10 alkynyl groups substituted by any of the
above-mentioned C.sub.6-14 aryl groups.
[1115] The term "aryloxy" is used herein to mean oxygen substituted
by one of the above-mentioned C.sub.6-14 aryl groups, which may be
optionally substituted. Useful aryloxy groups include phenoxy and
4-methylphenoxy.
[1116] The term "arylalkoxy" is used herein to mean any of the
above mentioned C.sub.1-10 alkoxy groups substituted by any of the
above-mentioned aryl groups, which may be optionally substituted.
Useful arylalkoxy groups include benzyloxy and phenethyloxy.
[1117] Useful haloalkyl groups include C.sub.1-10 alkyl groups
substituted by one or more fluorine, chlorine, bromine or iodine
atoms, e.g., fluoromethyl, difluoromethyl, trifluoromethyl,
pentafluoroethyl, 1,1-difluoroethyl, chloromethyl,
chlorofluoromethyl and trichloromethyl groups.
[1118] Useful acylamino (acylamido) groups are any C.sub.1-6 acyl
(alkanoyl) attached to an amino nitrogen, e.g., acetamido,
chloroacetamido, propionamido, butanoylamido, pentanoylamido and
hexanoylamido, as well as aryl-substituted C.sub.1-6 acylamino
groups, e.g., benzoylamido, and pentafluorobenzoylamido.
[1119] Useful acyloxy groups are any C.sub.1-6 acyl (alkanoyl)
attached to an oxy (--O--) group, e.g., formyloxy, acetoxy,
propionyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
[1120] The term heterocycle is used herein to mean a saturated or
partially saturated 3-7 membered monocyclic, or 7-10 membered
bicyclic ring system, which consists of carbon atoms and from one
to four heteroatoms independently selected from the group
consisting of O, N, and S, wherein the nitrogen and sulfur
heteroatoms can be optionally oxidized, the nitrogen can be
optionally quaternized, and including any bicyclic group in which
any of the above-defined heterocyclic rings is fused to a benzene
ring, and wherein the heterocyclic ring can be substituted on
carbon or on a nitrogen atom if the resulting compound is
stable.
[1121] Useful saturated or partially saturated heterocyclic groups
include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl,
pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl,
pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
[1122] The term "heteroaryl" as employed herein refers to groups
having 5 to 14 ring atoms; 6, 10 or 14 .pi. electrons shared in a
cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen,
nitrogen or sulfur heteroatoms.
[1123] Useful heteroaryl groups include thienyl (thiophenyl),
benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl
(furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,
pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl,
pyrazolyl, pyridyl (pyridinyl), including without limitation
2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,
indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl,
carbazolyl, .beta.-carbolinyl, phenanthridinyl, acridinyl,
perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl,
1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin,
pyrido[1,2-a]pyrimidin-4-one, pyrazolo[1,5-a]pyrimidinyl, including
without limitation pyrazolo[1,5-a]pyrimidin-3-yl,
1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and
2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen
atom in a ring, such nitrogen atom may be in the form of an
N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl
N-oxide.
[1124] The term "heteroaryloxy" is used herein to mean oxygen
substituted by one of the above-mentioned heteroaryl groups, which
may be optionally substituted. Useful heteroaryloxy groups include
pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy
and thiophenyloxy.
[1125] The term "heteroarylalkoxy" is used herein to mean any of
the above-mentioned C.sub.1-10 alkoxy groups substituted by any of
the above-mentioned heteroaryl groups, which may be optionally
substituted.
[1126] Some of the compounds of the present invention may exist as
stereoisomers including optical isomers. The invention includes all
stereoisomers and both the racemic mixtures of such stereoisomers
as well as the individual enantiomers that may be separated
according to methods that are well known to those of ordinary skill
in the art.
[1127] Examples of pharmaceutically acceptable addition salts
include inorganic and organic acid addition salts, such as
hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate,
tartrate, maleate, fumarate, mandelate and oxalate; and inorganic
and organic base addition salts with bases, such as sodium hydroxy,
Tris(hydroxymethyl)aminomethane (TRIS, tromethane) and
N-methyl-glucamine.
[1128] Examples of prodrugs of the compounds of the invention
include the simple esters of carboxylic acid containing compounds
(e.g., those obtained by condensation with a C.sub.1-4 alcohol
according to methods known in the art); esters of hydroxy
containing compounds (e.g., those obtained by condensation with a
C.sub.1-4 carboxylic acid, C.sub.3-6 dioic acid or anhydride
thereof, such as succinic and fumaric anhydrides according to
methods known in the art); imines of amino containing compounds
(e.g., those obtained by condensation with a C.sub.1-4 aldehyde or
ketone according to methods known in the art); carbamate of amino
containing compounds, such as those described by Leu, et. al., (J.
Med. Chem. 42:3623-3628 (1999)) and Greenwald, et. al., (J. Med.
Chem. 42:3657-3667 (1999)); and acetals and ketals of alcohol
containing compounds (e.g., those obtained by condensation with
chloromethyl methyl ether or chloromethyl ethyl ether according to
methods known in the art).
[1129] The compounds of this invention may be prepared using
methods known to those skilled in the art, or the novel methods of
this invention. Specifically, the compounds of this invention with
Formulae I-VIb can be prepared as illustrated by the exemplary
reaction in Scheme 1. Reaction of optionally substituted
quinazoline-2,4-dione with phosphorylchloride produces the
corresponding 2,4-dichloroquinazoline, which is reacted with an
optionally substituted aniline, such as N-methyl-4-methoxy-aniline,
to produce the substituted 2-chloro-4-anilino-quinazoline.
##STR31##
[1130] Compounds of this invention with Formulae I-VIb also could
be prepared as illustrated by the exemplary reaction in Scheme 2.
Reaction of the substituted 2-chloro-4-anilino-quinazoline with a
nucleophile (R.sub.2), such as hydroxylamine, in isopropanol heated
by microwave produces the 2-nucleophile
substituted-4-anilino-quinazoline, such as substituted
hydroxylamino. Other nucleophiles that can be used in the reaction
include NaOMe, NaN.sub.3, NaSMe, NH.sub.3, NH.sub.2Me, or
NHMe.sub.2, and the reaction can be run at room temperature or
elevated temperature. ##STR32##
[1131] Compounds of this invention with Formulae I-VIb, wherein Ar
is a substituted aryl or heteroaryl, could be prepared as
illustrated by the exemplary reaction in Scheme 3. Reaction of
2,4-dichloroquinazoline with a substituted arylamine or
heteroarylamine (Ar), such as a substituted pyridin-3-ylamine,
produces the corresponding 4-Ar-amino substituted
2-chloro-quinazoline, which is alkylated with a haloalkyl, such as
methylated by reaction with methyl iodide in the presence of a base
such as NaH, to produce the corresponding 4-N-methyl-Ar-amino
substituted 2-chloro-quinazoline. ##STR33##
[1132] Alternatively, compounds of this invention with Formulae
I-VIb also could be prepared as illustrated by the exemplary
reaction in Scheme 4. The N-alkyl-arylamine or
N-alkyl-heteroarylamine could be prepared by reaction of the
arylamine or heteroarylamine with a ketone or aldehyde, such as
acetone, in the presence of a reducing agent, such as NaCNBH.sub.3.
The N-alkyl-arylamine or N-alkyl-heteroarylamine is then reacted
with optionally substituted 2,4-dichloroquinazoline to produce the
corresponding 4-substituted 2-chloro-quinazoline. ##STR34##
[1133] Compounds of this invention with Formulae I-VIb also could
be prepared as illustrated by the exemplary reaction in Scheme 5.
Reaction of optionally substituted 2-amino-benzoic acid, such as
2-amino-5-methyl-benzoic acid, with potassium cyanate in the
presence of an acid, such as acetic acid, produces the
corresponding optionally substituted quinazoline-2,4-dione, such as
6-methyl-quinazoline-2,4-dione, which is converted to the
corresponding optionally substituted 2,4-dichloroquinazoline, such
as 6-methyl-2,4-dichloroquinazoline by reaction with
phosphorylchloride. Reaction of optionally substituted
2,4-dichloroquinazoline, such as 6-methyl-2,4-dichloroquinazoline
with a substituted arylamine or heteroarylamine, such as
N-methyl-4-methoxy-aniline, produces the corresponding
4-substituted 2-chloro-quinazoline, such as substituted
2-chloro-4-anilino-quinazoline. ##STR35##
[1134] Compounds of this invention with Formulae I-VIb, wherein
R.sub.2 is an optionally substituted alkyl group, could be prepared
as illustrated by the exemplary reaction in Scheme 6. Reaction of
2-amino-benzoic acid methyl ester with an optionally substituted
acetonitrile, such as fluoro-acetonitrile, in the presence of HCl
produces the corresponding 2-substituted quinazoline-4(3H)-one,
such as 2-fluoromethyl-quinazoline-4(3H)-one, which is converted to
2-substituted 4-chloro-quinazoline, such as
4-chloro-2-fluoromethyl-quinazoline by reaction with
phosphorylchloride. Reaction of 2-substituted 4-chloro-quinazoline,
such as 4-chloro-2-fluoromethyl-quinazoline with a substituted
aniline, such as N-methyl-4-methoxy-aniline, produces the
corresponding 2-substituted 4-anilino-quinazoline, such as
2-fluoromethyl-4-anilino-quinazoline. Other substituted
acetonitriles that can be used for the reaction include
chloro-acetonitrile and bromo-acetonitrile, as well as acetonitrile
and propionitrile. ##STR36##
[1135] Compounds of this invention with Formulae I-VIb, wherein
R.sub.2 is a substituted alkyl group, could also be prepared as
illustrated by the exemplary reaction in Scheme 7. Reaction of a
substituted 2-chloroalkyl-4-(N-alkyl-arylamine or
N-alkyl-heteroarylamine)-quinazoline, such as
N-methyl-2-chloromethyl-4-anilino-quinazoline, with a nucleophile,
such as NHMe.sub.2, produces the substituted
2-dimethylaminomethyl-4-anilino-quinazoline. Other nucleophiles
that can be used in the reaction include NaOMe, NaN.sub.3, NaSMe,
NH.sub.3, NH.sub.2Me, or NHMe.sub.2, and the reaction can be run at
room temperature and elevated temperature. ##STR37##
[1136] Compounds of this invention with Formulae I-VIb, wherein
R.sub.1 is a substituted alkyl, could be prepared as illustrated by
the exemplary reaction in Scheme 8. For example, reaction of an
optionally substituted 4-(arylamine or
heteroarylamine)-quinazoline, such as
2-methyl-4-(6-methoxy-pyridin-3-ylamino)-quinazoline, with a
substituted haloalkyl, such as difluoromethyl chloride, in the
presence of a base such as NaH, produces the corresponding
4-(N-alkyl-arylamine or N-alkyl-heteroarylamine)-quinazoline, such
as
2-methyl-N.sup.4-difluoromethyl-4-(4-methoxy-pyridin-3-ylamino)-quinazoli-
ne. ##STR38##
[1137] Compounds of this invention with Formula I-VIb, wherein
R.sub.2 is an alkyl group, could be prepared as illustrated by the
exemplary reaction in Scheme 9. Reaction of a substituted
2-amino-benzoic acid, such as 2-amino-5-nitro-benzoic acid, with
acetic anhydride, produces the corresponding substituted
2-methyl-4H-benzo[d][1,3]oxazine-4-one, such as
2-methyl-6-nitro-4H-benzo[d][1,3]oxazine-4-one, which is converted
to the corresponding quinazoline-4(3H)-one, such as
2-methyl-6-nitro-quinazoline-4(3H)-one, by treatment with ammonia
in dioxane. The compound is then converted to the corresponding
4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline
by reaction with phosphorylchloride. Reaction of the
4-chloro-quinazoline, such as 4-chloro-2-methyl-6-nitro-quinazoline
with a substituted arylamine or heteroarylamine, such as
N-methyl-4-methoxy-aniline, produces the corresponding 4-(arylamino
or heteroarylamino)-quinazoline, such as substituted
2-methyl-6-nitro-4-anilino-quinazoline. Other substituted
2-amino-benzoic acid that can be used for the reaction include
2-amino-4-nitro-benzoic acid, 2-amino-5-chloro-benzoic acid.
##STR39##
[1138] Compounds substituted with a nitro group can be reduced by
hydrogenation under H.sub.2 with Pd to produce the amino compound,
which can be converted to the azido compounds by diazotization
followed by treatment with NaN.sub.3. ##STR40##
[1139] Compounds of this invention with Formula I-VIb, wherein ring
A is a carbocycle, could be prepared as illustrated by the
exemplary reaction in Scheme 10. Reaction of optionally substituted
5,6,7,8-tetrahydro-quinazoline-4(3H)-one with phosphorylchloride
produces the corresponding optionally substituted
5,6,7,8-tetrahydro-4-chloroquinazoline, which is reacted with an
optionally substituted N-alkyl-arylamine or
N-alkyl-heteroarylamine, such as N-methyl-4-methoxy-aniline, to
produce the corresponding optionally substituted
5,6,7,8-tetrahydro-4-(N-alkyl-arylamine or
N-alkyl-heteroarylamine)-quinazoline. ##STR41##
[1140] Compounds of this invention with Formula I-VIb, wherein ring
A is a heteroaryl or heterocycle, such as pyrido, could be prepared
as illustrated by the exemplary reaction in Scheme 11. Reaction of
an amino-nicotinic acid, such as 2-amino-nicotinic acid, with
acetyl chloride, in the presence of base, such as triethylamine,
produces the corresponding amide, which is treated with ammonium
acetate to produce the corresponding
2-methyl-pyrido[2,3-d](heteroaryl or heterocycle)-4-ol, such as
2-methyl-pyrido[2,3-d]pyrimidin-4-ol. The resulting compound is
then converted to the corresponding
4-chloro-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle), such as
4-chloro-2-methyl-pyrido[2,3-d]pyrimidine by reaction with
phosphorylchloride, which is treated with an optionally substituted
arylamino or heteroarylamino, such as N-methyl-4-methoxy-aniline to
produce the corresponding optionally substituted 4-(arylamino or
heteroarylamino)-2-methyl-pyrido[2,3-d](heteroaryl or heterocycle),
such as substituted 4-anilino-2-methyl-pyrido[2,3-d]pyrimidine.
##STR42##
[1141] Additional exemplary compounds may be synthesized according
to the synthesis schemes below: ##STR43## ##STR44## ##STR45##
##STR46## ##STR47## ##STR48## ##STR49## ##STR50## ##STR51##
##STR52## ##STR53## ##STR54## ##STR55## ##STR56##
[1142] An important aspect of the present invention is the
discovery that compounds having Formulae I-VIb are activators of
caspases and inducers of apoptosis. Another important aspect of the
invention is the discovery that compounds having Formulae I-Vc are
inhibitors of tubulin polymerization. Therefore, these compounds
are useful in treating diseases that are responsive to activating
caspases, inducing apoptosis, or inhibiting tubulin. For example,
these compounds are useful in a variety of clinical conditions in
which there is uncontrolled cell growth and spread of abnormal
cells, such as in the case of cancer.
[1143] The present invention also includes a therapeutic method
comprising administering to an animal an effective amount of a
compound, or a pharmaceutically acceptable salt or prodrug of said
compound of Formulae I-Vc, wherein said therapeutic method is
useful to treat cancer, which is a group of diseases characterized
by the uncontrolled growth and spread of abnormal cells. Such
diseases include, but are not limited to, Hodgkin's disease,
non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic
lymphocytic leukemia, multiple myeloma, neuroblastoma, breast
carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor,
cervical carcinoma, testicular carcinoma, soft-tissue sarcoma,
primary macroglobulinemia, bladder carcinoma, chronic granulocytic
leukemia, primary brain carcinoma, malignant melanoma, small-cell
lung carcinoma, stomach carcinoma, colon carcinoma, malignant
pancreatic insulinoma, malignant carcinoid carcinoma,
choriocarcinoma, mycosis fungoides, head or neck carcinoma,
osteogenic sarcoma, pancreatic carcinoma, acute granulocytic
leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma,
Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma,
esophageal carcinoma, malignant hypercalcemia, cervical
hyperplasia, renal cell carcinoma, endometrial carcinoma,
polycythemia vera, essential thrombocytosis, adrenal cortex
carcinoma, skin cancer, and prostatic carcinoma.
[1144] In practicing the therapeutic methods, effective amounts of
compositions containing therapeutically effective concentrations of
the compounds formulated for oral, intravenous, local and topical
application, for the treatment of neoplastic diseases and other
diseases, are administered to an individual exhibiting the symptoms
of one or more of these disorders. The amounts are effective to
ameliorate or eliminate one or more symptoms of the disorders. An
effective amount of a compound for treating a particular disease is
an amount that is sufficient to ameliorate, or in some manner
reduce, the symptoms associated with the disease. Such amount may
be administered as a single dosage or may be administered according
to a regimen, whereby it is effective. The amount may cure the
disease but, typically, is administered in order to ameliorate the
symptoms of the disease. Typically, repeated administration is
required to achieve the desired amelioration of symptoms.
[1145] Another aspect of the present invention is to provide a
pharmaceutical composition, containing an effective amount of a
compound of Formulae I-VIb, or a pharmaceutically acceptable salt
of said compound, in admixture with one or more pharmaceutically
acceptable carriers or diluents.
[1146] In one embodiment, a pharmaceutical composition comprising a
compound of Formulae I-Vc disclosed herein, or a pharmaceutically
acceptable salt of said compound, in combination with a
pharmaceutically acceptable vehicle is provided.
[1147] Preferred pharmaceutical compositions comprise compounds of
Formulae I-VIb, and pharmaceutically acceptable salts, esters, or
prodrugs thereof, that are able to induce caspase activation as
determined by the method described in Example 145, preferably at an
EC.sub.50 no greater than 1,000 nM, more preferably at an EC.sub.50
no greater than 500 nM, more preferably at an EC.sub.50 no greater
than 200 nM, more preferably at an EC.sub.50 no greater than 100,
and most preferably at an EC.sub.50 no greater than 10 nM. Other
preferred compositions comprise compounds of Formula I-VIb, and
pharmaceutically acceptable salts, esters, or prodrugs thereof,
that are able to inhibit tubulin polymerization as determined by
the method described in Example 147.
[1148] Another embodiment of the present invention is directed to a
composition effective to inhibit neoplasia comprising a compound,
or a pharmaceutically acceptable salt or prodrug of said compound
of Formulae I-VIb, which functions as a caspase cascade activator
and inducer of apoptosis or inhibitor of tubulin polymerization, in
combination with at least one known cancer chemotherapeutic agent,
or a pharmaceutically acceptable salt of said agent. Examples of
known cancer chemotherapeutic agents which may be used for
combination therapy include, but not are limited to alkylating
agents, such as busulfan, cis-platin, mitomycin C, and carboplatin;
antimitotic agents, such as colchicine, vinblastine, paclitaxel,
and docetaxel; topo I inhibitors, such as camptothecin and
topotecan; topo II inhibitors, such as doxorubicin and etoposide;
RNA/DNA antimetabolites, such as 5-azacytidine, 5-fluorouracil and
methotrexate; DNA antimetabolites, such as
5-fluoro-2'-deoxy-uridine, ara-C, hydroxyurea and thioguanine; EGFR
inhibitors, such as Iressa.RTM. (gefitinib) and Tarceva.RTM.
(erlotinib); proteosome inhibitors; antibodies, such as campath,
Herceptin.RTM. (trastuzumab), Avastin.RTM. (bevacizumab), or
Rituxan.RTM. (rituximab). Other known cancer chemotherapeutic
agents which may be used for combination therapy include melphalan,
chlorambucil, cyclophosamide, ifosfamide, vincristine, mitoguazone,
epirubicin, aclarubicin, bleomycin, mitoxantrone, elliptinium,
fludarabine, ocreotide, retinoic acid, tamoxifen, Gleevec.RTM.
(imatinib mesylate) and alanosine.
[1149] In practicing the methods of the present invention, the
compound of the invention may be administered together with at
least one known chemotherapeutic agent as part of a unitary
pharmaceutical composition. Alternatively, the compound of the
invention may be administered apart from at least one known cancer
chemotherapeutic agent. In one embodiment, the compound of the
invention and at least one known cancer chemotherapeutic agent are
administered substantially simultaneously, i.e. the compounds are
administered at the same time or one after the other, so long as
the compounds reach therapeutic levels in the blood at the same
time. On another embodiment, the compound of the invention and at
least one known cancer chemotherapeutic agent are administered
according to their individual dose schedule, so long as the
compounds reach therapeutic levels in the blood.
[1150] It has been reported that alpha-1-adrenoceptor antagonists,
such as doxazocin, terazosin, and tamsulosin can inhibit the growth
of prostate cancer cell via induction of apoptosis (Kyprianou, N.,
et al., Cancer Res 60:4550-4555, (2000)). Therefore, another
embodiment of the present invention is directed to a composition
effective to inhibit neoplasia comprising a compound, or a
pharmaceutically acceptable salt or prodrug of a compound described
herein, which functions as a caspase cascade activator and inducer
of apoptosis or inhibitor of tubulin polymerization, in combination
with at least one known alpha-1-adrenoceptor antagonists, or a
pharmaceutically acceptable salt of said agent. Examples of known
alpha-1-adrenoceptor antagonists, which can be used for combination
therapy include, but are not limited to, doxazocin, terazosin, and
tamsulosin.
[1151] It has been reported that sigma-2 receptors are expressed in
high densities in a variety of tumor cell types (Vilner, B. J., et
al., Cancer Res. 55: 408-413 (1995)) and that sigma-2 receptor
agonists, such as CB-64D, CB-184 and haloperidol activate a novel
apoptotic pathway and potentiate antineoplastic drugs in breast
tumor cell lines. (Kyprianou, N., et al., Cancer Res. 62:313-322
(2002)). Therefore, another embodiment of the present invention is
directed to a composition effective to inhibit neoplasia comprising
a compound, or a pharmaceutically acceptable salt or prodrug of a
compound described herein, which functions as a caspase cascade
activator and inducer of apoptosis or inhibitor of tubulin
polymerization, in combination with at least one known sigma-2
receptor agonist, or a pharmaceutically acceptable salt of said
agonist. Examples of known sigma-2 receptor agonists which can be
used for combination therapy include, but are not limited to,
CB-64D, CB-184 and haloperidol.
[1152] It has been reported that combination therapy with
lovastatin, a HMG-CoA reductase inhibitor, and butyrate, an inducer
of apoptosis in the Lewis lung carcinoma model in mice, showed
potentiating antitumor effects (Giermasz, A., et al., Int. J.
Cancer 97:746-750 (2002)). Therefore, another embodiment of the
present invention is directed to a composition effective to inhibit
neoplasia comprising a compound, or a pharmaceutically acceptable
salt or prodrug of a compound described herein, which functions as
a caspase cascade activator and inducer of apoptosis or inhibitor
of tubulin polymerization, in combination with at least one known
HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt
of said agent. Examples of known HMG-CoA reductase inhibitors,
which can be used for combination therapy include, but are not
limited to, lovastatin, simvastatin, pravastatin, fluvastatin,
atorvastatin and cerivastatin.
[1153] It has been reported that HIV protease inhibitors, such as
indinavir or saquinavir, have potent anti-angiogenic activities and
promote regression of Kaposi sarcoma (Sgadari, C., et al., Nat.
Med. 8:225-232 (2002)). Therefore, another embodiment of the
present invention is directed to a composition effective to inhibit
neoplasia comprising a compound, or a pharmaceutically acceptable
salt or prodrug of a compound described herein, which functions as
a caspase cascade activator and inducer of apoptosis or inhibitor
of tubulin polymerization, in combination with at least one known
HIV protease inhibitor, or a pharmaceutically acceptable salt of
said agent. Examples of known HIV protease inhibitors, which can be
used for combination therapy include, but are not limited to,
amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir,
nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776,
and BMS-232,632.
[1154] It has been reported that synthetic retinoids, such as
fenretinide (N-(4-hydroxyphenyl)retinamide, 4HPR), have good
activity in combination with other chemotherapeutic agents, such as
cisplatin, etoposide or paclitaxel in small-cell lung cancer cell
lines (Kalemkerian, G. P., et al., Cancer Chemother. Pharmacol.
43:145-150 (1999)). 4HPR also was reported to have good activity in
combination with gamma-radiation on bladder cancer cell lines (Zou,
C., et al., Int. J. Oncol. 13:1037-1041 (1998)). Therefore, another
embodiment of the present invention is directed to a composition
effective to inhibit neoplasia comprising a compound, or a
pharmaceutically acceptable salt or prodrug of a compound described
herein, which functions as a caspase cascade activator and inducer
of apoptosis or inhibitor of tubulin polymerization, in combination
with at least one known retinoid and synthetic retinoid, or a
pharmaceutically acceptable salt of said agent. Examples of known
retinoids and synthetic retinoids, which can be used for
combination therapy include, but are not limited to, bexarotene,
tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,
.alpha.-difluoromethylornithine, ILX23-7553, fenretinide, and
N-4-carboxyphenyl retinamide.
[1155] It has been reported that proteasome inhibitors, such as
lactacystin, exert anti-tumor activity in vivo and in tumor cells
in vitro, including those resistant to conventional
chemotherapeutic agents. By inhibiting NF-kappaB transcriptional
activity, proteasome inhibitors may also prevent angiogenesis and
metastasis in vivo and further increase the sensitivity of cancer
cells to apoptosis (Almond, J. B., et al., Leukemia 16:433-443
(2002)). Therefore, another embodiment of the present invention is
directed to a composition effective to inhibit neoplasia comprising
a compound, or a pharmaceutically acceptable salt or prodrug of a
compound described herein, which functions as a caspase cascade
activator and inducer of apoptosis or inhibitor of tubulin
polymerization, in combination with at least one known proteasome
inhibitor, or a pharmaceutically acceptable salt of said agent.
Examples of known proteasome inhibitors, which can be used for
combination therapy include, but are not limited to, lactacystin,
MG-132, and PS-341.
[1156] It has been reported that tyrosine kinase inhibitors, such
as ST1571 (Gleevec.RTM. (imatinib mesylate)), have potent
synergetic effect in combination with other anti-leukemic agents,
such as etoposide (Liu, W. M., et al. Br. J. Cancer 86:1472-1478
(2002)). Therefore, another embodiment of the present invention is
directed to a composition effective to inhibit neoplasia comprising
a compound, or a pharmaceutically acceptable salt or prodrug of a
compound described herein, which functions as a caspase cascade
activator and inducer of apoptosis or inhibitor of tubulin
polymerization, in combination with at least one known tyrosine
kinase inhibitor, or a pharmaceutically acceptable salt of said
agent. Examples of known tyrosine kinase inhibitors, which can be
used for combination therapy include, but are not limited to,
Gleevec.RTM. (imatinib mesylate), ZD1839 Iressa.RTM. (gefitinib),
SH268, genistein, CEP2563, SU6668, SU11248, and EMD121974.
[1157] It has been reported that prenyl-protein transferase
inhibitors, such as farnesyl protein transferase inhibitor R115777,
possess preclinical antitumor activity against human breast cancer
(Kelland, L. R., et. al., Clin. Cancer Res. 7:3544-3550 (2001)).
Synergy of the protein farnesyltransferase inhibitor SCH66336 and
cisplatin in human cancer cell lines also has been reported (Adjei,
A. A., et al., Clin. Cancer. Res. 7:1438-1445 (2001)). Therefore,
another embodiment of the present invention is directed to a
composition effective to inhibit neoplasia comprising a compound,
or a pharmaceutically acceptable salt or prodrug of a compound
described herein, which functions as a caspase cascade activator
and inducer of apoptosis, in combination with at least one known
prenyl-protein transferase inhibitor, including farnesyl protein
transferase inhibitor, inhibitors of geranylgeranyl-protein
transferase type I (GGPTase-I) and geranylgeranyl-protein
transferase type-II, or a pharmaceutically acceptable salt of said
agent. Examples of known prenyl-protein transferase inhibitors,
which can be used for combination therapy include, but are not
limited to, R115777, SCH66336, L-778,123, BAL9611 and TAN-1813.
[1158] It has been reported that cyclin-dependent kinase (CDK)
inhibitors, such as flavopiridol, have potent synergetic effect in
combination with other anticancer agents, such as CPT-11, a DNA
topoisomerase I inhibitor in human colon cancer cells (Motwani, M.,
et al., Clin. Cancer Res. 7:4209-4219, (2001)). Therefore, another
embodiment of the present invention is directed to a composition
effective to inhibit neoplasia comprising a compound, or a
pharmaceutically acceptable salt or prodrug of a compound described
herein, which functions as a caspase cascade activator and inducer
of apoptosis or inhibitor of tubulin polymerization, in combination
with at least one known cyclin-dependent kinase inhibitor, or a
pharmaceutically acceptable salt of said agent. Examples of known
cyclin-dependent kinase inhibitor, which can be used for
combination therapy include, but are not limited to, flavopiridol,
UCN-01, roscovitine and olomoucine.
[1159] It has been reported that in preclinical studies COX-2
inhibitors were found to block angiogenesis, suppress solid tumor
metastases, and slow the growth of implanted gastrointestinal
cancer cells (Blanke, C. D., Oncology (Huntingt) 16(No. 4 Suppl.
3):17-21 (2002)). Therefore, another embodiment of the present
invention is directed to a composition effective to inhibit
neoplasia comprising a compound, or a pharmaceutically acceptable
salt or prodrug of a compound described herein, which functions as
a caspase cascade activator and inducer of apoptosis or inhibitor
of tubulin polymerization, in combination with at least one known
COX-2 inhibitor, or a pharmaceutically acceptable salt of said
inhibitor. Examples of known COX-2 inhibitors which can be used for
combination therapy include, but are not limited to, celecoxib,
valecoxib, and rofecoxib.
[1160] Another embodiment of the present invention is directed to a
composition effective to inhibit neoplasia comprising a
bioconjugate of a compound described herein, which functions as a
caspase cascade activator and inducer of apoptosis or inhibitor of
tubulin polymerization, in bioconjugation with at least one known
therapeutically useful antibody, such as Herceptin.RTM.
(trastuzumab) or Rituxan.RTM. (rituximab), growth factors, such as
DGF, NGF; cytokines, such as IL-2, IL-4, or any molecule that binds
to the cell surface. The antibodies and other molecules will
deliver a compound described herein to its targets and make it an
effective anticancer agent. The bioconjugates could also enhance
the anticancer effect of therapeutically useful antibodies, such as
Herceptin.RTM. (trastuzumab) or Rituxan.RTM. (rituximab).
[1161] Similarly, another embodiment of the present invention is
directed to a composition effective to inhibit neoplasia comprising
a compound, or a pharmaceutically acceptable salt or prodrug of a
compound described herein, which functions as a caspase cascade
activator and inducer of apoptosis or inhibitor of tubulin
polymerization, in combination with radiation therapy. In this
embodiment, the compound of the invention may be administered at
the same time as the radiation therapy is administered or at a
different time.
[1162] Yet another embodiment of the present invention is directed
to a composition effective for post-surgical treatment of cancer,
comprising a compound, or a pharmaceutically acceptable salt or
prodrug of a compound described herein, which functions as a
caspase cascade activator and inducer of apoptosis or inhibitor of
tubulin polymerization. The invention also relates to a method of
treating cancer by surgically removing the cancer and then treating
the animal with one of the pharmaceutical compositions described
herein.
[1163] A wide range of immune mechanisms operate rapidly following
exposure to an infectious agent. Depending on the type of
infection, rapid clonal expansion of the T and B lymphocytes occurs
to combat the infection. The elimination of the effector cells
following an infection is one of the major mechanisms for
maintaining immune homeostasis. The elimination of the effector
cells has been shown to be regulated by apoptosis. Autoimmune
diseases have lately been determined to occur as a consequence of
deregulated cell death. In certain autoimmune diseases, the immune
system directs its powerful cytotoxic effector mechanisms against
specialized cells, such as oligodendrocytes in multiple sclerosis,
the beta cells of the pancreas in diabetes mellitus, and thyrocytes
in Hashimoto's thyroiditis (Ohsako, S. & Elkon, K. B., Cell
Death Differ. 6:13-21 (1999)). Mutations of the gene encoding the
lymphocyte apoptosis receptor Fas/APO-1/CD95 are reported to be
associated with defective lymphocyte apoptosis and autoimmune
lymphoproliferative syndrome (ALPS), which is characterized by
chronic, histologically benign splenomegaly, generalized
lymphadenopathy, hypergammaglobulinemia, and autoantibody
formation. (Infante, A. J., et al., J. Pediatr. 133:629-633 (1998)
and Vaishnaw, A. K., et al., J. Clin. Invest. 103:355-363 (1999)).
It was reported that overexpression of Bcl-2, which is a member of
the bcl-2 gene family of programmed cell death regulators with
anti-apoptotic activity, in developing B cells of transgenic mice,
in the presence of T cell dependent costimulatory signals, results
in the generation of a modified B cell repertoire and in the
production of pathogenic autoantibodies (Lopez-Hoyos, M., et al.,
Int. J. Mol. Med. 1:475-483 (1998)). It is therefore evident that
many types of autoimmune disease are caused by defects of the
apoptotic process. One treatment strategy for such diseases is to
turn on apoptosis in the lymphocytes that are causing the
autoimmune disease (O'Reilly, L. A. & Strasser, A., Inflamm.
Res. 48:5-21 (1999)).
[1164] Fas-Fas ligand (FasL) interaction is known to be required
for the maintenance of immune homeostasis. Experimental autoimmune
thyroiditis (EAT), characterized by autoreactive T and B cell
responses and a marked lymphocytic infiltration of the thyroid, is
a good model to study the therapeutic effects of FasL. Batteux, F.,
et al., (J. Immunol. 162:603-608 (1999)) reported that by direct
injection of DNA expression vectors encoding FasL into the inflamed
thyroid, the development of lymphocytic infiltration of the thyroid
was inhibited and induction of infiltrating T cells death was
observed. These results show that FasL expression on thyrocytes may
have a curative effect on ongoing EAT by inducing death of
pathogenic autoreactive infiltrating T lymphocytes.
[1165] Bisindolylmaleimide VIII is known to potentiate Fas-mediated
apoptosis in human astrocytoma 1321N1 cells and in Molt-4T cells;
both of which were resistant to apoptosis induced by anti-Fas
antibody in the absence of bisindolylmaleimide VIII. Potentiation
of Fas-mediated apoptosis by bisindolylmaleimide VIII was reported
to be selective for activated, rather than non-activated, T cells,
and was Fas-dependent. Zhou T., et al., (Nat. Med. 5:42-48 (1999))
reported that administration of bisindolylmaleimide VIII to rats
during autoantigen stimulation prevented the development of
symptoms of T cell-mediated autoimmune diseases in two models, the
Lewis rat model of experimental allergic encephalitis and the Lewis
adjuvant arthritis model. Therefore, the application of a
Fas-dependent apoptosis enhancer, such as bisindolylmaleimide VIII,
may be therapeutically useful for the more effective elimination of
detrimental cells and inhibition of T cell-mediated autoimmune
diseases. Therefore, an effective amount of a compound, or a
pharmaceutically acceptable salt or prodrug of the compound of
Formulae I-Vc, which functions as a caspase cascade activator and
inducer of apoptosis, is an effective treatment for autoimmune
diseases.
[1166] Psoriasis is a chronic skin disease that is characterized by
scaly red patches. Psoralen plus ultraviolet A (PUVA) is a widely
used and effective treatment for psoriasis vulgarism Coven, et al.,
Photodermatol. Photoimmunol. Photomed. 15:22-27 (1999), reported
that lymphocytes treated with psoralen 8-MOP or TMP and UVA,
displayed DNA degradation patterns typical of apoptotic cell death.
Ozawa, et al., J. Exp. Med. 189:711-718 (1999) reported that
induction of T cell apoptosis could be the main mechanism by which
312-nm UVB resolves psoriasis skin lesions. Low doses of
methotrexate may be used to treat psoriasis to restore a clinically
normal skin. Heenen, et al., Arch. Dermatol. Res. 290:240-245
(1998), reported that low doses of methotrexate may induce
apoptosis and that this mode of action could explain the reduction
in epidermal hyperplasia during treatment of psoriasis with
methotrexate. Therefore, an effective amount of a compound, or a
pharmaceutically acceptable salt or prodrug of the compound of
Formulae I-Vc, which functions as a caspase cascade activator and
inducer of apoptosis, is an effective treatment for
hyperproliferative skin diseases, such as psoriasis.
[1167] Synovial cell hyperplasia is a characteristic of patients
with rheumatoid arthritis (RA). It is believed that excessive
proliferation of RA synovial cells, as well as defects in synovial
cell death, may be responsible for synovial cell hyperplasia.
Wakisaka, et al., Clin. Exp. Immunol. 114:119-128 (1998), found
that although RA synovial cells could die via apoptosis through a
Fas/FasL pathway, apoptosis of synovial cells was inhibited by
proinflammatory cytokines present within the synovium. Wakisaka, et
al. also suggested that inhibition of apoptosis by the
proinflammatory cytokines may contribute to the outgrowth of
synovial cells, and lead to pannus formation and the destruction of
joints in patients with RA. Therefore, an effective amount of a
compound, or a pharmaceutically acceptable salt or prodrug of the
compound of Formulae I-Vc, which functions as a caspase cascade
activator and inducer of apoptosis, is an effective treatment for
rheumatoid arthritis.
[1168] There has been an accumulation of convincing evidence that
apoptosis plays a major role in promoting resolution of the acute
inflammatory response. Neutrophils are constitutively programmed to
undergo apoptosis, thus limiting their pro-inflammatory potential
and leading to rapid, specific, and non-phlogistic recognition by
macrophages and semi-professional phagocytes (Savill, J., J.
Leukoc. Biol. 61:375-380 (1997)). Boirivant, et al.,
Gastroenterology 116:557-565 (1999), reported that lamina propria T
cells, isolated from areas of inflammation in Crohn's disease,
ulcerative colitis, and other inflammatory states, manifest
decreased CD2 pathway-induced apoptosis. In addition, studies of
cells from inflamed Crohn's disease tissue indicate that this
defect is accompanied by elevated Bcl-2 levels. Therefore, an
effective amount of a compound, or a pharmaceutically acceptable
salt or prodrug of the compound of Formulae I-Vc, which functions
as a caspase cascade activator and inducer of apoptosis, is an
effective treatment for inflammation.
[1169] Caspase cascade activators and inducers of apoptosis may
also be a desirable therapy in the elimination of pathogens, such
as HIV, Hepatitis C and other viral pathogens. The long lasting
quiescence, followed by disease progression, may be explained by an
anti-apoptotic mechanism of these pathogens leading to persistent
cellular reservoirs of the virions. It has been reported that HIV-1
infected T leukemia cells or peripheral blood mononuclear cells
(PBMCs) underwent enhanced viral replication in the presence of the
caspase inhibitor Z-VAD-fink. Furthermore, Z-VAD-fmk also
stimulated endogenous virus production in activated PBMCs derived
from HIV-1-infected asymptomatic individuals (Chinnaiyan, A., et
al., Nat. Med. 3:333 (1997)). Therefore, apoptosis serves as a
beneficial host mechanism to limit the spread of HIV and new
therapeutics using caspase/apoptosis activators are useful to clear
viral reservoirs from the infected individuals. Similarly, HCV
infection also triggers anti-apoptotic mechanisms to evade the
host's immune surveillance leading to viral persistence and
hepatocarcinogenesis (Tai, D. I., et al. Hepatology 3:656-64
(2000)). Therefore, apoptosis inducers are useful as therapeutics
for HIV, HCV, HBV, and other infectious disease.
[1170] Stent implantation has become the new standard angioplasty
procedure. However, in-stent restenosis remains the major
limitation of coronary stenting. New approaches have been developed
to target pharmacological modulation of local vascular biology by
local administration of drugs. This allows for drug applications at
the precise site and time of vessel injury. Numerous
pharmacological agents with antiproliferative properties are
currently under clinical investigation, including actinomycin D,
rapamycin or paclitaxel coated stents (Regar E., et al., Br. Med.
Bull. 59:227-248 (2001)). Therefore, apoptosis inducers, which are
antiproliferative, are useful as therapeutics for the prevention or
reduction of in-stent restenosis.
[1171] Another important aspect of the present invention is the
surprising discovery that compounds of the present invention are
potent and highly efficacious activators of caspase-3, inhibitors
of tubulin polymerization, and inhibitors of topoisomerase even in
drug resistant cancer cells, which enables these compounds to
inhibit the growth and proliferation of drug resistant cancer
cells, and to cause apoptosis and cell death in the drug resistant
cancer cells. Specifically, the compounds of the present invention
are not substrates for the MDR transporters such as Pgp-1 (MDR-1),
MRP-1 and BCRP. This is particularly surprising in view of the fact
that almost all of the commercially available tubulin-interacting
chemotherapeutics are substrates for multidrug resistance
transporters (MDRs).
[1172] Multidrug resistance is the major cause of chemotherapy
failure. Drug resistance is typically caused by ATP-dependent
efflux of drug from cells by ATP-binding cassette (ABC)
transporters. In particular, the ABC transporters ABCB1 (MDR-1, P
glycoprotein); ABCC1 (MRP1); and ABCG2 (BCRP, MXR) are typically
over-expressed in drug resistant tumors and thus are implicated in
drug resistance. In comparison to most standard anti-cancer drugs,
which are not effective in killing drug resistant cancer cells, the
compounds of the present invention are effective in killing drug
resistant cancer cells. Therefore, compounds of this invention are
useful for the treatment of drug resistant cancer.
[1173] Thus, another aspect of the present invention is the
application of the methods and compounds of the present invention
as described above to tumors that have acquired resistance to other
anticancer drugs. In one embodiment, a compound of the present
invention is administered to a cancer patient who has been treated
with another anti-cancer drug. In another embodiment, a compound of
the present invention is administered to a patient who has been
treated with and is not responsive to another anti-cancer drug or
developed resistance to such other anti-cancer compound. In another
embodiment, a compound of the present invention is administered to
a patient who has been treated with another anti-cancer drug and is
refractory to said other anti-cancer drug. The compounds of the
present invention can be used in treating cancer in a patient who
is not responsive or is resistant to any other anti-cancer agent.
Examples of such other anti-cancer agent may include alkylating
agents, antimitotic agents, topo I inhibitors, topo II inhibitors,
RNA/DNA antimetabolites, EGFR inhibitors, angiogenesis inhibitors,
tubulin inhibitors (e.g., vinblastine, Taxol.RTM. (paclitaxel), and
analogues thereof), proteosome inhibitors, etc., some of the
exemplary compounds of which are provided above and are general
known in the art, e.g., melphalan, chlorambucil, cyclophosamide,
ifosfamide, vincristine, mitoguazone, epirubicin, aclarubicin,
bleomycin, mitoxantrone, elliptinium, fludarabine, ocreotide,
retinoic acid, tamoxifen, Gleevec.RTM. (imatinib mesylate) and
alanosine. The compounds can be used in treating patients having
any type of diseases responsive to the inhibition of tubulin or
inhibition of topoisomerase (including but not limited to the types
of cancer described above) who are not responsive or become
resistant to another therapeutic agent, e.g., another anti-cancer
agent.
[1174] Pharmaceutical compositions within the scope of this
invention include all compositions wherein the compounds of the
present invention are contained in an amount that is effective to
achieve its intended purpose. While individual needs vary,
determination of optimal ranges of effective amounts of each
component is within the skill of the art. Typically, the compounds
may be administered to animals, e.g., mammals, orally at a dose of
0.0025 to 50 mg/kg of body weight, per day, or an equivalent amount
of the pharmaceutically acceptable salt thereof, to a mammal being
treated. Preferably, approximately 0.01 to approximately 10 mg/kg
of body weight is orally administered. For intramuscular injection,
the dose is generally approximately one-half of the oral dose. For
example, a suitable intramuscular dose would be approximately
0.0025 to approximately 25 mg/kg of body weight, and most
preferably, from approximately 0.01 to approximately 5 mg/kg of
body weight. If a known cancer chemotherapeutic agent is also
administered, it is administered in an amount that is effective to
achieve its intended purpose. The amounts of such known cancer
chemotherapeutic agents effective for cancer are well known to
those skilled in the art.
[1175] The unit oral dose may comprise from approximately 0.01 to
approximately 50 mg, preferably approximately 0.1 to approximately
10 mg of the compound of the invention. The unit dose may be
administered one or more times daily, as one or more tablets, each
containing from approximately 0.1 to approximately 10 mg,
conveniently approximately 0.25 to 50 mg of the compound or its
solvates.
[1176] In a topical formulation, the compound may be present at a
concentration of approximately 0.01 to 100 mg per gram of
carrier.
[1177] In addition to administering the compound as a raw chemical,
the compounds of the invention may be administered as part of a
pharmaceutical preparation containing suitable pharmaceutically
acceptable carriers comprising excipients and auxiliaries, which
facilitate processing of the compounds into preparations that may
be used pharmaceutically. Preferably, the preparations,
particularly those preparations which may be administered orally
and that may be used for the preferred type of administration, such
as tablets, dragees, and capsules, and also preparations that may
be administered rectally, such as suppositories, as well as
suitable solutions for administration by injection or orally,
contain from approximately 0.01 to 99 percent, preferably from
approximately 0.25 to 75 percent of active compound(s), together
with the excipient.
[1178] Also included within the scope of the present invention are
the non-toxic pharmaceutically acceptable salts of the compounds of
the present invention. Acid addition salts are formed by mixing a
solution of the compounds of the present invention with a solution
of a pharmaceutically acceptable non-toxic acid, such as
hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, citric acid, tartaric acid, carbonic acid, phosphoric acid,
oxalic acid, and the like. Basic salts are formed by mixing a
solution of the compounds of the present invention with a solution
of a pharmaceutically acceptable non-toxic base, such as sodium
hydroxide, potassium hydroxide, choline hydroxide, sodium
carbonate, Tris, N-methyl-glucamine and the like.
[1179] The pharmaceutical compositions of the invention may be
administered to any animal, which may experience the beneficial
effects of the compounds of the invention. Foremost among such
animals are mammals, e.g., humans and veterinary animals, although
the invention is not intended to be so limited.
[1180] The pharmaceutical compositions of the present invention may
be administered by any means that achieve their intended purpose.
For example, administration may be by parenteral, subcutaneous,
intravenous, intramuscular, intraperitoneal, transdermal, buccal,
intrathecal, intracranial, intranasal or topical routes.
Alternatively, or concurrently, administration may be by the oral
route. The dosage administered will be dependent upon the age,
health, and weight of the recipient, kind of concurrent treatment,
if any, frequency of treatment, and the nature of the effect
desired.
[1181] The pharmaceutical preparations of the present invention are
manufactured in a manner, which is itself known, e.g., by means of
conventional mixing, granulating, dragee-making, dissolving, or
lyophilizing processes. Thus, pharmaceutical preparations for oral
use may be obtained by combining the active compounds with solid
excipients, optionally grinding the resulting mixture and
processing the mixture of granules, after adding suitable
auxiliaries, if desired or necessary, to obtain tablets or dragee
cores.
[1182] Suitable excipients are, in particular: fillers, such as
saccharides, e.g. lactose or sucrose, mannitol or sorbitol;
cellulose preparations and/or calcium phosphates, e.g. tricalcium
phosphate or calcium hydrogen phosphate; as well as binders, such
as starch paste, using, e.g., maize starch, wheat starch, rice
starch, potato starch, gelatin, tragacanth, methyl cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or
polyvinyl pyrrolidone. If desired, disintegrating agents may be
added, such as the above-mentioned starches and also
carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof, such as sodium alginate.
Auxiliaries are, above all, flow-regulating agents and lubricants,
e.g., silica, talc, stearic acid or salts thereof, such as
magnesium stearate or calcium stearate, and/or polyethylene glycol.
Dragee cores are provided with suitable coatings which, if desired,
are resistant to gastric juices. For this purpose, concentrated
saccharide solutions may be used, which may optionally contain gum
arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or
titanium dioxide, lacquer solutions and suitable organic solvents
or solvent mixtures. In order to produce coatings resistant to
gastric juices, solutions of suitable cellulose preparations, such
as acetylcellulose phthalate or hydroxypropylmethyl-cellulose
phthalate, are used. Dye stuffs or pigments may be added to the
tablets or dragee coatings, e.g., for identification or in order to
characterize combinations of active compound doses.
[1183] Other pharmaceutical preparations, which may be used orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules may contain the active compounds in
the form of: granules, which may be mixed with fillers, such as
lactose; binders, such as starches; and/or lubricants, such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as fatty oils, or liquid
paraffin. In addition, stabilizers may be added.
[1184] Possible pharmaceutical preparations, which may be used
rectally include, e.g., suppositories, which consist of a
combination of one or more of the active compounds with a
suppository base. Suitable suppository bases are, e.g., natural or
synthetic triglycerides, or paraffin hydrocarbons. In addition, it
is also possible to use gelatin rectal capsules, which consist of a
combination of the active compounds with a base. Possible base
materials include, e.g., liquid triglycerides, polyethylene
glycols, or paraffin hydrocarbons.
[1185] Suitable formulations for parenteral administration include
aqueous solutions of the active compounds in water-soluble form,
e.g., water-soluble salts and alkaline solutions. In addition,
suspensions of the active compounds as appropriate oily injection
suspensions may be administered. Suitable lipophilic solvents or
vehicles include fatty oils, e.g., sesame oil, or synthetic fatty
acid esters, e.g., ethyl oleate or triglycerides or polyethylene
glycol-400 (the compounds are soluble in PEG-400), or cremophor, or
cyclodextrins. Aqueous injection suspensions may contain substances
which increase the viscosity of the suspension include, e.g.,
sodium carboxymethyl cellulose, sorbitol, and/or dextran.
Optionally, the suspension may also contain stabilizers.
[1186] In accordance with one aspect of the present invention,
compounds of the invention are employed in topical and parenteral
formulations and are used for the treatment of skin cancer.
[1187] The topical compositions of this invention are formulated
preferably as oils, creams, lotions, ointments and the like by
choice of appropriate carriers. Suitable carriers include vegetable
or mineral oils, white petrolatum (white soft paraffin), branched
chain fats or oils, animal fats and high molecular weight alcohol
(greater than C.sub.12). The preferred carriers are those in which
the active ingredient is soluble. Emulsifiers, stabilizers,
humectants and antioxidants may also be included, as well as agents
imparting color or fragrance, if desired. Additionally, transdermal
penetration enhancers may be employed in these topical
formulations. Examples of such enhancers are found in U.S. Pat.
Nos. 3,989,816 and 4,444,762.
[1188] Creams are preferably formulated from a mixture of mineral
oil, self-emulsifying beeswax and water in which mixture of the
active ingredient, dissolved in a small amount of an oil, such as
almond oil, is admixed. A typical example of such a cream is one
which includes approximately 40 parts water, approximately 20 parts
beeswax, approximately 40 parts mineral oil and approximately 1
part almond oil.
[1189] Ointments may be formulated by mixing a solution of the
active ingredient in a vegetable oil, such as almond oil, with warm
soft paraffin and allowing the mixture to cool. A typical example
of such an ointment is one which includes approximately 30% almond
oil and approximately 70% white soft paraffin by weight.
[1190] The following examples are illustrative, but not limiting,
of the method and compositions of the present invention. Other
suitable modifications and adaptations of the variety of conditions
and parameters normally encountered in clinical therapy and which
are obvious to those skilled in the art are within the spirit and
scope of the invention.
EXAMPLE 1
[1191] ##STR57##
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1192] a) 2,4-Dichloroquinazoline: A suspension of
2,4-quinazolinedione (5.0 g, 30.8 mmol) in neat phosphorylchloride
(50 mL) was heated under reflux for 18 h. The reaction mixture was
concentrated under vacuum. The crude product was purified by
chromatography (Silica gel) using ethyl acetate and hexane (1:4) to
give 2,4-dichloroquinazoline as white solid (4.8 g, 96%). .sup.1H
NMR (CDCl.sub.3): 8.29 (ddd, J=8.4, 2.1 and 0.9 Hz, 1H), 8.04-8.00
(m, 2H), 7.75 (ddd, J=8.1, 4.8 and 3.0 Hz, 1H).
[1193] b)
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A
solution of 2,4-dichloroquinazoline (300 mg, 1.51 mmol) and
4-methoxy-N-methylaniline (248 mg, 1.81 mmol) in 5 ml isopropanol
with a drop of concentrated HCl was stirred at room temperature for
8 h. White precipitates were observed in the reaction mixture. The
reaction was filtered, and the solid was washed with isopropanol,
and dried under vacuum to give white powder (260 mg, 87%). .sup.1H
NMR (CDCl.sub.3): 8.66 (dd, J=8.4 and 0.9 Hz, 1H), 7.75 (ddd,
J=8.1, 7.5 and 0.9 Hz, 1H), 7.26-7.19 (m, 3H), 7.14 (ddd, J=8.1,
7.5, 0.9 Hz, 1H), 7.06 (dd, J=6.9 and 2.4 Hz, 2H), 6.75 (d, J=8.7
Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H).
EXAMPLE 2
[1194] ##STR58##
(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine
[1195] The title compound was prepared from 2,4-dichloroquinazoline
(250 mg, 1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43
mmol) by a procedure similar to example 1b and was isolated as
white powder (210 mg, 84%). .sup.1H NMR (CDCl.sub.3): 8.69 (d,
J=8.4 Hz, 1H), 7.75 (dd, J=8.1 and 7.5 Hz, 1H), 7.39 (d, J=7.8 Hz,
2H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.74 (d, J=8.7
Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H).
EXAMPLE 3
[1196] ##STR59##
(2-Chloro-quinazolin-4-yl)-(4-chloro-phenyl)-methyl-amine
[1197] The title compound was prepared from 2,4-dichloroquinazoline
(60 mg, 0.302 mmol) and 4-chloro-N-methylaniline (50 mg, 0.332
mmol) by a procedure similar to example 1b and was isolated as
white powder (30 mg, 50%). .sup.1H NMR (CDCl.sub.3): 8.66 (d, J=8.4
Hz, 1H), 7.78 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.57 (d, J=8.7 Hz,
2H), 7.28 (d, J=8.7 Hz, 2H), 7.19 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H),
6.79 (d, J=8.4 Hz, 1H), 3.83 (s, 3H).
EXAMPLE 4
[1198] ##STR60##
(2-Chloro-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine
[1199] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol)
by a procedure similar to example 1b and was isolated as yellow
powder (6 mg, 12%). .sup.1H NMR (CDCl.sub.3): 8.24 (d, J=8.7 Hz,
2H), 7.81 (dd, J=8.1, and 2.4 Hz, 1H), 7.68 (ddd, J=8.1, 7.5 and
2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.18 (ddd, J=8.1, 7.5 and 2.4
Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 3.75 (s, 3H).
EXAMPLE 5
[1200] ##STR61##
(2-Chloro-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-methyl-amine
[1201] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and 4-trifluoromethoxy-N-methylaniline (20
.mu.L, 0.302 mmol) by a procedure similar to example 1b and was
isolated as white powder (22 mg, 44%). .sup.1H NMR (CDCl.sub.3):
7.93 (dd, J=8.4, and 0.6 Hz, 1H), 7.61 (ddd, J=8.4, 4.5 and 1.2 Hz,
1H), 7.29-7.22 (m, 4H), 7.06 (ddd, J=8.4, 4.5 and 1.2 Hz, 1H), 6.91
(d, J=8.7 Hz, 1H), 3.65 (s, 3H).
EXAMPLE 6
[1202] ##STR62##
(2-Chloro-quinazolin-4-yl)-phenyl-methyl-amine
[1203] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and N-methylaniline (20 .mu.L, 0.301 mmol) by a
procedure similar to example 1b and was isolated as white powder
(40 mg, 80%). .sup.1H NMR (CDCl.sub.3): 7.76 (dd, J=8.7, and 1.5
Hz, 1H), 7.56 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.46-7.35 (m, 3H),
7.24-7.20 (m, 2H), 6.98 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 6.90 (dd,
J=8.7 and 1.5 Hz, 1H), 3.65 (s, 3H).
EXAMPLE 7
[1204] ##STR63##
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine
[1205] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and 4-methoxyaniline (45 mg, 0.326 mmol) by a
procedure similar to example 1b and was isolated as off white
powder (55 mg, 77%). .sup.1H NMR (CDCl.sub.3): 10.25 (s, 1H), 8.58
(d, J=8.4 Hz, 1H), 7.88 (t, J=7.2 Hz, 1H), 7.71-7.63 (m, 4H),
7.03-6.99 (m, 2H), 3.79 (s, 3H).
EXAMPLE 8
[1206] ##STR64##
(2-Chloro-quinazolin-4-yl)-(4-methyl-phenyl)-amine
[1207] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and 4-methylaniline (32 mg, 0.30 mmol) by a
procedure similar to example 1b and was isolated as white powder
(15 mg, 30%). .sup.1H NMR (CDCl.sub.3): 7.97-7.89 (m, 3H), 7.71 (d,
J=6.6 Hz, 2H), 7.64 (ddd, J=8.4, 6.6 and 2.1 Hz, 1H), 7.33 (d,
J=6.6 Hz, 2H), 2.47 (s, 3H).
EXAMPLE 9
[1208] ##STR65##
2-Chloro-4-(5-methoxyindol-1-yl)quinazoline
[1209] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and 5-methoxyindole (40 mg, 0.302 mmol) similar
to example 1b and was isolated as white powder (14 mg, 28%).
.sup.1H NMR (CDCl.sub.3): 8.91 (s, 1H), 8.70 (ddd, J=8.4, 2.8 and
1.5 Hz, 1H), 8.01 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 7.92 (dd, J=6.9
and 1.5 Hz, 1H), 7.87 (m, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.61 (ddd,
J=8.4, 6.9 and 1.2 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.97 (dd, J=9.0
and 2.4 Hz, 1H), 3.88 (s, 3H).
EXAMPLE 10
[1210] ##STR66##
N.sup.2-Hydroxyl-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,4-
-diamine
[1211] A mixture of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg,
0.050 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol) in
isopropanol was heated by microwave at 130.degree. C. for 20 min.
The solvent was evaporated under reduced pressure. The product was
isolated by preparative TLC as white solid (6 mg, 40%) using
acetone:hexane (1:1) as eluent. .sup.1H NMR (CDCl.sub.3): 7.65 (d,
J=8.4 Hz, 1H), 7.47 (ddd, J=8.4, 6.9 and 1.8 Hz, 1H), 7.08 (d,
J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.88-6.75 (m, 2H), 3.86 (s,
3H), 3.48 (s, 3H).
EXAMPLE 11
[1212] ##STR67##
N.sup.2-(2-Hydroxylethyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-quinaz-
oline-2,4-diamine
[1213] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg,
0.050 mmol) and 2-hydroxylethylamine (20 .mu.L) by a procedure
similar to example 10 and was isolated as white solid (12 mg, 80%).
.sup.1H NMR (CDCl.sub.3): 7.43 (ddd, J=8.4, 1.5 and 0.9 Hz, 1H),
7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.92-6.90
(m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H), 6.66 (ddd, J=7.2, 6.3 and
1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H), 3.69-3.65 (m, 2H),
3.48 (s, 3H).
EXAMPLE 12
[1214] ##STR68##
N.sup.4-(4-Methoxy-phenyl)-N.sup.4-methyl-quinazoline-2,4-diamine
[1215] Title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg,
0.033 mmol) and 7 M ammonia in methanol (1 mL) by a procedure
similar to example 10 (5 mg, 50%). .sup.1H NMR (CDCl.sub.3): 7.44
(m, 2H), 7.16 (m, 2H), 6.96-6.95 (m, 2H), 6.88 (dd, J=8.4 and 1.5
Hz, 1H), 6.72 (ddd, J=8.7, 6.6 and 1.8 Hz, 1H), 3.86 (s, 3H), 3.72
(s, 3H).
EXAMPLE 13
[1216] ##STR69##
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4--
methyl-quinazoline-2,4-diamine
[1217] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (45 mg,
0.151 mmol) and 3,7-dimethyl-2,6-diene-octamine (60 .mu.L, 0.301
mmol) by a procedure similar to example 10 and was isolated as
white powder (15 mg, 33%). .sup.1H NMR (CDCl.sub.3): 7.42 (d, J=8.1
Hz, 1H), 7.32 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 7.12-7.07 (m, 2H),
6.91-6.85 (m, 3H), 6.65 (ddd, J=8.7, 6.6 and 1.5 Hz, 1H), 5.41 (t,
J=7.5 Hz, 1H), 5.11 (ddd, J=6.6, 5.1 and 1.2 Hz, 1H), 4.15 (d,
J=6.9 Hz, 2H), 3.85 (s, 3H), 3.50 (s, 3H), 2.12-2.03 (m, 4H), 1.75
(s, 3H), 1.70 (s, 3H), 1.61 (s, 3H).
EXAMPLE 14
[1218] ##STR70##
N.sup.4-(4-Methoxy-phenyl)-N.sup.4-methyl-N.sup.2-(2-morpholin-4-yl-ethyl)-
-quinazoline-2,4-diamine
[1219] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg,
0.033 mmol) and 2-morpholin-4-yl-ethylamine (30 .mu.L) by a
procedure similar to example 10 and was isolated as white powder
(10 mg, 100%). .sup.1H NMR (CDCl.sub.3): 7.42 (dd, J=8.7 and 1.2
Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.10-7.09 (m, 2H),
6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and 1.4 Hz, 1H), 3.82 (s,
3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44 (m, 6H).
EXAMPLE 15
[1220] ##STR71##
(4-Methoxy-phenyl)-methyl-(2-morpholin-4-yl-quinazolin-4-yl)-amine
[1221] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg,
0.050 mmol) and morpholine (30 .mu.L) by a procedure similar to
example 10 and was isolated as white powder (10 mg, 66%). .sup.1H
NMR (CDCl.sub.3): 7.46 (d, J=8.4 Hz, 1H), 7.35 (ddd, J=8.4, 6.6 and
1.5 Hz, 1H), 7.13-7.07 (m, 2H), 6.91-6.85 (m, 3H), 6.67 (ddd,
J=8.4, 6.6 and 1.5 Hz, 1H), 3.94-3.90 (m, 4H), 3.85-3.81 (m, 7H),
3.52 (s, 3H).
EXAMPLE 16
[1222] ##STR72##
N.sup.2-(3,7-Dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methyl-phenyl)-N.sup.4-m-
ethyl-quinazoline-2,4-diamine
[1223] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine (50 mg,
0.177 mmol) and 3,7-dimethyl-2,6-diene-octamine (50 .mu.L, 0.265
mmol) by a procedure similar to example 10 and was isolated as
white powder (7 mg, 14%). .sup.1H NMR (CDCl.sub.3): 7.45 (d, J=8.1
Hz, 1H), 7.35 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.16 (d, J=7.8 Hz,
2H), 7.06 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.66 (ddd,
J=8.1, 6.6 and 1.5 Hz, 1H), 5.41 (dd, J=6.9 and 5.7 Hz, 1H), 5.11
(dd, J=5.7 and 4.2 Hz, 1H), 4.15 (t, J=6.9 Hz, 2H), 3.50 (s, 3H),
2.36 (s, 3H), 2.12-2.03 (m, 4H), 1.75 (s, 3H), 1.68 (s, 3H), 1.61
(s, 3H).
EXAMPLE 17
[1224] ##STR73##
[1225]
N.sup.6-(4-Methoxy-phenyl)-N.sup.6-methyl-9H-purine-2,6-diamine
[1226] The title compound was prepared from
2-amino-6-chloro-9H-purine (100 mg, 0.546 mmol) and
4-methoxy-N-methyl-aniline (127 mg, 0.656 mmol) by a procedure
similar to example 1b and was isolated as white powder (5 mg, 5%).
.sup.1H NMR (CDCl.sub.3): 7.54 (s, 1H), 7.25 (d, J=8.7 Hz, 2H),
6.98 (d, J=8.7 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 3H).
EXAMPLE 18
[1227] ##STR74##
N.sup.2,N.sup.4-Dimethyl-N.sup.2,N.sup.4-diphenyl-quinazoline-2,4-diamine
[1228] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and N-methylaniline (40 .mu.L, 0.401 mmol) by a
procedure similar to example 1b and was isolated as white powder
(33 mg, 66%). .sup.1H NMR (CDCl.sub.3): 7.54 (dd, J=8.2 and 0.6 Hz,
1H), 7.45 (dd, J=8.4 and 1. Hz, 1H), 7.44-7.29 (m, 6H), 7.21-7.10
(m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz, 1H), 6.67 (ddd, J=8.4, 7.2 and
1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).
EXAMPLE 19
[1229] ##STR75##
[1230]
N.sup.2,N.sup.4-Bis(4-chloro-phenyl)-N.sup.2,N.sup.4-dimethyl-quin-
azoline-2,4-diamine
[1231] The title compound was prepared from 2,4-dichloroquinazoline
(60 mg, 0.3.02 mmol) and 4-chloro-N-methylaniline (72 mg, 0.513
mmol) by a procedure similar to example 1b and was isolated as
white powder (50 mg, 83%). .sup.1H NMR (CDCl.sub.3): 8.93 (d, J=8.4
Hz, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.47-7.44 (m, 4H), 7.32-7.27 (m,
2H), 7.18-7.14 (m, 2H), 6.95 (t, J=7.5 Hz, 1H), 6.67 (d, J=8.4 Hz,
1H), 4.02 (s, 3H), 3.25 (s, 3H).
EXAMPLE 20
[1232] ##STR76##
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1233] A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg,
0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0.401 mmol) and
sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and
water (2.5 mL) was stirred at room temperature for 48 h. The
reaction mixture was evaporated to dryness and the residue was
crystallized using ethanol/water and isolated as white solid (60
mg, 60%). .sup.1H NMR (CDCl.sub.3): 8.19 (s, 1H), 7.32-7.26 (m,
2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H),
3.75 (s, 3H), 3.32 (s, 3H).
EXAMPLE 21
[1234] ##STR77##
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine
[1235] The title compound was prepared from
2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and
4-methoxyaniline (49 mg, 0.386 mmol) by a procedure similar to
example 1b and was isolated as white powder (10 mg, 10%). .sup.1H
NMR (CDCl.sub.3): 8.10 (s, 1H), 7.70-7.68 (m, 2H), 7.23 (s, 1H),
6.96-6.94 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.85 (s, 3H).
EXAMPLE 22
[1236] ##STR78##
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methyl-phenyl)-methyl-amine
[1237] The title compound was prepared from
2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and
N-methyl-p-tolylamine (49 mg, 0.386 mmol) by a procedure similar to
example 1b and was isolated as white powder (8 mg, 8%). .sup.1H NMR
(CDCl.sub.3): 7.27 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.08
(s, 1H), 6.26 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H), 3.28 (s, 3H),
2.37 (s, 3H).
EXAMPLE 23
[1238] ##STR79##
6,7-Dimethoxy-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-N.sup.2-(2-morphol-
in-4-yl-ethyl)-quinazoline-2,4-diamine
[1239] The title compound was prepared from
(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
(50 mg, 0.139 mmol) and 2-morpholin-4-yl-ethylamine (25 .mu.L,
0.167 mmol) by a procedure similar to example 10 and was isolated
as white powder (27 mg, 54%). .sup.1H NMR (CDCl.sub.3): 7.21 (d,
J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 6.13 (s, 1H),
3.95 (s, 3H), 3.84 (s, 3H), 3.77-3.74 (m, 4H), 3.71-3.66 (m, 2H),
3.60 (s, 3H), 3.25 (s, 3H), 2.70 (t, J=7.2 Hz, 2H), 2.59-2.56 (m,
4H).
EXAMPLE 24
[1240] ##STR80##
6,7-Dimethoxy-N.sup.2-(3,7-dimethyl-octa-2,6-dienyl)-N.sup.4-(4-methoxy-ph-
enyl)-N.sup.4-methyl-quinazoline-2,4-diamine
[1241] The title compound was prepared from
(2-chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
(60 mg, 0.167 mmol) and 3,7-dimethyl-2,6-diene-octamine (50 mg,
0.424 mmol) by a procedure similar to example 10 and was isolated
as white powder (68 mg, 85%). .sup.1H NMR (CDCl.sub.3): 7.15 (d,
J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.85 (s, 1H), 6.29 (s, 1H),
5.41 (dd, J=6.9 and 6.0 Hz, 1H), 5.12 (ddd, J=6.9, 5.1 and 4.2 Hz,
1H), 4.69 (t, J=4.5 Hz, 1H), 4.12 (t, J=5.7 Hz, 2H), 3.91 (s, 3H),
3.79 (s, 3H), 3.49 (s, 3H), 3.30 (s, 3H), 2.13-2.05 (m, 4H), 1.75
(s, 3H), 1.69 (s, 3H), 1.61 (s, 3H).
EXAMPLE 25
[1242] ##STR81##
(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1243] a) 4-Chloro-5,6,7,8-tetrahydroquinazoline: The title
compound was prepared from 5,6,7,8-tetrahydro-4-quinazolinone (50
mg, 0.301 mmol) and phosphorylchloride (5 mL) by a procedure
similar to example 1a and was isolated as off white solid (20 mg,
40%). .sup.1H NMR (CDCl.sub.3): 8.60 (s, 1H), 2.75 (m, 2H), 1.76
(m, 4H), 1.53 (m, 2H).
[1244] b)
(5,6,7,8-Tetrahydro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl--
amine: The title compound was prepared from
4-chloro-5,6,7,8-tetrahydroquinazoline (20 mg, 0.099 mmol) and
4-methoxy-N-methylaniline (16 mg, 0.111 mmol) by a procedure
similar to example 1b and was isolated as white powder (25 mg,
83%). .sup.1H NMR (CDCl.sub.3): 8.60 (s, 1H), 7.02-6.96 (m, 2H),
6.87-6.82 (m, 2H), 3.83 (s, 3H), 3.39 (s, 3H), 2.75 (t, J=6.6 Hz,
2H), 1.76 (m, 4H), 1.53 (m, 2H).
EXAMPLE 26
[1245] ##STR82##
(2-Chloro-quinazolin-4-yl)-(4-methoxy-benzyl)-methyl-amine
[1246] The title compound was prepared from 2,4-dichloroquinazoline
(50 mg, 0.251 mmol) and N-methyl-4-methoxybenzylamine (45 mg, 0.302
mmol) by a procedure similar to example 1b and was isolated as
white powder (30 mg, 60%). .sup.1H NMR (CDCl.sub.3): 7.93 (dd,
J=8.4 and 1.2 Hz, 1H), 7.78 (dd, J=8.4 and 1.5 Hz, 1H), 7.68 (ddd,
J=8.4, 7.5 and 1.5 Hz, 1H), 7.34-7.26 (m, 3H), 6.96-6.92 (m, 2H),
4.94 (s, 2H), 3.83 (s, 3H), 3.31 (s, 3H).
EXAMPLE 27
[1247] ##STR83##
(2-Chloro-quinazolin-4-yl)-pyridin-4-yl-amine
[1248] To a stirred suspension of 2,4-dichloroquinazoline (42 mg,
0.21 mmol) and 4-aminopyridine (21 mg, 0.22 mmol) in 3 mL of
anhydrous isopropanol was added a drop of concentrated HCl and the
mixture was stirred overnight. Solid precipitates were observed and
the mixture was filtered. The solid was washed with cold
isopropanol and dried to give the title compound as white solid (38
mg, 0.13 mmol, 61%). .sup.1H NMR (DMSO-d.sub.6): 8.60 (d, J=7.5 Hz,
2H), 8.18-8.20 (m, 2H), 8.07-8.10 (m, 1H), 7.90-7.96 (m, 1H), 7.18
(d, J=7.8 Hz, 2H).
EXAMPLE 28
[1249] ##STR84##
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine
[1250] A mixture of 2,4-dichloroquinazoline (61 mg, 0.31 mmol),
5-amino-2-methoxy pyridine (40 mg, 0.32 mmol) and sodium acetate
(38 mg, 0.46 mmol) in 3 mL of solvent (THF:water/1:1) was stirred
at 60.degree. C. for 45 min. The reaction mixture was diluted with
25 mL of ethyl acetate. It was washed with saturated NaCl, dried
over anhydrous MgSO.sub.4, filtered and concentrated. The crude
product was purified by chromatography (40% ethyl acetate/hexanes)
on silica gel to give the title compound (86 mg, 0.30 mmol, 98%).
.sup.1H NMR (CDCl.sub.3): 8.38 (d, J=3.0 Hz, 1H), 8.07 (dd, J=8.7
and 3.0 Hz, 1H), 7.89-7.79 (d, J=8.4 Hz, 1H), 7.86 (m, 2H),
7.59-7.53 (m, 2H), 6.84 (d, J=8.7 Hz, 1H), 3.96 (s, 3H).
EXAMPLE 29
[1251] ##STR85##
(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine
[1252] The title compound was prepared from 2,4-dichloroquinazoline
and 2,3-dimethoxyaniline by a procedure similar to example 28 (84%
yield). .sup.1H NMR (CDCl.sub.3): 8.57 (s, broad, 1H), 8.38 (d,
J=8.4 Hz, 1H), 7.77-7.86 (m, 3H), 7.55-7.61 (m, 1H), 7.15 (t, J=8.7
Hz, 1H), 6.73-6.75 (m, 1H), 4.00 (s, 3H), 3.91 (s, 3H).
EXAMPLE 30
[1253] ##STR86##
(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine
[1254] The title compound was prepared from 2,4-dichloroquinazoline
and 2,4-dimethoxyaniline by a procedure similar to example 28 (92%
yield). .sup.1H NMR (CDCl.sub.3): 8.59 (d, J=8.7 Hz, 1H), 8.22 (s,
broad, 1H), 7.75-7.81 (m, 3H), 7.52 (ddd, J=8.4, 6.6 and 2.1 Hz,
1H), 6.52-6.59 (m, 2H), 3.95 (s, 3H), 3.82 (s, 3H).
EXAMPLE 31
[1255] ##STR87##
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine
[1256] The title compound was prepared from 2,4-dichloroquinazoline
and 2,5-dimethoxyaniline by a procedure similar to example 28 (98%
yield). .sup.1H NMR (CDCl.sub.3): 8.59 (d, J=3.0 Hz, 1H), 8.53 (s,
broad, 1H), 7.78-7.87 (m, 3H), 7.57 (ddd, J=8.4, 6.6 and 1.8 Hz,
1H), 6.88 (d, J=9.0 Hz, 1H), 6.60 (dd, J=8.7 and 3.0 Hz, 1H), 3.97
(s, 3H), 3.87 (s, 3H).
EXAMPLE 32
[1257] ##STR88##
(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine
[1258] The title compound was prepared from 2,4-dichloroquinazoline
and 3-methoxyaniline by a procedure similar to example 28 (80%
yield). .sup.1H NMR (CDCl.sub.3): 7.79-7.87 (m, 3H), 7.54-7.62 (m,
3H), 7.20-7.35 (m, 3H), 6.76 (dd, J=8.4 and 2.1 Hz, 1H), 3.87 (s,
3H).
EXAMPLE 33
[1259] ##STR89##
(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine
[1260] The title compound was prepared from 2,4-dichloroquinazoline
and 2-methoxyaniline by a procedure similar to example 28 (35%
yield). .sup.1H NMR (CDCl.sub.3): 8.76-8.79 (m, 1H), 8.50 (s,
broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m,
2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H).
EXAMPLE 34
[1261] ##STR90##
(4-Methoxy-phenyl)-methyl-quinazolin-4-yl-amine
[1262] The title compound was prepared from 4-chloroquinazoline and
4-methoxy-N-methylaniline by a procedure similar to example 28 (79%
yield). .sup.1H NMR (CDCl.sub.3): 8.81 (s, 1H), 7.81 (d, J=8.1 Hz,
1H), 7.57 (ddd, J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H),
7.03-7.06 (m, 2H), 6.9-6.93 (m, 2H).
EXAMPLE 35
[1263] ##STR91##
(4-Methyl-phenyl)-methyl-quinazolin-4-yl-amine
[1264] The title compound was prepared from 4-chloroquinazoline and
4-methyl-N-methylaniline by a procedure similar to example 28 (80%
yield). .sup.1H NMR (CDCl.sub.3): 8.23 (s, 1H), 7.82 (d, J=8.4 Hz,
1H), 7.57 (ddd, J=8.4, 6.3 and 1.8 Hz, 1H), 7.17-7.20 (m, 2H),
7.00-7.10 (m, 4H), 3.61 (s, 3H), 2.39 (s, 3H).
EXAMPLE 36
[1265] ##STR92##
(2-Chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
[1266] To a solution of
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine (19.4 mg,
0.068 mmol) in 1 mL of DMF cooled at 0.degree. C. was added methyl
iodide (100 uL, 1.61 mmol), followed by sodium hydride (60% oil
suspension, 5 mg, 0.13 mmol). The mixture was stirred at 0.degree.
C. for 1 h, then allowed to warm to room temperature and stirred
for 1 h. The reaction mixture was quenched by adding 50 uL of
water, diluted with 25 mL of ethyl acetate, washed with water (25
mL.times.3), saturated NaCl, dried over anhydrous MgSO.sub.4,
filtered and concentrated. The residue was purified by
chromatography (20% ethyl acetate/hexanes) to give the title
compound (14.3 mg, 0.048 mmol, 70%). .sup.1H NMR (CDCl.sub.3) 8.06
(d, J=2.7 Hz, 1H), 7.57-7.79 (m, 1H), 7.60 (ddd, J=8.1, 6.6 and 1.2
Hz, 1H), 7.44 (dd, J=8.7 and 2.7 Hz, 1H), 7.09 (ddd, J=8.1, 6.6 and
1.2 Hz, 1H), 6.99-7.02 (m, 1H), 6.82 (dd, J=8.7 and 0.6 Hz, 1H),
3.97 (s, 3H), 3.61 (s, 3H).
EXAMPLE 37
[1267] ##STR93##
(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine
[1268] a) Isopropyl-(4-methoxy-phenyl)-amine: To a stirred solution
of p-methoxy-aniline (443 mg, 3.60 mmol) and acetone (265 uL, 3.61
mmol) in 10 mL of anhydrous methanol at room temperature was added
a drop of glacial acetic acid followed by NaCNBH.sub.3 (226 mg,
3.60 mmol) portion wise over 0.5 h. The reaction mixture was then
stirred for 3 h at room temperature. The solvents were removed
under vacuum, and the residue was dissolved in 50 mL of ethyl
acetate. The solution was washed with 5% NaHCO.sub.3, saturated
NaCl, dried over anhydrous MgSO.sub.4, filtered and concentrated.
The crude was purified by chromatography (10% ethyl
acetate/hexanes) to give the title compound (287 mg, 1.92 mmol,
48%). .sup.1H NMR (CDCl.sub.3): 6.77 (d, J=8.7 Hz, 2H), 6.57 (d,
J=6.7 Hz, 2H), 3.74 (s, 3H), 3.54 (m, 1H, J=6.3), 2.94 (s, broad,
1H), 1.92 (d, J=6.3 Hz, 6H).
[1269] b)
(2-Chloro-quinazolin-4-yl)-isopropyl-(4-methoxy-phenyl)-amine: The
title compound was prepared from isopropyl-(4-methoxy-phenyl)-amine
and 2,4-dichloroquinazoline by a procedure similar to example 27
(51% yield). .sup.1H NMR (DMSO-d.sub.6): 8.30-8.34 (m, 1H),
8.17-8.22 (m, 1H), 8.05-8.08 (m, 1H), 7.90-7.96 (m, 1H), 7.77 (d,
J=8.1 Hz, 2H), 1.09 (d, J=8.4 Hz, 2H), 3.62 (m, 1H), 3.79 (s, 3H),
1.24 (d, J=6.0 Hz, 6H).
EXAMPLE 38
[1270] ##STR94##
(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine
[1271] a) Cyclohexyl-(4-methoxy-phenyl)-amine: The title compound
was prepared from cyclohexanone and p-methoxy aniline by a
procedure similar to example 37a (60% yield). .sup.1H NMR
(CDCl.sub.3): 6.76 (d, J=9.0 Hz, 2H), 6.57 (d, J=9.0 Hz, 2H), 3.75
(s, 3H), 3.16 (m, 1H), 2.34 (m, 1H), 1.61-1.89 (m, 5H), 1.05-1.42
(m, 5H).
[1272] b)
(2-Chloro-quinazolin-4-yl)-cyclohexyl-(4-methoxy-phenyl)-amine: The
title compound was prepared from
cyclohexyl-(4-methoxy-phenyl)-amine and 2,4-dichloroquinazoline by
a procedure similar to example 27 (93% yield). .sup.1H NMR
(DMSO-d.sub.6): 8.32 (dd, J=8.4 and 1.5 Hz, 1H), 8.22 (ddd, J=8.4,
7.5 and 1.5 Hz, 1H), 8.05-8.09 (m, 1H), 7.93 (ddd, J=8, 6.9, 0.9
Hz, 1H), 7.45 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 3.27-3.34
(m, 1H), 1.89-1.92 (m, 2H), 1.73-1.76 (m, 2), 1.36-1.62 (m, 3H),
1.07-1.28 (m, 3H).
EXAMPLE 39
[1273] ##STR95##
(2-Chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-methyl-amine
[1274] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyl
iodide by a procedure similar to example 36 (71% yield). .sup.1H
NMR (CDCl.sub.3): 7.74 (d, J=8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12
(t, J=8.4 Hz, 1H), 6.94-7.01 (m, 3H), 6.87 (dd, J=8.1 and 1.5 Hz,
1H), 3.89 (s, 3H), 3.56 (s, 3H).
EXAMPLE 40
[1275] ##STR96##
(2-Chloro-quinazolin-4-yl)-ethyl-(4-methoxy-phenyl)-amine
[1276] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl
iodide by a procedure similar to example 36 (58% yield). .sup.1H
NMR (CDCl.sub.3): 7.69-7.72 (m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5
Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H),
4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).
EXAMPLE 41
[1277] ##STR97##
(2-Chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-methyl-amine
[1278] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(2,4-dimethoxy-phenyl)-amine and methyl
iodide by a procedure similar to example 36 (91% yield). .sup.1H
NMR (CDCl.sub.3): 7.70-7.73 (m, 1H), 7.54 (ddd, J=8.7, 6.3 and 2.1
Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.93-7.23 (m, 2H), 6.50-6.57 (m,
2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.52 (s, 3H).
EXAMPLE 42
[1279] ##STR98##
(2-Chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-methyl-amine
[1280] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl
iodide by a procedure similar to example 36 (78% yield). .sup.1H
NMR (CDCl.sub.3): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1
Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H),
3.75 (s, 3H), 3.58 (s, 3H), 3.56 (s, 3H).
EXAMPLE 43
[1281] ##STR99##
(2-Chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-methyl-amine
[1282] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl
iodide by a procedure similar to example 36 (60% yield). .sup.1H
NMR (CDCl.sub.3): 7.74-7.76 (m, 1H), 7.57 (ddd, J=8.4, 6.0 and 1.8
Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 6.98-7.03 (m, 2H), 6.89 (dd, J=8.1
and 2.4 Hz, 1H), 6.75-6.81 (m, 2H), 3.65 (s, 3H), 3.37 (s, 3H).
EXAMPLE 44
[1283] ##STR100##
(2-Chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-methyl-amine
[1284] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(2-methoxy-phenyl)-amine and methyl
iodide by a procedure similar to example 36 (72% yield). .sup.1H
NMR (CDCl.sub.3): 7.72 (d, J=8.1 Hz, 1H), 7.54 (ddd, J=8.4, 6.6 and
1.5 Hz, 1H), 7.20 (dd, J=8.4 and 1.8 Hz, 1H), 6.87-7.04 (m, 4H),
3.67 (s, 3H), 3.56 (s, 3H).
EXAMPLE 45
[1285] ##STR101##
(2-Chloro-quinazolin-4-yl)-cyclopentyl-(4-methoxy-phenyl)-amine
[1286] a) Cyclopentyl-(4-methoxy-phenyl)-amine: The title compound
was prepared from cyclopentanone and p-methoxy aniline by a
procedure similar to example 37a (68% yield). .sup.1H NMR
(CDCl.sub.3): 6.78 (d, J=8.7 Hz, 2H), 6.57 (d, J=8.7 Hz, 2H), 3.74
(s, 3H), 3.18 (m, 1H), 2.23 (m, 1H), 1.82-2.01 (m, 2H), 1.52-1.73
(m, 4H), 1.38-1.49 (m, 2H).
[1287] b)
(2-Chloro-quinazolin-4-yl)-cyclopentyl-(4-methoxy-phenyl)-amine- :
The title compound was prepared from
cyclopentyl-(4-methoxy-phenyl)-amine and 2,4-dichloroquinazoline by
a procedure similar to example 27 (39% yield). .sup.1H NMR
(CDCl.sub.3): 8.31 (dd, J=8.7 and 1.3 Hz, 1H), 8.12 (ddd, J=8.4,
7.2 and 1.3 Hz, 1H), 8.12-8.08 (m, 1H), 7.93 (ddd, J=8.3, 7.2 and
1.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H),
3.24-3.33 (m, 1H), 2.22-2.01 (m, 2H), 1.51-1.75 (m, 4H), 1.32-1.49
(m, 2H).
EXAMPLE 46
[1288] ##STR102##
N.sup.2-[2-(1H-Imidazol-4-yl)-ethyl]-N.sup.4-(4-methoxy-phenyl)-N.sup.4-me-
thyl-quinazoline-2,4-diamine
[1289] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (10 mg,
0.033 mmol) and histamine hydrochloride (16 mg, 0.10) by a
procedure similar to example 10 and was isolated as white solid (7
mg, 70%). .sup.1H NMR (CDCl.sub.3): 7.52 (s, 1H), 7.49 (brd, J=3.9
Hz, 2H), 7.20-7.15 (m, 2H), 7.03-6.96 (m, 3H), 6.83 (ddd, J=8.4,
4.5 and 3.9 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.88 (s, 3H), 3.85 (t,
J=6.6 Hz, 2H), 3.63 (s, 3H), 3.03 (t, J=6.6 Hz, 2H).
EXAMPLE 47
[1290] ##STR103##
N.sup.2-(3-Dimethylamino-propyl)-N-(4-methoxy-phenyl)-N.sup.4-methyl-quina-
zoline-2,4-diamine
[1291] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg,
0.050 mmol) and N.sup.1,N.sup.1-dimethyl-propane-1,3-diamine (16
.mu.l, 0.070 mmol) by a procedure similar to example 10 and was
isolated as white powder (11 mg, 73%). .sup.1H NMR (CDCl.sub.3):
7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8, 6.6 and 1.2 Hz,
1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd, J=8.1, 6.6
and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49 (s,
3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).
EXAMPLE 48
[1292] ##STR104##
N.sup.2-(2-Hydroxyethyl)-N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-qu-
inazoline-2,4-diamine
[1293] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
(12 mg, 0.040 mmol) and ethanolamine (28 .mu.l) by a procedure
similar to example 10 and was isolated as off white solid (8 mg,
66%). .sup.1H NMR (CDCl.sub.3): 8.03 (brd, J=3.0 Hz, 1H), 7.47-7.35
(m, 3H), 6.91 (brd, J=8.7 Hz, 1H), 6.78-6.73 (m, 2H), 5.56 (brs,
1H), 3.94 (s, 3H), 3.93-3.90 (m, 2H), 3.70-3.56 (m, 2H), 3.48 (s,
3H).
EXAMPLE 49
[1294] ##STR105##
N.sup.4-(6-methoxypyridin-3-yl)-N.sup.4-methyl-quinazoline-2,4-diamine
[1295] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10
mg, 0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure
similar to example 10 (3 mg, 30%). .sup.1H NMR (CDCl.sub.3): 8.04
(dd, J=2.9, 0.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7
Hz, 1H), 6.92 (brd, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H),
3.96 (s, 3H), 3.54 (s, 3H).
EXAMPLE 50
[1296] ##STR106##
N.sup.2-(2-Hydroxyethyl)-N.sup.4-(4-methoxy-phenyl)-N.sup.4-methyl-6,7-dim-
ethoxyquinazoline-2,4-diamine
[1297] The title compound was prepared from
(2-Chloro-6,7-dimethoxyquinazolin-4-yl)-(4-methoxy-phenyl)-amine
(26 mg, 0.079 mmol) and ethanolamine (30 .mu.l) by a procedure
similar to example 10 and was isolated as white powder (14 mg,
54%). .sup.1H NMR (CDCl.sub.3): 7.14 (dd, J=6.6 and 2.1 Hz, 2H),
6.91 (d, J=6.6 and 2.1 Hz, 2H), 6.81 (s, 1H), 6.25 (s, 1H), 3.90
(s, 3H), 3.92-3.88 (m, 2H), 3.80 (s, 3H), 3.69-3.65 (m, 2H), 3.49
(s, 3H), 3.28 (s, 3H).
EXAMPLE 51
[1298] ##STR107##
(2-Chloro-9H-purin-6-yl)-(4-methoxy-phenyl)-methyl-amine
[1299] The title compound was prepared from 2,6-dichloro-9H-purine
(50 mg, 0.265) and 4-methoxy-N-methylaniline (40 mg, 0.291 mmol) by
a procedure similar to example 1b and was isolated as off white
powder (10 mg, 20%). .sup.1H NMR (CDCl.sub.3): 7.81 (s, 1H), 7.37
(d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 3.93 (s, 3H), 3.77 (s,
3H).
EXAMPLE 52
[1300] ##STR108##
(2-Chloro-quinazolin-4-yl)-(4-methylcarboxyphenyl)-methyl-amine
[1301] The title compound was prepared from 2,4-dichloroquinazoline
(30 mg, 0.152 mmol) and 4-methylamino-benzoic acid methyl ester (27
mg, 0.167 mmol) by a procedure similar to example 1b and was
isolated as off white powder (25 mg, 83%). .sup.1H NMR
(CDCl.sub.3): 8.08-8.04 (m, 2), 7.81 (ddd, J=8.4, 5.4 and 1.2 Hz,
1H), 7.62 (ddd, J=8.7, 3.9 and 1.8 Hz, 1H), 7.26-7.21 (m, 2H), 7.06
(ddd, J=8.4, 7.8 and 0.9 Hz, 1H), 6.99 (ddd, J=7.5, 1.2 and 0.9 Hz,
1H), 3.94 (s, 3H), 3.70 (s, 3H).
EXAMPLE 53
[1302] ##STR109##
(2-methoxy-quinazolin-4-yl)-(4-methoxyphenyl)-methylamine
[1303] To a solution of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (50 mg,
0.167 mmol) in 2 ml methanol was added sodium methoxide (500 .mu.l,
25% by wt. in methanol). The solution was stirred at 80.degree. C.
for 1 h, and it was diluted with 50 ml ethylacetate. The solution
was washed with water, dried and concentrated. The product was
purified using small silica column and isolated as off white solid
(22 mg, 54%). .sup.1H NMR (CDCl.sub.3): 7.89 (d, J=8.4 Hz, 1H),
7.53 (ddd, J=8.7, 5.4 and 2.4 Hz, 1H), 7.19-7.14 (m, 2H), 6.99-6.93
(m, 2H), 6.90-6.85 (m, 2H), 4.14 (s, 3H), 3.86 (s, 3H), 3.64 (s,
3H).
EXAMPLE 54
[1304] ##STR110##
(2-Chloro-quinazolin-4-yl)-(4-hydroxyphenyl)-methylamine
[1305] To a solution of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg,
0.334 mmol) in 30 ml dichloromethane cooled at -20.degree. C. was
added slowly 60 .mu.l of BBr.sub.3 (0.668 mmol). The reaction
mixture was stirred at -20.degree. C. for 2 h then it was warmed to
room temperature. It was stirred another 2 h at this temperature.
The reaction mixture was diluted with ethyl acetate (50 ml) and
washed with cold 5% sodium bicarbonate. The organic phase was dried
and concentrated. The residue was purified by a small silica column
using ethyl acetate and hexane (1:3) as eluents to give the product
(57 mg, 57%). .sup.1H NMR (CDCl.sub.3): 7.65-7.56 (m, 2H),
7.04-6.87 (m, 5H), 3.59 (s, 3H).
EXAMPLE 55
[1306] ##STR111##
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1307] a) 2-Fluoromethyl-quinazolin-4(3H)-one: To a solution of
2-amino-benzoic acid methyl ester (151 mg, 1 mmol) and
fluoro-acetonitrile (0.14 ml, 2.5 mmol) in dioxane (5 ml) at room
temperature was added concentrated HCl (0.05 ml) dropwise. The
mixture was heated at 80.degree. C. for 24 h and then cooled to
room temperature. The resulting solid was collected and dissolved
in water (10 ml), and the solution was neutralized with saturated
aqueous NaHCO.sub.3 to pH 7. The solution was extracted by ethyl
acetate. The extracts were evaporated, and the residue was purified
by column chromatography on silica gel with ethyl acetate and
hexane (1:1) as eluent, yielding 70 mg (39%) of the title
compound.
[1308] b)
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin- e:
A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39
mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035
ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction
mixture was poured onto ice and the precipitate was collected by
filtration, then washed and dried to give
4-chloro-2-fluoromethyl-quinazoline, which was used directly for
the next reaction. To a solution of
4-chloro-2-fluoromethyl-quinazoline with
(4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl
alcohol (5 ml) was added concentrated HCl (0.05 ml) and the
solution was stirred at room temperature overnight. The solution
was neutralized with saturated aqueous NaHCO.sub.3, and was
extracted by ethyl acetate. The extracts were evaporated, and the
residue was purified by column chromatography on silica gel with
ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of
the title compound. .sup.1H NMR (CDCl.sub.3): 7.87-7.84 (m, 1H),
7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91
(m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s,
3H).
EXAMPLE 56
[1309] ##STR112##
(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1310] a) 6-Methyl-quinazoline-2,4-dione: To a suspension of
2-amino-5-methyl benzoic acid (0.758 g, 5 mmol) and potassium
cyanate (0.673 g, 8.3 mmol) in water (20 mL) was added acetic acid
(0.5 mL). The mixture was stirred at room temperature for 24 h. A
white solid was collected by vacuum filtration, washed with water,
and dried in vacuo (0.736 g, 84%): .sup.1H NMR (DMSO-d.sub.6) 9.90
(br s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.29
(dd, J=2.4, 8.7 Hz, 1H), 6.50 (br s, 1H), 2.25 (s, 3H).
[1311] b)
(2-Chloro-6-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-a-
mine: The above 6-methyl-quinazoline-2,4-dione (201 mg, 1.14 mmol)
and N,N-dimethylaniline (0.2 mL) were refluxed in phosphorus
oxychloride (5 mL) under argon overnight. The solvent was removed
by distillation under reduced pressure. The purple residue was
dissolved in isopropanol (10 mL). N-methyl-p-anisidine (201 mg,
1.465 mmol) was added. The mixture was stirred at room temperature
overnight. The solvent was evaporated and the residue was purified
by column chromatography (SiO.sub.2, EtOAc:hexanes 5-25%) to give
the product as a light yellow solid (62 mg, 17%): .sup.1H NMR
(CDCl.sub.3) 7.62 (d, J=8.7 Hz, 1H), 7.38 (dd, J=1.8, 8.7 Hz, 1H),
7.16-7.10 (m, 2H), 6.89-6.86 (m, 2H), 6.63 (s, 1H), 3.86 (s, 3H),
3.60 (s, 3H), 2.09 (s, 3H).
[1312] Compounds of EXAMPLE 57-64 were prepared similar to Example
56.
EXAMPLE 57
[1313] ##STR113##
(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1314] a) 7-Methyl-quinazoline-2,4-dione: White solid: .sup.1H NMR
(DMSO-d.sub.6) 10.07 (br s, 1H), 8.24 (s, 1H), 7.79 (d, J=8.1 Hz,
1H), 6.78 (dd, J=0.6, 9.0 Hz, 1H), 6.54 (br s, 1H), 2.30 (s,
3H).
[1315] b)
(2-Chloro-7-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-a-
mine: Light yellow solid: .sup.1H NMR (CDCl.sub.3) 7.51 (m, 1H),
7.16-7.10 (m, 2H), 6.96-6.91 (m, 2H), 6.83 (dd, J=1.8, 8.7 Hz, 1H),
6.78 (d, J=8.7 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 3H), 2.38 (s,
3H).
EXAMPLE 58
[1316] ##STR114##
(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1317] a) 5-Methyl-quinazoline-2,4-dione: Off-white solid: .sup.1H
NMR (CDCl.sub.3) 11.04 (s, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.01 (d,
J=7.8 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 2.65 (s, 3H).
[1318] b)
(2-Chloro-5-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-a-
mine: Light yellow solid: .sup.1H NMR (CDCl.sub.3) 7.64-7.61 (m,
1H), 7.54 (dd, J=7.2, 8.4 Hz, 1H), 6.99-6.96 (m, 1H), 6.75-6.68 (m,
4H), 3.75 (s, 3H), 3.63 (s, 3H), 2.11 (s, 3H).
EXAMPLE 59
[1319] ##STR115##
(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1320] a) 8-Methyl-quinazoline-2,4-dione: Light brown solid:
.sup.1H NMR (DMSO-d.sub.6) 11.43 (s, 1H), 10.50 (s, 1H), 7.86 (d,
J=8.1 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 2.43
(s, 3H).
[1321] b)
(2-Chloro-8-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-a-
mine: .sup.1H NMR (CDCl.sub.3) 7.42-7.39 (m, 1H), 7.14-7.04 (m,
2H), 6.94-6.87 (m, 3H), 6.84 (dd, J=1.5, 8.4 Hz, 1H), 3.84 (s, 3H),
3.60 (s, 3H), 2.63 (s, 3H).
EXAMPLE 60
[1322] ##STR116##
(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1323] a) 6-Chloro-quinazoline-2,4-dione: white solid: .sup.1H NMR
(DMSO-d.sub.6) 11.44 (s, 1H), 11.28 (s, 1H), 7.81 (d, J=2.1 Hz,
1H), 7.69 (dd, J=9.0, 2.1 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H).
[1324] b)
(2,6-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:
Yellow solid: .sup.1H NMR (CDCl.sub.3) 7.66 (d, J=8.7 Hz, 1H), 7.49
(dd, J=2.1, 8.7 Hz, 1H), 7.18-7.12 (m, 2H), 7.02-6.96 (m, 2H), 6.78
(dd, J=0.6, 2.1 Hz, 1H), 3.88 (s, 3H), 3.61 (s, 3H).
EXAMPLE 61
[1325] ##STR117##
6-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl-q-
uinazoline-2,4-diamine
[1326] The title compound was isolated from the reaction of Example
60. Yellow solid: .sup.1H NMR (CDCl.sub.3) 7.41 (d, J=9.0 Hz, 1H),
7.35-7.30 (m, 2H), 7.29 (d, J=2.4 Hz, 1H), 7.26 (t, J=1.5 Hz, 1H),
7.09-7.04 (m, 2H), 6.94-6.80 (m, 5H), 6.72 (d, J=2.4 Hz, 1H), 3.84
(s, 3H), 3.83 (s, 3H), 3.62 (s, 3H), 3.27 (s, 3H).
EXAMPLE 62
[1327] ##STR118##
(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1328] a) 7-Chloro-quinazoline-2,4-dione: White solid: .sup.1H NMR
(DMSO-d.sub.6) 11.42 (s, 1H), 11.26 (s, 1H), 7.88 (d, J=8.7 Hz,
1H), 7.22 (dd, J=1.2, 8.1 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H).
[1329] b)
(2,7-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:
Light yellow solid: .sup.1H NMR (CDCl.sub.3) 7.70 (d, J=2.4 Hz,
1H), 7.16-7.11 (m, 2H), 6.98-6.92 (m, 3H), 6.80 (d, J=9.3 Hz, 1H),
3.86 (s, 3H), 3.60 (s, 3H).
EXAMPLE 63
[1330] ##STR119##
5-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-dimethyl-q-
uinazoline-2,4-diamine
[1331] a) 5-Chloro-quinazoline-2,4-dione: White solid: .sup.1H NMR
(DMSO-d.sub.6) 11.28 (s, 2H), 7.55 td (td, J=8.4, 0.6 Hz, 1H), 7.19
(d, J=7.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H).
[1332] b)
5-Chloro-N.sup.2,N.sup.4-bis-(4-methoxy-phenyl)-N.sup.2,N.sup.4-
-dimethyl-quinazoline-2,4-diamine: Yellow solid: .sup.1H NMR
(CDCl.sub.3) 7.43 (d, J=8.4 Hz, 1H), 7.32-7.26 (m, 3H), 6.93-6.88
(m, 2H), 6.81 (dd, J=1.2, 7.2 Hz, 1H), 6.75-6.65 (m, 4H), 3.83 (s,
3H), 3.73 (s, 3H), 3.61 (s, 3H), 3.33 (s, 3H).
EXAMPLE 64
[1333] ##STR120##
(5-Chloro-2-isopropoxy-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1334] The title compound was isolated from the reaction of Example
63. White solid: .sup.1H NMR (CDCl.sub.3) 7.45-7.36 (m, 2H),
7.26-7.21 (m, 2H), 7.13 (dd, J=2.1, 6.9 Hz, 1H), 6.94-6.89 (m, 2H),
5.09 (m, 1H), 3.85 (s, 3H), 3.57 (s, 3H), 1.30 (d, J=6.3 Hz,
6H).
EXAMPLE 65
[1335] ##STR121##
(Isoquinolin-1-yl)-(4-methoxy-phenyl)-methyl-amine
[1336] A mixture of 1-chloroisoquinoline (50 mg, 0.31 mmol) and
(4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a
sealed tube at 140.degree. C. overnight. The crude product was
purified by chromatography (5-6% ethyl acetate/hexanes) on silica
gel to give the title compound (46 mg, 0.17 mmol, 57%). .sup.1H NMR
(CDCl.sub.3): 8.22 (d, 1H, 5.7),7.68 (d, 1H, J=8.1),7.62 (d, 1H,
J=8.7), 7.47 (ddd, 1H, J=0.9, 6.9, 8.1), 7.24 (d, 1H, J=6.0), 7.19
(ddd, 1H, J=1.5, 6.9, 8.7), 6.94 (m, 2H), 6.79 (m, 2H), 3.76 (s,
3H), 3.52 (s, 3H).
EXAMPLE 66
[1337] ##STR122##
(4-Methoxy-phenyl)-methyl-(quinolin-4-yl)-amine
[1338] A mixture of 4-chloroquinoline (50 mg, 0.31 mmol) and
(4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a
sealed tube at 140.degree. C. overnight. The crude product was
purified by chromatography (20-40% ethyl acetate/hexanes) on silica
gel to give the title compound (60 mg, 0.23 mmol, 74%). .sup.1H NMR
(CDCl.sub.3): 8.77 (d, 1H, J=5.1), 8.00-8.04 (m, 1H), 7.61-7.64 (m,
1H), 7.55 (ddd, 1H, J=1.5, 6.9, 8.4), 7.22 (ddd, 1H, J=1.5, 6.9,
8.1), 6.99 (d, 1H, J=4.8), 6.92 (m, 2H), 6.89 (m, 2H), 3.77 (s,
3H), 3.43 (s, 3H).
EXAMPLE 67
[1339] ##STR123##
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine
[1340] a)
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine: The
title compound was prepared from 3,4-methylenedioxyphenylamine and
2,4-dichloroquinazoline by a procedure similar to example 1b and
was isolated as solids (45% yield). .sup.1H NMR (CDCl.sub.3):
7.81-7.83 (m, 3H), 7.51-7.56 (m, 2H), 7.44 (d, 1H, J=2.1), 6.98
(dd, 1H, J=2.1, 8.1), 6.82 (d, 1H, J=8.1), 6.01 (s, 2H).
[1341] b).
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-methyl-amine:
The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine by a
procedure similar to example 36 and was isolated as solids (66%
yield). .sup.1H NMR (CDCl.sub.3): 7.73-7.76 (m, 1H), 7.58 (m, 1H),
7.07 (m, 2H), 6.82 (d, 1H, J=8.4), 6.72 (m, 1H), 6.68 (m, 1H), 6.06
(s, 2H), 3.59 (s, 3H).
[1342] Compounds of EXAMPLE 68-70 were prepared similar to Example
67.
EXAMPLE 68
[1343] ##STR124##
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine
[1344] a) (2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-amine:
.sup.1H NMR (CDCl.sub.3): 7.77-7.86 (m, 3H), 7.51-7.60 (m, 3H),
7.12 (dd, 1H, J=2.4, 8.4), 6.90 (d, 1H, J=8.4), 3.94 (s, 3H), 3.91
(s, 3H).
[1345] b).
(2-Chloro-quinazolin-4-yl)-(3,4-dimethoxy-phenyl)-methyl-amine:
.sup.1H NMR (CDCl.sub.3): 7.72-7.75 (m, 1H), 7.57 (ddd, 1H, J=1.5,
6.6, 8.4), 7.01 (ddd, 1H, J=1.2, 6.9, 8.7), 6.88-6.96 (m, 2H),
6.73-6.81 (m, 2H), 3.94 (s, 3H), 3.80 (s, 3H), 3.63 (s, 3H).
EXAMPLE 69
[1346] ##STR125##
(2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl-amine
[1347] a) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-amine:
.sup.1H NMR (CDCl.sub.3): 7.78-7.87 (m, 3H), 7.68-7.74 (m, 2H),
7.60 (s, broad, 1H), 7.56 (ddd, 1H, J=3.3, 9.9, 12.0), 7.33-7.39
(m, 2H), 7.03-7.16 (m, 5H).
[1348] b) (2-Chloro-quinazolin-4-yl)-(4-phenoxy-phenyl)-methyl
amine: .sup.1H NMR (CDCl.sub.3): 7.74-7.77 (m, 1H), 7.59 (ddd, 1H,
J=1.5, 6.6, 8.4), 7.36-7.42 (m, 2H), 7.10-7.20 (m, 3H), 7.03-7.10
(m, 5H), 6.97-7.00 (m, 1H), 3.64 (s, 3H).
EXAMPLE 70
[1349] ##STR126##
(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine
[1350] a) (2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-amine:
.sup.1H NMR (CDCl.sub.3): 7.76-7.84 (m, 3H), 7.52-7.62 (m, 4H),
6.95 (m, 2H), 3.94 (t, 2H, J=6.6), 1.83 (hex, 2H, J=7.2), 1.05 (t,
3H, J=7.5)
[1351] b)
(2-Chloro-quinazolin-4-yl)-(4-propoxy-phenyl)-methyl-amine: .sup.1H
NMR (CDCl.sub.3): 7.71-7.74 (m, 1H), 7.55 (ddd, 1H, J=1.5, 6.9,
8.4), 7.10-7.16 (m, 2H), 7.00 (ddd, 1H, J=1.5, 6.9, 8.4), 6.91-6.96
(m, 3H), 3.96 (t, 2H, J=6.6), 1.84 (hex, 2H, J=7.5), 1.08 (t, 3H,
J=7.5).
EXAMPLE 71
[1352] ##STR127##
4-(4-Methoxy-phenoxy)-quinazoline
[1353] To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol)
and 4-chloro-quinazoline (125 mg, 76 mmol) in 3 mL of DMF was added
sodium hydride (60% oil suspension, 30 mg, 0.75 mmol) at 0.degree.
C., then the reaction mixture was allowed to warm to room
temperature and stirred for 5 h. The reaction was quenched by
adding 50 uL of water and diluted with 25 mL of ethyl acetate. It
was washed with water (25 mL.times.3), saturated NaCl, dried over
anhydrous MgSO.sub.4, filtered and concentrated. The residue was
purified by chromatography (25% ethyl acetate/hexanes) to give the
title compound (134 mg, 0.53 mmol, 89%). .sup.1H NMR (CDCl.sub.3):
8.78 (s, 1H), 8.38 (m, 1H), 7.89-8.02 (m, 2H), 7.67 (m, 1H), 7.19
(m, 1H), 7.00 (m, 1H), 3.86 (s, 3H).
EXAMPLE 72
[1354] ##STR128##
(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine
hydrochloride
[1355] a) 4-Chloro-2-methyl-quinazoline: A stirred suspension of
2-methyl-4(3H)-quinazolinone (5 g, 31.2 mmol) in POCl.sub.3 (100
mL) was heated at 120.degree. C. for 3 h. The excess POCl.sub.3 was
removed under vacuum, then to the residue was added crushed ice and
200 mL of saturated NaHCO.sub.3, and the mixture was extracted with
ethyl acetate (200 mL.times.2). The combined extracts were washed
with water, saturated NaCl, dried over anhydrous MgSO.sub.4,
filtered and concentrated. The crude product was purified by column
chromatography (5-8% ethyl acetate/hexane) to give the title
compound (2.5 g, 14.0 mmol, 45%). .sup.1H NMR (CDCl.sub.3):
8.21-8.25 (m, 1H), 7.89-7.99 (m, 2H), 7.66 (ddd, 1H, J=1.8, 6.6,
8.7), 2.87 (s, 3H).
[1356] b)
(4-Methoxy-phenyl)-methyl-(2-methyl-quinazolin-4-yl)-amine
hydrochloride: The title compound was prepared from
4-chloro-2-methyl-quinazoline (2.31 g, 12.9 mmol) and (4-methoxy
phenyl)-methyl-amine (2.0 g, 14.6 mmol) by a procedure similar to
example 1b and was isolated as solids (2.90 g, 9.18 mmol, 71%).
.sup.1H NMR (CDCl.sub.3): 8.53 (dd, 1H, J=0.6, 8.1), 7.7 (ddd, 1H,
J=1.2, 7.2, 8.4), 7.22 (m, 2H), 7.13 (ddd, 1H, J=1.2, 7.2, 8.7),
7.05 (m, 2H), 6.76 (d, 1H, J=8.7), 3.91 (s, 3H), 3.78 (s, 3H), 2.96
(s, 3H).
EXAMPLE 73
[1357] ##STR129##
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1358] a) 2-Chloromethyl-quinazolin-4(3H)-one: To a solution of
2-amino-benzoic acid methyl ester (0.26 ml, 2 mmol) and
chloro-acetonitrile (0.16 ml, 4.0 mmol) in dioxane (8 ml) at room
temperature was added concentrated HCl (1.0 ml) dropwise. The
mixture was heated at 80.degree. C. for 24 h and then cooled to
room temperature. The resulting solid was collected and dissolved
in water (10 ml), and the solution was neutralized with 2 N NaOH
aqueous to pH 7. The precipitation was collected by filtration,
then washed with water and dried to give 309 mg (79.6%) of the
title compound.
[1359] b)
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amin- e:
A mixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32
mmol), phosphoryl chloride (1.23 ml, 13.2 mmol) and
N,N-dimethylaniline (0.34 ml, 2.64 mmol) in chloroform (10 ml) was
heated under reflux for 4 h. The reaction mixture was poured onto
ice and extracted by ethyl acetate. The solvent was evaporated, and
the residue was purified by column chromatography on silica gel
with acetate and hexane (1:1) as eluent, yielding 180 mg of
4-chloro-2-chloromethyl-quinazoline. The intermediate (170 mg, 0.80
mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96 mmol) in
isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) was
stirred at room temperature overnight. The precipitation was formed
and collected by filtration, then washed and dried to give 231 mg
(92%) of the title compound. .sup.1H NMR (CDCl.sub.3): 7.82 (d,
J=8.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.03-7.00 (m,
2H), 6.95-6.91 (m, 2H), 4.73 (s, 2H), 3.85 (s, 3H), 3.62 (s,
3H).
EXAMPLE 74
[1360] ##STR130##
(2-Ethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1361] The title compound was prepared in three steps by a
procedure similar to Example 73. .sup.1H NMR (CDCl.sub.3): 7.76 (d,
J=8.4 Hz, 1H), 7.55-7.49 (m, 1H), 7.13-7.09 (m, 2H), 7.03-6.89 (m,
4H), 3.83 (s, 3H), 3.60 (s, 3H), 2.97 (q, J=7.5 Hz, 2H), 1.44 (t,
J=7.8 Hz, 3H).
EXAMPLE 75
[1362] ##STR131##
(2-Methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-amine
[1363] The title compound was prepared from
4-chloro-2-methyl-quinazoline (108 mg, 0.605 mmol) and
4-methoxy-phenylamine (89.4 mg, 0.73 mmol) by a procedure similar
to Example 72b. .sup.1H NMR (DMSO-d.sub.6): 11.28 (brs, 1H), 8.73
(d, J=8.4 Hz, 1H), 8.06 (t, J=7.5 Hz, 1H), 7.85-7.78 (m, 2H), 7.66
(d, J=9 Hz, 2H), 7.06 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.60 (s,
3H).
EXAMPLE 76
[1364] ##STR132##
(2-Hydroxymethyl-quinazolin-4-yl)-4-methoxy-phenyl)-methyl-amine
[1365] To a solution of
(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
hydrochloride salt (67 mg, 0.19 mmol) in 1,4-dioxane (3 ml) was
added 2 N NaOH aqueous (1 ml). The mixture was heated at 80.degree.
C. for 24 h and then was cooled to room temperature. The reaction
mixture was diluted with ethyl acetate, then was washed with water
and dried with NaSO.sub.4. The solvent was evaporated, and the
residue was purified by column chromatography on silica gel with
acetate and hexane (1:1) as eluent, yielding 25 mg of title
compound (44%). .sup.1H NMR (CDCl.sub.3): 7.78-7.75 (m, 1H),
7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.02-7.00 (m, 2H), 6.94-6.91
(m, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 3.59 (s, 3H).
EXAMPLE 77
[1366] ##STR133##
(2-Dimethylaminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1367] The title compound was prepared from
(2-chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
and dimethylamine by a procedure similar to Example 76. .sup.1H NMR
(DMSO-d.sub.6): 7.71 (d, J=8.7 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H),
7.20 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.1 Hz, 1H), 7.00-6.96 (m, 3H),
3.78 (s, 3H), 3.63 (s, 2H), 3.50 (s, 3H), 2.33 (s, 6H).
EXAMPLE 78
[1368] ##STR134##
(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1369] A mixture of 4-chloro-2-methyl-quinazoline (450 mg, 2.52
mmol), 4-difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and
sodium acetate (248.07 mg, 3.02 mmol) in 6 mL of solvent
(THF:water=1:1) was stirred at 70.degree. C. for 1 h. The reaction
mixture was diluted with 30 mL of ethyl acetate. It was washed with
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by chromatography on
silica gel with acetate and hexane (1:5) as eluent, yielding 713 mg
of title compound (94%). .sup.1H NMR (CDCl.sub.3): 7.87-7.76 (m,
5H), 7.51 (t, J=8.4 Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J=8.7 Hz,
2H), 6.76-6.27 (three single peaks, 1H), 2.71 (s, 3H).
EXAMPLE 79
[1370] ##STR135##
(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1371] The title compound was prepared from
4-chloro-2-methyl-quinazoline (150 mg, 0.84 mmol),
3-fluoro-4-methoxy-phenylamine (118.5 mg, 0.84 mmol) by a procedure
similar to example 78. .sup.1H NMR (CDCl.sub.3): 7.89-7.75 (m, 4H),
7.53-7.48 (m, 1H)), 7.38-7.34 (m, 2H), 7.0 (t, J=8.7 Hz, 1H), 3.92
(s, 3H), 2.71 (s, 3H).
EXAMPLE 80
[1372] ##STR136##
(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1373] The title compound was prepared from
4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol),
4-isopropoxy-phenylamine (84.66 mg, 0.56 mmol) by a procedure
similar to example 78. .sup.1H NMR (CDCl.sub.3): 7.84-7.72 (m, 3H),
7.70-7.66 (m, 2H)), 7.50-7.45 (m, 1H), 7.30 (brs, 1H), 6.96-6.93
(m, 2H), 4.59-4.51 (m, 1H), 2.68 (s, 3H), 1.36 (d, J=6.3 Hz,
6H).
EXAMPLE 81
[1374] ##STR137##
(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1375] The title compound was prepared from
4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol),
4-ethyl-phenylamine (0.07 ml, 0.56 mmol) by a procedure similar to
example 78. .sup.1H NMR (CDCl.sub.3): 7.85-7.78 (m, 2H), 7.76-7.71
(m, 3H)), 7.49 (t, J=7.5 Hz, 1H), 7.36 (brs, 1H), 7.24 (s, 2H),
2.70-2.69 (m, 5H), 1.26 (t, J=7.5 Hz, 3H).
EXAMPLE 82
[1376] ##STR138##
(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine
[1377] The title compound was prepared from
4-chloro-2-methyl-quinazoline (89.3 mg, 0.5 mmol),
2,4,6-trimethoxy-phenylamine (91.6 mg, 0.5 mmol) by a procedure
similar to example 78. .sup.1H NMR (CDCl.sub.3): 7.86 (d, J=8.4 Hz,
1H), 7.80 (d, J=8.4 Hz, 1H), 7.71 (t, J=6.6 Hz, 1H), 7.41 (t, J=8.1
Hz, 1H), 6.81 (brs, 1H), 6.25 (s, 2H), 3.87 (s, 3H), 3.79 (s, 6H),
2.57 (s, 3H).
EXAMPLE 83
[1378] ##STR139##
(4-Methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-methyl-amine
[1379] The title compound was prepared from
(4-methoxy-phenyl)-(2-phenyl-quinazolin-4-yl)-amine (51 mg, 0.16
mmol) and methyl iodide (0.07 ml, 1.09 mmol) by a procedure similar
to Example 36. .sup.1H NMR (CDCl.sub.3): 8.64-8.61 (m, 2H), 7.90
(d, J=8.4 Hz, 1H), 7.59-7.48 (m, 4H), 7.18-7.14 (m, 2H), 7.08-6.98
(m, 2H), 6.94-6.91 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H).
EXAMPLE 84
[1380] ##STR140##
(4-Difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1381] The title compound was prepared from
(4-difluoromethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (710
mg, 2.36 mmol) and methyl iodide (1.03 ml, 16.52 mmol), by a
procedure similar to Example 36 (40.8% yield). .sup.1H NMR
(CDCl.sub.3): 7.77 (dd, J=8.4 Hz, J=0.9 Hz, 1H), 7.59-7.53 (m, 1H),
7.17-7.10 (m, 4H), 7.06-6.99 (m, 2H), 6.78 (d, J=0.6 Hz, 0.25H),
6.54 (d, J=0.9 Hz, 0.5H), 6.29 (d, J=0.9 Hz, 0.25H), 3.62 (s, 3H),
2.75 (s, 3H).
EXAMPLE 85
[1382] ##STR141##
(3-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1383] The title compound was prepared from
(3-fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (250
mg, 0.88 mmol) and methyl iodide (0.39 ml, 6.18 mmol) by a
procedure similar to example 36. .sup.1H NMR (CDCl.sub.3): 7.76 (d,
J=8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.09-6.82 (m, 5H), 3.91 (s, 3H),
3.58 (s, 3H), 2.73 (s, 3H).
EXAMPLE 86
[1384] ##STR142##
(4-Isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1385] The title compound was prepared from
(4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (164.3 mg,
0.56 mmol) and methyl iodide (0.25 ml, 3.92 mmol) by a procedure
similar to example 36. .sup.1H NMR (CDCl.sub.3): 7.73 (d, J=7.8 Hz,
1H), 7.54-7.49 (m, 1H), 7.10-6.86 (m, 6H), 4.57-4.52 (m, 1H), 3.58
(s, 3H), 2.72 (s, 3H), 1.36 (d, J=6 Hz, 6H).
EXAMPLE 87
[1386] ##STR143##
(4-Ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1387] The title compound was prepared from
(4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine (122 mg, 0.46
mmol) and methyl iodide (0.2 ml, 3.25 mmol) by a procedure similar
to example 36. .sup.1H NMR (CDCl.sub.3): 7.74 (d, J=8.1 Hz, 1H),
7.54-7.49 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61
(s, 3H), 2.73-2.63 (m, 5H), 1.26 (d, J=7.5 Hz, 3H).
EXAMPLE 88
[1388] ##STR144##
(2-Methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-methyl-amine
[1389] The title compound was prepared from
(2-methyl-quinazolin-4-yl)-(2,4,6-trimethoxy-phenyl)-amine (56 mg,
0.17 mmol) and methyl iodide (0.1 ml, 1.6 mmol) by a procedure
similar to example 36. .sup.1H NMR (CDCl.sub.3): 7.70 (d, J=8.4 Hz,
1H), 7.49 (t, J=7.8 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.93 (t, J=8.1
Hz, 1H), 6.18 (s, 2H), 3.86 (s, 3H), 3.63 (s, 6H), 3.44 (s, 3H),
2.70 (s, 3H).
Compounds of Example 89-90 were prepared by a procedure similar to
Example 56.
EXAMPLE 89
[1390] ##STR145##
(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1391] a) 8-Chloro-1H-quinazoline-2,4-dione: White solid: .sup.1H
NMR (DMSO-d.sub.6) 11.47 (s, 1H), 10.77 (s, 1H), 7.88 (m, 1H), 7.78
(m, 1H), 7.18 (m, 1H).
[1392] b)
(2,8-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:
Off-white solid: .sup.1H NMR (CDCl.sub.3) 7.66 (dd, J=2.7, 6.3 Hz,
1H), 7.14-7.10 (m, 2H), 6.97-6.89 (m, 4H), 3.86 (s, 3H), 3.62 (s,
3H).
EXAMPLE 90
[1393] ##STR146##
(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1394] a) 5-Chloro-1H,3H-quinazoline-2,4-dione: White solid:
.sup.1H NMR (DMSO-d.sub.6) 11.28 (s, 2H), 7.55 (m, 1H), 7.19 (d,
J=7.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H).
[1395] b)
(2,5-Dichloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine:
Yellow solid: .sup.1H NMR (CDCl.sub.3) 7.67 (m, 1H), 7.52 (m, 1H),
7.16 (m, 1H), 6.80-6.69 (m, 4H), 3.76 (s, 3H), 3.65 (s, 3H).
EXAMPLE 91
[1396] ##STR147##
(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1397] a) 5-Methoxy-2-methyl-quinazolin-4-ol: To a suspension of
2-amino-6-methoxy-benzoic acid (305 mg, 1.82 mmol) and
4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol) in DMF/toluene (2:6
mL) at 0.degree. C. was added triethylamine (1.1 mL, 7.9 mmol)
followed by slow addition of acetyl chloride (0.40 mL, 5.6 mmol)
under argon. The suspension was stirred at rt for 19 h. Ammonium
acetate (0.62 g, 8.0 mmol) was added and the reaction mixture was
further stirred at 90.degree. C. for 5 h. The solid was collected
by filtration, washed with water, and dried to give an off-white
solid (103 mg, 30%): .sup.1H NMR (CDCl.sub.3) 10.69 (s, 1H), 7.66
(t, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.49 (d, J=8.4 Hz, 1H),
4.01 (s, 3H), 2.53 (s, 3H).
[1398] b)
(5-Methoxy-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl--
amine: The title compound was prepared by a procedure similar to
that of Example 56b as white solid: .sup.1H NMR (CDCl.sub.3) 7.51
(t, J=8.4 Hz, 1H), 7.35 (dd, J=0.9, 8.4 Hz, 1H), 6.85-6.80 (m, 2H),
6.85-6.72 (m, 2H), 6.56 (dd, J=0.9, 7.8 Hz, 1H), 3.75 (s, 3H), 3.60
(s, 3H), 3.25 (s, 3H), 2.68 (s, 3H).
EXAMPLE 92
[1399] ##STR148##
(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methyl-amine
[1400] a) 2-Methyl-pyrido[2,3-d]pyrimidin-4-ol: To a solution of
2-amino-nicotinic acid (277 mg, 2 mmol),
4-N,N-dimethylaminopyridine (20 mg, 0.16 mmol), triethylamine (1.1
mL, 7.9 mmol) in DMF (2 mL) was added acetyl chloride (0.35 mL, 4.9
mmol) slowly at 0.degree. C. under argon. The white precipitate was
formed immediately. The mixture was then heated at 90.degree. C.
for 3.5 h, then ammonium acetate (0.601 g, 7.8 mmol) was added. The
mixture was stirred for 1 h, cooled to rt and diluted with water
(20 mL). It was extracted with EtOAc (2.times.50 mL), and the
extracts were dried over MgSO.sub.4, and evaporated. The crude was
purified by column chromatography (SiO.sub.2, EtOAc:MeOH/0-10%) to
give an off-white solid (47 mg, 16%): .sup.1H NMR (DMSO-d.sub.6)
11.40 (s, 1H), 9.01 (dd, J=2.1, 4.8 Hz, 1H), 8.61 (dd, J=2.4, 8.1
Hz, 1H), 7.44 (dd, J=4.8, 8.1 Hz, 1H), 2.66 (s, 3H).
[1401] b)
(4-Methoxy-phenyl)-(2-methyl-pyrido[2,3-d]pyrimidin-4-yl)-methy-
l-amine: To a solution of 2-methyl-pyrido[2,3-d]pyrimidin-4-ol (47
mg, 0.32 mmol) in toluene (2 mL) was added phosphorus oxychloride
(0.05 mL, 0.55 mmol) and diisopropylethyl amine (0.12 mL, 0.69
mmol). The solution was stirred at rt for 25 h, then
(4-methoxy-phenyl)-methylamine (45 mg, 0.33 mmol) was added. The
reaction mixture was stirred at rt for 22 h. The solvent was
evaporated and the crude was purified by column chromatography
(SiO.sub.2, EtOAc:hexanes/30-100%). The product was collected as an
off-white solid (6 mg, 7%): .sup.1H NMR (CDCl.sub.3) 8.22 (dd,
J=2.1, 4.5 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.15-7.10 (m, 2H),
6.96-6.92 (m, 2H), 6.88 (dd, J=4.2, 8.4 Hz, 1H), 3.85 (s, 3H), 3.60
(s, 3H), 2.05 (s, 3H).
EXAMPLE 93
[1402] ##STR149##
(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1403] To a solution of
(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
hydrochloride salt (106 mg, 0.336 mmol) in dichloromethane (10 mL)
at -78.degree. C. was added slowly boron tribromide (1M in
CH.sub.2Cl.sub.2, 0.75 mL) under argon. The cold bath was removed
and the reaction mixture was allowed to warm up slowly to
10.degree. C. in 1.5 h. The reaction mixture was quenched with
water (10 mL), basified with 2N NaOH to pH=10, and extracted with
EtOAc (2.times.25 mL). The EtOAc extracts were dried and evaporated
to give a light brown residue. The crude was purified by column
chromatography (SiO.sub.2, EtOAc:hexanes/15-50%) to give the
product as a white solid, which was further purified by
recrystallization from MeOH: .sup.1H NMR (acetone-d.sub.6) 8.74 (s,
1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.20-7.18 (m, 3H), 7.12 (m, 1H),
7.04-6.99 (m, 2H), 3.64 (s, 3H), 2.79 (s, 3H).
EXAMPLE 94
[1404] ##STR150##
(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine
[1405] The title compound was prepared from 2,4-dichloroquinazoline
and 4-ethoxyaniline by a procedure similar to example 28 (32%).
.sup.1H NMR (CDCl.sub.3): 7.81 (m, 1H), 7.65 (m, 1H), 7.32 (m, 2H),
7.03 (m, 1H), 6.73 (m, 3H), 4.09 (q, J=7.2, 2H), 1.49 (t, J=7.2,
3H).
EXAMPLE 95
[1406] ##STR151##
(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine
[1407] The title compound was prepared from
4-chloro-2-methylquinazoline and 3-amino-5-methoxypyridine by a
procedure similar to example 28 (32%). .sup.1H NMR (CDCl.sub.3):
8.51 (d, J=1.8, 1H), 8.12 (m, 1H), 7.72-7.89 (m, 3H), 7.49 (m, 2H),
6.81 (d, J=8.7, 1H), 3.89 (s, 3H), 2.68 (s, 3H).
EXAMPLE 96
[1408] ##STR152##
(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1409] The title compound was prepared from
4-chloro-2-methylquinazoline and 2-fluoro-4-methoxyaniline by a
procedure similar to example 28 (79%). .sup.1H NMR (CDCl.sub.3):
8.54 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.50 (m, 1H), 7.47 (s,
broad, 1H), 6.74-6.81 (m, 2H), 3.83 (s, 3H), 2.70 (s, 3H).
EXAMPLE 97
[1410] ##STR153##
(2-Chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-methylamine
[1411] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a procedure
similar to example 36 (28%). .sup.1H NMR (CDCl.sub.3): 7.73 (m,
1H), 7.55 (m, 1H), 7.12 (m, 2H), 7.00 (m, 1H), 6.93 (m, 3H), 4.07
(q, J=7.2, 2H), 3.61 (s, 3H), 1.46 (t, J=7.2, 3H).
EXAMPLE 98
[1412] ##STR154##
(2-Methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
[1413] The title compound was prepared from
(2-methyl-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-amine by a
procedure similar to example 36 (28%). .sup.1H NMR (CDCl.sub.3):
8.03 (d, J=2.7, 1H), 7.77 (m, 1H), 7.56 (ddd, J=8.1, 6.3, 1.8, 1H),
7.38 (dd, J=8.7, 3.0, 1H), 7.01 (m, 2H), 6.76 (d, J=9.0, 1H), 3.96
(s, 3H), 3.59 (s, 3H), 2.73 (s, 3H).
EXAMPLE 99
[1414] ##STR155##
(2-Fluoro-4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1415] The title compound was prepared from
(2-methyl-quinazolin-4-yl)-(2-fluoro-4-methoxy-phenyl)-amine by a
procedure similar to example 36 (51%). .sup.1H NMR (CDCl.sub.3):
7.76 (d, J=8.1, 1H), 7.55 (ddd, J=8.1, 6.3, 1.8, 1H), 6.98-7.11 (m,
3H), 6.66-6.76 (m, 2H), 3.83 (s, 3H), 3.54 (s, 3H), 2.73 (s,
3H).
EXAMPLE 100
[1416] ##STR156##
(2-Methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methyl-amine
[1417] To a solution of 4-chloro-2-methylquinazoline (1.4 g, 7.84
mmol) and (4-nitro-phenyl)-methylamine (1.09 g, 7.16 mmol) in 20 mL
of dimethylformamide cooled to 0.degree. C. was added sodium
hydride (0.6 g, 60 oil suspension, 15 mmol). The reaction mixture
was stirred at 0.degree. C. for 1 h and quenched by adding 200 uL
of water. It was diluted with 150 mL of ethyl acetate, washed with
water (100 mL.times.3), saturated NaCl, dried over anhydrous
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography (30% ethyl acetate/hexanes) to give the title
compound (1.41 g, 4.78 mmol, 67%). .sup.1H NMR (CDCl.sub.3): 8.14
(m, 2H), 7.91 (m, 1H), 7.71 (ddd, J=8.4, 6.6, 1.8, 1H), 7.19-7.32
(m, 2H), 7.05 (m, 2H), 3.76 (s, 3H), 2.82 (s, 3H).
EXAMPLE 101
[1418] ##STR157##
(4-Amino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1419] A mixture of
(2-methyl-quinazolin-4-yl)-(4-nitro-phenyl)-methylamine (200 mg,
0.68 mmol) in 25 mL of ethyl acetate was hydrogenated over
Palladium on carbon (70 mg) at 50 psi for 4 h, and the reaction
mixture was filtered through a pad of celite and concentrated. The
resulting crude product was purified by chromatography (50% ethyl
acetate/hexane) to obtain the title compound (140 mg, 78%). .sup.1H
NMR (CDCl.sub.3): 7.71 (m, 1H), 7.51 (ddd, J=8.4, 6.9, 1.5, 1H),
7.09 (m, 1H), 6.93-7.05 (m, 3H), 6.68 (m, 2H), 3.74 (s, broad, 2H),
3.56 (s, 3H), 2.71 (s, 3H).
EXAMPLE 102
[1420] ##STR158##
(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1421] To a solution of
(2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (20 mg,
0.076 mmol) in 1.2 mL of 1N HCl was added 100 uL of methanol and it
was cooled 0.degree. C. One drop of concentrated HCl was added and
the solution was stirred at 0.degree. C. for 0.25 h. To the
solution was added dropwise a solution of sodium nitrite (25 mg,
0.36 mmol) in 200 uL of water. The reaction mixture was stirred for
0.5 h, then was added a solution of sodium azide (25 mg, 0.38 mmol)
in 300 uL of water followed by another batch of sodium azide (25
mg, 0.38 mmol). The reaction mixture was stirred at the 0.degree.
C. for 1 h. The reaction mixture was diluted with 50 mL of ethyl
acetate, washed with saturated sodium bicarbonate followed by
saturated sodium chloride. The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by column chromatography (20-25% ethyl
acetate/hexanes) on silica gel to give the title compound (19.8 mg,
0.068 mmol, 90%). .sup.1H NMR (CDCl.sub.3): 7.76 (m, 1H), 7.56
(ddd, J=8.1, 6.3, 1.8, 1H), 7.13 (m, 2H), 6.98-7.13 (m, 4H), 3.61
(s, 3H), 2.74 (s, 3H).
EXAMPLE 103
[1422] ##STR159##
(4-Amino-2,6-dibromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
and
EXAMPLE 104
[1423] ##STR160##
(4-Amino-2-bromo-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1424] To a mixture of
(2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (53 mg,
0.20 mmol) in 1.8 mL of glacial acetic acid cooled at 12.degree. C.
was added dropwise a solution of Bromine (64 mg, 0.40 mmol) in 1 mL
of glacial acetic acid. The mixture was stirred for 1 min and the
reaction mixture was quenched by adding 1 mL of saturated sodium
thiosulfate. The reaction mixture was diluted with 50 mL of ethyl
acetate, and the organic layer was washed with saturated sodium
bicarbonate. The organic layer was dried over anhydrous MgSO.sub.4,
filtered and concentrated. The residue was purified by
chromatography (25-30% ethyl acetate/hexanes) to give the two
compounds.
(2-Methyl-quinazolin-4-yl)-(4-amino-2,6-dibromo-phenyl)-methyl-amine
(17.5 mg, 0.041 mmol, 21%). .sup.1H NMR (CDCl.sub.3): 7.78 (m, 1H),
7.58 (ddd, J=8.1, 6.6, 1.2, 1H), 7.24-7.27 (m, 2H), 7.15-7.19 (m,
1H), 7.09 (m, 1H), 4.62 (s, broad, 2H), 3.54 (s, 3H), 2.72 (s, 3H)
and
(2-methyl-quinazolin-4-yl)-(4-amino-2-bromo-phenyl)-methyl-amine.
(15 mg, 0.045 mmol, 22%). .sup.1H NMR (CDCl.sub.3): 7.75 (m, 1H),
7.55 (ddd, J=8.4, 6.9, 1.5, 1H), 7.31 (d, J=2.7, 1H), 7.13 (m, 1H),
7.03 (ddd, J=8.1, 6.9, 1.2, 1H), 6.91 (dd, J=8.1, 2.1, 1H), 6.74
(d, J=8.7, 1H), 4.18 (s, broad, 2H), 3.55 (s, 3H), 2.72 (s,
3H).
EXAMPLE 105
[1425] ##STR161##
(4-Dimethylamino-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1426] To a solution of
(2-methyl-quinazolin-4-yl)-(4-amino-phenyl)-methylamine (14 mg,
mmol) in 1.5 mL of 37% aqoues formaldehyde solution and 10 uL of
glacial acetic was added Sodium cyanoborohydride (15 mg, 0.24 mmol)
and the mixture was stirred at room temperature for 2 h. The
reaction mixture was quenched by adding 50 uL of 1N HCl. It was
diluted with 50 mL of ethyl acetate, washed with saturated sodium
bicarbonate, and followed by saturated sodium chloride. The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography
(25% ethyl acetate/hexanes) on silica gel to give the title
compound (12.4 mg, 0.042 mmol, 80%). .sup.1H NMR (CDCl.sub.3): 7.71
(m, 1H), 7.50 (ddd, J=8.4, 6.9, 1.5, 1H), 7.03-7.09 (m, 3H), 6.95
(ddd, J=8.1, 6.6, 0.9, 1H), 6.70 (m, 2H), 3.57 (s, 3H), 2.99 (s,
6H), 2.71 (s, 3H).
EXAMPLE 106
[1427] ##STR162##
(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1428] The title compound was prepared from
4-chloro-2-methylquinazoline and 4-ethoxyaniline by a procedure
similar to example 28 (93%). .sup.1H NMR (CDCl.sub.3): 7.83 (m,
1H), 7.81 (m, 1H), 7.42 (m, 1H), 7.65-7.71 (m, 2H), 7.46 (ddd,
J=8.4, 6.9, 1.5, 1H), 7.37 (s, broad, 1H), 6.92-6.97 (m, 2H), 4.06
(q, J=6.9, 2H), 2.68 (s, 3H), 1.43 (t, J=6.9, 3H).
EXAMPLE 107
[1429] ##STR163##
(4-Ethoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1430] The title compound was prepared from
(2-methyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-amine by a procedure
similar to example 36 (67%). .sup.1H NMR (CDCl.sub.3): 7.71-7.74
(m, 1H), 7.51 (ddd, J=8.1, 6.6, 1.5, 1H), 7.09 (m, 2H), 6.95-7.04
(m, 2H), 6.86-6.92 (m, 2H), 4.04 (q, J=6.9, 2H), 3.58 (s, 3H), 2.72
(s, 3H), 1.44 (t, J=6.9, 3H).
EXAMPLE 108
[1431] ##STR164##
(4-Methoxy-phenyl-2,3,5,6-d.sub.4)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1432] a) (4-Methoxy-phenyl-2,3,5,6-d.sub.4)-methylacetamide. To a
solution of (4-hydroxy-phenyl-2,3,5,6-d.sub.4)-acetamide (0.410 g,
2.46 mmol) in 15 mL of dimethylformamide was added methyl iodide (1
mL, 16.1 mmol) and the solution was cooled to 0.degree. C., then
sodium hydride (0.25 g, 60% oil suspension, 6.3 mmol) was added,
and the mixture was stirred for 2 h at 0.degree. C. The reaction
mixture was quenched by addition of 100 uL of water, and diluted
with 100 mL of ethyl acetate. It was washed with water (100
mL.times.3), saturated NaCl, dried over anhydrous MgSO.sub.4,
filtered and concentrated. The residue was purified by
chromatography (50% ethyl acetate/hexanes) to give the title
compound (0.380 g, 1.93 mmol, 78%). .sup.1H NMR (CDCl.sub.3): 3.83
(s, 3H), 3.23 (s, 3H), 1.86 (s, 3H).
[1433] b) (4-Methoxy-phenyl-2,3,5,6-d.sub.4)-methylamine. A mixture
of (4-methoxy-phenyl-2,3,5,6-d.sub.4)-methylacetamide (280 mg, 1.41
mmol) in 15 mL of 2N HCl was refluxed for 4 h. The reaction mixture
was cooled to 0.degree. C., basified using cold 2N NaOH and
extracted with ethyl acetate (50 mL.times.2). The combined organic
extracts were washed with saturated NaCl, dried over anhydrous
MgSO.sub.4, filtered and concentrated. The residue was purified by
chromatography (20% ethyl acetate/hexanes) to give the title
compound (199 mg, 1.28 mmol, 90%). .sup.1H NMR (CDCl.sub.3): 3.75
(s, 3H), 3.22 (s, broad, 1H), 2.80 (s, 3H).
[1434] c)
(4-Methoxy-phenyl-2,3,5,6-d.sub.4)-(2-methyl-quinazolin-4-yl)-m-
ethyl-amine. The title compound was prepared from
4-chloro-2-methylquinazoline and
(4-methoxy-phenyl-2,3,5,6-d.sub.4)-methylamine by a procedure
similar to example 28 (65%). .sup.1H NMR (CDCl.sub.3): 7.73 (m,
1H), 7.52 (ddd, J=8.4, 6.3, 1.8, 1H), 6.93-7.03 (m, 2H), 3.84 (s,
3H), 3.59 (s, 3H), 2.71 (s, 3H).
EXAMPLE 109
[1435] ##STR165##
(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine
[1436] a) 2-Methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one. A mixture
of 2-amino-5-nitrobenzoic acid (2.0 g, 10.9 mmol) in 20 mL of
acetic anhydride was refluxed for 2 h. The reaction mixture was
cooled to room temperature and the resulting precipitate was
collected and washed with cold diethylether and dried under vacuum
to obtain the title compound (1.45 g, 7.01 mmol, 64%). .sup.1H NMR
(CDCl.sub.3): 9.05 (d, J=2.4, 1H), 8.61 (dd, J=9.0, 2.7, 1H), 7.71
(d, J=7.9, 1H), 2.55 (s, 3H).
[1437] b) 2-Methyl-6-nitro-quinazoline-4-one. A solution of
2-methyl-6-nitro-4H-benzo[d][1,3]oxazin-4-one (200 mg, 0.97 mmol)
in a solution of ammonia in dioxane (0.5 M, 2.5 mL, 1.25 mmol) was
heated at 70.degree. C. for 4 h in a sealed tube. The reaction
mixture was cooled to room temperature, and the resulting
precipitate was collected and washed with cold diethylether and
dried. The crude product was used for the next step.
[1438] c) 4-Chloro-2-methyl-6-nitro-quinazoline. A mixture of
2-methyl-6-nitro-quinazoline-4-one (100 mg, 0.49 mmol) and
diisopropylethylamine (250 uL) in 3 mL of toluene was heated to
120.degree. C. for 1 h, then phosphorylchloride (50 uL, 0.54 mmol)
was added and the mixture was heated at 80.degree. C. for 3 h. The
reaction mixture was cooled to room temperature and poured into ice
(about 15 g), basified with saturated NaHCO.sub.3 and extracted
with 75 mL of ethyl acetate. The organic layer was washed with
water (50 mL), 1N citric acid (50 mL), water (50 mL) and saturated
NaCl, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography
(15% ethyl acetate/hexanes) on silica gel to give the title
compound (65.5 mg, 0.29 mmol, 60%). .sup.1H NMR (CDCl.sub.3): 9.17
(d, J=2.4, 1H), 8.69 (dd, J=9.3, 2.4, 1H), 8.13 (d, J=9.3, 1H),
2.93 (s, 3H).
[1439] d)
(4-Methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-am-
ine. The title compound was prepared from
4-chloro-2-methyl-6-nitro-quinazoline and
(4-methoxy-phenyl)-methylamine by a procedure similar to example 28
(87% yield). .sup.1H NMR (CDCl.sub.3): 8.27 (dd, J=9.3, 2.7, 1H),
7.82 (d, J=2.4, 1H), 7.75 (d, J=9.0, 1H), 7.18 (m, 2H), 7.01 (m,
1H), 3.88 (s, 3H), 3.65 (s, 3H), 2.73 (s, 3H).
EXAMPLE 110
[1440] ##STR166##
(6-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1441] The title compound was prepared from
(4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-amine
by a procedure as described in example 101 (70%). .sup.1H NMR
(CDCl.sub.3): 7.59 (d, J=9.0, 1H), 7.07 (m, 2H), 6.99 (dd, J=8.7,
2.4, 1H), 6.88 (m, 2H), 6.16 (d, J=2.1, 1H), 3.48 (s, broad, 2H),
3.82 (s, 3H), 3.55 (s, 3H), 2.68 (s, 3H).
EXAMPLE 111
[1442] ##STR167##
(6-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1443] The title compound was prepared from
(6-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
by a procedure described for example 102 (83%). .sup.1H NMR
(CDCl.sub.3): 7.69 (d, J=9.0, 1H), 7.10-7.18 (m, 3H), 6.95 (m, 2H),
6.62 (d, J=2.4, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 2.70 (s, 3H).
EXAMPLE 112
[1444] ##STR168##
(4-Methoxy-phenyl)-methyl-(2-methyl-7-nitro-quinazolin-4-yl)-amine
[1445] The title compound was prepared from 2-amino-4-nitrobenzoic
acid by a procedure similar to example 109. .sup.1H NMR
(CDCl.sub.3): 8.56 (d, J=2.4, 1H), 7.68 (dd, J=9.3, 2.7, 1H),
7.08-7.14 (m, 3H), 6.92-6.97 (m, 2H), 3.86 (s, 3H), 3.61 (s, 3H),
2.73 (s, 3H).
EXAMPLE 113
[1446] ##STR169##
(7-Amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1447] The title compound was prepared from
(4-methoxy-phenyl)-(2-methyl-7-nitro-quinazolin-4-yl)-methyl-amine
by a procedure as described in example 101. .sup.1H NMR
(CDCl.sub.3/d.sub.4-methanol): 7.11-7.15 (m, 2H), 6.93-6.96 (m,
2H), 6.86 (m, 1H), 6.63 (d, J=9.3, 1H), 6.35 (dd, J=9.3, 2.4, 1H),
3.86 (s, 3H), 3.60 (s, 3H), 2.65 (s, 3H).
EXAMPLE 114
[1448] ##STR170##
(7-Azido-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1449] The title compound was prepared from
(7-amino-2-methyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
by a procedure as described for example 102. .sup.1H NMR
(CDCl.sub.3): 7.36 (d, J=2.4, 1H), 7.08-7.13 (m, 2H), 6.88-6.96 (m,
3H), 6.59 (dd, J=9.0, 2.4, 1H), 3.84 (s, 3H), 3.57 (s, 3H), 2.69
(s, 3H).
EXAMPLE 115
[1450] ##STR171##
(3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-yl)-methyl-a-
mine
[1451] a) N-(3,5-dibromo-4-hydroxyphenyl)acetamide: To a solution
of N-(4-hydroxyphenyl)acetamide (0.50 g, 3.03 mmol) in glacial
acetic acid (1 mL), methanol (1 mL) and methylene chloride (5 mL)
cooled at 0.degree. C. was added a solution of bromine (1 g, 6.25
mmol) in 1 mL of glacial acetic acid, and the mixture was stirred
at 0.degree. C. for 2 h. Additional bromine (1 g, 6.25 mmol) in 1
mL of glacial acetic acid was added and the mixture was stirred for
0.75 h at 0.degree. C. The reaction mixture was diluted with 100 mL
of ethyl acetate, washed with 1M Na.sub.2SO.sub.3 (100 mL), water,
half saturated NaHCO.sub.3 (100 mL) and saturated NaCl (100 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by column
chromatography (40-45% ethyl acetate/hexanes) on silica gel to give
the title compound (0.52 g, 1.61 mmol, 53%). .sup.1H NMR
(CDCl.sub.3): 9.96 (s, broad, 1H), 9.64 (s, broad, 1H), 7.77 (s,
2H), 2.01 (s, 3H).
[1452] b) N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide: The
title compound was prepared from
N-(3,5-dibromo-4-hydroxyphenyl)acetamide (510 mg, 1.58 mmol) by a
procedure similar to Example 108a (460 mg, 1.36 mmol, 86%). .sup.1H
NMR (CDCl.sub.3): 7.39 (s, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 1.92
(s, 3H).
[1453] c) (3,5-dibromo-4-methoxy-phenyl)-methylamine: The title
compound was prepared from
N-(3,5-dibromo-4-methoxyphenyl)-N-methylacetamide (426 mg, 1.26
mmol) by a procedure similar to Example 108b (323 mg, 1.09 mmol,
87%). .sup.1H NMR (CDCl.sub.3): 6.72 (s, 2H), 3.80 (s, 3H), 3.67
(s, broad, 1H), 2.78 (d, J=5.1, 3H).
[1454] d)
(3,5-Dibromo-4-methoxy-phenyl)-(2-methyl-6-nitro-quinazolin-4-y-
l)-methyl-amine. The title compound was prepared from
4-chloro-2-methyl-5-nitroquinazoline and
(3,5-dibromo-4-methoxy-phenyl)-methylamine by a procedure similar
to example 28 (61% yield). .sup.1H NMR (CDCl.sub.3): 8.35 (dd,
J=9.3, 2.4, 1H), 7.86 (d, J=2.1, 1H), 7.84 (d, J=9.0, 1H), 7.47 (m,
1H), 7.44 (s, 2H), 3.98 (s, 3H), 3.66 (s, 3H), 2.75 (s, 3H).
EXAMPLE 116
[1455] ##STR172##
4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic Acid
[1456] The title compound was prepared from
4-chloro-2-methylquinazoline and 4-(methylamino)benzoic acid by a
procedure described for example 1b. .sup.1H NMR (CDCl.sub.3):
8.42-8.39 (m, 1H), 8.28 (m, 2H), 7.84 (m, 1H), 7.45 (m, 2H), 7.37
(m, 1H), 7.22 (m, 1H), 6.84 (d, J=1H, 8.4), 3.91 (s, 3H), 3.01 (s,
3H).
EXAMPLE 117
[1457] ##STR173##
Ethyl
4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate
[1458] The title compound was prepared from ethyl
4-chloroquinazoline-2-carboxylate and
(4-methoxy-phenyl)-methylamine by using the procedure described for
example 1b. .sup.1H NMR (CDCl.sub.3): 7.98-8.02 (m, 1H), 7.61 (ddd,
J=1H, 8.1, 6.9, 1.5), 7.08-7.17 (m, 3H), 7.01-7.05 (m, 1H),
6.91-6.96 (m, 2H), 4.56 (q, J=2H, 7.2), 3.84 (s, 3H), 3.71 (s, 3H),
1.50 (t, J=2H, 7.2).
EXAMPLE 118
[1459] ##STR174##
4-(N-(4-Methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylic
Acid
[1460] A mixture of ethyl
4-(N-(4-methoxy-phenyl)-N-methylamino)quinazoline-2-carboxylate
(560 mg, 1.66 mmol) and sodium hydroxide (126 mg, 3.15 mmol) in 25
mL of methanol and water (1:3) was stirred at room temperature for
5 h. The solvents were removed under vacuum, and the residue was
dissolved in 50 mL of water and acidified to pH 3. The white
precipitate was collected and washed with water and dried (380 mg,
1.23 mmol, 74%). .sup.1H NMR (CDCl.sub.3): 8.02-8.05 (m, 1H), 7.68
(ddd, J=1H, 8.4, 6.9, 1.5), 7.14-7.20 (m, 3H), 7.02-7.05 (m, 1H),
6.94-6.99 (m, 2H), 3.87 (s, 3H), 3.74 (s, 3H).
EXAMPLE 119
[1461] ##STR175##
Succinimidyl 4-(N-Methyl-N-(2-methylquinazolin-4-yl)amino)benzoic
Acid Ester
[1462] A solution of
4-(N-methyl-N-(2-methylquinazolin-4-yl)amino)benzoic acid (250 mg,
0.852 mmol), N-hydroxysuccinimide (75 mg, 0.653 mmol) and
dicyclohexylcarbodiimide (135 mg, 0.653 mmol) in 50 mL of methylene
chloride was refluxed overnight. The reaction mixture was cooled to
room temperature and diluted with 100 mL of ethyl acetate, washed
with water (3.times.100 mL), saturated NaCl and the organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was purified by chromatography (75% ethyl
acetate/hexanes) on silica gel to give the title compound (170 mg,
0.435 mmol, 51%). .sup.1H NMR (CDCl.sub.3): 8.06 (m, 2H), 7.95 (m,
1H), 7.71 (m, 1H), 7.11-7.22 (m, 4H), 3.76 (s, 3H), 2.84 (s, 3H),
2.81-2.92 (m, 4H).
EXAMPLE 120
[1463] ##STR176##
(2-Methylthio-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1464] A mixture of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg,
0.5 mmol), sodium methanethiolate (105 mg, 1.5 mmol) in 5 mL of
solvent (THF:MeOH:water=3:1:1) was stirred at 70.degree. C. for 4
h. The reaction mixture was diluted with 30 mL of ethyl acetate and
it was washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The crude product was purified by
chromatography on silica gel with acetate and hexane (1:5) as
eluent, yielding 11 mg of title compound (7%). .sup.1H NMR
(CDCl.sub.3): 7.65 (d, J=8.4 Hz, 1H), 7.51-7.45 (m, 1H), 7.14-7.10
(m, 2H), 6.93-6.89 (m, 4H), 3.84 (s, 3H), 3.58 (s, 3H), 2.67 (s,
3H).
EXAMPLE 121
[1465] ##STR177##
(2-Azido-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1466] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg,
0.5 mmol), sodium azide (97.5 mg, 1.5 mmol) in 5 mL of solvent
(THF:MeOH:water=3:1:1) by a procedure similar to that of example
120 (4%). .sup.1H NMR (CDCl.sub.3): 8.45 (d, J=8.4 Hz, 1H),
7.78-7.72 (m, 1H), 7.27-7.22 (m, 2H), 7.19-7.14 (m, 2H), 6.95 (d,
J=8.7 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H).
EXAMPLE 122
[1467] ##STR178##
(2-Dimethylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1468] A mixture of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg,
0.5 mmol), 2.0 M dimethylamine in methanol (2.0 ml, 4 mmol) in a
sealed tube was stirred at 70-80.degree. C. overnight. The mixture
was filled and the filtration was concentrated by vacuum. The
residue was extracted with ethyl acetate and was washed with brine,
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated.
The crude product was purified by chromatography on silica gel with
acetate and hexane (1:9) as eluent, yielding 128 mg of title
compound (83%). .sup.1H NMR (CDCl.sub.3): 7.44 (d, J=7.8 Hz, 1H),
7.36-7.30 (m, 1H), 7.11-7.08 (m, 2H), 6.90-6.85 (m, 3H), 6.65-6.59
(m, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
EXAMPLE 123
[1469] ##STR179##
(2-Methylamino-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine
[1470] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg,
0.5 mmol), 2.0 M methylamine in THF (2.0 ml, 4 mmol) by a procedure
similar to that of example 122 (53.7%). .sup.1H NMR (CDCl.sub.3):
7.45 (d, J=7.8 Hz, 1H), 7.39-7.33 (m, 1H), 7.11-7.07 (m, 2H),
6.90-6.87 (m, 3H), 6.69-6.64 (m, 1H), 4.95 (brs, 1H), 3.82 (s, 3H),
3.50 (s, 3H), 3.11 (d, J=5.1 Hz, 3H).
EXAMPLE 124
[1471] ##STR180##
(4-Fluoro-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1472] The title compound was prepared from
4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol) and
(4-fluoro-phenyl)-methyl-amine (125 mg, 2.52 mmol) by a procedure
similar to example 28 (46.8%). .sup.1H NMR (CDCl.sub.3): 7.76 (dd,
J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.16-7.00 (m, 6H), 3.60
(s, 3H), 2.73 (s, 3H),
EXAMPLE 125
[1473] ##STR181##
(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1474] a) 3-Amino-6-methoxy-pyridazine: A mixture of
3-amino-6-chloro-pyridazine (500 mg, 3.86 mmol), sodium methoxide
(1.0 ml, 4.4 mmol, 25% w/w) and copper powder (331 mg, 5.17 mmol)
in methanol (3 ml) was heated in a sealed tube at 160.degree. C.
for 24 h. After cooling, the reaction mixture was diluted with
methanol (10 ml) and filtered, and the filtrate was concentrated by
vacuum. The residue was purified by chromatography on silica gel
with acetate and hexane (1:2) as eluent, yielding 413 mg of title
compound (85.7%). .sup.1H NMR (CDCl.sub.3): 6.81 (m, 2H), 4.62
(brs, 2H), 4.00 (s, 3H).
[1475] b) (6-Methoxy-pyridazin-3-yl)-methyl-amine: To a solution of
3-amino-6-methoxy-pyridazine (90 mg, 0.72 mmol) in THF (2 ml) at
0.degree. C. was added sodium hydride (44 mg, 1.08 mmol, 60% oil
dispersion), followed by methyl iodide (0.07 ml, 1.08 mmol). The
mixture was stirred at 0.degree. C. for 1 h, then allowed to warm
to room temperature and stirred for another 2 h. The reaction
mixture was diluted with EtOAc (10 ml), washed with saturated
NaHCO.sub.3 aq., brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated by vacuum. The residue was purified by chromatography
on silica gel with acetate and hexane (1:2 to 1:1) as eluent,
yielding 6.0 mg of title compound (6.0%). .sup.1H NMR (CDCl.sub.3):
6.79 (d, J=9.0 Hz, 1H), 6.68 (d, J=10.5 Hz, 1H), 4.29 (brs, 1H),
4.01 (s, 3H), 3.01 (d, J=4.8 Hz, 3H).
[1476] c)
(6-Methoxy-pyridazin-3-yl)-(2-methyl-quinazolin-4-yl)-methyl-am-
ine: To a solution of (6-methoxy-pyridazin-3-yl)-methyl-amine (10
mg, 0.072 mmol) in DMF (1 ml) at 0.degree. C. was added sodium
hydride (4.3 mg, 0.11 mmol, 60% oil dispersion), followed by
4-chloro-2-methyl-quinazoline (12.9 mg, 0.072 mmol). The mixture
was stirred at 0.degree. C. for 1 h, then allowed to warm to room
temperature and stirred for another 2 h. The reaction mixture was
diluted with EtOAc (10 ml), washed with saturated NaHCO.sub.3 aq.,
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated by
vacuum. The residue was purified by chromatography on silica gel
with acetate and hexane (1:2 to 1:1) as eluent, yielding 2.0 mg of
title compound (10%). .sup.1H NMR (CDCl.sub.3): 7.90 (d, J=8.1 Hz,
1H), 7.73 (t, J=8.4 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.34-7.31 (m,
1H), 6.94 (d, J=9.3 Hz, 1H), 6.81 (d, J=9.6 Hz, 1H), 4.12 (s, 3H),
3.85 (s, 3H), 2.78 (s, 3H).
EXAMPLE 126
[1477] ##STR182##
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1478] a) 2-Amino-5-methoxy-pyrazine: The title compound was
prepared from 2-amino-5-bromo-pyrazine (500 mg, 2.87 mmol) and
sodium methoxide (1.0 ml, 4.4 mmol, 25% w/w) by a procedure similar
to example 125a (29%). .sup.1H NMR (CDCl.sub.3): 7.76 (s, 1H), 7.56
(s, 1H), 4.20 (brs, 2H), 3.88 (s, 3H).
[1479] b)
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The
title compound was prepared from 2-amino-5-methoxy-pyrazine (105
mg, 0.84 mmol) and 4-chloro-2-methyl-quinazoline (150 mg, 0.84
mmol) by a procedure similar to example 125c, yielding 106 mg of
the title product.
[1480] c)
(5-Methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amin- e:
The title compound was prepared from
(5-methoxy-pyrazin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (106 mg,
0.40 mmol) by a procedure similar to example 36 (56%). .sup.1H NMR
(CDCl.sub.3): 8.06 (d, J=1.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.74 (d,
J=1.5 Hz, 1H), 7.65-7.60 (m, 1H), 7.17-7.05 (m, 2H), 3.94 (s, 3H),
3.70 (s, 3H), 2.78 (s, 3H).
EXAMPLE 127
[1481] ##STR183##
(4-hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1482] The title compound was prepared from
4-chloro-2-methyl-quinazoline (818 mg, 4.58 mmol),
4-hydroxy-aniline (500 mg, 4.58 mmol) by a procedure similar to
example 1b to give 498 mg (43%) of off white solids. .sup.1H NMR
(DMSO-d.sub.6): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H),
7.77 (t, J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H),
2.45 (s, 3H).
EXAMPLE 128
[1483] ##STR184##
(2-Dimethylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
[1484] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
(69 mg, 0.23 mmol) and 2.0 M dimethylamine in methanol (4 ml, 8
mmol) by a procedure similar to example 122 (51%). .sup.1H NMR
(CDCl.sub.3): 8.02 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H),
7.38-7.34 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75-6.66 (m, 2H), 3.94
(s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
EXAMPLE 129
[1485] ##STR185##
(2-Methylamino-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
[1486] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine
(69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a
procedure similar to example 122 to give 20 mg (30%) of yellow
solids. .sup.1H NMR (CDCl.sub.3): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1
Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H),
5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J=5.1 Hz,
3H).
EXAMPLE 130 AND 131
[1487] ##STR186##
(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine and
(2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine
[1488] The title compounds were prepared from
2,4-dichloro-quinazoline and 4-methylcyclohexyl-amine by a
procedure similar to example 28. The isomers were separated by
chromatography (10-12% ethyl acetate/hexane).
(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine. .sup.1H
NMR (CDCl.sub.3): 7.66-7.79 (m, 3H), 7.46 (ddd, J=1.8, 6.3, 8.4,
1H), 5.96 (d, broad, J=6.6, 1H), 4.49 (m, 1H), 1.68-1.87 (m, 7H),
1.25 (m, 2H), 0.99 (d, J=6.6, 3H).
(2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine.
.sup.1H NMR (CDCl.sub.3): 7.67-7.78 (m, 3H), 7.43 (ddd, J=1.8, 6.6,
8.4, 1H), 5.78 (d, broad, J=7.5, 1H), 4.22 (m, 1H), 2.15-2.21 (m,
2H), 1.76-1.82 (m, 2H), 1.11-1.46 (m, 5H), 0.94 (d, J=6.6, 3H).
EXAMPLE 132
[1489] ##STR187##
(2-Chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-methyl-amine
[1490] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(cis-4-methylcyclohexyl)-amine by a
procedure similar to example 36. .sup.1H NMR (CDCl.sub.3): 7.88 (m,
1H), 7.75-7.78 (m, 1H), 7.68 (ddd, J=1.5, 6.9, 8.4, 1H), 7.37 (ddd,
J=1.5, 6.9, 8.4, 1H), 4.36 (m, 1H), 3.24 (s, 3H), 1.86-2.00 (m,
3H), 1.61-1.75 (m, 6H), 1.05 (d, J=7.2, 3H).
EXAMPLE 133
[1491] ##STR188##
(2-Chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-methyl-amine
[1492] The title compound was prepared from
(2-chloro-quinazolin-4-yl)-(trans-4-methylcyclohexyl)-amine by a
procedure similar to example 36. .sup.1H NMR (CDCl.sub.3): 7.89 (m,
1H), 7.74-7.78 (m, 1H), 7.68 (ddd, 0.9, 6.6, 8.1, 1H), 7.37 (ddd,
J=1.2, 6.6, 8.1, 1H), 4.38 (m, 1H), 3.21 (s, 3H), 1.67-1.95 (m,
6H), 1.39 (m, 1H), 1.4-1.25 (m, 2H), 0.93 (d, J=6.3, 3H).
EXAMPLE 134
[1493] ##STR189##
(2-Methyl-quinazolin-4-yl)-(pyrazin-2-yl)-methyl-amine
[1494] The title compound was prepared from
4-chloro-2-methyl-quinazoline and 2-amino-pyrazine in two steps by
a procedure similar to examples 100 and 36. .sup.1H NMR
(CDCl.sub.3): 8.27 (dd, J=1.5, 2.4, 1H), 8.13-8.14 (m, 2H), 7.95
(d, J=8.4, 1H), 7.77 (ddd, J=1.5, 6.6, 8.4, 1H), 7.45-7.48 (m, 1H),
7.34 (ddd, J=0.9, 6.6, 8.1, 1H), 3.78 (s, 3H), 2.83 (s, 3H).
EXAMPLE 135
[1495] ##STR190##
(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-amine
[1496] The title compound was prepared from
4-chloro-2-methyl-quinazoline and 4-amino-pyridine by a procedure
similar to examples 100. .sup.1H NMR (CDCl.sub.3): 8.58 (m, 1H),
7.79-7.93 (m, 5H), 7.70 (s, broad, 1H), 7.55 (ddd, J=1.2, 6.9, 8.1,
1H), 2.79 (s, 3H).
EXAMPLE 136
[1497] ##STR191##
(2-Methyl-quinazolin-4-yl)-(pyridin-4-yl)-methyl-amine
[1498] The title compound was prepared from
4-chloro-2-methyl-quinazoline (0.178 g, 2.13 mmol) and
(pyridin-4-yl)-methyl-amine (0.108 g, 1.84 mmol) by a procedure
similar to examples 125c (0.224 g, 49%). .sup.1H NMR (CDCl.sub.3):
8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4, 1H),
7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H),
2.83 (s, 3H).
EXAMPLE 137
[1499] ##STR192##
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine
[1500] a) 2-Amino-5-methoxy-pyridine. A mixture of
2-amino-5-iodo-pyridine (1 g, 4.54 mmol) in 20 mL of absolute
methanol with 400 mg of copper powder and sodium methoxide (6 mmol)
was heated at 160.degree. C. overnight in a seal tube. The reaction
mixture was cooled to room temperature, diluted with 80 mL of
methanol and filtered through a pad of celite. The filtrate was
concentrated and the residue was purified by chromatography (80%
ethyl acetate/hexane) to give the title compound (174 mg, 31%).
.sup.1H NMR (CDCl.sub.3): 7.78 (d, J=2.7, 1H), 7.09 (dd, J=3.0,
9.0, 1H), 6.48 (d, J=9.0, 1H), 3.78 (s, 3H).
[1501] b)
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The
title compound was prepared from 4-chloro-2-methyl-quinazoline and
2-amino-5-methoxy-pyridine by a procedure similar to example
28.
EXAMPLE 138
[1502] ##STR193##
(5-Methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1503] The title compound was prepared from
(5-methoxy-pyridin-2-yl)-(2-methyl-quinazolin-4-yl)-amine by a
procedure similar to example 36. .sup.1H NMR (CDCl.sub.3): 8.31 (d,
3.3, 1H), 7.80 (d, J=8.4, 1H), 7.58 (ddd, J=1.5, 6.6, 8.4, 1H),
7.13 (dd, J=3.3, 9.0, 1H), 6.99-7.10 (m, 2H), 6.82 (d, J=9.0, 1H),
3.87 (s, 3H), 3.70 (s, 3H), 2.76 (s, 3H).
EXAMPLE 139
[1504] ##STR194##
Difluoromethyl-(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine
[1505] A solution of
(4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35
mmol) in 3 mL of dimethylformamide in a 15 mL high pressure
reaction vessel was cooled to -78.degree. C. Difluorochloromethane
(about 0.8 mL) was condensed into the solution, then cesium
carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was
capped and heated at 80.degree. C. overnight. The reaction mixture
was cooled to room temperature and cooled to -78.degree. C. and the
seal tube was uncapped, warm to room temperature and allowed to
stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl
acetate and the organic layer was washed with water (50
mL.times.3), followed by saturated aqueous NaCl. The organic layer
was dried over anhydrous sodium sulfate, filtered and concentrated.
The residue was purified by chromatography (30% ethyl
acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give
the title compound (35 mg, 0.111 mmol, 32%). .sup.1H NMR
(CDCl.sub.3): 8.35 (dd, J=1.8, 8.1, 1H), 7.35- (m, 3H), 7.25 (t,
J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H),
2.48 (s, 3H).
EXAMPLE 140
[1506] ##STR195##
(4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine
[1507] a) 4-Chloro-2-methyl-pteridine. A mixture of
6-chloro-2-methyl-pyrimidine-4,5-diamine (37 mg, 0.233 mmol) and
1,4-dioxane-2,3-diol (32 mg, 0.266 mmol) in 0.8 mL of absolute
ethanol was stirred at room temperature for 2 h. The reaction
mixture was evaporated to dryness and the residue was purified by
column chromatography (50% ethyl acetate/hexane) to give the title
compound (41 mg, 0.227 mmol, 97%). .sup.1H NMR (CDCl.sub.3): 9.24
(d, J=1.8, 1H), 9.05 (d, J=1.5, 1H), 2.99 (s, 3H).
[1508] b) (4-Methoxy-phenyl)-(2-methyl-pteridin-4-yl)-methyl-amine.
The title compound was prepared from 4-chloro-2-methyl-pteridine
and (4-methoxy-phenyl)-methyl-amine by a procedure similar to
example 28 (67%). .sup.1H NMR (CDCl.sub.3): 8.73 (d, J=1.8, 1H),
8.22 (d, J=1.8, 1H), 7.07-7.10 (m, 2H), 6.86-6.92 (m, 2H), 3.85 (s,
3H), 3.69 (s, 3H), 2.73 (s, 3H).
EXAMPLE 141
[1509] ##STR196##
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine
[1510] a) 2-Amino-5-methoxy-pyrimidine: The title compound was
prepared from 2-amino-5-iodo-pyrimidine (2.0 g, 9.0 mmol) and
sodium methoxide (10 ml, 44 mmol, 25% w/w) by a procedure similar
to example 125a (21%). .sup.1H NMR (CDCl.sub.3): 8.05 (s, 2H), 4.78
(brs, 2H), 3.81 (s, 3H).
[1511] b)
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine: The
title compound was prepared from 2-amino-5-methoxy-pyrimidine (240
mg, 1.92 mmol) and 4-chloro-2-methyl-quinazoline (343 mg, 1.92
mmol) by a procedure similar to example 125c, yielding 283 mg of
the title product (55%). .sup.1H NMR (CDCl.sub.3): 8.69 (dd, J=1.5
Hz, J=8.1 Hz, 1H), 8.43 (s, 2H), 7.73-7.67 (m, 1H), 7.60 (d, J=7.2
Hz, 1H), 7.49-7.43 (m, 1H), 3.95 (s, 3H), 2.58 (s, 3H).
EXAMPLE 142
[1512] ##STR197##
(5-Methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-methyl-amine
[1513] The title compound was prepared from
(5-methoxy-pyrimidin-2-yl)-(2-methyl-quinazolin-4-yl)-amine (170
mg, 0.64 mmol) by a procedure similar to example 36 (50%). .sup.1H
NMR (CDCl.sub.3): 8.12 (s, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.74-7.69
(m, 1H), 7.38-7.34 (m, 1H), 7.30-7.24 (m, 1H), 3.85 (s, 3H), 3.78
(s, 3H), 2.83 (s, 3H).
EXAMPLE 143
Identification of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and
Analogs as Caspase Cascade Activators and Inducers of Apoptosis in
Solid Tumor Cells
[1514] Human breast cancer cell lines T-47D and DLD-1 were grown
according to media component mixtures designated by American Type
Culture Collection+10% FCS (Invitrogen Corporation), in a 5%
CO.sub.2-95% humidity incubator at 37.degree. C. T-47D and DLD-1
cells were maintained at a cell density between 50 and 80%
confluency at a cell density of 0.1 to 0.6.times.10.sup.6 cells/mL.
Cells were harvested at 600.times.g and resuspended at
0.65.times.10.sup.6 cells/mL into appropriate media+10% FCS. An
aliquot of 22.5 .mu.L of cells was added to a well of a 384-well
microtiter plate containing 2.5 .mu.L of a 10% DMSO in RPMI-1640
media solution containing 0.16 to 100 .mu.M of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine or other
test compound (0.016 to 10 .mu.M final). An aliquot of 22.5 .mu.L
of cells was added to a well of a 384-well microtiter plate
containing 2.5 .mu.L of a 10% DMSO in RPMI-1640 media solution
without test compound as the control sample. The samples were mixed
by agitation and then incubated at 37.degree. C. for 48 h in a 5%
CO.sub.2-95% humidity incubator. After incubation, the samples were
removed from the incubator and 25 .mu.L of a solution containing 14
.mu.M of N--(Ac-DEVD)-N'-ethoxycarbonyl-R110 fluorogenic substrate
(Cytovia, Inc.; WO99/18856), 20% sucrose (Sigma), 20 mM DTT
(Sigma), 200 mM NaCl (Sigma), 40 mM Na PIPES buffer pH 7.2 (Sigma),
and 500 .mu.g/mL lysolecithin (Calbiochem) was added. The samples
were mixed by agitation and incubated at room temperature. Using a
fluorescent plate reader (Model SPECTRAfluor Plus, Tecan), an
initial reading (T=0) was made approximately 1-2 min after addition
of the substrate solution, employing excitation at 485 nm and
emission at 530 nm, to determine the background fluorescence of the
control sample. After the 3 h incubation, the samples were read for
fluorescence as above (T=3 h).
[1515] Calculation:
[1516] The Relative Fluorescence Unit values (RFU) were used to
calculate the sample readings as follows: RFU.sub.(T=3h)-Control
RFU.sub.(T=0)=Net RFU.sub.(T=3h)
[1517] The activity of caspase cascade activation was determined by
the ratio of the net RFU value for
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine or other
test compounds to that of control samples. The EC.sub.50 (nM) was
determined by a sigmoidal dose-response calculation (Prism 3.0,
GraphPad Software Inc.).
[1518] The caspase activity (Ratio) and potency (EC.sub.50) are
summarized in Table I: TABLE-US-00001 TABLE I Caspase Activity and
Potency T-47D (24 hr) T-47D (48 hr) Exa. Cmpd. Ratio EC.sub.50 (nM)
Ratio EC.sub.50 (nM) 1 8.7 2 NA NA 2 6.7 31 NA NA 3 8.1 79 NA NA 4
7.1 872 NA NA 5 10.3 24 NA NA 6 6.7 219 NA NA 7 1.2 >10000 1.0
>10000 8 1.0 >10000 NA NA 9 NA NA 1.8 >10000 10 NA NA 12.8
48 11 9.0 8 12.5 10 12 5.3 8 12.8 9 13 8.9 260 NA NA 14 9.7 1345
12.3 1326 15 5.7 56 11.5 89 16 7.6 296 NA NA 17 3.0 7945 NA NA 18
1.0 >10000 1.0 >10000 19 1.0 >10000 1.0 >10000 20 13.1
161 NA NA 21 1.0 >10000 1.0 >10000 22 1.0 >10000 1.0
>10000 23 1.0 >10000 1.0 >10000 24 1.0 >10000 2.4 9460
25 NA NA 5.8 42 26 NA NA 15.7 178 27 NA NA 1.0 >10000 28 1.0
>10000 1.0 >10000 29 NA NA 1.0 >10000 30 NA NA 1.0
>10000 31 8.0 317 14.7 563 32 NA NA 1.0 >10000 33 NA NA 1.0
>10000 34 7.5 7 NA NA 35 7.2 141 NA NA 36 6.7 6 NA NA 37 3.3
2693 NA NA 38 3.4 2933 NA NA 39 4.5 693 NA NA 40 NA NA 6.1 47 41 NA
NA 12.4 20 42 8.6 282 14.6 265 43 NA NA 14.7 34 44 NA NA 14.3 501
45 NA NA 1.0 >10000 46 12.8 2184 9.4 2272 47 NA NA 11.5 187 48
NA NA 12.5 137 49 7.5 29 13.4 22 50 NA NA 1.0 >10000 51 NA NA
0.9 >10000 52 NA NA 10.8 6 53 8.3 5 11.4 11 54 NA NA 12.5 46 55
NA NA 9.0 1 56 NA NA 4.9 5 57 NA NA 6.2 432 58 NA NA 10.8 1 59 NA
NA 7.1 11 60 NA NA 6.5 13 61 NA NA 9.2 4046 62 NA NA 12.7 316 63 NA
NA 10.9 427 64 NA NA 1 >10000 65 NA NA 13.7 599 66 7.2 18 12.5
22 67 NA NA 12.5 38 68 NA NA 13.1 4 69 NA NA 1 >1000 70 NA NA
11.3 42 71 NA NA 6.9 2265 72 9.0 2 7.4 2 73 6.2 679 5.7 543 74 6.6
15 5.3 36 75 1.5 >10000 NA NA 76 5.6 7 14.1 8 77 5.7 700 12.3
2107 78 0.6 >10000 NA NA 79 0.7 >10000 NA NA 80 8.3 5752 NA
NA 81 1.9 >10000 NA NA 82 1.0 >10000 NA NA 83 NA NA 10.8 168
84 6.7 8 NA NA 85 7.6 2 NA NA 86 6.2 41 NA NA 87 6.3 25 NA NA 88
7.6 556 NA NA 89 NA NA 7.8 24 90 10.6 2 NA NA 91 8.3 4 NA NA 92
10.1 16 NA NA 93 11.3 65 NA NA 94 NA NA 1.0 >10000 95 1.0
>10000 NA NA 96 1.0 >10000 NA NA 97 NA NA 9.0 5 98 5.4 14
12.9 8 99 6.9 4 NA NA 100 8.9 474 NA NA 101 9.5 175 NA NA 102 8.8 5
11.3 16 103 9.3 552 NA NA 104 8.6 134 NA NA 105 8.5 2 NA NA 106 1.1
>10000 NA NA 107 5.2 5 NA NA 108 4.8 1 NA NA 109 4.6 274 NA NA
110 8.8 7 NA NA 111 9.4 32 NA NA 112 1.0 >10000 NA NA 113 3.7
735 NA NA 114 7.2 130 NA NA 115 1.0 >10000 NA NA 116 1.0
>10000 NA NA 117 7.4 134 NA NA 118 1.0 >10000 NA NA 119 11.8
4288 NA NA 120 5.2 8 NA NA 121 8.8 30 NA NA 122 8.2 16 NA NA 123
8.2 8 NA NA 124 5.2 408 NA NA 125 8.3 385 NA NA 126 7.6 55 NA NA
127 1.2 >10000 NA NA 128 10 58 NA NA 129 10 27 NA NA 130 1.2
>10000 NA NA 131 1.2 >10000 NA NA 132 1.2 >10000 NA NA 133
1.2 >10000 NA NA 134 1.2 >10000 NA NA 135 1.2 >10000 NA NA
136 1.2 >10000 NA NA 137 1.2 >10000 NA NA 138 5.0 15 NA NA
139 5.6 4662 NA NA 140 7.0 27 NA NA 141 1.2 >10000 NA NA 142 7.5
141 NA NA NA = Not available
[1519] The following substituted
N'-methyl-N'-(quinazolin-4-yl)benzohydrazides and analogs also are
identified as potent caspase cascade activators and inducers of
apoptosis and are thus useful in treating the various diseases and
disorders discussed above. TABLE-US-00002 T-47D T-47D (24 hr) (48
hr) EC.sub.50 EC.sub.50 Compound Ratio (nM) Ratio (nM) ##STR198##
NA NA 14.4 138 ##STR199## NA NA 10.1 737 ##STR200## NA NA 14.7 149
##STR201## NA NA 13.7 184 ##STR202## NA NA 13.8 290 ##STR203## NA
NA 12.7 46 ##STR204## NA NA 13.1 39
[1520] Thus,
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example
1) and analogs are identified as potent caspase cascade activators
and inducers of apoptosis and are thus useful in treating the
various diseases and disorders discussed above.
EXAMPLE 144
Identification of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and
Analogs as Antineoplastic Compounds that Inhibit Cell Proliferation
(GI.sub.50)
[1521] T-47D, DLD, H1299, MX-1 and SW620 cells were grown and
harvested as in Example 143. An aliquot of 90 .mu.L of cells
(4.4.times.10.sup.4 cells/mL) was added to a well of a 96-well
microtiter plate containing 5 .mu.L of a 10% DMSO in RPMI-1640
media solution containing 10 nM to 100 .mu.M of
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (1 nM to
10 .mu.M final). An aliquot of 45 .mu.L of cells was added to a
well of a 96-well microtiter plate containing 5 .mu.L of a 10% DMSO
in RPMI-1640 media solution without compound as the control sample
for maximal cell proliferation (L.sub.Max). The samples were mixed
by agitation and then incubated at 37.degree. C. for 48 h in a 5%
CO.sub.2-95% humidity incubator. After incubation, the samples were
removed from the incubator and 25 .mu.L of CellTiter-Glo.TM.
reagent (Promega) was added. The samples were mixed by agitation
and incubated at room temperature for 10-15 min. Plates were then
read using a luminescent plate reader (Model SPECTRAfluor Plus,
Tecan) to give L.sub.test values.
[1522] Baseline for GI.sub.50 (dose for 50% inhibition of cell
proliferation) of initial cell numbers was determined by adding an
aliquot of 45 .mu.L of cells or 45 .mu.L of media, respectively, to
wells of a 96-well microtiter plate containing 5 .mu.L of a 10%
DMSO in RPMI-1640 media solution. The samples were mixed by
agitation and then incubated at 37.degree. C. for 0.5 h in a 5%
CO.sub.2-95% humidity incubator. After incubation, the samples were
removed from the incubator and 25 .mu.L of CellTiter-Glo.TM.
reagent (Promega) was added. The samples were mixed by agitation
and incubated at 37.degree. C. for 10-15 min at room temperature in
a 5% CO.sub.2-95% humidity incubator. Fluorescence was read as
above, (L.sub.start) defining luminescence for initial cell number
used as baseline in GI.sub.50 determinations.
[1523] Calculation:
[1524] GI.sub.50 (dose for 50% inhibition of cell proliferation) is
the concentration where
[(L.sub.Test-L.sub.start)/(L.sub.Max-L.sub.start)]=0.5.
[1525] The GI.sub.50 (nM) are summarized in Table II:
TABLE-US-00003 TABLE II GI.sub.50 in Cancer Cells GI.sub.50 (nM)
Cell lines Example 1 Example 7 Example 34 Example 36 T-47D 8
>10000 503 111 DLD 8 >10000 76 89 H1299 6 >10000 59 53
MX-1 5 >10000 73 73 SW620 3 >10000 55 70
EXAMPLE 145
Identification of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and
Analogs as Inhibitors of Tubulin Polymerization
[1526] Lyophilized tubulin (Cytoskeleton #ML113, 1 mg, MAP-rich)
was assayed for the effect of the test compound on tubulin
polymerization as measured by change in fluorescence for
4',6-diamidino-2-phenylindole (DAPI) (Barron, D. M. et al.
Analytical Biochem., 2003, 315, 49-56). 1 .mu.l of serial dilutions
of each test compound (from 100.times.DMSO stock) was added in 96
well plate format and preincubated for 30 minutes with 94 ul of the
non-GTP supplemented tubulin supernatant. 5 .mu.l of DAPI/GTP
solution was added to initiate polymerization and incubated for 30
minutes at 37.degree. C. Fluorescence was read with excitation 350
nm, emission wavelength 485 nm on a Tecan Spectraflour Plus.
Polymerized tubulin (DMSO and with the tubulin stabilizer
Taxol.RTM. (paclitaxel)) gives a higher DAPI fluorescence as
compared to non-polymerized tubulin (vinblastine and colchicine
used to determine baseline). The IC.sub.50 for tubulin inhibition
was the concentration found to decrease the fluorescence of DAPI by
50% as calculated with Prism 3.0. The IC.sub.50 are summarized in
Table III. TABLE-US-00004 TABLE III Inhibition of Tubulin
Polymerization Activity Inhibition of tubulin Caspase activation
polymerization Example (EC.sub.50 nM) (IC.sub.50, nM) 1 2 <500 2
31 3000 6 219 4000 7 >10000 >50000 12 8 2000 13 260 6000 20
161 3000 25 42 2000 31 317 10000 34 7 1000 35 141 4000 36 6
<1000 41 20 <1000 42 282 5000 43 34 2000 44 501 10000 65 599
10000 72 2 <1000
[1527] Thus,
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example
1) and analogs are identified as potent inhibitors of tubulin
polymerization and are thus useful in treating diseases and
disorders discussed above.
EXAMPLE 146
Identification of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as a
Cytotoxic Compound in Multidrug Resistant Cells
[1528] Cytotoxicity of compounds in multidrug resistant cells can
be determined by administering compounds to cell lines that
overexpress the multidrug resistance pump MDR-1 and determining the
viability of the cell lines. NCI-ADR/Res and P388/ADR cell lines
are known to over-express the multidrug resistance pump MDR-1 (also
known as P-glycoprotein-1; Pgp-1); whereas MCF-7 and P388 cell
lines do not overexpress the multidrug resistance pumps MDR-1,
MRP-1, or BCRP.
[1529] NCI-ADR/Res, MCF-7, P388, and P388/ADR cell lines were
obtained from American Type Culture Collection (Manassas, Va.) and
maintained in RPMI-1640 media supplemented with 10% FCS, 10
units/ml penicillin and streptomycin, 2 mM Glutamax and 1 mM sodium
pyruvate (Invitrogen Corporation, Carlsbad, Calif.). For compound
testing, cells were plated in 96 well dishes at a concentration of
1.5.times.10.sup.4 cells/well. Cells were allowed to adhere to the
plate overnight and then incubated with compounds at final
concentrations ranging from 0.13 nM to 10 uM for 72 hours. Cell
viability was then assessed using the ATP-lite reagent (Perkin
Elmer, Foster City, Calif.). Plates were read on a Wallac Topcount
luminescence reader (Perkin Elmer, Foster City, Calif.) and the
results graphed in Prism software (Graphpad Software, Inc., San
Diego, Calif.). Non-linear regression with variable slope analysis
was performed to obtain IC.sub.50 concentration values.
[1530] Example 1 compound, docetaxel, and vinblastine were tested
for their ability to kill multidrug resistant cells by
administering the compounds to NCI-ADR/Res, MCF-7 cells, P388 and
P388/ADR cells and determining the viability of the cells. Example
1 compound maintained nearly equal potency in all four cell lines,
whereas known MDR-1 substrates vinblastine and docetaxel showed a
loss of potency in the MDR-1 over-expressing cell lines as shown in
Table IV below: TABLE-US-00005 TABLE IV Cytotoxicity of Exa 1 Cmpd
in MDR-1 over-expressing cell lines IC.sub.50 (nM) Cell Line Exa 1
Cmpd Vinblastine Docetaxel MCF-7 2.9 0.5 2 NCI/ADR-RES 1.3 3 410
P388 1.1 2.6 7 P388/ADR 2.7 2.8 127
[1531] Thus,
(2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine is
identified as a cytotoxic compound in multidrug resistant cells and
is thus useful in treating diseases and disorders discussed
above.
EXAMPLE 147
Propidium Iodide and Annexin V Flow Cytometer-Based Assay to Detect
Apoptosis
[1532] Necrotic versus apoptotic killing of human cell lines by
compounds can be determined using dual annexin V-FITC and propidium
iodide (PI) staining. Flipping of phosphatidylserine to the outer
leaflet of the plasma membrane is a characteristic of all apoptotic
cells. AnnexinV is a serum protein that binds to phosphatidylserine
in the presence of the divalent cations (calcium). PI is a DNA
stain that is excluded from live cells and is used to discriminate
between cells with intact or damaged plasma membranes.
[1533] Cells are plated at varying densities in 6 well plates and
treated with varying concentrations of compounds for 18-72 hours.
Cells are grown in RPMI-1640 media supplemented with 10% FCS. DMSO
concentrations do not exceed 0.1% v:v in any assay. All cells in
the wells are harvested and rinsed 1.times. with cold Hanks
buffered saline solution (HBSS) containing calcium and magnesium
(Invitrogen, Carlsbad Calif.). Carefully aspirate supernatant after
the wash and resuspend in 100 .mu.l Annexin V-FITC (Annexin V/PT
Apoptosis Detection Kit; R & D Systems TA4638; Minneapolis,
Minn.) in binding buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 5 mM
KCl, 1 mM MgCl.sub.2, 1.8 mM CaCl.sub.2 and 2% bovine serum albumin
w:v). Incubate in dark for 15 minutes on ice. Prior to analyzing
samples, the volume is adjusted to 500 .mu.l with 1.times. Binding
Buffer and 25 .mu.l PI is added per sample. Staining can be
quantified on a flow cytometer (Becton-Dickenson, Franklin Lake,
N.J.).
EXAMPLE 148
[1534] TABLE-US-00006 Injection Formulation Excipients Amount
Active Compound 5 mg PEG-400 5 grams TPGS 10 grams Benzyl alcohol
0.5 gram Ethanol 2 grams D5W Add to make 50 mL
[1535] An injection formulation of a compound selected from Formula
IV (the "Active Compound") can be prepared according to the
following method. 5 mg of the Active Compound is dissolved into a
mixture of the d-.alpha.-tocopheryl polyethylene glycol 1000
succinate (TPGS), PEG-400, ethanol, and benzyl alcohol. D5W is
added to make a total volume of 50 mL and the solution is mixed.
The resulting solution is filtered through a 0.2 .mu.m disposable
filter unit and is stored at 25.degree. C. Solutions of varying
strengths and volumes are prepared by altering the ratio of Active
Compound in the mixture or changing the total amount of the
solution.
EXAMPLE 149
[1536] TABLE-US-00007 Tablet Formulation Active Compound 100.0 mg
Lactose 100.0 mg Corn Starch 50.0 mg Hydrogenated Vegetable Oil
10.0 mg Polyvinylpyrrolidone 10.0 mg 270.0 mg
[1537] A formulation of tablets of a compound selected from
Formulae I-VIb (e.g. Example 1 compound) (the "Active Compound")
can be prepared according to the following method. 100 mg of Active
Compound) is mixed with 100 mg lactose. A suitable amount of water
for drying is added and the mixture is dried. The mixture is then
blended with 50 mg of corn starch, 10 mg hydrogenated vegetable
oil, and 10 mg polyvinylpyrrolidinone. The resulting granules are
compressed into tablets. Tablets of varying strengths are prepared
by altering the ratio of Active Compound in the mixture or changing
the total weight of the tablet.
EXAMPLE 150
[1538] TABLE-US-00008 Capsule Formulation Active Compound 100.0 mg
Microcrystalline Cellulose 200.0 mg Corn Starch 100.0 mg Magnesium
Stearate 400.0 mg 800.0 mg
[1539] A formulation of capsules containing 100.0 mg of a compound
selected from Formulae I-VIb (e.g. Example 1 compound) (the "Active
Compound") can be prepared according to the following method. 100
mg of Active Compound is mixed with 200 mg of microcrystalline
cellulose and 100 mg of corn starch. 400 mg of magnesium stearate
is then blended into the mixture and the resulting blend is
encapsulated into a gelatin capsule. Doses of varying strengths can
be prepared by altering the ratio of the Active Compound to
pharmaceutically acceptable carriers or changing the size of the
capsule.
EXAMPLE 151
Identification of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine as an
Inhibitor of Topoisomerase
[1540] The ability of compounds to inhibit Topoisomerase II
activity in relaxing supercoiled DNA can be determined by adding
compounds to DNA samples and measuring the formation of
topoisomers. The addition of Topoisomerase II to DNA samples
results in the formation of topoisomers, which migrate faster than
open circular DNA and slower than supercoiled DNA substrate when
run on a gel. Ethidium Bromide, a known intercalator, and etoposide
(VP16), a known topoisomerase II inhibitor, are used as
controls.
[1541] Assay reagents were obtained from TopoGEN, Inc. (Columbus,
Ohio). Samples were prepared by combining 10 .mu.l of D/W, 2 .mu.l
of 10.times.TOPO II assay buffer, and 1 .mu.l (0.25 .mu.g) pRYG
DNA. 5 .mu.l of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example
1 Compound), Ethidium Bromide, or VP16 were added to samples at
varying concentrations. 2 .mu.l of TOPO II (4 units in 20 .mu.l
reaction) was added to the samples and the samples were incubated
at 37.degree. C. in a water bath for 50 minutes. 2 .mu.l of 10% SDS
was added and 0. Proteinase K (500 .mu.g/ml) was added and the
samples were incubated again at 37.degree. C. in a water bath for
50 minutes. Half of the reaction was loaded on a 1% gel without
ethidium bromide and run in 1.times.TAE buffer at 20 volts/cm for 2
hours. The gel was stained with 0.5 .mu.g/ml Ethidium Bromide for
10 seconds and destained in D/W for 30 seconds. The resulting gel
image is shown in FIG. 1.
[1542] Inspection of the amount of supercoiled DNA present in the
sample with 100 .mu.M of Example 1 Compound indicates that
inhibition of DNA relaxation is substantial. The results are
consistent with topoisomerase II inhibition as well as with an
effect of the compound not on topoisomerase II, but rather on the
DNA itself, such as intercalation of the compound into the DNA
substrate. In order to distinguish between direct inhibition of
topoisomerase II activity and intercalation, the effect of Example
1 Compound is determined on topoisomerase I-mediated relaxation of
supercoiled DNA.
[1543] Samples were prepared by combining 10 .mu.l of D/W, 2 .mu.l
of 10.times.TOPO II assay buffer, and 1 .mu.l (0.25 .mu.g) Form I
DNA. 5 .mu.l of
(2-Chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (Example
1 Compound), Ethidium Bromide, or VP16 were added to samples at
varying concentrations. 1 .mu.l of TOPO I (5 units in 20 .mu.l
reaction) was added to the samples and the samples were incubated
at 37.degree. C. in a water bath for 50 minutes. 2 .mu.l of 10% SDS
was added and 0. Proteinase K (500 .mu.g/ml) was added and the
samples were incubated again at 37.degree. C. in a water bath for
50 minutes. Half of the reaction was loaded on a 1% gel without
ethidium bromide and run in 1.times.TAE buffer at 20 volts/cm for 2
hours. The gel was stained with 0.5 .mu.g/ml Ethidium Bromide for
10 seconds and destained in D/W for 30 seconds. The resulting gel
image is shown in FIG. 2.
[1544] As shown in FIG. 2, the known intercalator, Ethidium
Bromide, completely eliminated topoisomerase I-dependent relaxation
of supercoiled DNA, just as it eliminated topoisomerase
II-dependent relaxation of supercoiled DNA (see FIG. 1). In
contrast, Example 1 Compound and the known topoisomerase II
inhibitor, VP-16, have no apparent effect on topoisomerase I
activity.
EXAMPLE 152
Identification of Radiolabeled
(4-Azido-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine as an
Inhibitor of Topoisomerase
[1545] 30 Units (15 ul) Human Type II Topoisomerase (p170 Form)
(from TopoGEN, Inc., Columbus, Ohio) was incubated with 50 nM
radiolabeled Example 102 compound for 60 minutes at room
temperature. ##STR205##
Radiolabeled Example 102 Compound
[1546] (Radiolabeled Example 102 compound stock is 16.67 uM, 60
Ci/mmol, 1 mCi/ml American Radiolabeled Chemicals, Inc., St. Louis,
Mo. Samples were either UV irradiated (+) with a short wavelength
UV Source (254 nm) for 10 minutes at a distance of 3.5 cm or not
irradiated (-). 8 ul of 5.times. sample buffer (150 mM Tris, pH
6.8, 50% glycerol, 1% SDS, 50 mM dithiothreitol, 62 mg/ml
bromophenol blue) was added to the samples and boiled for 5
minutes. The entire sample was then loaded onto a 6% Tris-Glycine
SDS-gel (10 well, 1.5 mm thickness) (Invitrogen, Carlsbad, Calif.).
The gel was stained with 1% Coomassie Brilliant Blue in 40%
methanol, 7.5% acetic acid for 2 hours then de-stained in several
changes of de-stainer (40% methanol, 7.5% acetic acid). The gel was
then incubated in Amplify (Amersham, Piscataway, N.J.) for 30
minutes at room temperature and then dried down on Whatman filter
paper at 80.degree. C. for 2 hours on a gel dryer. The dried gel
was put on Hyperfilm (Amersham) in a film cassette and placed at
-80.degree. C. for 5-7 days. The resulting gel image is shown in
FIG. 3. These results indicate that the compound binds sufficiently
well to Topoisomerase II to crosslink to the enzyme when
photoactivated.
[1547] Having now fully described this invention, it will be
understood by those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents, patent
applications and publications cited herein are fully incorporated
by reference herein in their entirety.
* * * * *