TRICYCLIC COMPOUNDS CAPABLE OF INHIBITING TYROSINE KINASES OF THE EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY

COMPOSES TRICYCLIQUES POUVANT INHIBER LES TYROSINES KINASES DE LA FAMILLE DES RECEPTEURS DU FACTEUR DE CROISSANCE EPIDERMIQUE

English Abstract

Epidermal growth-factor inhibitors of formula (I), wherein: 1) Y and Z are
both C (carbon), both N or one N and the other C, in which case the ring
structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is
C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two
aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle,
or 3) one of Y and Z is N, O or S, whereupon the other one of Y or Z is simply
a bond between the two aromatic rings, then the ring structure is a fused 6,5
(5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can
be nitrogen, whereupon the remaining atoms must be carbon, or any two
contiguous positions in A-E can be a single heteroatom, N, O or S, forming a
five membered fused ring, in which case one of the two remaining atoms must be
carbon, and the other can be either carbon or nitrogen. X = O, S, NH or NR9,
such that R9 = lower alkyl, OH, NH2, lower alkoxy or lower monoalkylamino m =
0-3, and Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl,
imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl,
benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl.

French Abstract

Inhibiteurs du facteur de croissance épidermique ayant la formule (I), dans laquelle 1) Y et Z représentent tous deux C (carbone), tous deux N ou l'un représente N et l'autre C, auquel cas la structure du cycle est un tricycle 6,6 (5 ou 6) fusionné linéairement, ou 2) l'un de Y et Z représente C=C, C=N, et l'autre de Y et Z représente simplement une liaison entre les deux cycles aromatiques, la structure du cycle étant alors un tricycle 6,6 (5 ou 6) non linéaire, ou 3) l'un de Y et Z représente N, O ou S, l'autre de Y et Z représentant simplement alors une liaison entre les deux cycles aromatiques, la structure cyclique étant un tricycle 6,5 (5 ou 6) fusionné; A, B, D et E peuvent tous représenter des carbones, ou bien deux d'entre eux au plus peuvent être l'azote, auquel cas les atomes restants doivent être des carbones, ou deux positions contiguës quelconques dans A-E peuvent être un seul hétéroatome, N, O ou S, formant un cycle fusionné à 5 membres, auquel cas l'un des deux atomes restants doit être le carbone et l'autre étant soit du carbone soit de l'azote. X représente O, S, NH ou NR?9¿, R?9¿ représentant un alkyle inférieur, OH, NH¿2?, alcoxy inférieur ou monoalkylamino inférieur, m = 0-3, et Ar représente phényle, thiényle, furanyle, pyrrolyle, pyridyle, pyrimidyle, imidazolyle, pyrazinyle, oxazolyle, thiazolyle, naphtyle, benzothiényle, benzofuranyle, indolyle, quinolinyle, isoquinolinyle et quinazolinyle.

Claims

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What Is Claimed Is:
1. For use in inhibiting epidermal growth factor receptor tyrosine kinase in a
mammal, an effective amount of a compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,

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lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n=0, 1 or2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R~ is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),

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cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl( 1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,

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lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,

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amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
2. The compound of claim 1 wherein n = 0, A-E, Y & Z being carbon, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen.
3. The compound of claim 2 having the ring structure:
<IMG>

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4. The compound of claim 1 wherein is = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, along with Y
and Z, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair
of electrons.
5. The compound of claim 4 having the ring structure:
<IMG>
6. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being carbon, along with Y
and Z, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen.
7. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, along with Y
and Z, X =
NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or lower
alkyl if on
nitrogen.
8. The compound of claim 7 having the ring structure:
<IMG>
9. The compound of claim 1 wherein n = 0 or 1, A & B taken together as oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, Y and
Z both carbon,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair of
electrons.

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10. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, Y and
Z both carbon,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair of
electrons.
11. The compound of claim 10 having the ring structure:
<IMG>
12. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and E as
nitrogen, Y and Z both carbon, X = NH, Ar a benzene ring, optionally
substituted, and R5-R8
hydrogen or lower alkyl if on nitrogen, or a lone pair of electrons.
13. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, Y and
Z both carbon,
X = NH, Ar a benzene ring, optionally substituted. and R5-R8 hydrogen, lower
alkyl, or a lone
pair of electrons.
14. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, Y and
Z both carbon,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen, lower
alkyl, or a lone
pair of electrons.
15. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as
nitrogen, or D & E taken together, and B as nitrogen, Y and Z both carbon, X =
NH, Ar a
benzene ring, optionally substituted, and R5-R8 hydrogen, lower alkyl, or a
lone pair of
electrons.

-126-
16. The compound of claim 15 having the ring structure:
<IMG>
17. The compound of claim 1 wherein n = 0, A & B taken together, with D & E
taken separately, all as nitrogen, Y and Z both carbon, X = NH, Ar a benzene
ring, optionally
substituted, and R5-R8 hydrogen or lower alkyl if on nitrogen, or a lone pair
of electrons.
18. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E as
nitrogen, the remaining three being carbon, along with Y and Z, X = NH, Ar a
benzene ring,
optionally substituted, and R5-R8 hydrogen or a lone pair of electrons.
19. The compound of claim 1 wherein n = 0, with any two of A, B, D or E as
nitrogen, the remaining two being carbon, along with Y and Z, X = NH, Ar a
benzene ring,
optionally substituted, and R5-R8 hydrogen or a lone pair of electrons.
20. The compound of claim 1 wherein n = 0, A-E, and one of Y and Z being
carbon, the other nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen or a lone pair of electrons.
21. The compound of claim 20 having the ring structure:
<IMG>
22. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, along with one
of Y and Z,

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the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen or a lone pair of electrons.
23. The compound of claim 22 having the ring structure:
<IMG>
24, The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being; carbon, along with
one of Y and Z, the
other being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and
R5-R8 hydrogen
or a lone pair of electrons.
25. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, along with
one of Y and Z,
the other being nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen, or optionally lower alkyl if on nitrogen in the pyrrole ring, or a
lone pair of
electrons.
26. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of
Y and Z being
carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen or a lone pair of electrons.
27. The compound of claim 26 having the ring structure:
<IMG>

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28. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of
Y and Z being
carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen or a lone pair of electrons.
29. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and E as
nitrogen, one of Y and Z being carbon the other nitrogen, X = NH, Ar a benzene
ring,
optionally substituted, and R5-R8 hydrogen or optionally lower alkyl if on
nitrogen or a lone
pair of electrons.
30. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of
Y and Z
being carbon the other nitrogen, X = NH, Ar a benzene ring, optionally
substituted, and R5-R8
hydrogen, lower alkyl, or a lone pair of electrons.
31. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of
Y and Z being
carbon the other nitrogen, X = NH, Ar a benzene ring, optionally substituted,
and R5-R8
hydrogen, lower alkyl, or a lone pair of electrons.
32. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as
nitrogen, or D & E taken together, and B as nitrogen, one of Y and Z being
carbon the other
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, lower alkyl,
or a lone pair of electrons.
33. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E as
nitrogen, the remaining three being carbon, along with one of Y and Z, the
other being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.

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34. The compound of claim 33 having the ring structure:
<IMG>
35. The compound of claim 1 wherein n = 0, with any two of A, B, D or E as
nitrogen, the remaining two being carbon, along with one of Y and Z, the other
being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.
36. The compound of claim 1 wherein n = 0, A-E carbon, Y and Z nitrogen, X =
NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone
pair of electrons.
37. The compound of claim 36 having the ring structure:
<IMG>
38. The compound of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z
being ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen.
39. The compound of claim 38 having the ring structure:
<IMG>

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40. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, one of Y & Z
being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.
41. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being carbon, one of Y & Z
being ethylidene,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair of
electrons.
42. The compound of claim 1 wherein n = d or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, one of Y & Z
being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or lower
alkyl if on nitrogen.
43. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of
Y & Z being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.
44. The compound of claim 1 wherein n - 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of
Y & Z being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.
45. The compound of claim 1 wherein n = 0, A & B taken together, and E as
nitrogen, one of Y & Z being ethylidene, X = NH, Ar a benzene ring, optionally
substituted,
and R5-R8 hydrogen or lower alkyl if on nitrogen or a lone pair of electrons.

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46. The compound of claim 44 having the ring structure:
<IMG>
47. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D h E taken together as oxygen and B as nitrogen, one of
Y & Z being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, lower
alkyl, or a lone pair of electrons.
48. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of
Y & Z being
ethylidene, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, lower
alkyl, or a lone pair of electrons.
49. The compound of claim 48 having the ring structure:
<IMG>
50. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as
nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being
ethylidene, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen, lower alkyl, or
a lone pair of
electrons.

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51. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E as
nitrogen, the remaining three being carbon, one of Y & Z being ethylidene, X =
NH, Ar a
benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair of
electrons.
52. The compound of claim 1 wherein n = 0, with any two of A, B, D or E as
nitrogen, the remaining two being carbon, one of Y & Z being ethylidene, X =
NH, Ar a
benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair of
electrons.
53. The compound of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z
being sulfur, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair of electrons.
54. The compound of claim 53 having the ring structure:
<IMG>
55. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, one of Y & Z
being sulfur, X
= NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone
pair of
electrons.
56. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being carbon, one of Y & Z
being sulfur, X =
NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone
pair of electrons.
57. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, one of Y & Z
being sulfur,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair or lower
alkyl if on nitrogen.

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58. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of
Y & Z being
sulfur, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen
or a lone pair
of electrons.
59. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of
Y & Z being
sulfur, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen
or a lone pair
of electrons.
60. The compound of claim 59 having the ring structure:
<IMG>
61. The compound of claim 1 wherein n = 0, A & B taken together, and E as
nitrogen, one of Y & Z being sulfur, X = NH, Ar a benzene ring, optionally
substituted, and
R5-R8 hydrogen or lower alkyl if on nitrogen or a lone pair of electrons.
62. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of
Y & Z being
sulfur, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen,
lower alkyl, or
a lone pair of electrons.
63. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of
Y & Z being
sulfur, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen,
lower alkyl, or
a lone pair of electrons.
64. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as

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nitrogen, or D & E taken together, and Y as nitrogen, one of Y & Z being
sulfur, X = NH, Ar
a benzene ring, optionally substituted, and R5-R8 hydrogen, lower alkyl, or a
lone pair of
electrons.
65. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E as
nitrogen, the remaining three being carbon, one of Y & Z being sulfur, X = NH,
Ar a benzene
ring, optionally substituted, and R5-R8 hydrogen or a lone pair of electrons.
66. The compound of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z
being nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, or
lower alkyl if on nitrogen.
67. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, one of Y & Z
being nitrogen,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair or lower
alkyl if on nitrogen.
68. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being carbon, one of Y & Z
being nitrogen,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair
or lower alkyl if
on nitrogen.
69. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, one of Y & Z
being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or lower
alkyl if on nitrogen.
70. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of
Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair or lower alkyl if on nitrogen.

-135-
71. The compound of claim 70 having the ring structure:
<IMG>
72. The compound of claim I wherein n = 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of
Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a lone
pair where appropriate, or lower alkyl if on nitrogen.
73. The compound of claim 1 wherein n = 0, A & B taken together, and E as
nitrogen, one of Y & Z being nitrogen, X = NH, Ar a benzene ring, optionally
substituted, and
R5-R8 hydrogen or lower alkyl if on nitrogen or a lone pair of electrons.
74. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of
Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, lower alkyl,
or a lone pair of electrons where appropriate.
7:5. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of
Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen, lower alkyl,
or a lone pair of electrons where appropriate.
76. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as
nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being
nitrogen, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen, lower alkyl, or
a lone pair of
electrons where appropriate.

-136-
77. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E as
nitrogen, the remaining three being carbon. one of Y & Z being nitrogen, X =
NX, Ar a
benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair of
electrons.
78. The compound of claim 1 wherein n = 0 or 1, A-E being carbon, one of Y & Z
being oxygen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8
hydrogen or a
lone pair of electrons.
79. The compound of claim 78 having the ring structure:
<IMG>
80. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as oxygen, the remaining pair both being carbon, one of Y & Z
being oxygen,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair of
electrons.
81. The compound of claim 1 wherein n - 0 or 1, with one of A & B or D & E
taken together as sulfur, the remaining pair both being carbon, one of Y & Z
being oxygen, X
= NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a lone
pair of
electrons.
82. The compound of claim 1 wherein n = 0 or 1, with one of A & B or D & E
taken together as nitrogen, the remaining pair both being carbon, one of Y & Z
being oxygen,
X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen or a
lone pair of
electrons where appropriate or lower alkyl if on nitrogen.
83. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and E as nitrogen, or D & E taken together as oxygen and A as nitrogen, one of
Y & Z being

-137-
oxygen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen
or a lone pair
of electrons.
84. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and E as nitrogen, or D & E taken together as sulfur and A as nitrogen, one of
Y & Z being
oxygen, X = NH, Ar a benzene ring, optionally substituted, and R5-R8 hydrogen
or a lone pair
of electrons.
85. The compound of claim 84 having the ring structure:
<IMG>
86. The compound of claim 1 wherein n = 0, A & B taken together, and E as
nitrogen, one of Y & Z being oxygen, X = NH, Ar a benzene ring, optionally
substituted, and
R5-R8 hydrogen or optionally lower alkyl if on nitrogen or a lone pair of
electrons.
87. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
oxygen,
and D as nitrogen, or D & E taken together as oxygen and B as nitrogen, one of
Y & Z being
oxygen, X - NH, Ar a benzene ring;, optionally substituted, and R5-R8
hydrogen, lower alkyl,
or a lone pair of electrons.
88. The compound of claim 1 wherein n = 0 or 1, A & B taken together as
sulfur,
and D as nitrogen, or D & E taken together as sulfur and B as nitrogen, one of
Y & Z, being
oxygen, X = NH, Ar a benzene ring. optionally substituted, and R5-R8 hydrogen,
lower alkyl,
or a lone pair of electrons.
89. The compound of claim 1 wherein n = 0 or 1, A & B taken together, and D as
nitrogen, or D & E taken together, and B as nitrogen, one of Y & Z being
oxygen, X = NH,
Ar a benzene ring, optionally substituted, and R5-R8 hydrogen, lower alkyl, or
a lone pair of

-138-
electrons.
90. The compound of claim 1 wherein n = 0 or 1, with one of A, B, D or E ag
nitrogen, the remaining three being carbon, one of Y & Z being oxygen, X = NH,
Ar a
benzene ring, optionally substituted, and R5-R8 hydrogen or a lone pair of
electrons.
91. The compound of claim 1 wherein any of the substituents R1, R2, R3 or R4
contain chiral centers, or in the case of R1 create chiral centers on the
linking atoms, then all
stereoisomers thereof both separately and as racemic and/or diastereoisomeric
mixtures are
included therein.
92. The compound of claim 1 wherein the compound is selected from the group
consisting of:
4-(3-Bromoanilino)benzo[g]quinazoline;
4-([R]-1-Phenylethylamino)benzo[g]quinazoline;
4-(3-Bromoanilino)pyrrolo[3,2-g]quinazoline;
4-(3-Bromoanilino)thiazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)oxazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)imidazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)triazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)-6N-methylimidazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)-8N-methylimidazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)pyrazolo[2,3-g]quinazoline;
4-(3-Bromoanilino)imidazolo[4,5-h]quinazoline;
4-(3-Bromoanilino)benzothieno[3,2-d]pyrimidine;
4-(3-Bromoanilino)-8-nitrobenzothieno[3,2-d]pyrimidine;
8Amino-4-(3-bromoanilino)benzothieno[3,2-d]pyrimidine;
4-(3-Bromoanilino)-8-methoxybenzothieno[3,2-d]pyrimidine;
4-(3-Bromoanilino)thiazolo[4'5':4,5]thieno[3,2-d]pyrimidine;
4-(3-Bromoanilino)indolo[3,2-d]pyrimidine;
4-(3-Bromoanilino)indolo[2,3-d]pyrimidine.

-139-
93. A compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a live membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;

-140-
n=0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and

-141-
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members:
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl:
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),

-142-
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms).
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substitu tints R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,

-143-
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included;
with the proviso that the ring containing A-E is aromatic;
and with the proviso that if A and B taken together and E are nitrogen, and if
neither
Y nor Z is a heteroatom, and if X = NH, and n = 1 , and R1 = H and Ar = Ph,
then one of the
imidazole nitrogen atoms must have a substituent from the R3-R6 group other
than lone pair
or hydrogen;
and with the proviso that if A-E are carbon, and Y is a bond, and Z is sulfur,
and
X=NH, and n = 0, then Ar cannot be unsubstituted phenyl, unsubstituted or
substituted
pyridyl or unsubstituted or substituted pyrimidyl.
and with the further provisos that when
1) A, B, D and E are carbon, R3 to R6 are hydrogen, Y is a bond, R7 is not
present, Z is
C=C, R8 is not present, R10 is amino, X is NH, n is 0 and m is 0, then Ar
cannot be phenyl;
2) A, B, D and E are carbon, R3 to R6 are hydrogen, Y and Z are nitrogen, R7
and R8 are
not present, R10 is hydrogen, X is NH, n is 0, m is 0, then Ar cannot be
phenyl;
3) A is nitrogen, B is carbon, D and E taken together is nitrogen, R4 and R5
are not

-144-
present, R3 and R6 are methyl, Y is nitrogen, R7 is not present, Z is carbon,
R8 is hydrogen, R10
is hydrogen, X is NH, n is 1, R1 is H, m is 0, then Ar cannot be phenyl, 2-
furyl or 2-pyridyl;
4) A, B, D and E; are carbon, R5 and R6 are hydrogen, R3 and R4 are hydrogen,
hydroxy or
alkoxy, Y is nitrogen, R7 is H, Z is a bond, R8 is not present, R10 is
hydrogen, lower alkyl or
amino, X: is NH or NR9 where R9 is lower alkyl, n is 0, 1 or 2, R1 is
hydrogen, then Ar cannot
be phenyl unsubstituted or substituted 1, 2 or 3 times by halo or lower
alkoxy;
5) A, B, D and E are carbon, R3 to R6 are hydrogen, Y is N, R7 is hydrogen, Z
is a bond,
R8 is not present, R10 is hydrogen, X is O, n is 0, m is 0, then Ar cannot be
phenyl;
6) A, B, D and E are carbon, R5 and R6 are hydrogen, R3 and R4 are both
methoxy, Z is
nitrogen, R8 is hydrogen, Y is a bond, R7 is not present, R10 is hydrogen, X
is NH, n is 0, then
Ar cannot be unsubstituted phenyl or phenyl para substituted by chloro,
methoxy, nC4H9,
hydroxy, cyano or methyl;
7) A and B together is nitrogen, D is carbon, E is sulphur, R3, R5 and R6 are
not present,
R4 is hydrogen or methylthio, Y is a hand, R7 is not present, Z is sulphur, R8
is not present,
R10 is hydrogen, X is NH, n is l, R1 is hydrogen, m is 0, then Ar cannot be
phenyl or 2-furyl;
8) A is nitrogen, B, D and E are carbon, R4 is hydrogen, R3 and R6 are methyl,
R5 is not
present, Z is sulphur, R8 is not present, Y is a bond, R7 is not present, R10
is methyl, X is NH
or S, n is 0, m is 0, then Ar cannot be phenyl;
9) A,B,D and E are carbon, R3 to R6 are hydrogen, Z is oxygen, R8 is not
present, Y is a
bond, R7 is not present, R10 is hydrogen, X is sulphur, n is 1, R1 is
hydrogen, m is 0, then Ar
cannot be phenyl;
l0) A, B, D and E are carbon, R3 to R6 are hydrogen, Z is nitrogen, R8 is
hydrogen, Y is a
bond, R7 is not present, R10 is hydrogen, and
X is NH, n is 0, 1 or 2, R1 is hydrogen or methyl, m is 0, then Ar cannot be
phenyl, or
X is S, n is l, R1 is hydrogen, m is 0, then Ar cannot be phenyl, or
X is O, n is 0, then Ar cannot be phenyl para substituted by chloro, methyl or
methoxy;
11) A, B, D and E are carbon, R3 to R6 are hydrogen, Z is sulphur, R8 is not
present, Y is a
bond, R7 is not present, R10 is hydrogen, and
X is O, n is 0, m is 0, then Ar cannot be phenyl, or
X is S, n is 0 or I, R1 is hydrogen, m is 0, then Ar cannot be phenyl;

-145-
12) A, B, D and E are carbon, R3 to R6 are hydrogen, Z is oxygen, R8 is not
present, Y is a
bond, R7 is not present, R10 is methyl, and
X is oxygen, n is 0, then Ar canot be unsubstituted phenyl or phenyl ortho or
para substituted by chlorine, or
X is sulphur, n is 0, then Ar cannot be unsubstituted phenyl or phenyl ortho
or
meta substituted by chlorine, or
X is sulphur, n is I ,R1 is hydrogen, m is 0, then Ar canot be phenyl;
13) A, B, D and E are carbon, R3 to R6 are hydrogen, Z is oxygen, R8 is not
present, Y is a
bond, R7 is not present, R10 is hydrogen, and
X is NH, n is 0, then Ar cannot be phenyl unsubstituted or ortho, meta or para
substituted by chlorine, para by bromine or ortho or para by ethoxy, or
X is NH, n is l, R1 is i , m is 0, then Ar cannot be phenyl; or
X is O, n is 0, then Ar cannot be unsubstituted phenyl or phenyl ortho, meta
or
para substituted by methyl, ortho, meta or para substituted by chloro or meta
or
para substituted by methoxy, or
X is S, n is 0, then Ar cannot be unsubstituted phenyl or phenyl ortho or meta
substituted by chlorine; and
14) A, B, D and E are carbon, R3 to R6 are hydrogen, hydroxy, methoxy,
dimethylamino,
amino or loweracylamino, Y is a bond, R7 is not present, Z is oxygen or
sulphur, R8 is not
present, R10 is hydrogen or lower alkyl, X is NH or NR9 where R9 is lower
alkyl, n is 0, the Ar
cannot be unsubstituted phenyl, pyridyl unsubstituted or substituted by lower
alkyl, pyrimidyl
unsubstituted or substituted once or twice by methyl.
94. The compound of claim 93 having the further provisos:
that if A-E are carbon, Y and L cannot be both carbon or one ethylidene and
the other
a bond, unless at least one of R3-R6 is not hydrogen; and
that if A-E are carbon one of Y and Z, cannot be nitrogen, substituted with
hydrogen,
and the other a bond.
95. The compound of claim 93 wherein the compound is selected from the group
consisting of : 4-(3-Bromoanilino)pyrrolo[3,2-g]quinazoline;
4-(3-Bromoanilino) thiazolo [4,5-g] quinazoline;

-146-
4-(3-Bromoanilino) oxazolo [4,5-g] quinazoline;
4-(3-Bromoanilino) imidazolo[4,5-g] quinazoline;
4-(3-Bromoanilino) triazolo [4,5-g] quinazoline;
4-(3-Bromoanilino)-6N-methylimidazolo [4,5-g] quinazoline;
4-(3-romoanilino) -8N-methylimidazolo[4,5-g]quinazoline;
4-(3-Bromoanilino)pyrazolo[2,3-g]quinazoline;
4-(3-Bromoanilino) imidazolo [4,5-h] quinazoline;
4-(3-Bromoanilino) benzothieno [3,2-d] pyrimidine;
4-(3-Bromoanilino)-8-nitrobenzothieno[3,2-d]pyrimidine;
8-Amino-4-(3-bromoanilino)benzothieno[3,2-d]pyrimidine;
4-(3-Bromoanilino)-8-methoxybenzothieno[3,2-d]pyrimidine;
4-(3-Bromoanilino) thiazolo [4'5':4,5] thieno [3,2d]pyrimidine.
96. For use in inhibiting Erb-B2 or Erb-B3 or Erb-B4 receptor tyrosine kinase
in a
mammal, an effective amount of a compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the

-147-
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and F taken all together may he three nitrogen atoms;
X is selected from the group consisting of :
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carhop atoms), and
lower monoalkylamino (1-4 carbon atoms):
R1 is H or lower alkyl;
n=0, 1 or2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,

-148-
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms).
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-6 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,

-149-
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,

-150-
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.

-151-
97. A pharmaceutical composition adapted for administration as an inhibitor of
the
epidermal growth factor receptor family of tyrosine kinases, comprising a
therapeutically
effective amount of a compound of the following structure in admixture with a
pharmaceutically acceptable excipient, diluent or carrier:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,

-152-
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n = 0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms).
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms).
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),

-153-
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),

-154-
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms).
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,

-155-
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
98. For use in treating cancer in a mammal, an effective amount of a compound
of
the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,

-156-
wherein:
~) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n = 0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,

-157-
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,

-158-
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl 1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),

-159-
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl. piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),

-160-
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
99. For use in treating psoriasis in a mammal, an effective amount of a
compound
of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 ar 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:

-161-
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH.
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n=0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms).
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),

-162-
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of
H,

-163-
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
tlriomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,

-164-
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.

-165-
100. For use in preventing blastocyte implantation in a mammal, an effective
amount of a compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z ;ire both C (carbon), both N or one N and the other C, in which
case the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carbon atoms), and

-166-
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n=0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms).
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino.
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and

-167-
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),

-168-
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,

-169-
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then it any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms):
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
101. A contraceptive composition comprising a contraceptively effective amount
of
a compound of the following formula in admixture with a contraceptively
acceptable
excipient, diluent or carrier:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or one N and the other C, in which case
the

-170-
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z, is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon or any two contiguous positions in A-E can be a
single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n = 0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),

-171-
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,

-172-
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl ( 1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),

-173-
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and

-179-
lower dialkylamino ( 1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
102. For use in treating pancreatitis in a mammal, an effective amount of a
compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N or cane N and the other C, in which
case the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon. or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E takers all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,

NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH;,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);
R1 is H or lower alkyl;
n=0, 1 or 2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting, of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms).
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),

-16-
sulfonylcycloalky) (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),

-177-
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
carbonato (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazino,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain

-178-
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of :
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.

-179-
103. For use in treating kidney disease in a mammal, an effective amount of a
compound of the formula:
<IMG>
or a pharmaceutical salt or hydrate thereof,
wherein:
1) Y and Z are both C (carbon), both N car one N and the other C, in which
case the
ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z
is C=C, C=N,
whereupon the other one of Y or Z is simply a bond between the two aromatic
rings, then the
ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is
N, O or S, whereupon
the other one of Y or Z is simply a bond between the two aromatic rings, then
the ring
structure is a fused 6, 5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to two of them can be nitrogen,
whereupon the
remaining atoms must be carbon, or any two contiguous positions in A-E can be
a single
heteroatom, N, O or S, forming a five membered fused ring, in which case one
of the two
remaining atoms must be carbon, and the other can be either carbon or
nitrogen, with the
exception that A, B, D and E taken all together may be three nitrogen atoms;
X is selected from the group consisting of:
O,
S,
NH, and
NR9 where R9 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
OH,
NH2,
lower alkoxy (1-4 carbon atoms), and
lower monoalkylamino (1-4 carbon atoms);

-180-
R1 is H or lower alkyl;
n=0, 1 or2
wherein if n = 2, R1 can be independently H or lower alkyl (1-4 carbon atoms)
on either
linking carbon atom, and both R and S stereocentres on either linker are
included;
R2 is selected from the group consisting of:
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
nitro,
halo,
lower perfluoroalkyl (1-4 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino (1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),
hydroxymethyl,
lower acyl (1-4 carbon atoms),
cyano,
lower thioalkyl (1-4 carbon atoms),
lower sulfinylalkyl (1-4 carbon atoms),
lower sulfonylalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms),
sulfonylcycloalkyl (3-8 carbon atoms),
mercapto,
lower alkoxycarbonyl (1-4 carbon atoms),
cycloalkoxycarbonyl (3-8 carbon atoms),
lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), and
lower alkynyl (2-4 carbon atoms),

-181-
where R is alkyl(1-4 carbon atoms) or cycloalkyl(3-8 carbon atoms);
or two R2 taken together can form a carbocyclic ring of 5-7 members;
m = 0-3,
Ar is selected from the group consisting of:
phenyl,
thienyl,
furanyl,
pyrrolyl,
pyridyl,
pyrimidyl,
imidazoyl,
pyrazinyl,
oxazolyl,
thiazolyl,
naphthyl,
benzothienyl,
benzofuranyl,
indolyl,
quinolinyl,
isoquinolinyl, and
quinazolinyl;
R3, R4, R5 and R6 are independently selected from the group consisting of
H,
lower alkyl (1-4 carbon atoms),
cycloalkyl (3-8 carbon atoms),
lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms),
hydroxy,
lower acyloxy (1-4 carbon atoms),
amino,
lower mono or dialkylamino(1-4 carbon atoms),
lower mono or dicycloalkylamino (3-8 carbon atoms),

-182-
carbonate (-OC(O)OR) where R is alkyl (1-4 carbon atoms) or cycloalkyl (3-8
carbon
atoms),
ureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms),
thioureido optionally substituted by mono or di-lower alkyl (1-4 carbon atoms)
or
cycloalkyl (3-8 carbon atoms),
N- or O- linked urethane optionally substituted by mono or di-lower alkyl (1-4
carbon
atoms) or cycloalkyl (3-8 carbon atoms),
lower thioalkyl (1-4 carbon atoms),
thiocycloalkyl (3-8 carbon atoms),
mercapto,
lower alkenyl (2-4 carbon atoms),
hydrazine,
N- and/or N'- mono- or di lower alkylhydrazino (1-4 carbon atoms),
lower acylamino (1-4 carbon atoms),
hydroxylamino, and
N- and/or O- mono- or di lower alkylhydroxylamino (1-4 carbon atoms),
or any two substituents on contiguous carbon atoms taken together can be
methylenedioxy,
ethylenedioxy or propylenedioxy,
or any two substituents on contiguous carbon atoms taken together can form a
fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholino or
thiomorpholino ring;
wherein one, two or three of substituents R3-R6 may independently not be
present;
R7 and R8 can be independently as appropriate, not present, lone pairs of
electrons, H,
or lower alkyl (1-4 carbon atoms);
wherein any lower alkyl group substituent on any of the substituents in R3-R8
which contain
such a moiety can be optionally substituted with one or more substituents
selected from the
group consisting of:
hydroxy,
amino,
lower monoalkylamino,
lower dialkylamino,
N-pyrrolidyl,

-103-
N-piperidinyl,
N-pyridinium,
N-morpholino,
N-thiomorpholino, and
N-piperazino groups;
wherein if one or two of A through E are N, then if any of R3-R6 is on a
neighbouring C atom
to one of the N atoms, that substituent cannot be either OH or SH; and
R10 is selected from the group consisting of:
H,
lower alkyl (1-4 carbon atoms),
amino,
lower monoalkylamino(1-4 carbon atoms), and
lower dialkylamino (1-4 carbon atoms);
and wherein one, two or three of substituents R3-R6 may be independently not
present;
and wherein if any of the substitutents R1, R2, R3 or R4 contain chiral
centers, or in the case of
R1 create chiral centers on the linking atoms, then all stereoisomers thereof
both separately
and as racemic and/or diastereoisomeric mixtures are included.
104. A commercial package comprising a container containing therein a compound
according to any one of Claims 1-95 and written matter which states that the
compound can
or should be used for inhibiting epidermal growth factor receptor tyrosine
kinase.
105. A commercial package comprising a container containing therein a compound
according to Claim 96 and written matter which states that the compound can or
should be
used for inhibiting Erb-B2 or Erb-B3 or Erb-B4 receptor tyrosine kinase.
106. A commercial package comprising a container containing therein a
composition according to Claim 97 and written matter which states that the
composition can
or should be used as an inhibitor of the epidermal growth factor receptor
family of tyrosine
kinases.
107. A commercial package comprising a container containing therein a compound

-184-
according to Claim 98 and written matter which states that the compound can or
should be
used for treating cancer.
108. A commercial package comprising a container containing therein a compound
according to Claim 99 and written matter which states that the compound can or
should be
used for treating psoriasis.
109. A commercial package comprising a container containing therein a compound
according to Claim 100 and written matter which states that the compound can
or should be
used for preventing blastocyte implantation.
110. A commercial package comprising a container containing therein a
composition according to Claim 101and written matter which states that the
composition can
or should be used as a contraceptive.
111. A commercial package comprising a container containing therein a compound
according to Claim 102 and written matter which states that the compound can
or should be
used for treating pancreatitis.
112. A commercial package comprising a container containing therein a compound
according to Claim 103 and written matter which states that the compound can
or should be
used for treating kidney disease.

Description

~O 95119970 PCTIUS95100911
TRICYCLIC COMPOUNDS CAPABLE OF
EVHI813'IrTG TYROSINE KINASES OF THE
EPIDERMAL GROWTH FACTOR RECEPTOR FAMILY
~'echnical Field
The present invention relates to tricyclic
heteroaromatic compounds which inhibit the epidermal
growth factor receptor and related receptors and, in
particular, their tyrosine kinase enzymic activity.
BaC grOUnd Art
Cancer is generally a disease of the intra-
cellular signalling system, or signal transduction
mechanism. Cells receive instructions from many ex-
tracellular sources, instructing them to either pro-
liferate or not to proliferate. The purpose of the
signal transduction system is to receive these and
other signals at the cell surface, get them into the
cell, and then pass the signals on to the nucleus, the
cytoskeleton, and transport and protein synthesis
machinery. The most common cause of cancer is a se-
ries of defects, either in these proteins, when they
are mutated, or in the regulation of the quantity of
SUBSTITUTE SHEET (RULE 26)

WO 95!19970 PCT/US95/00911
-2-
the-protein in the cell such that it is over or under
produced. Most often, there are key lesions in the
cell which lead to a constitutive state whereby the
cell nucleus receives a signal to proliferate, when
this signal is not actually present. This can occur
through a variety of mechanisms. Sometimes the cell
may start to produce an authentic growth factor for
its own receptors when it should not, the so-called
autocrine loop mechanism. Mutations to the cell sur-
face receptors, which usually signal into the cell by
means of tyrosine kinases, can lead to activation of
the kinase in the absence of ligand, and passing of a
signal which is not really there. Alternatively, many
surface kinases can be overexpressed on the cell aur-
face leading to an inappropriately strong response to
a weak signal. There are many levels inside the cell
at which mutation or overexpression can lead to the
same spurious signal arising in the cell, and there
are many other kinds of signalling defect involved in
cancer. This invention touches upon cancers which are
driven by the three mechanisms just described, and
which involve cell surface receptors of the epidermal
growth factor receptor tyrosine kinase family (EGFR).
This family consists of the EGF receptor (also known
as Erb-B1), the Erb-B2 receptor, and its constitui-
tively active oncoprotein mutant Neu, the Erb-B3 re-
ceptor and the Erb-B4 receptor. Additionally, other
biological processes driven through members of the EGF
family of receptors can also be treated by compounds
of the invention described below.
The EGFR has as its two most important
ligands Epidermal Growth Factor (EGF) and Transforming
Growth Factor alpha (TGFalpha). The receptors appear
SUBSTITUTE SHEET (RULE 26)

~WO 95/19970 PCTIL7595I00911
-3-
to have only minor functions in adult humans, but are
apparently implicated inthe disease process of a
large portion of all cancers, especially colon and
m
breast cancer. The closely related Erb-B2 Erb-B3 and
Erb-B4 receptors have a family of Heregulins as their
major ligands, and receptor overexpression and muta-
tion have been unequivocally demonstrated as the major
risk factor in poor prognosis breast cancer. Addi-
tionally, it has been demonstrated that all four of
the members of this family of receptors can form
heterodimeric signalling complexes with other members
of the family, and that this can lead to synergistic
transforming capacity if more than one member of the
family is overexpreased in a malignancy. Overexpres-
sion of more than one family member has been shown to
be relatively common in human malignancies.
The proliferative skin disease psoriasis has
no good cure at present. It is often treated by anti-
cancer agents such as methotrexate, which have very
serious side effects, and which are not very effective
at the toxicity-limited doses which have to be used.
It is believed that TGFalpha is the major growth fac-
tor overproduced in psoriasis, since 50% of transgenic
mice which overexpress TGF alpha develop psoriasis.
This suggests that a good inhibitor of EGFR signalling
could be used as ari antipsoriatic agent, preferably,
but not necessarily, by topical dosing.
EGF is a potent mitogen for renal tubule
cells. Fourfold increases in both EGF urinary secre-
tion and EGF mRNA have been noted in mice with early
stage streptozoicin-induced diabetes. In addition
SUBSTITUTE SHEET (RULE 26)

WO 95119970 2 ~ 7 ~ ~ 9 2 PCTIUS95I00911
-4-
increased expression of the EGFR has been noted in ~
patients with proliferative glomerulonephritis
(Roychaudhury et al. Pathology 1993, 25, 327). The
compounds of the current invention should be useful in
treating both proliferative glomerulonephritis and
diabetes-induced renal disease.
Chronic-pancreatitis in patients has been
reported to correlate with large increases in expres-
sion for both EGFR and TGF alpha. (Korc et al. Gut
l0 1994, 35, 1468). In patients showing a more severe
form of the disease, typified by an enlargement of the
head of the pancreas, there was also shown to be over-
expression of the erb-B2 receptor (Friess et al. Ann_
Surg. 1994, 220, 183). The compounds of the current
invention should prove useful in the treatment of
pancreatitis.
In the processes of blastocyte maturation,
blastocyte implantation into the uterine endometrium,
and other periimplantation events, uterine tissues
produce EGF and TGF alpha (Tags Nippon Sanka Fujinka
Gakkai Zasshi 1992, 44, 939), have elevated levels of
EGFR (Brown et al. Endocrinology, 1989, 124, 2882),
and may well be induced to produce heparin-binding EGF
by the proximity of the developing, but not arrested,
blastocyte (Das et al. Development 1994, 120, 1071).
In turn the blastocyte has quite a high level of TGF
alpha and EGFR expression tAdamson Mol. Reprod. Dev.
1990, 27, 16). Surgical removal of the submandibular
glands, the major site of EGF secretion in the body, '
and treatment With anti-EGFR monoclonal antibodies
both greatly reduce fertility in mice (Tsutsumi et al.
J. Endocrinology 1993, I3B, 437), by reducing success-

-WO 95119970 2 1 7 7 3 9 2 p~~595/00911
-5-
ful blastocyte implantation. Therefore, compounds of
the current invention should prove to have useful
contraceptive properties.
PCT patent application Nos. W092/07844 pub-
s lished May 14, 1992 and W092/14716 published September
3, 1992 describe 2,4-diaminoquinazoline as potentia-
tors of chemotherapeutic agents in the treatment of
cancer.
PCT published application No. W092/20642
published November 26, 1992 discloses bismono- and
bicyclic aryl and heteroaryl compounds which inhibit
EGF and/or PDGF receptor tyrosine kinase.
It is an object of the present invention to
inhibit the mitogenic effects of epidermal growth
factor utilizing an effective amount of tricyclic
pyrimidine derivatives, in particular fused heterocy-
clic pyrimidine derivatives.
It is another object of the present inven-
tion to describe tricyclic pyrimidine derivatives, in
particular fused heterocyclic pyrimidine derivatives,
as inhibitors of the EGF, Erb-B2 and Erb-B4 receptor
tyrosine kinases.
It is yet another object of the present
invention to describe tricyclic pyrimidine deriva-
tives, in particular fused heterocyclic pyrimidine
derivatives, that are useful at low dosages as inhibi-
tors of EGF-induced mitogenesis. This therefore leads
to a further object of compounds having extremely low
cytotoxicity.
SUBSTITUTE SHEET (RULE 26)

21 ?'792
WO 95119970 PCTYUS95100911
-6-
It is a further object of the present inven-
tion to describe-tricyclic pyrimidine derivatives, in
particular fused heterocyclic pyrimidine derivatives,
that are useful in suppressing tumors, especially
breast cancers, where mitogenesis is heavily driven by
EGFR family members.
It is another object of the present inven-
tion to describe tricyclic pyrimidine derivatives, in
particular fused heterocyclic pyrimidine derivatives,
that have utility as chronic therapy as inhibitors of
EGF-induced responses.
It is another object of the current inven-
tion to describe tricyclic pyrimidine derivatives, in
particular fused heterocyclic pyrimidine derivatives,
that have utility as therapeutic agents against pro-
liferative overgrowth diseases, including but not
limited to, synovial pannus invasion in arthritis,
vascular restenosis and angiogenesis. Additional
utility of these materials is for pancreatitis and
2d kidney disease as well as contraception.
$ummarv of the Invention
Described is a method to inhibit epidermal
growth factor by treating, with an effective inhibit
ing amount, a mammal, in need thereof, a compound of
the following formula:

-WO 95119970 2 ~ ~ ? ~ ~ ~ PCTlUS95/00911
Ri
W
,.
wherein: 1) Y and Z are both C (carbon),
both N or one N and the other C, in which case the
ring structure is a linearly fused 6,6 (5 or 6) tricy-
cle, or 2) one of Y and Z is C=C, C=N whereupon the
other one of Y or Z is simply a bond between the two
aromatic rings, then the ring structure is a nonlinear
6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, O or
S, whereupon the other one of Y or Z is simply a bond
between the two aromatic rings, then the ring struc-
ture is a fused 6,5 (5 or 6) tricycle;
A, B, D and E can all be carbon, or up to
two of them can be nitrogen, whereupon the remaining
atoms must be carbon, or any two contiguous positions
in A-E can be a single heteroatom, N, O or S, forming
a five membered fused ring, in which case one of the
two remaining atoms must be carbon, and the other can
be either carbon or nitrogen, except that the case
where A and B taken together, and D and E taken sepa-
rately are all three nitrogen atoms;
S, NH or NR'
X = 0
such that R' = lower
,
,
alkyl (1-4 carbon atoms), OH, NHa, lower alkoxy (1-4
carbon atoms) or lower monoalkylamino (1-4 carbon
atoms);
R1 = H or-lower alkyl;
n = 0, 1 or 2;
SUBSTITUTE SHEET (RULE 26)

W0 95II9970 PCTIUS95/00911
_g_
if n = 2, R' can be independently H or lower
v
alkyl on either linking carbon atom, and both R and S
atereocentres on either linker are included;
Rz is lower alkyl (1-4 carbon atoms), cyclo-
alkyl (3-8 carbon atoms), lower alkoxy (1-4 carbon
atoms), cycloalkoxy (3-8 carbon atoms), nitre, halo,
lower perfluoroalkyl (1-4 carbon atoms), hydroxy,
lower acyloxy (1-4 carbon atoms; -0-C(0)-R), amino,
lower mono or dialkylamino (1-4 carbon atoms), lower
mono or dicycloalkylamino (3-8 carbon atoms), hydroxy-
methyl, lower acyl (1-4 carbon atoms; -C(O)R), cyano,
lower thioalkyl (1-4 carbon atoms), lower sulfinyl-
alkyl (1-4 carbon atoms), lower sulfonylalkyl (1-4
carbon atoms), thiocycloalkyl (3-8 carbon atoms),
sulfinylcycloalkyl (3-8 carbon atoms), sulfonylcyclo-
alkyl (3-8 carbon atoms), mercapto, lower alkoxy-
carbonyl (1-4 carbon atoms), cycloalkoxycarbonyl (3-8
carbon atoms), lower alkenyl (2-4 carbon atoms),
cycloalkenyl (4-8 carbon atoms), lower alkynyl (2-4
carbon atoms), or two R' taken together can form a
carbocyclic ring of 5-7 members; and
m = 0-3, wherein Ar is phenyl, thienyl,
furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazoyl,
pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzo-
thienyl, benzofuranyl, indolyl, quinolinyl, isoquino-
linyl and quinazolinyl;
R', R°, RS and R6 are independently, not pres-
ent, H, lower alkyl (1-4 carbon atoms), cycloalkyl (3-
8 carbon atoms), lower alkoxy (1-4 carbon atoms),
cycloalkoxy (3-8 carbon atoms), hydroxy, lower acyloxy
(1-4 carbon atoms), amino, lower mono or dialkylamino
(1-4 carbon atoms), lower mono or dicycloalkylamino
(3-8 carbon atoms), lower alkyl (1-4 carbon atoms) or
cycloalkyl (3-8 carbon atoms), carbonate (-OC(O)OR)
SUBSTITUTE SHEET (RULE 26)

WO 95/19970 PCTIUS95/00911
_g_
where R is alkyl of from 1-4 carbon atoms or cyclo-
' alkyl of from 3-B carbon atoms;
or ureido or thioureido or N- or O- linked
' urethane any one of which is optionally substituted by
mono or di-lower alkyl (1-4 carbon atoms) or cyclo-
alkyl (3-S carbon atoms);
lower thioalkyl (1-4 carbon atoms), thio-
cycloalkyl (3-8 carbon atoms), mercapto, lower alkenyl
(2-4 carbon atoms), hydrazino, N- and/or N'- mono- or
di lower alkylhydrazino (1-4 carbon atoms), lower
acylamino (1-4 carbon atoms), hydroxylamino, N- and/or
O- mono- or di lower alkylhydroxylamino (1-4 carbon
atoms), or taken together can be methylene-, ethylene-
or propylenedioxy, or taken together form a fused
pyrrolidine, tetrahydrofuranyl, piperidinyl, piper-
azinyl, morpholino or thiomorpholino ring;
R' and R°can be independently as appropriate,
lone pairs of electrons, H, or lower alkyl;
any lower alkyl group substituent on any of
the substituents in R'-R8 which contain such a moiety
can be optionally substituted with one or more of
hydroxy, amino, lower monoalkylamino, lower dialkyl-
amino, N-pyrrolidyl, N-piperidinyl, N-pyridinium, N-
morpholino, N-thiomorpholino or N-piperazino groups;
if one or two of A through E are N, then if
any of R'-R6 is on a neighboring C atom to one of the
N atoms, that aubstituent cannot be either OH or SH;
and
R'° is H or lower alkyl (1-4 carbon atoms),
amino or lower mono- or dialkylamino (1-4 carbon
atoms) ;
if any of the substitutents Rl, R2, R' or R'
contain chiral centers, or in the case of R1 create
SUBSTITUTE SHEET (RULE 26)

WO 95/19970 PCTIUS95/00911
-10-
chiral centers on the linking atoms, then all stereo- .
isomers thereof both separately and as racemic and/or
diastereoisomeric mixtures are included;
or a pharmaceutical salt or hydrate thereof.
The invention pertains to the compounds, per
se:
with the proviso that the ring containing A-
E is aromatic;
and with the proviso that if A and B taken
together and E are nitrogen, and if neither Y nor Z is
a heteroatom, and if X = NH, and n = 1, and Ri = H and
Ar = Ph, then one of the imidazole nitrogen atoms must
have a substituent from the R'-R6 group other than lone
pair or hydrogen;
and with the proviso that if R-E are carbon,
and Y is a bond, and Z is sulfur, and X = NH, and n =
0, then Ar cannot be unsubstituted phenyl, unsubsti-
tuted or substituted pyridyl or unsubstituted or
substituted pyrimidyl.
Preferably, the compounds are subject to
additional provisos:
with the proviso that if A-E are carbon, Y
and Z cannot be both carbon-or one ethylidene and the
other a bond, unless at least one of R'-R6 is not hy
drogen;
with the proviso that if A-E are carbon one
of Y and Z cannot be nitrogen, substituted with hydro-
gen, and the other a bond.

WO 95/19970 PC17US95100911
-11-
Brief Description Of The Drawing
FIGURE 1 is an effect of Example 1 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 2 is an effect of Examples 6 and 17
on EGF receptor autophosphorylation in A431 human
epidermoid carcinoma;
FIGURE 3 is an effect of Example 8 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 4 is an effect of Example 10 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 5 is an effect of Example 15 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 6 is an effect of Example 25 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 7 is an effect of Example 28 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma;
FIGURE 8 is an effect of Example 29 on EGF
receptor autophosphorylation in A431 human epidermoid
carcinoma; and

WO 95!19970 PCTIU895100911
-12-
FIGURE 9 is an effect of Examples 6 and 17
on soft agar clone formation of MDA-MB-468 human
breast carcinoma.
Pescriotion of Preferred Embodiments
Nomeaclature aad Numberiaa ae used Hernia
4
NH -R B NH -R
t d Z
8 5 ~~ 7 X' ~ 5 2 ~ ~ \~ 3
~J
C q B b r ~ g d A a
8 2
a $ c b
Dubtezdlnea
Trthetaroaroma8c Syatema
Nomenclature. All tricycles containing a
benzene ring fused directly to the pyrimidine ring
have been named as quinazoline derivatives. All other
tricycles are named as pyrimidine derivatives, either
10 fused to a bicyclic nucleus such as indole or benzo-
thiophene, or to two separate monocyclic heterocycles
such as pyridothiophene. In such cases the first ring
given is always the one distal to the pyrimidine ring.
Ring fusion numbers. For quinazoline deriv-
atives the quinazoline nucleus is lettered counter-
clockwise with the N1-C2 bond being a, and the three
possible ring fusion positions being f, g and h. The
C-ring is numbered 1-5/6 from its highest atomic
weight heteroatom, with the ring fusion numbering
being decided by the numbered bridgehead atom which
first meets the counterclockwise flow of the quina- '
zoline lettering.

'WO 95/19970 ~ PCT/US95/00911
-13-
For systems with three fused heteroaromatic
rings, the pyrimidine ring (A) is always chosen as the
" root system and is d-fused to the B-ring lettering in
a clockwise direction. The central B-ring is numbered
1-5/6, starting at the heteroatom, and going first via
the B/C ring junction and then the B/A ring junction.
It can be numbered either clockwise, when the hetero-
atom is at the bottom, or counterclockwise, when the
heteroatom is at the top, (as is illustrated above),
and the ring fusion numbering is decided by the num-
bered bridgehead atom which first meets the clockwise
flow of the pyrimidine lettering. The C-ring is num-
bered 1'-5'/6' from the highest priority heteroatom,
towards lower priority heteroatoms if present, and if
there are no other heteroatoms, in the direction which
gives the lowest numbering to the ring junction. The
first C-ring fusion number is that of the bridgehead
atom which has the lowest numbering in the B-ring
numbering system. In the first set of parentheses the
C-ring numbers of the B/C bridgehead atoms are given,
followed after the colon by the B-ring numbers for the
same atoms. The second set of parentheses contain the
B-ring numbers for the A/B-bridgehead atoms, followed
after the dash by the shared bond in the A-ring let-
tering system. Thus, the example above illustrates a
(5',4':2,3]I5,6-d] tricyclic system.
Substituent Numbering. In all of the exam-
ples, the numbering is taken from the bottom nitrogen
of the pyrimidine A ring as 1, and then all nonbridge-
head atoms are counted consecutively in a counter-
clockwise direction from that point, as illustrated
above for a 6,6,6-system by the bolded numbers.

WO 95119970 PCTIUS95100911
-14-
1. A preferred form of the invention has n
= 0, A-E, Y & Z being carbon, X = NH, Ar a benzene
ring, optionally substituted, and RS-Re hydrogen. A
suitable ring structure is:'
NH
~m
000
2. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as oxygen, the remaining pair both being
carbon, along With Y and Z, X = NH, Ar a benzene ring,
optionally substituted, and R5-RB hydrogen or a lone
pair of electrons where appropriate. A suitable ring
structure is:
NH ~~
3. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as sulfur, the remaining pair both being
carbon, along with Y and Z, X = NH, Ar a benzene '
ring, optionally substituted, and RS-R° hydrogen or a
lone pair of electrons where appropriate. '

WO 95119970 PC1'/U&95100911
-15-
4. Another preferred form of the invention
~ has, n = 0 or 1, with one of A & B or D & E taken
together as nitrogen, the remaining pair both being
carbon, along with Y and Z, X = NH, Ar a benzene ring,
optionally substituted, and RS-RB hydrogen or optional-
ly lower alkyl if on nitrogen. A suitable ring struc-
ture is:
H
~(~m
c~OIG
H
5. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, Y and Z both carbon, X = NH, Ar a benzene
ring, optionally substituted, and RS-RB hydrogen or a
lone pair of electrons where appropriate.
6. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken-together as sulfur and A
as nitrogen, Y and Z both carbon, X ~ NH, Ar a benzene
ring, optionally substituted, and RS-RB hydrogen or a
lone pair of electrons where appropriate. A suitable
ring structure is:
NH ~~
s
\\N

W0 95/19970 PCTIUS95/00911
-16-
7. Another preferred form of the invention ,
has n = 0 or 1, A & B taken together, and E as nitro-
gen, Y and Z both carbon, X = NH, Ar a benzene ring,
optionally substituted, and RS-R° hydrogen or optional-
ly lower alkyl if on nitrogen. or a lone pair of elec-
trons where appropriate.
8. Another preferred form of the invention
has n = 0 or l, A & B taken together as oxygen, and D
as nitrogen, or D & E taken together as oxygen and B
as nitrogen, Y and Z both carbon, X = NH, Ar a benzene
ring, optionally substituted, and RS-R° hydrogen, lower
alkyl, or a lone pair of electrons where appropriate.
9. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and D
as nitrogen, or D & E taken together as sulfur and B
as nitrogen, Y and Z both carbon, X = NH, Ar a benzene
ring, optionally substituted, and R°-R° hydrogen, lower
alkyl, or a lone pair of electrons where appropriate.
10. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and D as nitro-
gen, or D & E taken together, and B as nitrogen, Y and
Z both carbon, X = NH, Ar a.benzene ring, optionally
substituted, and RS-R° hydrogen, lower alkyl, or a lone
pair of electrons where appropriate. A suitable ring
structure is:

2177392
iW0 95/19970 PC1'/US95100911
-17-
H HH ~IF~2lm
H
11. Another preferred form of the invention
has n = 0, A & B taken together, with D & E taken
separately as nitrogen, Y and Z both carbon, X = NH,
Ar a benzene ring, optionally substituted, and RS-R°
hydrogen or optionally lower alkyl if on nitrogen. or
a lone pair of electrons where appropriate.
12. Another preferred form of the invention
has n = 0 or 1, with one of A, B, D or E as nitrogen,
the remaining three being carbon, along with Y and Z,
X = NH, Ar a benzene ring, optionally substituted, and
RS-R° hydrogen or a lone pair of electrons where appro-
priate.
13. Another preferred form of the invention
has n = 0, with any two of A, B, D or E as nitrogen,
the remaining two being carbon, along with Y and Z, X
= NH, Ar a benzene ring, optionally substituted, and
RS-R° hydrogen or a lone pair of electrons where appro-
priate.
14. Another preferred form of the invention
has n = 0, A-E, and one of Y and Z being carbon, the
other nitrogen, X = NFi, Ar a benzene ring, optionally
substituted, and RS-R° hydrogen or a lone pair of elec-

WO 95119970 1 PCT/US95100911
-18-
trons where appropriate. A suitable ring structure ,
is:
~,jc o~
15. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as oxygen, the remaining pair both being
carbon, along with one of Y and Z, the other being
nitrogen, X = NFi, Ar a benzene ring, optionally sub-
stituted, and R5-RB hydrogen or a lone pair of elec-
trons where appropriate. A suitable structure is:
NH -~~
16. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as sulfur, the remaining pair both being .
carbon, along With one of Y and Z, the other being
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and RS-RB hydrogen or a lone pair of elec-
trons where appropriate. '
17. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken

~W095/19970 ~ ~ PCTIUS95100911
-19-
together as nitrogen, the remaining pair both being
carbon, along with one of Y and Z, the other being
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and RS-R° hydrogen, or optionally lower alkyl
if on nitrogen in the pyrrole ring, or a lone pair of
electrons where appropriate.
18. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, one of Y and Z being carbon the other
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and RS-R° hydrogen or a lone pair of elec-
trons where appropriate. A suitable ring structure
is:
NH
m
19. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken~together as sulfur and A
as nitrogen, one of Y and Z being carbon the other
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and R=-R° hydrogen or a lone pair of elec-
trons where appropriate.
20. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and E as nitro-
gen, one of Y and Z being carbon the other nitrogen, X
= NH, Ar a benzene ring, optionally substituted, and

21 ~~~~~
WO 95/19970 PCT/US95/00911
-20-
RS-RB hydrogen or optionally lower alkyl if on nitrogen
or a lone pair of electrons where appropriate.
2i. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen,and D
as nitrogen, or D & E taken together as oxygen and B
as nitrogen, one of Y and Z being carbon the other
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and RS-RB hydrogen, lower alkyl, or a lone
pair of electrons where appropriate.
22. Anothe-r preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and.D
as nitrogen, or D & E taken together as sulfur and B
as nitrogen, one of Y and Z being carbon the other
nitrogen, X = NH, Ar a benzene ring, optionally aub-
atituted, and R5-RB hydrogen, lower alkyl, or a lone
pair of electrons where appropriate.
23. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and D as nitro-
gen, or D & E taken together, and B as nitrogen, one
of Y and Z being carbon the other nitrogen, X = NH, Ar-
a benzene ring, optionally substituted, and RS-RB hy-
drogen, lower alkyl, or a lone pair of electrons where
appropriate.
24. Another preferred form of the invention
has n = 0 or 1, with one of A, B, D or E as nitrogen,
the remaining three being carbon, along with one of Y
and Z, the other being nitrogen, X = NH, Ar a benzene
ring, optionally aubatituted, and RS-RB hydrogen or a
lone pair of electrons where appropriate. A suitable
ring structure is:
SUBSTITUTE SHEET (RULE 26)

~WO 95/19970 PCT/US95100911
2? 71.~~~
-21-
NH ~(~m
N
25. Another preferred form of the invention
has n = 0, with any two of A, B, D or E as nitrogen,
the remaining two being carbon, along with one of Y
and Z, the other being nitrogen, X = NFi, Ar a benzene
ring, optionally substituted, and RS-R° hydrogen or a
lone pair of electrons where appropriate.
26. A preferred form of the invention has n
= 0, A-E carbon, Y and Z nitrogen, X = NFi, Ar a ben-
zene ring, optionally substituted, and RS-R° hydrogen
or a lone pair of electrons where appropriate. A
suitable ring structure is:
NH
(gym
~O ON
NJ
27. Another preferred form of the invention
has n = 0 or 1, A-E being carbon, one of Y & Z being
ethylidene, X = NFi, Ar a benzene ring, optionally
substituted, and RS-R° hydrogen. A suitable ring
structure is:

WO 95119970 ; PCTlUS95100911
-22-
NH ~~~m
O O
O
28. Another preferred form of the invention has, n =
0 or 1, with one of A & B or D & E taken together as
oxygen, the remaining pair both being carbon, one of Y
& Z being ethylidene, X = NH, Ar a benzene ring, op-
tionally substituted, and RS-R° hydrogen or a lone pair
of electrons where appropriate.
29. Another preferred form of the invention
has, n = 0 or 1, with'one of A & B or D & E taken
together as sulfur, the remaining pair both being
carbon, one of Y & Z being ethylidene, X = NH, Ar a
benzene ring, optionally substituted, and R5-R° hydro-
gen or a lone pair of electrons where appropriate.
30. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as nitrogen, the remaining pair both being
carbon, one of Y & Z being ethylidene, X = NH, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen or optionally lower alkyl if on nitrogen.
31. Another preferred form of the invention.
has n = 0 or 1, A & B taken together ae oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, one of Y & Z being ethylidene, X = NH, Ar

~O 95/19970 PCTIU595100911
-23-
a benzene ring, optionally substituted, and RS-RB hy-
drogen or a lone pair of electrons where appropriate.
32. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken together as sulfur and A
as nitrogen, one of Y & Z being ethylidene, X = NH, Ar
a benzene ring, optionally substituted, and RS-RB hy-
drogen or a lone pair of electrons where appropriate.
33. Another preferred form of the invention
has n = 0, A & B taken together, and E ae nitrogen,
one of Y & Z being ethylidene, X = NH, Ar a benzene
ring, optionally substituted, and RS-Rg hydrogen or
optionally lower alkyl if on nitrogen or a lone pair
of electrons where appropriate. A suitable ring
structure is:
NH
(Rxlm
0 0~
O~ ,N
34. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and D
as nitrogen, or D & E taken together as oxygen and B
as nitrogen, one of Y & Z being ethylidene, X = NH, Ar
a benzene ring, optionally substituted, and RS-RB hy-
drogen, lower alkyl, or a lone pair of electrons where
appropriate.
SUBSTITUTE SHEET (RULE 26)

W0 95/19970 PCf/US95I00911
-24-
35. Another-preferred form of the invention
has n = 0 or 1, A & B taken together-as sulfur, and D
as nitrogen, or D & E taken together as sulfur and B
as nitrogen, one of Y & Z being ethylidene, X = NH, Ar
a benzene ring, optionally substituted, and RS-Rg hy-
drogen, lower alkyl, or a lone pair of electrons where
appropriate. A suitable ring structure is:
NH
(gym
0 0~
o~
N_
36. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and D as ni-
trogen, or D & E taken together, and B as nitrogen,
one of Y & Z being ethylidene, X = NH, Ar a benzene
ring, optionally substituted, and RS-Re hydrogen, lower
alkyl, or a lone pair of electrons where appropriate.
37. Another preferred form of the invention
has n = 0 or 1, with one of A, B, D or E as nitrogen,
the remaining three being carbon, one of Y & Z being
ethylidene, X = NH, Ar a benzene ring, optionally
substituted, and RS-Rg hydrogen or a lone pair of elec-
trons where appropriate.
38. Another preferred form of the invention
has n = 0, with any two of A, B, D or E as nitrogen,
the remaining two being carbon, one of Y & Z being
SUBSTITUTE SHEET (RULE 26)

. WO 95119970 ~ PCTIUS95100911
-25-
ethylidene, X = NH, Ar a benzene ring, optionally
substituted, and RS-Re hydrogen or a lone pair of elec-
_ trons where appropriate.
39. Another preferred form of the invention
has n = 0 or 1, A-E being carbon, one of Y & Z being
sulfur, X = NH, Ar a benzene ring, optionally substi-
tuted, and RS-RB hydrogen or a lone pair of electrons
where appropriate. A suitable ring structure is:
NH
(R~m
OoOJ
40. Another preferred form of the invention
has, n ~ 0 or 1, with one of A & B or D & E taken
together as oxygen, the remaining pair both being
carbon, one of Y & Z being sulfur, X = NFi, Ar a ben-
zene ring, optionally substituted, and R5-Rg hydrogen
or a lone pair of electrons where appropriate.
41. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as sulfur, the remaining pair both being
carbon, one of Y-& Z being sulfur, X = NH, Ar a ben-
zene ring, optionally substituted, and RS-RB hydrogen
or a lone pair of electrons where appropriate.
42. Another preferred dorm of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as nitrogen, the remaining pair both being
SUBSTITUTE SHEET (RULE 26)

W095/19970 ~ ~ ~ ~ ~' ~ ~ PCTIUS95100911
J
-26-
carbon, one of Y & Z being sulfur, X = NH, Ar a ben-
zene ring, optionally substituted, and R5-R8 hydrogen
or a lone pair of electrons where appropriate or op- _
tionally lower alkyl if on nitrogen.
43. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, one of Y & Z being sulfur, X = NH, Ar a
benzene ring, optionally substituted, and RS-Re hydro-
gen or a lone pair of electrons where appropriate.
44. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken together as sulfur and A
as nitrogen, one of Y & Z being sulfur, X = NH, Ar a
benzene ring, optionally substituted, and R5-Re hydro-
gen or a lone pair of electrons where appropriate. A
suitable ring structure is:
NH
(Rxlm
<O~O~.
45. Another preferred form of the invention
has n = 0, A & B taken together, and E as nitrogen,
one of Y & Z being sulfur, X = NH, Ar a benzene ring,
optionally substituted, and RS-RB hydrogen or optional-
ly lower alkyl if on nitrogen. or a lone pair-of elec-
trons where appropriate. -
SUBSTITUTE SHEET (RULE 26)

_WO 95119970 PCTYUS9510D911
_27-
46. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and D
as nitrogen, or D & E taken together as oxygen and B
as nitrogen, one of Y & Z being sulfur, X = NFI, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
47. Another preferred form of the invention
has n = D or 1, A & B taken together as sulfur, and D
as nitrogen, or D & E taken together as sulfur and B
as nitrogen, one of Y & Z being sulfur, X =-NH, Ar a
benzene ring, optionally substituted, and R5-R8 hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
48. Another preferred form of the invention
has n = D or 1, A & B taken together, and D as nitro-
gen, or D & E taken together, and B as nitrogen, one
of Y & Z being sulfur, X = NH, Ar a benzene ring,
optionally substituted, and RS-Re hydrogen, lower al-
kyl, or a lone pair of electrons where appropriate.
49. Another preferred form of the invention
has n = 0 or 1, with one of_A, B, D or E as nitrogen,
the remaining three being carbon, one of Y & Z being
sulfur, X = NFi, Ar a benzene ring, optionally substi-
tuted, and RS-RB hydrogen or a lone pair of electrons
where appropriate.
50. Another preferred form of the invention
has n = 0 or 1, A-E being carbon, one of Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally sub-

WO 95119970 ~ ~ PCTIUS95100911
a.
-2a-
stituted, and RS-Ra hydrogen, or optionally lower alkyl
if on nitrogen.
51. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as oxygen, the remaining pair both being
carbon, one of Y & Z being nitrogen, X = NH, Ar a
benzene ring, optionally substituted, and RS-Re hydro-
gen or a lone pair of electrons where appropriate, or
optionally lower alkyl if on nitrogen.
52. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as sulfur, the remaining pair both being
carbon, one of Y & Z being nitrogen, Ar a benzene
ring, optionally substituted, and RS-RB hydrogen or a
lone pair of electrons where appropriate, or optional-
ly lower alkyl if on nitrogen.
53. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as nitrogen, the remaining pair both being
carbon, one of Y & Z being nitrogen, X = Nxi, Ar a
benzene ring, optionally substituted, and RS-RB hydro-
gen or optionally lower alkyl if on nitrogen.
54. Another preferred form of the invention
has n = 0 or.l, A & B taken together as oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, one of Y & Z being nitrogen, X = NH, Ar a
benzene ring, optionally substituted, and R5-R8 hydro-
gen or a lone pair of electrons where appropriate, or
optionally lower alkyl if on nitrogen. A suitable
ring structure is:
SUBSTITUTE SHEET (RULE 26)

~WO 95/19970 2 I 7 7 3 9 2 PC'f/US95100911
-29-
NN
~~ I 0 ~~
55. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken together as sulfur and A
as nitrogen, one of Y & Z being nitrogen, X = NFI, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen or a lone pair of electrons where appropriate, or
optionally lower alkyl if on nitrogen.
56. Another preferred form of the invention
has n = 0, A & B taken together, and E as nitrogen,
one of Y & Z being nitrogen, X = NH, Ar a benzene
ring, optionally substituted, and RS-R° hydrogen or
optionally lower alkyl if on nitrogen or a lone pair
of electrons where appropriate.
57. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and
D as nitrogen, or D & E taken together as oxygen and B
as nitrogen, one of Y & Z being nitrogen, X = NFi, Ar a
benzene ring, optionally substituted, and R5-R° hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
58. Another preferred form of the invention
' has n = 0 or 1, A & B taken together as sulfur, and D
as nitrogen, or D & E taken together as sulfur and B

W0 95/19970 PC1'IUS95/00911
-30-
as nitrogen, one of Y & Z being nitrogen, X =NH, Ar a
benzene ring, optionally substituted,and RS-RB hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
59. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and D as nitro-
gen, or D & E taken together, and B ae nitrogen, one
of Y & Z being nitrogen, X = NH, Ar a benzene ring,
optionally substituted, and RS-RB hydrogen, lower al-
kyl, or a lone pair of electrons where appropriate.
60. Another preferred form of the invention
has n = 0 or 1, with one of A, B, D or E as nitrogen,
the remaining three being carbon, one of Y & Z being
nitrogen, X = NH, Ar a benzene ring, optionally sub-
stituted, and RS-R8 hydrogen or a lone pair of elec-
trons where appropriate.
61. Another preferred form of the invention
has n = 0 or 1, A-E being carbon, one of Y & Z being
oxygen, X = NH, Ar a benzene ring, optionally substi-
tuted, and RS-RB hydrogen or a lone pair of electrons
where appropriate. A suitable ring structure is:
NH
(gym
OoOJ
62. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
SUBSTITUTE SHEET (RULE 26)

~'VO 95119970 PCTIUS95100911
-31-
together as oxygen, the remaining pair both being
carbon, one of Y & Z being oxygen, X = NH, Ar a ben-
zene ring, optionally substituted, and RS-R° hydrogen
or a lone pair of electrons where appropriate.
63. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as sulfur, the remaining pair both being
carbon, one of Y & Z being oxygen, X = NH, Ar a ben-
zene ring, optionally substituted, and R5-R° hydrogen
or a lone pair of electrons where appropriate.
64. Another preferred form of the invention
has, n = 0 or 1, with one of A & B or D & E taken
together as nitrogen, the remaining pair both being
carbon, one of Y & Z being oxygen, X = NH, Ar a ben-
zene ring, optionally substituted, and R5-R° hydrogen
or a lone pair of electrons where appropriate or op-
tionally lower alkyl if on nitrogen.
65. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and E
as nitrogen, or D & E taken together as oxygen and A
as nitrogen, one of Y & Z being oxygen, X = Nli, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen or a lone pair of electrons where appropriate.
66. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and E
as nitrogen, or D & E taken together as sulfur and A
as nitrogen, one of Y & Z being oxygen, X = NFi, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen or a lone pair of electrons where appropriate. A
suitable ring structure is:

WO 95/19970 ~ PCTIUS95/00911
-32-
NN ~~
~o o ON
N~
67. Another preferred form of the invention
has n = 0, A & B taken together, and E as nitrogen,
one of Y & Z being oxygen, X = NH, Ar a benzene ring,
optionally substituted, and R5-R° hydrogen or optional-
ly lower alkyl if on nitrogen or a lone pair where
appropriate.
68. Another preferred form of the invention
has n = 0 or 1, A & B taken together as oxygen, and D
as nitrogen, or D & E taken together as oxygen and B
as nitrogen, one of Y & Z being oxygen, X = NH, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
69. Another preferred form of the invention
has n = 0 or 1, A & B taken together as sulfur, and D
as nitrogen, or D & E taken together as sulfur and B
as nitrogen, one of Y & Z being oxygen, X = NH, Ar a
benzene ring, optionally substituted, and RS-R° hydro-
gen, lower alkyl, or a lone pair of electrons where
appropriate.
70. Another preferred form of the invention
has n = 0 or 1, A & B taken together, and D as nitro-

~
WO 95119970 217 7 ,5 ~ 2 pCT~TS95100911
-33-
gen, or D & E taken together, and B as nitrogen, one
of Y & Z being oxygen, X = I~I, Ar a benzene ring,
optionally substituted, and RS-RB hydrogen, lower al-
kyl, or a lone pair of electrons where appropriate.
71. Another preferred form of the invention
has n = 0 or 1, with one of A, B, D or E as nitrogen,
the remaining three being carbon, one of Y & Z being
oxygen, X = NH, Ar a benzene ring, optionally substi-
tuted, and RS-RB hydrogen or a lone pair of electrons
where appropriate.
Moat Preferred Forms of the Inveation
1. A most preferred form of the invention
is one where A-E, Y and Z are all carbon, n = 0, X =
NH, Ar is phenyl, R2 is meta-bromo, m = 1, and R'-RB are
all hydrogen.
2. A most preferred form of the invention
is one where A-E, Y and Z are all carbon, n = 1, X =
NH, Ar is phenyl, R1 is (R]-CH; and R2-RB are all
hydrogen.
3. A most preferred form of the invention
is one where A and B are carbon, D and E taken
together are nitrogen, Y and Z are carbon, n = 0, X =
NH, Ar is phenyl, R' is meta-bromo, m = 1, and R°-Ra are
all hydrogen.
4. A most preferred form of the invention
is one where A and B taken together are sulfur, E is
nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is
SUBSTITUTE SHEET (RULE 2G)

W O 95!19970 PCTIUS95/00911
-34-
phenyl, R2 is meta-bromo, m = 1, and R4 and R6-Rg are ,
all hydrogen.
5. A moat preferred form of the invention
is one where A and B taken together are oxygen, E is
nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is
phenyl, RZ is meta-bromo, m = 1, and R' and R6-R8 are
all hydrogen.
6. A most preferred form of the invention
is one where A and B taken together are-nitrogen, E is
l0 nitrogen, D, Y and Z are carbon, n = 0, X = NH, Ar is
phenyl, Rz is meta-bromo, m = 1, and R' and R6-RB are
all hydrogen.
7. A most preferred form of the invention
is one where A and B taken together are nitrogen, D
and E taken separately are nitrogen, Y and Z are
carbon, n = 0, X = ISH, Ar ie phenyl, R' is meta-bromo,
m = 1, and R6-RB are all hydrogen.
8. A moat preferred form of the invention
is one where A and B taken together are nitrogen, E is
nitrogen,~Y and Z are carbon, n = 0, X = NH, Ar is
phenyl, R2 is meta-bromo, m = 1, and R' ,R' and R8 are
hydrogen and Rs is methyl.
9. A most preferred form of the invention
is one where A and B taken together are nitrogen, E is
nitrogen, Y and Z are carbon, n = 0, X = NH, Ar is
phenyl, R' is meta-bromo, m = 1, and R' ,R' and R8 are
hydrogen and RS is methyl.
SUBSTITUTE SHEET (RULE 26)

-W0 95119970 PCTlUS95100911
-35-
10. A most preferred form of the invention
is one where A and E are nitrogen, B, D, Y and Z are
all carbon, n = 0, X = NH, Ar is phenyl, RZ is meta-
bromo, m = 1, and R'-RB are all hydrogen.
11. A most preferred form of the invention
is one where A and B taken together are nitrogen, E is
nitrogen, Z is ethylidene, and Y a C-C bond, n = 0, X
= NH, Ar is phenyl, R2 is meta-bromo, m = 1, and R° and
R6-Rg are all hydrogen.
12. A most preferred form of the invention
is one where A-E, are all carbon, Z is sulfur, and Y a
C-C bond, n = 0, X = NH, Ar is phenyl, R2 is meta-
bromo, m = 1, and R'-R6 are all hydrogen.
13. A most preferred form of the invention
is one where A-E, are all carbon, Z is sulfur, and Y a
C-C bond, n = 0, X = NH, Ar is phenyl, R' is meta-
bromo, m = 1, R5 is nitro R', R° and R6 are all
hydrogen.
14. A most preferred form of the invention
is one where A-E, are all carbon, Z is sulfur, and Y a
C-C bond, n = 0, X = NH, Ar is phenyl, RZ is meta-
bromo, m = 1, RS is amino R3, R' and R6 are all
hydrogen.
15. A most preferred form of the invention
is one where A-E, are all carbon, Z is sulfur, and Y a
C-C bond, n = O, X = NH, Ar is phenyl, RZ is meta-
bromo, m = 1, R6 is methoxy and R'-RS are all hydrogen.
SUBSTITUTE SHEET (RULE 26)

WO 95/19970 PCTIUS95I00911
-36-
16. A most preferred form of the invention
is one where A is nitrogen, D and E taken together,
and Z are sulfur and Y a C-C bond,n = 0, X = IsFi, Ar is
phenyl, R~ is meta-bromo, m = 1, and R3 is hydrogen.
17. A most preferred form of the invention
is one where A-E, are all carbon, Z is nitrogen, and Y
a C-C bond, n = 0, X = NH, Ar is phenyl, R' is meta-
bromo, m = 1, and R'-R6 and R° are all hydrogen.
18. A most preferred form of the invention
is one where A-E, are alI carbon, Y is nitrogen, and Z
a C-C bond, n = 0, X = NH, Ar is phenyl, R' is meta-
bromo, m = 1, and R'-R6 and R° are all hydrogen.
The compounds of the present invention are
prepared according to a number of alternative reaction
sequences.
It is to be appreciated that in the
tricyclic structure of Formula I, the ring having A-E
is aromatic. By "aromatic" is meant that all members
of the ring share electrons and there is a resonance
among the members of the ring.
Preparative Routes to
Comoounda of the Iaventipn
Scheme 1 for Preferred Group 1
Condensation of commercially available 3-
amino-2-naphthoic acid with formamide gives the benzo- '
quinazoline nucleus. (DMF is dimethyl formamide).
Conversion of the carbonyl to halide is followed by
displacement with the appropriate amine side chain.

~W095119970 ~ PC1'/US9510D911
-37-
Representative examples of compounds that can be made
' by this route are given in the table below.
sohelae 2 for Preferred Grouv 4 f3.2-a1 Isomer
Nitration of methyl 5-methyl-2-
nitrobenzoate, and isomer separation gives the 2,4-
dinitrobenzoate ester. This is converted to the
corresponding benzamide with methanolic ammonia, and
both the amide nitrogen and the benzylic methyl are
condensed with DMF di-t-butoxy acetal. On Raney
Nickel reduction of both vitro groups to amines both
the pyrrole and pyrimidone rings spontaneously cyclize
to give the desired pyrrolo[3,2-g]quinazolone.
Conversion on to the chloride with POC13 is followed by
displacement of the chlorine with the desired amine.
Scheme 3 - RouGe for Preferrnd Group 5 C4 5 -a7 Isomer
For the [4,5-g] isomer 7-chloroquinazol-4-
one is nitrated at the 6-position by methods familiar
to one skilled in the art. The activated 7-halide is
then displaced by methoxide, the methyl ether is
cleaved, the vitro group is reduced to amino, and the
oxazole ring is cyclized on with formic acid. Phos-
phorus pentasulfide followed by methyl iodide acti-
vates the 4-position, and the synthesis is completed
by displacement of the 4-methylthio group by an appro-
priate amine.

WO 95119970 PCTIUS95/00911
-38-
Scheme 4 - Route for Preferred f3rou~ 5 C5.4 -01 Isomer
For the [5,4-g] isomer the chlorine atom of
the known 5-chloro-2,4-dinitrobenzamide is displaced
with ROH, and the two vitro groups are then
catalytically reduced to the diaminohydroxybenzamide.
Treatment of this with excess orthoformate cyclizes
both the oxazole and pyrimidone rings simultaneously,
to give the desired tricyclic nucleus. Activation of
the 4-oxo group with POC1, or other suitable
to chlorinating agent followed by displacement with the
appropriate amine gives the desired compounds.
Soheme 5 - Route for Preferred arouo 6 f4 5 a1 Isomer
For the [4,5-g] isomer 7-chloroquinazol-4-
one is nitrated at the 6-position by methods familiar
to one skilled in the art. The activated 7-halide is
then displaced by methiolate ion, and the resultant
thiomethyl ether is cleaved under the reaction
conditions to give the corresponding thiol. The vitro
group is reduced by a noncatalytic method, such as
treatment with hydrosulfide ion or Zn/AcOH, and the
thiazole ring is cyclized on with orthoformate.
Phosphorus pentasulfide followed by methyl iodide
actuates the 4-position, and the synthesis is
completed by displacement of the 4-methylthio group by
an appropriate-amine.
theme 6 - Route for Preferred arouv 6 CS 4 a7 Isomer
For the (5,4-g] isomer the chlorine atom of
the known 5-chloro-2,4-dinitrobenzamide is displaced
with NaSH, and the 4-vitro group is concomitantly
,. 30 reduced to give an aminonitrobenzamide disulfide.

-WO 95119970 2 1 7 7 3 9 2 pCT/US95/00911
-39-
Treatment of this with borohydride, and then formic
acid cyclizes the thiazole ring, to give the
benzothiazole derivative. Reduction of the second
nitro group followed by orthoformate cyclization gives
the desired tricyclic pyrimidone. Activation of the
4-oxo group with POC1, or other suitable chlorinating
agent followed by displacement with the appropriate
amine gives the desired compounds.
scheme 7 - Route for Grouv 7
Nitration of 7-chloroquinazol-4-one at the
6-position by methods familiar to one skilled in the
art is followed by displacement of the 7-chloro
compound with ammonia. If a 3,N-alkyl substituent is
required, an appropriate primary amine can be used
instead of ammonia. Reduction with Pearlman's
catalyst gives 6,7-diaminoquinazolone which on
treatment with formic acid cyclizes to the
imidazoloquinazolone. Phosphorus pentasulfide
followed by methyl iodide activates the 4-position,
and the synthesis is completed by displacement of the
4-methylthio group by an appropriate amine.
Scheme 8 - Route to Preferred Group 10 f4~ 3-a1 Isomers
2,4-Dimethylaniline is diazotized, and
cyclized to a benzopyrazole. Nitration of this,
followed by chromic acid oxidation and RaNi reduction
of the nitro group gives the desired anthranilic acid
derivative. This is cyclized to the pyrimidone with
formamidine, and activated and displaced at the 4-
position in the usual fashion.

~17~~9~
WO 95119970 PCTIUS95100911
-40-
8srheme 9 - Route to Preferred Grouu 10 (3 4 a1 Isomers
2,5-Dimethylacetanilide is nitrated, and the
acetate group is saponified off. Diazotization leads
to the desired benaopyrazole, which in turn is
oxidized to the corresponding benzoic acid derivative.
Catalytic reduction of the vitro group with Pd/C is
followed by formamidine acetate ring cyclization. The
pyrimidone is activated to displacement in one of the
usual fashions, and a suitable amine is then
introduced at the 4-position to give the desired
compound.
&aheme 10 - Route to Preferred fir ~~ ra 5 e1 Isomers
6,7-Diaminoquinazoline is prepared as
described above in Scheme 7. This compound can be
cyclized to the triazoloquinazolone via a
diazotization, and then the carbonyl is activated via
phosphorus pentasulfide and methyl iodide, as
described previously and displaced with an appropriate
amine to give the desired product.
,&cheme 11 - Route to Preferred Grouv 13 A & E Nitrogen
6,7-Diaminoquinazoline is prepared as
described above. This compound can be cyclized to a
pyrazinoquinazolone by treatment with 2,5-dihydroxy-
1,4-dioxane, and then the carbonyl is activated via
phosphorus pentasulfide and methyl iodide, as
described previously and displaced with an appropriate
amine to give the desired product.

~W095I19970 ~ PCTIUS95I00911
-41-
~C~eme ~2 - Route to Preferred Grouv 13 8 & E Nitrogen
Reaction of 1,3-diaminobenzene with chloral
and hydroxylamine, followed by cyclization with conc.
sulfuric acid gives the bis-isatin type tricycle.
Oxidation with hydrogen peroxide gives the symmetric
diaminodiacid. This is doubly cyclized with
formamidine, and converted to the corresponding
dichloride with POC1, or equivalent. Monodisplacement
with the desired amine, can be followed by
displacement of the remaining chloride
hydrogenolytically or by a suitable nucleophile to put
in R5.
Nitration of 6-acetamidoquinazol-4-one gives
the 5-vitro derivative. Hydrolysis of the amide with
dilute HC1, followed by reduction with Pearlman's
catalyst gives the 5,6-diaminoquinazolone. Fusion of
the imidazole ring by a formic acid gives the parent
ring skeleton, and then the carbonyl is activated via
phosphorus pentasulfide and methyl iodide, as
described previously and displaced with an appropriate
amine to give the desired product.
Scheme 14 - Route to Preferred Group 33 f4 5-h1 Isomer
Nitration of 7-chloroquinazol-4-one by means
obvious to one skilled in the art gives the 8-vitro
_ derivative as a minor product. This is purified and
the chlorine is displaced by ammonia under high
temperature and pressure to give the 5-amino compound
which is then reduced by Pearlman's catalyst (Pd
hydroxide on carbon) to the 7,8-diaminoquinazolone.

WO 95/19970 PCTIUS95100911
-42-
Fusion of the imidazole ring by a formic acid
derivative gives the parent ring skeleton, and then
the carbonyl is activated via phosphorus pentasulfide
and methyl iodide, as described previously and
displaced with an appropriate amine to give the
desired product.
Seheme 15 - Route to Preferred Orour 39 (3,2-d1 Isomer
2-Fluorobenzonitrile or a suitably
substituted derivative of it is treated with ethyl
thioglycollate and a base in a dipolar aprotic solvent
to give an ethyl 3-aminobenzothiophene-2-carboxylate
derivative. This is cyclized to the desired
benzothienopyrimidone with formamide, and the carbonyl
is replaced by chlorine using standard techniques, and
the chloride is displaced by an appropriate amine to
give the desired compounds, or precursors that can
readily be converted into them.
Scheme 16 - Route to Preferred Group 39 13.2-d7 Isomer
In a variant of the route described in
2~ Scheme 15, lithiation of a suitably substituted
fluorobenzene ortho to the fluorine atom is followed
by carbonylation. The aldeliyde is converted onto a
suitable 2-fluorobenzonitrile derivative by oxime
formation and dehydration. Alternatively the initial
anion can be carboxylated and the resulting acid can
be converted via the amide to the desired nitrile.
This is then put through the sequence described in .
Scheme 15, to prepare derivatives which could not be
obtained by substitution on 2-fluorobenzonitrile.

~O 95/19970 ~ ~ ~ ~ ~ y ~ PCT/US95100911
-43-
Bc#eme 17 - Route to Preferred Grour 39 t2,3-d1 Isomer
Commercially available 4,6-
dichloropyrimidine can be monodisplaced with 2-
bromobeazenethiolate to give a diarylsulfide. This
compound can be metalated at the 5-position of the
pyrimidine ring with LDA, and quenched with Me3SnCl, to
form a halostannane. This halostannane is
intramolecularly Stille coupled to give the desired 4-
chlorobenzothieno[2,3-d]pyrimidine, from which
chlorine can be displaced to give the desired product.
Scheme 18 -
tioute to Preferred Orouv 41 t3'.2':2.31t4 5-d7 Isomer
Halogen-metal exchange on 3-bromothiophene
in ether at low temperature, followed by treatment
with sulfur and then methyl bromoacetate gives methyl
(thien-3-ylthio)acetate. Vilsmeier formylation using
N-methylformanilide introduces a 2-formyl group on the
thienyl ring, without inducing aldol cyclization.
Reaction of the aldehyde to the oxime, followed by
mesyl chloride/NEt3 dehydration gives the corresponding
nitrile, which cyclizes to methyl 3-aminothieno[3,2-
b]thiophene-2-carboxylate on heating to 100'C in DMSO
with NEt,. Pyrimidone fusion~is carried out with
formamide or an equivalent thereof, and the 4-keto
aubstituent is activated and displaced in the usual
manner to give the desired products.
6cheme 19 -
RQUt<s to Preferred Grour 41 t2' 3'~ 2 3115 4-d1 Isomer
Metalation of 3-bromothiophene with LDA
occurs at the 2-position. Quenching of this anion

WO 95119970 PCTIITS95I00911
-44-
with 1 equivalent of sulfur, followed by one
equivalent of 4,6-dichloropyrimidine gives the '
thienopyrimidosulfide. Selective metalation with LDA
at the 5-position of the pyrimidine ring, followed by
stannylation gives a precursor for Stille coupling.
After the coupling the 4-chlorine is displace with the
appropriate amine to give the desired product.
Scheme 2D -
l3pute to Preferred Grouv 44 4~.5~~ 2 3114 5-d~ Isomer
to Reaction of thiazolidin-2,4-dione with POC13
and DMF gives 2,4-dichlorothiazole-5-carbaldehyde.
Protection of the aldehyde as an acetal is followed by
selective removal of the 2-chlorine by halogen-metal
exchange and hydrolysis. The aldehyde is oxidized up
to the corresponding nitrile by oxime formation and
dehydration, and 4-chloro-5-cyanothiazole on treatment
with fresh 2-mercaptoacetamide in basic conditions
gives 6-aminothieno(2,3-d]thiazole-5-carboxamide.
This can be cyclized to the tricycle with ethyl
orthoformate, and the carbonyl replaced by POC1, in the
usual manner, and the chloride is then displaced by a
suitable amine to give the desired product.
&cheme 21 - -
Route to Preferred Group 45 f4~ 5~~ 2 31f4 5-d7 Isomer
1,N-Benzyl-4,5-dibromoimidazole is lithiated
with butyl lithium and formylated with DMF. Reaction
of the bromoaldehyde with ethyl thioglycollate and
base in DMSO leads to the desired aminothienoimida-
zole. This in turn is annulated again with formamide
or an equivalent thereof, and the tricyclic pyrimidone

-WO 95/19970 ~ PCTIUS95100911
-45-
is chlorinated at the 4-position and displaced with a
suitable amine to give the desired product.
Scheme 22 -
Route to Preferred Grouv 49 (2'.3':2.31/4.5-d1 Isomer
Reaction of 2-chloronicotinonitrile with
methyl thioglycollate gives methyl 3-aminopyridol2,3-
d7thiophene-2-carboxylate. Fusion of the pyrimidone
ring with formamide gives the corresponding pyrrido
thienopyrimidone, which can then be chlorinated on the
l0 carbonyl and displaced with appropriate amines in the
usual fashion to yield the desired compounds.
Scheme 23 -
Route to Preferred Grouv 50 f3.2-d1 Isomer
A suitably substituted anthranilonitrile
derivative is N-alkylated with ethyl bromoacetate, and
the pyrrole ring is closed by treating the product of
that reaction with KOBu', to give ethyl 3-aminoindole-
2-carboxylate. The pyrimidone ring is fused onto this
with formamide, and the carbonyl converted to chloride
with POC1~. Displacement of the chlorine with a
suitable amine gives the desired compound.
Scheme 24 -
Route to Preferred Groun 50 f2.3-d7 Isomer
The fluoride of 2-fluoronitrobenzene is
displaced by the anion derived from methyl
cyanoacetate and KOBu'. Mild reduction of the vitro
group to amino is accompanied by spontaneous closure
of the pyrrole ring to give ethyl 2-aminoindole-3-
carboxylate. The pyrimidone ring is fused onto this

WO 95119970 PCTIIJS95I00911
-46-
with formamide, and the carbonyl converted to chloride
with POC1,. Displacement of the chlorine with a
suitable amine gives the desired compound.
Scheme 25 -
3~oute to Preferred Qrouo 61 t3.2-d7 Isomer
O-Alkylation of 2-cyanophenol with
methylbromoacetate, followed by treatment with a
strong base gives ethyl 3-aminobenzofuran-2-
carboxylate. The pyrimidone ring is fused onto this
with formamide, and the carbonyl converted to chloride
with Vilsmeier reagent. Displacement of the chlorine
with a suitable amine gives the desired compound.
These compounds are potent and selective
inhibitors of the human EGF receptor tyrosine kinase,
and other members of the EGF receptor family,
including the ERB-B2, ERB-B3 and ERB-B4 receptor
kinases, and are useful for the treatment of
proliferative diseases in mammals. These inhibitors
2D prevent mitogenesis in cells where mitogenesis is
driven by one or more of this family of receptor
kinases. This can include normal cells, where it is
desired to prevent mitogenesis, as exemplified by the
cells transformed by overexpresaion or mutation of
this kinase family as exemplified by poor prognosis
breast cancer where overexpreasion of EGFR, ERB-B2 and
ERB-B3 or mutation of ERB-B2 to the oncoprotein NEU is
a major factor in cellular transformation. As the
preferred compounds are not highly cytotoxic and do
not show potent growth inhibitory properties, because
of their high specificity toward inhibition of the

~'VO 95119970 ~ PCTII7595100911
-47-
EGFR kinase family, they should have a much cleaner
toxicity profile than most anti-cancer and anti-
proliferative drugs. Their very different mode of
action to current anti-cancer drugs should allow for
their use in multiple drug therapies, where synergism
with available agents is anticipated.
Compounds of the invention have been shown
to be very potent, reversible inhibitors of the EGF
receptor tyrosine kinase, by binding with high
1D affinity at the adenosine triphosphate (ATP) binding
site of the kinase. These compounds exhibit potent
ICsos, varying from 10 micromolar to SD picomolar, for
the tyrosine kinase activity of the enzyme, based on
an assay examining phosphorylation of a peptide
derived from the phosphorylation site of the protein
PLCgammal, a known EGFR phosphorylation substrate.
This data is shown in Table 1.
Ei.oloaical Data
Materials and Methods
Purification of Epidermal Growth Factor
Receptor Tyrosine Kinase - Human EGF receptor tyrosine
kinase was isolated from A431 human epidermoid
carcinoma cells which overexpress EGF receptor by the
following methods. Cells were grown in roller bottles
in 50% Delbuco's Modified Eagle and 50% HAM F-12
nutrient media (Gibco) containing 10% fetal calf
serum. Approximately 10' cells were lysed in two
volumes of buffer containing 20 mM 2-(4N-[2-
hydroxyethyl]piperazin-1-yl)ethanesulfonic acid
(hepes), pH 7.4, 5 mM ethylene glycol bis(2-aminoethyl

CA 02177392 2002-03-08
-4$-
ether) N,N,N',N'-tetraacetic acid, 1% Triton X-100,
10% glycerol, 0.1 mM sodium orthovanadate, 5 mM sodium
fluoride, 4 mM pyrophosphate, 4 mM benzamide, 1 mM
dithiothreitol, 80 ~cg/caL aprotinin, 40 ~cg/mL leupeptin
and 1 mM phenylmethylsulfonyl fluoride. After
centrifugation at 25,000 x g for l0 minutes, the
supernatant was equilibrated for 2 h at 4'C with 10 mL
of wheat germ agglutinin sepharose that was previously
equilibrated with 50 mM Hepes, 10% glycerol, 0.1%
Triton X-100 and 150 mM NaCl, pH 7.5, (equilibration
buffer). Contaminating proteins were washed from the
resin with 1 M NaCl in equilibration buffer, and the
enzyme was eluted with 0.5 M N-acetyl-1-D-glucosamine
in equilibration buffer, followed by 1 mM urea. The
enzyme was eluted with 0.1 mg/ml EGF. The receptor
appeared to be homogeneous as assessed by Coomassie
blue stained polyacrylamide electrophoretic gels.
Determination of ICSp values - enzyme assays
for ICso determinations were performed in a total
volume of 0.1 mL, containing 25 mM Hepes, pH 7.4, 5 mM
MgClz, 2 mM MnClz, 50 ~cM sodium vanadate, 5-10 ng of
EGF receptor tyrosine kinase, 200 uM of a substrate
peptide, (Ac-Lys-His-Lys-Lys-Leu-Ala-Glu-Gly-Ser-Ala-
Tyr"~_Glu-Glu-Val-NHz, derived from the amino acid
(Tyr"~ has been shown to be one of four tyrosines in
PLC (phospholipaseC)-gamma 1 that are phosphorylated
by the EGF receptor tyrosine kinase [Wahl, M. I.;
Nishibe, S.; Kim, J. w.; Kim, H.; Rhee, S. G.;
Carpenter, G., J. Bioi. Chem_, (1990), 265, 3944-
3948.], and peptides derived from the enzyme sequence
surrounding this site are excellent substrates for the
enzyme.),10 ~M ATP containing 1 ~Ci of I'~P]ATP and
incubated for ten minutes at room temperature. The
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CA 02177392 2002-03-08
-49-
reaction was terminated by the addition of 2 m.L of 75
mM phosphoric acid and passed through a 2.5 cm
phosphocellulose filter disc to bind the peptide. The
filter was washed five times with 75 mM phosphoric
acid and placed in a vial along with 5 mL of
scintillation fluid (Ready gel*Beckman).
Table 1
BGF Receptor T~r~rosine lcinae~ Inhibition
Exaarple ICso in EGFR
#
1 c100 pM
2 21 nM
3 760 pM
4 44 nM
5 75 pM
1. 5 6 6 pM
7 4 .1 nM
8 30 pM
9 -10 pM
10 1.7 nM
11 272 nM
12 29 nM
13 191 nM
14 538 nM
15 1.8 nM
16 12.3 nM
17 270 pM
18 36% ~ 10 nM
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W0 95119970 PCTIUS95/00911
-50-
8xample # ICso in BGFR
19 40 nM
20 1.3 ~tM
21 732 nM
2 2 2 .11 /tM
23 460 nM
24 419 nM
25 72 nM
26 132 nM
27 264 nM
28 31 nM
29 732 nM
30 4.1 /tM
31 220 nM
32 160 nM
33 4.3 uM
34 740 nM
Cells
Swiss 3T3 mouse fibroblaets, A431 human
epidermoid carcinoma cells, and MCF-7 (Michigan Cancer
Foundation human mammary carcinoma cells), SK-BR-3
(human mammary carcinoma cells), MDA-MB-231 and MDA-
MB-468 (human mammary carcinoma cells) breast
carcinomas were obtained from the American Type
Culture Collection, Rockville, Maryland and maintained
as monolayers in dMEM (Dulbecco's modified eagle
medium)/F12, 50: SD (Gibco/BRL) containing 10% fetal

W O 95!19970 PCfIITS95100911
-5I-
bovine serum. To obtain conditioned medium, MDA-MB-231
cells were grown to confluency in an 850 cm2 roller
bottle and the medium replaced with 50 ml of serum-
free medium. After 3 days the conditioned medium was
removed, frozen down in aliquots and used as a
heregulin source to stimulate erbB-2, 3, 4.
Agtibodiea
Monoclonal antibodies raised to
phosphotyrosine were obtained from Upstate
Biotechnology, Inc., Lake Placid, NY. Anti-EGF
receptor antibodies were obtained from Oncogene
Science, Uniondale, NY.
opreciDitation and Weatera Blot
Cells were grown to 100% confluency in 100
mm Petrie dishes (Corning). After the cells were
treated for 5 minutes with either EGF (epidermal
growth factor), PDGF, or bFGF (basic fibroblast growth
factor) (20 ng/ml) or 1 ml of conditioned media from
MDA-MB-231 cells, the media was removed and the
monolayer scraped into 1 ml of ice cold lysis buffer
(50 mM Hepes, pH 7.5, 150 mM NaCl, 10%~glycerol, 1%
triton X-100, 1 mM EDTA, 1 mM EGTA, 10 mM sodium
pyrophosphate, 30 mM p-nitrophenyl phosphate, 1 mM
orthovanadate, 50 mM sodium fluoride, 1 mM
phenylmethylsulfonylfluoride, 10 ~Cg/ml of aprotinin,
and 10 ~.g/ml of leupeptin). The lysate was
- transferred to a microfuge tube (small centrifuge that
holds 1-2 ml plastic centrifuge tubes), allowed to sit
on ice 15 minutes and centrifuged 5 minutes at 10,000
x g. The supernatant was transferred to a clean

CA 02177392 2002-03-08
-52-
microfuge tube and 5 ~g of antibody was added to
designated samples. The tubes were rotated for 2 hours
at 4° C after which 25 ~1 of protein A sepharose was
added and then rotation continued for at least 2 more
hours. The protein A eeparose was washed 5 times with
50 mM Hepes, pH 7.5, 150 mM NaCl, 10% glycerol and
0.02% sodium azide. The precipitates were resuspended
with 30 ~cl of Laemlli buffer (Laemmli, NATQRE, Vol.
727, pp. 680-685, 1970), heated to 100'C for 5 minutes
l0 and centrifuged to obtain the supernatant. Whole cell
extracts were made by scraping cells graven in the
wells of 6 well plates into 0.2 ml of boiling Laemmli
buffer. The extract were transferred to a microfuge
tube and heated to 100° C for 5 minutes. The entire
supernatant from the immuaoprecipitation or 35 ~cl of
the whole cell extract was loaded onto a
polyacrylamide gel (4-20%) and electrophoresis carried
out by the method of Laemlli (Laemmli, 1970). Proteins
in the gel were electrophoretically transferred to
2o nitrocellulose and the membrane was Washed once in 10
mM Tris buffer, pH 7.2, 150 mM NaCl, 0.01% Azide (TNA)
and blocked overnight in TNA containing 5% bovine
serum albumin and 1% ovalbumin (blocking buffer). The
membrane was blotted for 2 hours with the primary
antibody (l~cg/ml in blocking buffer) and then washed 2
times sequentially in TNA, TNA containing 0.05% Tween-
20 and 0.05% Nonidet P-40 (commercially available
detergent) and TNA. The membranes were then incubated
for 2 hours in blocking buffer containing 0.1 ~Ci/ml
of ('ZSII protein A and then washed again as above.
After the blots were dry they were loaded into a film
cassette and exposed to X-AR X-ray film for 1-7 days.
Protein A is a bacterial protein that specifically
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CA 02177392 2002-03-08
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bonds certain IgG subtypes and is useful in binding to
and isolating antibody-antigen complexes.
Growth Inhibition Aasav
Cells (2 x 10') were seeded in 24-well plates
(1.7 x 1.6 cm, flat bottom? in two mls of medium with
or without various concentrations of drug. Plates were
incubated for 3 days at 37o in a humidified atmosphere
containing 5~ C02 in air. Cell growth was determined by
cell count with a Coulter Model AM electronic cell
counter (Coulter Electronics, Inc., Hialeah, FL).
INHIBITION OF $aF-INDUCED J1DTOP80SPHORYLATION
IN X1431 BP~tOZD CA&CINO~ CELLS 11ND CONDITIONED
I~IA-INDUC3fl Afl't'OP80SP80It7fLATION IN b1C-8R-3 BREAST
TOMOR CELLS HY COMPOUNDS OF THE C'QRRHNT IN«ENTION
Example EGFR ICso A431 ICso SIR-3 ICso nM
# nM nM
1 <0.1 17 ND
6 0.008 46 55
8 0.03 26 10
10 1.7 31 -700
15 1.8 170 ND
17 0.27 86 23
19 90 ND -1500
25 72 93 1000
28 31 630 10
29 732 109 1100
The gels shown in the drawings, developed as
detailed in the experimental section, demonstrate the
efficacy of compounds of the current invention at
docking certain EGF-stimulated mitogenic signalling
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W O 95/19970 PCT'IUS95IOD911
-54-
events in whole cells. The numbers to the left of gels
indicate the positions of molecular weight standards
in kiloDaltons. The lane labelled control shows the
degree of expression of the growth-related signal in
the absence of EGF stimulation, whereas the lane
labelled EGF (or PDGF or b-FGF) shows the magnitude of
the growth factor-stimulated signal. The other lanes
show the effect of the stated quantities of the named
drug on the growth factor-stimulated activity being
measured, demonstrating that the compounds of the
present invention have potent effects in whole cells,
consistent with their ability to inhibit the tyrosine
kinase activity of the EGF receptor.
See also the results as shown in Figures 1-
B.
ANTIPROLIFERATIYE PROPERTIES OF
TYROSINE RINASE INHIBITORS ICsp (nM)
Example 6 Example 17
B1D4-1-1 3200 2900
SK-BR-3 200 1800
MDA-468 20000 1800
B104-1-1 - NIH-3T3 mouse fibroblasts transfected by
the neu oncogene: Stern et al., Sci»cs, 234, pp. 321-
324 (1987);
SK-BR-3 - Human breast carcinoma overexpresaing erbB-2
and erbB-3;
MDA-46B'- Human breast carcinoma overexpressing the
EGF receptor.

CA 02177392 2005-03-17
-5S-
Soft Agar Clonocenic Aseava
Cell monolayers were exposed to the
appropriate compound for 1-3 days and were then washed
free of drug with warmed serum-free media. The cells
were trypsinised and 10,000/mL were seeded into
DMEMJF12 media containing 10% fetal calf serum and
0.4% agarose, but no drug. One ml of this solution
was placed over a bottom layer of the same medium
containing 0.8% agarose in a 35 mm Petri dish, and Was
to incubated at 37'C in a humidified atmosphere
containing 5% carbon dioxide in air. After 3 weeks
colonies were counted using an image analyzer for
quantification. See Figure 9.
It is to be appreciated that the compounds
described herein can be used in combination with other
components to enhance their activity. Such additional
components are anti-neoplastic materials as,
doxorubicin, taxol, cis platin, and the like.
It has been found that the compounds
described herein may inhibit both the erb-B2 and erb-
B4 receptors and therefore have significantly
increased clinical activity advantageously in
combination with the aforementioned anti-neoplastic
agents.
See J. Basalga et al., Antitumor Effects of
Doxorubicin in Combination With Anti-Epidermal Growth
Factor Receptor Monoclonal Antibodies. JNC1, 1993, 85
1327, and Z. Fan e~ al., Antitumor Effect of Anti-
Epidezmal Growth Factor Receptor Monoclonal Antibodies
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WO 95/19970 PCTIUS95/00911
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Plus Cis Diamminedichloroplatinum on Well Established
A431 Cell Xenografts. Cancer Res. 1993, 53, 4637.
Listed below are preferred embodiments
wherein all temperatures are in degrees Centigrade and
all parts are parts by weight unless otherwise
indicated.
Example 1
4-(3-bromoanilino)benzofalauina-~i~np hvArnrhlnrir3P
3H-Benzo(a7auinazol-4-one. 3-Amino-2-
naphthoic acid (3.74 g, 20 mmol) in stirred formamide
is heated under N2 to 135°C for 30 min, and to 175°C
for 2 h. The reaction mixture is poured onto
vigorously stirred dilute NaOH solution (0.2 M, 50
mL), containing ice, and the solid is collected by
vacuum filtration, rinsed with water (2 x 25 mL), and
dried in a vacuum oven at 60°C to give benzo[g]-3H-
quinazol-4-one (3.49 g, 89%) as a pale khaki solid.
'H NMR (DMSO) d 12.08 (1H, brs), 8.84 (iH, s), 8.24
(1H, s), 8.21 (1H, d, J = 7 Hz), B.10 (1H, d, J = 7
Hz), 8.09 (1H, s), 7.62 ( 2H., apparent d of pentets, Jd
s 1.3 Hz, JP = 6.7 Hz).
4-Chlorobenzo(alquinazoline. A suspension
of benzo[g]-3H-quinazol-4-one (3.49 g, 18 mmol) in
POC13 (40 mL) was refluxed under N2 for 3 h. The
volatiles were removed under reduced pressure, and the
residue was partitioned between chloroform (200 mL)
and dilute aqueous Na~HPO, solution (1 M, 50 mL). The
organic phase was filtered through a silica gel plug

WO 95119970 ~ PCT/US95100911
_57_
(50 g), and the plug was then eluted with 20% EtOAc in
CHC13 (500 mL). The combined eluents were concentrated
under reduced pressure to give 4-chlorobenzo[g]quin-
azoline (1.20 g, 31%) as an orange-yellow solid. 'H
NMR (DMSO) d 9.04 (1H, s), 8.91 (1H, s), 8.65 (1H, s),
8.20-8.09 (2H, m), 7.75-7.60 (2H, m).
4-(3-Bromoanilino)benzo~Qlgn;na~nl;ne
hvdrochloride. 4-Chlorobenzo[g]quinazoline (214 mg,
1.0 mmol), 3-bromoaniline (213 mg, 1.25 mmol) and NEt;
(202 mg, 2.0 mmol) in stirred methoxyethanol (5 mL)
were heated under N, at 95°C for 6 h. The volatiles
were removed under reduced pressure and the residual
solid was triturated with MeOH. The solid was
recrystallized at o°C from an EtOH/ dilute
hydrochloric acid mixture (1:4, 0.05 M acid, 50 mL)
after celite filtration to give 4-(3-bromoanilino)-
benzoIg]quinazoline hydrochloride (71 mg, 18%) as a
yellow-green solid. 'H NMR (DMSO) d 14.0 (1H brs),
9.65 (1H, s), 9.01 (1H, s), 8.47 (1H, s), 8.29 (1H, d,
J = 8.4 Hz), 8.24 (1H, d, J = 8.4 Hz), 8.18 (1H,
slbrs), 7.9-7.82 (2H, m), 7.78 (1H, t, J = 7.5 Hz),
7.58 (1H, d, J = 8 Hz), 7.51 (1H, t, J = 8 Hz).
_r07~~:

WO 951199'70 PC1'/US95100911
-58-
Example 2
4-(fRl-1-phenvlethvlamino)benzofatguinazoline hvdrochloride
4-Chlorobenzo[g7quinazoline (107 mg, 0.5
mmol), [R7-1-phenylethylamiae (72 mg, 0.6 mmol) and
NEt3 (202 mg, 2.D mmol) in stirred methoxyethanol (2
mL) are heated under N= at 100°C for 90 min. On cool-
ing the reaction mixture is diluted with CHC13 (1o mL),
and is shaken with dilute hydrochloric acid (0.2 M, 15
mL). The heavy yellow precipitate is collected by
Buchner filtration, rinsed with water (5 mL), and
dried in vacuo at 60°C to give 4-([R7-1-phenylethyl-
amino)benzo[g7quinazoline hydrochloride hydrate (122
mg, 64k) as a yellow solid. 'H NMR (DMSO) d 14.75 (1H
brs), 10.85 (1H, d, J ~ 8.0 Hz), 9.61 (1H, s), 8.90
(1H, s), 8.36 (1H, s), 8.18 (1H, d, J = 8.2 Hz), 7.82
(1H, t, J = 7.6 Hz), 7.74 (1H, t, J = 7.4 Hz), 7.56
(2H, d, J = 7.5 KHz), 7.39 (2H, t, J = 7.6 Hz), 7.30
(1H, t, J = 7.4 Hz), 5.92 (1H, pentet, J = 7.2 Hz),
1.76 (3H, d, J = 7.2 Hz).
Example 3
4-(3-Bromoanilino)ovrrolo(3.2-alauinazoline
N-(5-(E.2-dimethvlaminoethtenvl)-2.4-dinitr-
flbenzovl)-N~N~-dimethvlformamidine. To a solution of
5-methyl-2,4-dinitrobenzamide (Blatt, A. H. J. Org.
Chem 1960, 25, 2D3D.) (2.25 g, 10 mmol) in DMF (10 mL)
is added t-butoxy-bis(dimethylamino)methane (6.2 mL,
mL). The reaction mixture is stirred at 55 °C for
2 h. The solvent is evaporated under reduced pressure
and the residue is suspended in water. The precipi-
30 tote is filtered and washed with water and ethyl ether
to give N-i5-(E,2-dimethylaminoethtenyl)-2,4-dinitro-

2177392
~WO 95!19970 PCTILT595/00911
-59-
benzoyl)-N'N'-dimethylformamidine, 2.76 g (84%). 1H
NMR (DMSO) d 8.55 (1H, s), 8.47 (1H, s),8.04 (1H, d, J
= 13.0 Hz), 7.?6 (1H, s), 5.95 (iH, d, J = 13.0 Hz),
3.21 (3H, s), 3.00 (9H, m).,
4-Oxo-3H-DVrro~oau~nazo~~ne A mixture of
N-(5-(E,2-dimethylaminoethtenyl)-2,4-dinitrobenzoyl)-
N'N'-dimethylformamidine (600 mg, 1.79 mmol) and Raney
nickel (200 mg) in THF-MeOH (25 :25 mL) is hydrogenat-
ed in a rocking autoclave at 1500 psi at room tempera-
ture for 22 h. The catalyst is filtered off and the
filtrate is concentrated in vacuo. The crude product
is triturated in isopropanol and filtered. The solid
is then washed with isopropanol and ethyl ether and
dried in a vacuum oven at 40 °C to give 4-oxo-3H-
pyrroloquinazoline(190 mg, 58%) as a bright red solid
'H NMR (DMSO) d 11.8 (1H, brs), 11.6 (1H, brs,) 8.43
(1H, s), 7.95 (1H, s, J = 3.1 Hz), 7.73 (1H, d, J =
3.4 Hz), 7.55 (1H, s), 6.58 (1H, d, J = 3.4 Hz).
4-(3-Bromoanilino)DVrrnlr,ta ~-glc~ainazoline
4-Oxo-3H-pyrroloquinazoline (100 mg, 0.54 mmol) in
POC1, (5 mL) is refluxed under N, for 20 h. The re-
sulting dark red solution is cooled to room tempera-
ture and extracted with ethyl acetate (2 x 20 mL).
The organic layer is dried (Na,SO,) and concentrated to
give a red solid (3o mg). Without further purifi-
cation, this is suspended in 2-propanol (2 mL) con-
taining m-bromoaniline ( 0.1 mL, 0.8 mmol). The reac-
tion mixture is then refluxed for 1 h. The resulting
bright yellow precipitate is filtered and washed with
water and ether to yield 4-(3-bromoanilino)pyrrolo-
(3,2-g]quinazoline(15 mg, 8 %). ~H NMR (DMSO) d 11.7
(1H, brs), 10.5 (1H, brs), 8.89 (1H, s), 8.73 (1H,

2~1T~9-
W 0 95/19970 PCTIUS95I00911
-60-
brs), 8.16 (1H, s), 7.80 (3H, m), 7.35 (2H, s), 6.77
(1H, s) .
5,5'-Dithiobis(4-amino-2-nitrobenzami~P~. A
solution of NaSH in aqueous MeOH (prepared according
to Vogel, in "Elementary Practical Organic Chemistry,
Part 1") is added dropwise with stirring to a solution
of 5-chloro-2,4-dinitrobenzamide (5.00 g, 0.020 mmol)
in a mixture of THF/MeOH (1:1, 200 mL) until no
further reaction is observed (TLC analysis). The
solution is then diluted with water and washed with
CH=Clz. The aqueous portion is acidified with
concentrated HC1, extracted with EtOAc, and the
extract is worked up to give an oily solid which is
stirred vigorously with MeOH for 3 h. The resultant
precipitate is removed by filtration to give 5,5'-
dithiobis(4-amino-2-nitrobenzamide) (3.118, 64%) as a
tan powder. 'H NMR (DMSO) d B.BB (1H, brs), 8.33 (1H,
brs), 7.99 (1H, s), 7.94 (1H, s), 3.6-3.3 (2H, brs).
5-Nitrobenzothiazole-6-carboxamide. NaBH,
(O.5D g, 0.013 mmol) is added to a vigorously stirred
suspension of 5,5'-dithiobis(4-amino-2-nitrobenzamide)
(3.00 g, 7.13 mmol) in MeOH (60 mL). After '10 min the
solution is acidified with concentrated HC1, extracted
with EtOAc, and worked up rapidly to give 4-amino-5-
mercapto-2-nitrobenzamide as an unstable solid which
is used directly. The crude material is dissolved in
formic acid (50 m:.) heated under gentle reflux for 2
h, and then concentrated to dryness. The .residue is
triturated with MeOH/EtOAc (1:19), and unreacted

_WO 95119970 ~ ~ ~ ~ J ~ ~ PCTIUS95100911
-61-
disulfide (1.41 g) is recovered by filtration. The
filtrate is concentrated and chromatographed on
silica. Elution with EtoAc/petroleum ether (4:1) gives
foreruns, while EtOAc gives 5-nitrobenzothiazole-6-
carboxamide (1.318, 41%) as a yellow powder. 'H NN112
(DMSO) B 9.70 (IH, s), 8.71 (1H, s), 8.52 (1H, s),
8.25 (1H, brs), 7.78 (1H, brs).
Thiazolo(5,4-alauinazol-4(3H)-one. A
solution of 5-nitrobenzothiazole-6-carboxamide (0.30
g, 1.34 mmol) in MeOH/EtOAc (1:1, 25 mL) is
hydrogenated over 5% Pd/C at 60 psi for 1 h to give 5-
aminobenzothiazole-6-carboxamide. This is immediately
dissolved in triethyl orthoformate (30 mL) and the
mixture is heated under gentle reflex for 18 h. An
equal volume of petroleum ether is added to the cooled
solution, precipitating thiazolo[5,4-g]quinazol-4(3H)-
one (0.17 g, 57%) as a tan powder. 'H NMR (DMSO) d
12.30 (1H, brs), 9.67 (1H, s). 9.00 (1H, s), 8.31 (1H,
s), 8.14 (1H, s).
4-(3-Bromoanilino)thiazolo(5,4-
alouinazoline. A suspension of the thiazolo[5,4-
g]quinazol-4(3H)-one (0.25 g, 1.23 mmol) in POC13 (20
mL) is heated under reflex for 3-h, then concentrated
to dryness. The residue is partitioned between
saturated aqueous NaHCO, and EtOAc, and the organic
portion is worked up to give 4-chlorothiazolo[4,5-
g]guinazoline (0.21 g, 0.95 mmol) as a yellow solid
which is used directly. The crude product and 3-
bromoaniline (0.21 mL, 1.90 mmol) are heated under
reflex for 45 min in THF/propan-2-of (1:1, 20 mL)
' ' containing a trace of concentrated HC1, and then
concentrated to dryness. After'trituration with EtOAc,

WO 95119970 PCTIUS95100911
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the residue is partitioned between saturated aqueous
NaHC03 and EtOAc and the organic portion is worked up
to give 4-(3-bromoanilino)thiazolo[5,4-g]quinazoline
(0.19 g, 49~), . 'H NMR (DMSO) d 10.05 (1H, brs), 9.74
(1H, s), 9.38 (1H, s), 8.71 (1H, s), 8.48 (1H, s),
8.31 (1H, brs), 7.96 (Hi, d, J = 7.7 Hz), 7.39 (1H, t,
J = 7.7 Hz,), 7.33 (lH,d, J = 7.7 Hz).
Example 5
4-(3-Bromoanilino)oxazolof5.4-a]auinazoline
2.4-Dinitro-5-hvdroxvbenzamide. A solution
of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol)
in p-dioxane/methanol (l:l, 120 mL) and 6N aqueous KOH
(20 mL) is stirred at room temperature for 2 h. After
acidification with concentrated HC1, the mixture is
diluted with water and extracted into EtOAc. Workup
gives 2,4-dinitro-5-hydroxybenzamide (4.918, 98b) as
yellow cubes. 'H NMR (DMSO) 3 8.64 (1H, s), 8.16 (1H,
brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80 (1H, brs).
4-Oxo-3H-oxazolof5.4-alaninazoline. A
solution of 2,4-dinitro-5-hydroxybenzamide (4.00 g,
0.018 mmol) in MeOH/EtOAc (1:1, 50 mL) is hydrogenated
over 5~ Pd/C at 60 psi for 3 h to give 2,4-diamino-5-
hydroxybenzamide, which is used directly. Formic acid
(50 mL) is added and the solution is heated under
reflux for 48 h. then the volatiles are removed under
reduced pressure. The residue is triturated with EtOAc
to give crude 4-oxo-3H-oxazolo[5,4-g]quinazoline(3.27
g, 97~) as a tan powder which is used directly.
4-Chlorooxazolo(5.4-allauinazoline. A
suspension of 4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98

~WO 95119970 ~ PCTIUS95100911
-63-
g, 5.24 mmol) in POC13 (30 mL) is heated under reflux
with vigorous stirring for 18 h, and then concentrated
to dryness. The residue is partitioned between EtOAc
and saturated aqueous NaHCO, and the organic portion is
worked up to give 4-chlorooxazolo[5,4-g]quinazoline
(0.24g, 22%) as a yellow solid which is used directly.
4-(3-Bromoanilino)oxaz~~~rs 4-Q7~yinazo>;nP.
A mixture of 4-chlorooxazolo[5,4-g]quinazoline (0.24
g, 1.16 mmol) and 3-bromoaniline (0.25 mL, 2.33 mmol)
in a THF/propan-2-of mixture (1:1, 40 mL) containing a
trace of concentrated HC1 is heated under reflux for
min, then concentration to dryness under reduced
pressure. The residue is triturated with EtOAc, and
then partitioned between,saturated aqueous NaFiCO, and
15 EtOAc. Workup of the organic portion gives 4-(3-
bromoanilino)oxazolo[5,4-g]quinazoline (0.18 g, 33%)
as a yellow powder, mp (MeOH) 232 °C (dec.).
Example 6
4-l3-Bromoanilino)~m~~a~~i~ra 5-Q)myinaz~i~np
A mixture of 4-methylthio-6H-imidazo[4,5-
g]quinazoline (0.5 g, 1.6 mmol) [Leonard, N.J.;
Morrice, A.G.; Sprecker, M.~..; J. Org. Cheia., 1975,
40, 356-363], 3-bromoaniline (0.35 g, 2.0 mmol), and
3-bromoaniline hydrochloride (0.4 g, 1.9 mmol) in
isopropanol (200 mL) is heated under reflux for 1 h to
give a precipitate of 4-(3-bromoanilino)-6H-
imidazo[4,5-g]quinazoline hydrochloride (0.63 g, 72
%). 1H NMR (DMSO) d 9.93 (1H, brs), 9.01 (1H, s), 8.66
(2H, s), 8.39 (1H, s), 8.04 (2H, m), 7.39 (1H, t, J =
7.9 Hz), 7.31 (1H, brd, J = 8.0 Hz).

R'O 95/19970 PCR'IOS95/00911
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NH
N ~~ Br
N N
H
Example 7
d-l'i-Rrnmnanilinnltr;a~nln~4.5-Clauinazoline
hydrochloride
a_nXn-aH-triazolo(4 5-alauinazoline. A
solution of 6,7-diamino-4-oxo-3H-quinazoline (91 g,
5.7 mmol) [Leonard, N.J.; Morrice, A.G.; Sprecker,
M.A.; J. Org. Chem., 1975, 40 ,356-363] in 0.1 M HC1
(250 mL) is cooled to below 10 °C, and a solution of
NaNOx (0.41 g, 6 mmol) in water (10 mL) is added over 2
min. After 15 min the solution is neutralized with 0.1
M KOH solution to give a precipitate of 4-oxo-3H-
triazolo[4,5-g]quinazoline (1.01 g, 94 ic). 1H NMR
(DMSO) d 12.22 (2H, m), 8.76 (1H, s), 8.12 (1H, s),
8.07 (1H, s).
4-Thiono-3H-triazolot4.5-alQUinazoline. A
mixture of 4-oxo-3H-triazolo(4,5-g]quinazoline (0.56
g, 3 mmol) and P,SS (1.3 g, 6 mmol) in pyridine (20 mL)
is heated under reflux for 2 h, and the solvent is
removed under reduced pressure. The residue is treated
with boiling water (30 mL) to give a yellow solid
which is collected by filtration and dissolved in 0.1
M KOH solution. After filtration to remove insolubles,
the clear yellow solution is neutralized with dilute

~WO 95119970 _ ~ ~ ~ PCT/US95/00911
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HC1 to give 4-thiono-3H-triazolo[4,5-g]quinazoline
(0.26 g, 43 %). 1H NMR (DMSO) d 9.20 (1H, s), 8.15
(1H, s), 8.14 (1H, s).
Methvlthiotriazolof4.5-alguinazoline. A
solution of 4-thiono-3Ff-triazolo[4,5-g]quinazoline
(0.203 g, 1 mmol) and~KOH (0.15 g, 2.7 mmol) in 50 %
MeOH-HZO (15 mL) is treated with MeI (65 ~.L, 1.0 mmol)
and the mixture is stirred at room temperature
overnight. The MeOH is removed under vacuum and the
solution neutralized with dilute HC1 to give crude 4-
methylthiotriazolo[4,5-g)quinazoline (0.12 g, 55 %). 'H
NMR (DMSO) d 8.96 (1H, s), 8.79, (1H, s), 8.40 (1H,
s) , 2.74 (3H, s) .
4-(3-Bromoanilino)-triazolo(4.5-
crlauinazoline hydrochloride. A mixture of 4-
methylthiotriazolo[4,5-g]quinazoline (0.30~g, 1.38
mmol), 3-bromoaniline (2.1 mmol) and 3-bromoaniline
hydrochloride (2.1 mmol) in isopropanol (400 mL) is
heated under reflex for 6 h, and the solution is
concentrated to give 4-(3-bromoanilino)-triazolo[4,5-
g]quinazoline hydrochloride (0.33 g, 63 %). 1H NMR
(DMSO) d 12.01 (1H, brs), 9.86 (1H, s), 9.02 (1H, s),
8.63 (1H, s), 8.39 (1H, s),'8.13 (1H, dd, J = 1.9, 1.5
Hz), 7.85 (1H, ddd, J = 7.7, 1.9, 1.5 Hz), 7.56 (1H,
ddd, J = 8.0, 1.7, 1.5 Hz), 7.41 (1H t, J = 7.8 Hz).
Exa~gle S
4-(3-Bromoanilinol-8 N-methvlimidazolo(4.5-
alauinazoline
S.N-Methyl-3H-imidazo[4.5-d auinazolin-4-
thione. A mixture of of S,N-methyl-3H-imidazo[4,5-

R'O 95/19970 PCTIUS95100911
-66-
g]quinazolin-4-one (2.32 g, 11.1 mmol) [Lee, C.-H.;
Gilchrist, J.H.; Skibo, E.B.; J. Org. Chem., 1986, SI,
4784-4792] and Pass (3.96 g, 17.8 mmol) in pyridine (25
mL) is heated under reflex for ~6 h. The pyridine is
removed under vacuum, and the residue is treated with
boiling water (50 mL)..The precipitate iscollected,
washed with water, and_ dissolved in 0.1 M KOH. After
filtration to remove insolubles, the clear yellow
solution is acidified with AcOH to give 8,N-methyl-3H-
imidazo[4,5-g]quinazoline-4-thione (2.12 g, 88 %). 1H
NMR (DMSO) d 8.91 (1H, s), 8.53 (1H, s), 8.12 (1H, s),
7.91 (1H, s), 3.93 (3H,s).
B.N-Methvl-4-met~rlthioimidazof4.5
alouinazoline. MeI (0.61 ml, 9.5 mmol) is added to a
solution of 8,N-methyl-3H-imidazo[4,5-g]quinazoline-4-
thione(1.87 g, 8.65 mmol) and KOH (0.58 g, 10 mmol) in
100 ml 50 % MeOH-H=O, and the resulting mixture is
stirred at room temperature for 30 min. The
precipitated product is filtered off, and dried, to
give B,N-methyl-4-methylthioimidazo[4,5-g]quinazoline
(1.89 g, 82 %). iH NMR (DMSO) d 8.96 (1H, s), 8.64 (1H,
s), 8.39 (1H, s), 8.16 (1H, s), 3.98 (3H, s), 2.74
(3H, s) .
4-(3-Bromoanilino)-8,N-methvlimidazolof4.5-
alauinazoline. A mixture of" B,N-methyl-4-
methylthioimidazo(4,5-g]quinazoline (1.50 g, 6.5
mmol), 3-bromoaniline (1.7 g, 10 mmol), and 3-
bromoaniline hydrochloride (2.1 g, 10 mmol) in
isopropanol (400 mL) is heated under reflex for 4 h to
give a precipitate of the product hydrochloride, which
is treated with aqueous NH3 to give 4-(3-bromoanilino)-
8,N-methylimidazo[4,5-g]quinazoline (1.22 g, 52 %). =H

~VVO 95119970 ~ PCTIUS95100911
-67-
NMR (DMSO) d 9.86 (1H, s), 9.02 (1H, s), 8.63 (1H,
s), 8.54 (1H, s), 8.37 (1H, s), 8.01 (2H, m), 7.36
(1H, t, J = 8.0 Hz), 7.28 (1H, brd), 3.96 (3H, s).
NH
Example 9 _
4-(3-Bromoanilino)-6.N-methvlimidazolof4.5-
alauinazoline
2.4-Dinitro-5-methvlaminobenzamide. A
solution of 5-chloro-2,4-dinitrobenzamide (6.14 g, 25
mmol) IGoldstein, H.; Stamm, R.; Helv. Chim. Actor,
1952, 35, 1330-1333] and 40% aqueous methylamine (20
mL) in ethanol (80 mL) is heated in a sealed pressure
vessel at 100 °C for 2 h. After cooling, dilution with
water gives 2,4-dinitro-5-methylaminobenzamide (5.89
g, 98 ~). 1H NMR (DMSO) d 8.88 (1H, q, J = 4.9 Hz),
8.76 (1H, s), 8.07 (1H, brs~, 7.77 (1H, brs), 6.98
(lH,s ), 3.07 (3H, d, J = 5.0 Hz)
6.N-methyl-3H-imidazol4.5-alauinazolin-4-
Qne. A suspension of 2,4-dinitro-5-
methylaminobenzamide(4.80 g, 20 mmol) in ethanol and
formic acid (2.5 mL, 66 mmol) is hydrogenated over 5k
Pd/C, and the solvent is removed under reduced
pressure. The resulting crude salt is dissolved in
formic acid (100 mL) and the mixture is heated under

W 0 95/19970 PCT/US95/00911
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reflux for 2 h. The formic acid is removed under
reduced pressure, and the residue is dissolved in the
minimum volume of 0.1 M HC1. After clarification with
charcoal and filtration through celite, the aqueous
solution is neutralized with dilute aqueous NHS , and
allowed to stand overnight, to give 6,N-methyl-3H-
imidazo[4,5-g]quinazolin-4-one (2.99 g, 75 %). 1H NMR
(DMSO) d 11.91 (12H, brs), 8.50 (iH, s), 8.33 (1H, s),
8.00 (1H, s), 7.89 (1H, s), 3.95 (3H, s).
6 N-Methyl-3H-imidazol4 5-alcuinazolin-4-
thione. A mixture of 6,N-methyl-3H-imidazo[4,5-
g]quinazolin-4-one (2.50 g, 12.5 mmol) and PzSs (5.55
g, 25 mmol) in pyridine (30 mL) is heated under reflux
for 16 h, and the pyridine is removed under reduced
pressure. The residue is treated with boiling water
(50 mL), and the resulting yellow precipitate is
collected by filtration and dissolved in 0.1 M KOH
solution. After filtration to remove insolubles, the
solution is neutralized with NH, C1 to give 6,N-methyl-
3H-imidazo[4,5-g]quinazolin-4-thione (1.58 g, 59 %). 1H
NMR (DMSO) d 13.65 (1H, brs), 8.76 (1H, s), 8.61 (1H,
s), 8.11 (1H, s), 7.98 (1H, s), 3.99 (3H, s).
6.N-Methyl-4-methVlthioimidazo(4.5-
alauinazoline. A solution of 6,N-methyl-3H-
imidazo[4,5-g]quinazolin-4-thione (1.08 g, 5 mmol) and
KOH (0.40 g, 7 mmol) in 50 % aqueous MeOH (100 mL) is
treated with MeI (0.33 mL, 5.3 mmol) and the resulting
mixture is stirred at room temperature for 1 h. The
methanol is then removed under reduced pressure, and
the residual aqueous solution is kept at 5 °C
overnight to give crystals of 6,N-methyl-4-
methylthioimidazo[4,5-g]quinazoline (0.62 g, 54 %). 1H

~WO 95119970 PCT/US95100911
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NMR (DMSO) d 8.93 (1H, s), 8.67 (1H, s), 8.22 (1H, s),
8.21 (1H, s), 4.01 (3H, s), 2.74 (3H, s).
4-(3-Bromoanilino)-6 N-methvlimidazo(4,5-
c~~,;na~nline hvdroch~oride A mixture of 6,N-methyl-
-4-methylthioimidazo[4,5-g]quinazoline (0.3 g, 1.3
mmol), 3-bromoaniline (0.34 g, 1.95 mmol), and 3-
bromoaniline hydrochloride (0.41 g, 1.95 mmol) in
isopropanol (400 mL) is heated under reflex for 6 h.
After cooling the precipitated solid is collected by
filtration and recrystallized from EtOH to give 4-(3-
bromoanilino)-6,N-methylimidazo[4,5-g]quinazoline
hydrochloride (0.43 g, 85 %). 1H NMR (DMSO) d 11.66 1H,
brs), 9.43 (1H, s), 8.96 (1H, s), 8.80 (1H, s), 8.19
(1H, e), 8.16 (1H, brs), 7.89 (1H, brd, J = 7.1 Hz),
7.54-7.43 (2H, m), 4.05 (3H, s).
Example 10 ___ _ _ _
4 (3-Bromoanilino)pvrazinof2 3-glauinazoline
7-Acetamido-6-vitro-3H-auinazol;n-4-one. A
solution of 7-amino-6-vitro-3H-quinazolin-4-one (5.90
g, 28.6 mmol) [Leonard, N.J.; Morrice, A.G.; Sprecker,
M.A.; J. Org. Chem., 1975, 40, 356-363] in a mixture
of glacial acetic acid (300 mL) and acetic anhydride
(100 mL) is heated under reflex for 6 h, and water
(100 mL) is added.-The solution is then concentrated
to a small- volume to give 7-acetamido-6-vitro-3H-
quinazolin-4-one (5.37 g, 76 %). 1H NMR (DMSO) d 10.51
(1H, brs), 8.57 (IH, s), 8.24 (1H, s), 7.97 (1H, s),
2.15 -(3H, s) .
_7-Acetamido-4-(3-bromoanilino)-6-
";r,-oau;nazoline. A solution of 7-acetamido-6-nitro-
SUBSTITUTE SHEET (RULE 26)

WO 95119970 PC1YUS95100911
_70_
3H-quinazolin-4-one (5.00 g, 20 mmol) in POC13 (250 mL)
is heated under reflux for 2 h, the excess of POC1; is
removed under vacuum, and the residue is dissolved in
CHzCh and washed with aqueous Na2C03 solution. Workup
gives the crude 4-chloro derivative, which is coupled
directly with 3-bromoaniline in isopropanol as above,
and the resulting hydrochloride is converted directly
to the free base, by treatment with aqueous NH3, to
give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline
(3.60 g, 45 %). 1H NMR (DMSO) d 10.56 (1H, s), 10.29
(1H, s), 9.34-(1H, s), 8.70 (1H, s), 8.19 (1H, brs),
7.97 (1H, s), T.88 (1H, d, J = 6.0 Hz), 7.43-7.35 (2H,
m), 2.13 (3H, s).
7-Amino-4-(3-bromoanilino)-6-
nitroouinazoline. A solution of 7-acetamido-4-(3-
bromoanilino)-6-nitroquinazoline (1.50 g, 3.73 mmol)
and KOH (2 g) in MeOH (190 mL) and HBO (10 mL) is
heated under reflux for 30 min, and the solvent volume
is reduced to give 7-amino-4-(3-bromoanilino)-6-
nitroquinazoline (1.17 g, 87 %). 1H NMR (DMSO) d 10.17
(1H, brs), 9.43 (1H, s), 8.43 (1H, s), 8.15 (lH,m
brs), 7.86 (1H, d, J = 7.1 Hz), 7.42 (2H, brs), 7.40-
7.31 (2H, m), 7.12 (1H, s).
4-(3-Bromoanilino)-6.7-diaminoauinazoline.
Iron dust reduction of 7-amino-4-(3-bromoanilino)-6-
nitroquinazoline (0.5 g, 1.4 mmol) in 65 % aqueous
EtOH containing sufficient aqueous HC1 to ensure
solubility gives 4-(3-bromoanilino)-6,7-
diaminoquinazoline (0.30 g, 65 %). 1H NMR (DMSO) d 9.14
(1H, s), 8.27 (1H, s), 8.23 (1H, brs), 7.85 (1H, d, J
= 8.0 Hz), 7.31-7.14 (2H, in), 7.29 (1H, s), 6.79 (1H,
s), 5.73 (2H, brs), 5.13 (2H, brs).
SUBSTITUTE SHEET (RULE 26)

-WO 95119970 ~ PCT/U595/00911
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4-(3-Bromoanilino)pvrazinof2,3-
cxlauinazoline. A mixture of 4-(3-bromoanilino)-6,,7-
diaminoquinazoline (90 mg, 0.27 mmol) and 1,4-dioxane-
2,3-diol (0.2 g, 1.6 mmol) [Venuti, M.C.; Synthesis,
1982, 61-63] in MeOH (20 mL) is stirred at room
temperature overnight to give a precipitate of 4-(3-
bromoanilino)pyrazino[2,3-g]quinazoline (80 mg, 83 %).
1H NMR (DMSO) d 10.45 (1H, brs), 9.52 (1H, s), 9.09
(1H, d, J = 1.6 Hz), 9.06 (1H, d, J = 1.6 Hz), 8.71
(1H, s), 8.44 (1H, s), 8.32 (1H, brs), 7.99 (1H, m),
7.45-7.34 (2H, m).
NH
N
Exa~ggle 11
4-(3-Bromoanilino)imidazolof4.5-h)guinazoline
hydrochloride
6-Methvlthioimidazof4,5-hlauinazoline. A
solution of 3H-imidazo[4,5-h]quinazoline-4-thione
(0.41 g, 2 mmol) [Morrice, A.G.; Sprecker, M.A.;
Leonard, N.J.; J. Org. Chem., 1975, 40, 363-366] and
KOH (0.15 g, 27 mmol) in 50 % MeOH-H20 (50 mL) is
treated with MeI (0.13 mL) and the mixture is stirred
at room temperature for 3 h to give a precipitate of
4-methylthioimidazo[4,5-h]quinazoline (0.35 g, 80 %).
1H NMR (DMSO) d 13.80 (1H, brs), 9.09 (1H, s), 8.49
(1H, s), 7.98 (1H, d, J = 8.8 HzH), 7.85 (1H, d, J =
8.8 Hz), 2.72 (3H, s).
SUBSTITUTE SHEET (RULE 26)

W0 95119970 PCTIUS95100911
-72-
4-!3-Bromoanilino)imidazolof4,5-
hlauinazoline.. A mixture of 4-methylthioimidazo[4,5-
h]quinazoline (0.216 g, 1 mmol), 3-bromoaniline (0.25
g, 1.5 mmol), and 3-bromoaniline hydrochloride (0.31
g, 1.5 mmol) in N-methylpyrrolidone (50 mL) is heated
120 °C for 2 h. The solvent is removed under vacuum
and the residue is triturated with EtOH to give a
solid which is recrystallized from MeOH to give 4-(3-
bromoanilino)imidazo[4,5-h]quinazoline hydrochloride
(0.23 g, 61 %).. 1H NMR (DMSO) d 11.11 (1H, brs), 8.93
(2H, s), 8.66 (1H, d, J = 9.0 Hz), 8.11 (1H, brs),
8.07 (1H, d, J = 9.0 Hz), 7.83 (1H, brd, J = 6.8 Hz),
7.50-7.40 (2H,m).
Example 12
4-(3-Bromoanilino)imidazolof4.5-flauinazoline
4-Methvlthioimidazof4,5-flguinazoline. A
solution of 3H-imidazo[4,5-f]quinazoline-4-thione
(1.01 g, 5 mmol) [Morrice, A.G.; Sprecker, M.A.;
Leonard, N.J.; J. Org. Chem., 1975, 40, 363-366] and
KOH (0.36 g, 6.5 mmol) in 50 % MeOH-H20 (50 mL) is
treated with MeI (0.34 mL) and the mixture is stirred
overnight at room temperature. The MeOH is removed
under vacuum to give a precipitate of .4-
methylthioimidazo[4,5-f]quinazoline (0.61 g, 57 %). 'H
NMR (DMSO) b 13.23 (1H, m), 9.05 (1H, s), 8.60 (1H,
s), 8.24 (1H, d, J = 8.7 Hz), 7.81 (1H, d, J = 8.9
Hz), 2.71 (3H, S).
4-(3-bromoanilino)imidazof4,5-flauinazoline.
A solution of 4-methylthioimidazo[4,5-f]quinazoline
(0.43 g, 2 mmol), 3-bromoaniline (0.5 g, 3 mmol), and
3-bromoaniline hydrochloride (0.63 g, 3 mmol) is
SUBSTITUTE SHEET (RULE 26)

'rV0 95/19970 ~ PCTI0595/00911
-73-
heated under-reflux for 16 h. The precipitate of
hydrochloride salt is converted directly to the free
base with aqueous NH3, and recrystallized from EtOH to
give 4-(3-bromoanilino)imidazo[4,5-f]quinazoline (0.52
g, 77%). 1H NMR (DMSO) d 11.53 (1H, brs), 8.79 (1H,
s), 8.68 (1H, s), 8.53 (1H, dd, J = 1.8, 1.9 Hz),
8.15 (1H, d, J = 8.8 Hz), 7.81 (1H, brd, J = 8.6 Hz),
7.71 (1H, d, J = 8.9 Hz; 1 H), 7.41 (1H, t, J = 8.0
Hz), 7.32 (1H, brd, J = 7.8 Hz).
Example 13
4-Benzvlaminobenzothieno[3.2-d7pyrimidine
4-Chlorobenzothieno[3,2-d)pyrimidine (111
mg, 0.5 mmol), (aee following experimental) and
benzylamine (114 mg, 1.0 mmol) (111 mg, 1.1 mmol) in
stirred 2-propanol (2 mL) are heated at reflux under Nz
for 26 h. The mixture is allowed to cool, and the
precipitate is collected by Buchner filtration, rinsed
with 2-propanol and water and dried in an oven to give
4-benzylaminobenzothieno[3,2-d]pyrimidine (100 mg,
68%) as a white powder. 1H NMR (DMSO) d 8.60 (1H, s),
8.51 (1H, t, J = 5.9 Hz), 8.31 (1H, ddd, J = 0.7,
1.4, 8.0 Hz), 8.17 (1H, ddd, J = 0.7, 1.8, 8.1 Hz),
7.68 (1H, ddd, J = 1.2, 7.0, 8.1 Hz), 7.59 (1H, ddd, J
= 1., 7.0, 8.1 Hz), 7.36 (2H, d, J = 7.4 Hz), 7.33
(2H, t,-J = 7.3 Hz), 7.24 (1H, t, J = 7.2 Hz), 4.79
(2H, d, J = 6.0 Hz).
Example 14
4-([R1-1-Phenylethvlamino)benzothieno[3.2-dlgvrimidine
~)~ 3-aminobenzothiophene-2-carboxvlate.
2-Fluorobenzonitrile (0.61 g, 5 mmol), ethyl
SUBSTITUTE SHEET (RULE 26)

W0 95/19970 PCT/US95I00911
-74-
thioglycollate (0.60 g, 5 mmol) and NEt3 (1.52 g, 15
mmol) are stirred in DMSO (5 mL) at 100°C under Nz for
3 h. The reaction mixture is poured onto ice-water
(50 mL), and the solid is collected by suction
filtration, rinsed with water, and air dried to give
ethyl 3-aminobenzothiophene-2-carboxylate (0.78 g,
70%) as a grey-brown solid. 1H NMR (DMSO) d 8.14- (1H,
d, J = 7.7 Hz), 7.88 (1H, d, J = 8.1 Hz), 7.50 (IH,
dt, Jd = 1.2 Hz, Jt = 7.5 Hz), 7.39 (1H, dt, Ja = 1.2
Hz, Jt = 7.6 Hz), 7.17 (2H, brs), 4.26 (2H, q, J = 7.1
Hz), 1.29 (3H; t, J = 7.1 Hz).
Benzothienof3.2-dl-3H-pyrimid-4-one: Ethyl
3-aminobenzothiophene-2-carboxylate (764 mg, 3.45
mmol) is heated in formamide (2 mL) under NZ at 140°C
for 2 h, and at 180°C for 20 h. The solution is
allowed to cool to 25°C, and the slurry is diluted
with EtOH (5 mL). The solid is collected by suction
filtration, rinsed with EtOH (2x5 mL), and air dried
to give benzothieno[3,2-d]-3H-pyrimid-4-one (0.55 g,
79%) as a highly crystalline dark brown solid. 1H NMR
(DMSO) d 12.85 (1H, brs), 8.35 (lH,s), 8.16 (1H, d J =
7.3 Hz), 7.67 (1H, dt, Jd = 1.6 Hz, J~ = 7.5 Hz), 7.59
(1H, dt, Jd = 1.2 Hz, Jt = 7.5 Hz,).
4-Chlorobenzothienof3.2-dlpvrimidine. DMF
(0.27 g, 3.5 mmol) is added dropwise to a solution of
oxalyl chloride (0.44 g, 3.5 mmol) in 1,2-
dichloroethane (10 mL), stirred under N2 at 25°C. When
the vigorous gas evolution ceases, benzothieno[3,2-d]- ,
3H-pyrimid-4-one (337 mg, 1.53 mmol) is added and the
reaction mixture is heated to reflux. After 20 min, _
the reaction mixture is allowed to cool, and is then
.quenched with saturated aqueous NaHC03 solution (20
SUBSTfTUTE SHEET (RULE 26)

~'V0 95/19970 ~ PCTIUS95700911
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mL). The phases are separated, and the aqueous phase
is extracted with CHC13 (3 x 10- mL). The combined
. organic phases are washed with water (2 x10 mL),
saturated brine (10 mL), and dried iNazS04). The
solvent is removed under reduced pressure to give 4-
chlorobenzothieno[3,2-d]pyrimidine (249 mg, 74%) as a
light brown solid. iH NMR (CDC13 ) d 9.09 (1H, s),
8.53 (1H, dd, J = 1.8, 7.6 Hz), 7.95 (1H, d, J = 7.8
Hz), 7.73 (1H, dt, Jd = 1.4 Hz, Jt = 7.7 Hz), 7.62 (1H,
dt, Jd = 1.2 Hz, Jt = 7.5 Hz).
4-(fR1-1-Phenvlethylamino)benzothieno(3,2-
dlpvrimidine 4-Chlorobenzothieno[3,2-d]pyrimidine
(110.1 mg, 0.5 mmol), [R]-1-phenylethylamine (74 mg,
0.6 mmol) and NEt3 (111 mg, 1.1 mmol) in stirred
propanol (2 mL) are heated at reflux under N2 for 9 h.
The mixture is allowed to cool, and is then purified
by preparative tlc on silica, eluting once with 2%
MeOH in CHC13. The yellow solid is recrystallized from
EtOH at 0'C to give 4-([R]-1-phenylethylamino)benzo-
thieno[3,2-d]pyrimidine, (75 mg, 49%) as pale yellow
cubic crystals. 1H NMR (DMSO) d 8.53(1H, s), 8.30(1H,
d, J = 7.2 Hz), 8.15 (1H, d, J = 8.2 Hz), 7.68 (1H,
dt, Jd =1.2 Hz, Jt = 7.5Hz), 7.58 (1H, dt, Jd =1 Hz, JC
= 7.5Hz)-, 7.44 (1H, dd, J = 1, 8 Hz), 7.31 (2H, t, J =
7.7 Hz), 7.21 (1 H, tt, J = 1, 7.7 Hz), 5.58( 1H, q, J
= 7 Hz), 1.58 (3H, d, J = 7 Hz).
Example 15
. 4-(3-Bromoanilino)benzothieno[3,2-dlpvrimidine
4-Chlorobenzothieno[3,2-d]pyrimidine (110.1
mg, 0.5 mmol), (see preceding example) 3- bromoaniline
(107.2 mg, 0.62 mmol) and NEt3 (102.8 mg, 1.0 mmol) in
SUBSTITUTE SHEET (RULE 26)

WO 95119970 PCT/US95f00911
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stirred ethoxyethanol-(2 mL) are heated at 110°C under ,
Na for 18 h. The solvent is removed under reduced
pressure, and the dark oily residue is purified by
preparative layer chromatography, eluting once with 2%
MeOH in CHCL3. - The major band Rf 0.40 is extracted to
give a yellowish solid (147 mg) which is
recrystallized_from EtOH (20 mL) to give 4-(3-
bromoanilino)benzothieno[3,2-d]pyrimidine (70 mg, 39%)
as pale beige glistening plates. 1H NMR (CDC13 ) d
8.88(1H, s), 8.49(1H, dd; J = 1.7, 7.1 Hz), 7.96 (1H,
t, J = 1.9 Hz), 7.89 (1H, dd, J = 1.6, 7.0 Hz), (1H,
d, J = 7.8 Hz), 7.65 (1H, dt, Jd = 1.5 Hz, Jt = 7 Hz),
7.60 (1H, dd, J = 1.5, 7.5 Hz), 7.57 (1H, dt, Jd = 1.5
Hz, Jt = 7 Hz), 7.40 (1H, dt, Jd = 1.7 Hz, Jt = 8
Hz),7.28 (1H, t, J = 7.8 Hz), 6.90 (1H, brs).
NH
0
N
Example 16 _
4-(3-Bromoanilino)-8-nitrobenzofbtthieno(3,2-
r,~jpvrimidine
2-Fluoro-S-nitrobenzonitrile. A mixture of-
70% nitric acid and concentrated sulfuric acid (1:1,
mL) is added dropwise over 30 min to a solution of
2-fluorobenzonitrile (12.11 g, 0.10 mol) in
concentrated sulfuric acid (50 mL), stirred under Nz at
0°C. After a further 3h at 0°C the yellow solution is
25 poured onto ice (400 g), and the solid is collected by
SUBSTITUTE SHEET (RULE 26)

~O 95119970 ~ ~ ~ ~ ~ 9 ~ PCT/ITS951D0911
_77_
Buchner filtration, rinsed with water (4 x 50 mL), and
dried in vacuo to give 2-fluoro-5-nitrobenzonitrile
(15.43 g, 93%) as a pale yellow crystalline solid. 1H
NMR (CDC13 ) d 8.56 (1H, dd, J = 2.8, 5.5 Hz), 8.51
(1H, ddd, J = 2.8, 4.4, 9.I Hz~, 7.44 (1H, dd, J =
7.8, 9.0 Hz).
F~hvl 3-amino-5-nitrobenzothiorJhene-2-
carboxvlate. 2-Fluoro-5-nitrobenzonitrile (1.664 g,
mmol), ethyl thioglycollate (1.21 g; 10 mmol) and
10 NEt3 (3.06 g, 30 mmol) are stirred in DMSO (5 mL) at
100°C under N2 for h h. The deep orange-red reaction
mixture is poured onto ice-water (50 mL), and the
solid is collected by suction filtration, rinsed with
water, and dried in a vacuum oven at 60°C to give
ethyl 3-amino-5-nitrobenzothiophene-2-carboxylate
(2.675 g, 100%) as a bright orange solid. 1H NMR (DMSO)
d 9.23 (1H, d, J = 2.1 Hz), 8.28 (1H, dd, J = 2.3, 8.9
Hz), 8.10 (1H, d, J = 9.0 Hz). 7.45 (2H, brs), 4.29
(2H, q, J = 7.1 Hz), 1.30 (3H, t, J = 7.1 Hz).
8-Nitrobenzofblthienof3 2-dl-3H-pyrimid-4-
one. Ethyl 3-amino-5-benzothiophene-2-carboxylate
(2.66 g, 10 mmol) is heated in formamide (10 mL) under
NZ at 190°C for 4 h, and precipitates after 2 h. The
solution is allowed to cool to 25°C, and the solid is
collected by suction filtration, rinsed with EtOH (2x5
mL), and dried in a vacuum oven at 60°C to give 8-
nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one (1.91 g,
. 77,%) as a highly crystalline orange-brown solid. 1H
NMR (DMSO) d 13.00 (1H, brs), 8.85 (lH,s), 8.45 (3H,
s) .
SUBSTITUTE SHEET (RULE 26)

WO 95119970 PCT/US95100911 1
-78-
4-Chloro-8-nitrobenzo[b)thieno[3,2-
dlpvrimidine. DMF (Q.75 g, 10.3 mmol) is added
dropwise to a solution of oxalyl chloride (1.27 g, 1D .
mmol) in 1,2-dichloroethane (25 mL), stirred under Na
at 25°C. -When the vigorous gas evolution ceases, 8-
nitrobenzo[b]thieno[3,2-d]-3H-pyrimid-4-one (1.236 g,
5 mmol) is added and the reaction mixture is heated to
reflex. After 40 min, the hot reaction mixture is
celite filtered, and-then recrystallized at 0°C to
give 4-chloro-8-nitrobenzothieno[3,2-d]pyrimidine
(759 mg, 57%) as a light brown solid. 1H NMR (DMSO)
d 9.24 (1H, s), 8.99 (1H, d, J = 2.0 Hz), 8.57, 8.53
(1H, 1H, ABq of d, J~ = 9.0 Hz, Jd = 2, 0 Hz).
4-(3-Bromoanilino)-8-nitrobenzofblthieno-
[3.2-d7p3rrimidine. 4-Chloro-8-nitrobenzo[b]thieno-
[3,2-d]pyrimidine (266 mg, 1.0 mmol), 3- bromoaniline
(187.4 mg, 1.1 mmol) and NEt3 (200 mg, 2.0 mmol) in
stirred 1-propanol (4 mL) are heated at 110°C under N~
for 48 h, becoming a thick yellow paste.- The mixture
is cooled to 0°C, and the solid is collected by
Buchner filtration, and air-dried to give 4-(3-bromo-
anilino)-8-nitrobenzo[b]thieno[3,2-d]pyrimidine (275
mg, 69%) as a bright yellow solid. 1H NMR (DMSO) d
10.12 (1H, bra), 9.03 (1H, s), 8.88(1H, d, J = 1.8
Hz), 8.54, 8.52 (1H, 1H, ABq of d, J~ = 7.5 Hz, Jd =
0, 1.8 Hz), 8.18 (1H, d, J = 1.7 Hz), 7.83 (1H, dd, J
= 1.5, 7.7 Hz), 7.37, 7.34 (1H, 1H, ABq of d, J~ _
7.7 Hz, Jd = 7.7, 1.5 Hz).
SUBSTITUTE SHEET (RULE 26)

2177:592
-WO 95119970 PCT/CTS95I00911
_79_
Hxamnle 17
8-Amino-4-(3-bromoanilino)benzofblthienof3,2-dlpyrimi-
dine
4-(3-Bromoanilino)-8-nitrobenzoLb]thieno-
[3,2-d]pyrimidine (97 mg, 0.24 mmol) (see previous
experimental) in THF (75 mL) is hydrogenated at 52 psi
for 3 h, in the presence of Raney nickel (5 mg). The
reaction mixture is filtered, and the filtrate is
concentrated to small volume under reduced pressure,
and the residue is purified by preparative thin layer
chromatography on silica, eluting with 5% MeOH in
CHC13. The band Rf 0.28 is extracted to give 8-amino-
4-(3-bromoanilino)benzoLb]thieno[3,2-d]pyrimidine
(47.2 mg, 53%) as a yellow solid. 1H NNfft (DMSO) d
9.66 (1H, bra), 8.72 (1H, s), 8.18 (1H, t, J = 1.9
Hz), 7.84 (1H, ddd, J = 1.2, 2.0, 8.1 Hz), 7.78 (1H,
d, J = 8.5 Hz), 7.50 (1H, d, J = 2.2 Hz), 7.33 (1H, t,
J = 8.1 Hz), 7.27 (1H, ddd, J = 1.2, 1.8, 8.0 Hz),
7.02 (1H, dd, J = 2.3, 8.5 Hz), 5.47 (2H, bra).
NH
N OoOJ
Hxample 18
4-(3-Bromoanilino)-9-methoxvbenzofblthienof3,2-dlpvri-
midine hydrochloride. .
2-Fluoro-6-methox,~rbenzaldoxime. NH20HHC1
(334 mg, 4.76 mmol) is added in portions to a solution
SUBSTITUTE SHEET (RULE 26)

WO 95!19970 PCTIUS95100911
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of NaHC03 (395 mg, 4.7 mmol) in water (lDmL) at r.t. To
this solution was added dropwise a mixture of 2-
fluoro-6-methoxybenzaldehyde (made from 3-fluoroani-
sole as described in Tetrahedron Lett. 1992, 33, 7499)
(725 mg, 4.7 mmol) and EtOH (10 mL). The resulting
mixture is stirred at r.t for 2hr. The precipitate is
collected by filtration and dried in a vacuum oven at
-50C overnight to give 2-fluoro-6-methoxybenzaldoxime
(720 mg, 89%). 1H NMR (DMSO) d 11.44, (1H, s), 8.16
(1H, s), 7.40, (1H, m) 6.85-.6.95 (2H, m),3.84 (3H, s).
-6-methoxvbenzonitrile. A solution
of 2-fluoro-6-methoxybenzaldoxime (714 mg, 4.2 mmol)
in Ac20 (3.6 mL) is heated at reflux for 4 hr.-The
reaction is cooled to r.t. and the volatiles are
stripped off to give a beige solid, which is dried at
50 °C in a vacuum oven to give 2-fluoro-6-methoxy-
benzonitrile (635 mg, 84%). 1H NMR (DMSO) d 7.8-7.7
(1H, m), 7.14-7.07 (2H, m),3.95 (3H, s).
Methyl 3-amino-4-methoxvbenzothio~hene-2-
carboxvlate. Methyl thioglycollate (0.18 mL, 1.9
mmol) is added dropwise to a suspension of NaH (60%
oil suspension, 176 mg, 4.4 mmol) in DMSO (5 mL),
stirred under Nz at 25 °C. When gas evolution ceases,
2-fluoro-6-methoxybenzonitrile (266 mg, 1.76 mmol)
inDMSO 5 mL is added in one portion. After 3 h, the
reaction mixture is poured onto ice-water, and the
beige precipitate is collected by suction filtration,
rinsed and air dried to give methyl 3-amino-4-
methoxybenzothiophene-2-carboxylate (345 mg, 83%).1H
NMR (DMSO) d 7.44-7.37 (2H, m), 7.00, (2H brs), 6.90
(1H, d, J = 7.7Hz), 3.95 (3H, s), 3.76 (3H, s).
SUBSTITUTE SHEET (RULE 26)

~WO 95119970 PCT/US95/00911
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9-Methoxv-4-oxo-3H-benzothieno[3,2-
dlpvrimidine. A mixture of methyl 3-amino-4-
methoxybenzothiophene-2-carboxylate (202mg, O.S5mmo1)
and formamide (2mL) is heated at 135C for lhr and the
temperature is raised to 190C. After 8hr the reaction
is cooled to r.t. Upon cooling, black solid forms and
is collected by filtration. The precipitate is air
dried to give 9-methoxy-4-oxo-3H-benzothieno[3,2-
d]pyrimidine (45 mg, 22.5%). 1H NMR (DMSO) d 12.0 (1H,
bra), 8.31 (1H, s)7.70-7.55 (2H, m), 7.10 (1H, d, J =
7.7 Hz), 3.97 (3H, s).
4-Chloro-9-methoxvlaenzothieno(3.2-
dlpvrimidine. DMF (0.125 mL, 1.7 mmol) is added
dropwise to a solution of (COC1)2 (0.15 mL, 1.68 mmol)
in 1,2-dichloroethane (4.5 mL) at r.t. After gas
evolution ceases, 9-methoxy-4-oxo-3H-benzothieno[3,2-
d]pyrimidine (73.2 mg, 0.32 mmol) is added. The
resulting mixture is heated at reflux for 4hr. After
the reaction is cooled to r.t., the black tar is
filtered off. The filtrate is stripped to dryness and
then mixed with water. A yellow solid forms and is
collected via filtration. The solid-is washed with
water and air dried to give 4-chloro-9-
methoxybenzothieno[3,2-d]pyrimidine (53 mg, 66%). 1H
NMR (DM50) d 9.17 (1H, s), 7.82-7.78 (2H, m), 7.3-7.2
(1H, m), 4.06 (3H, s).
4-(3-bromoanilino)-9-methoxvbenzofb7thieno-
(3.2-dlpvrimidine hydrochloride. A-mixture of 4-
chloro-9-methoxybenzothieno[3,2-d]pyrimidine (53 mg,
0.21 mmol), 2-methoxyethanol (3 mL) and m-bromoaniline
(0.03 mL, 0.28 mmol) is heated at 80C for 1 h. The
'reaction is cooled to r.t. and yellow solid
SUBSTITUTE SHEET (RULE 26)

WO 95119970 PCT/US95I0091 I
-82-
precipitates. The solid is collected by filtration and ,
dried in a vacuum oven at -50C overnight to give 4-(3-
bromoanilino)-9-methoxybenzo[b]thieno[3,2-d]pyrimidine
hydrochloride (60 mg, 68%). 1H NMR (DMSO) d 11.14
(1H, brs); 8.95 (1H, s),-8.07 (1H, J = l.7Hz), 7.87
d,
(1H, d, = 8.2 Hz),7.80(1H, d, -J 8.2 Hz), 7.76
J =
(1H, d, = 7.5 Hz),7.49(1H, d, J 8.2 Hz), 7.44
J =
(1H, t, = 8.0 Hz),7.25(1H, d, J 8.0 Hz), 4.10
J =
(3H, s)
.
Example 19
4-(3-Bromoanilino)thiazolof4'.5': 4.5]thienof3.2-
dlnvrimidine
A mixture of 5=chlorothiazolo[4',5';4,5]-
thieno[3,2-d]pyrimidine (prepared as described by
Athmani and Iddon, Tetrahedron , 48, 7689, 1992)(66
mg, 0.29 mmol), 3-bromoaniline (0.033 mL, 0.3 mmol)
and 2-methoxyethanol (3 mL) is heated at 95C for 2.5 h
and then cooled to room temperature. The reaction ie
added to water, and the precipitate is collected by
Buchner filtration and purified by preparative tlc on
silica (2% MeOH/CHCl,). The major band is extracted
with 20% MeOH/CHC13. After removal of the solvent under
reduced pressure 4-(3-bromoanilino)thiazolo[4',5';
4,5]thieno[3,2-d]pyrimidine (25 mg, 23%) ie obtained.
'H NMR (DMSO) d 9.98 (1H, s), 9.67 (1H, s), 8.75
(lH,s), 8.17 (1H, s), 7.82 (1H, d, J = 7.8 Hz), 7.38-
7.31 (2H, m).
SUBSTITUTE SHEET (RULE 26)

~
WO 95119970 PCT/US95100911
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NH
~~N Br
J
N
Example 20
4-(3-Chloroanilino)~yridof3'.2':4.SlthiPnof3 2-
dlovrimidine
Ethyl 3-aminoovridof3 2-blthio~hene-2-
5 carboxylate. A solution of 2-chloro-3-cyanopyridine (
0.14 g, 1.0 mmol) in DMSO (2 mL) is added dropwise to
a mixture of ethyl thioglycolate (0.12 mL, 1.1 mmol),
NaH (0.06 g, 1.5 mmol) and DMSO ( 1 mL) stirred under
N= at 25°C. After 3 h the reaction is worked up by
pouring the reaction mixture onto stirred ice water.
The light yellow precipitate is collected by Buchner
filtration and dried in a vacuum oven to give ethyl 3-
aminopyrido[3,2-b]thiophene-2-carboxylate (197 mg,
89k). 'H NMR (DMSO) d 8.68 (1H, dd, J = 4.6, 1.6 Hz),
8.54 (1H, dd. J = 8.2, 1.6 Hz), 7.46 (1H, dd, J = 8.2,
4.5 Hz), 7.31 (2H, brs), 4.~ (2H, q, J = 7.1 Hz), 1.29
(3H, t, J = 7.1 Hz).
~H-Pvridof3'.2'; 4.Slthienof3.2-dlpvrimid-4-
one. A mixture of ethyl 3-aminopyrido(3,2-
b]thiophene-2-carboxylate (0.92 g, 4.14 mmol) and
formamide (10 mL) is heated at 135C for 1 h and then
at 190C for 4 h. The reaction mixture is cooled to
25°C producing a precipitate. The solid is collected
by vacuum filtration and is washed with water and

WO 95119970 PCTIUS95100911
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dried in a vacuum oven at 60°C to give 3H- ,
pyrido[3',2'; 4,5]thieno[3,2-d]pyrimid-4-one (0.61 g,
72.6%) as yellow-brown needles. iH NMR (DMSO) d 13.0
(iH, bra), 8.86 (1H, dd, J = 4.6, 1.6 Hz}, 8.63 (1H,
dd, J = 8.0, 1.6 Hz), 8.4 (1H, s), 7.68 (1H, dd, J =
8.1, 4.6 Hz).
4-ChloroDVridof3' 2'' 4 5lthieno(3 2-
dlDVrimidine. To a solution of (COC1)z (1.3 mL,lS
mmol) in 1,2-dichloroethane (75 mL) DMF (1.1 mL, 15
mmol) is added dropwise and stirred under N, at 25°C.
After gas evolution ceases, 3H-pyrido[3',2';
4,5]thieno[3,2-d]pyrimid-4-one (0.61 g, 3.0 mmol) is
added to the mixture and the temperature is raised to
SSC. After 2 h, the reaction mixture is cooled to 25°C
and extracted with CHC13. The combined extracts are
washed with water, saturated brine and dried (MgSO').
The solvent is removed in vacuo to give 4-
chloropyrido[3',2'; 4,5]thieno[3,2-d]pyrimidine
(0.64g, 96%) as a yellow solid. 1H NMR (DMSO) d 9.3
(1H, brs), 9.0 (1H, d, J = 1.7 Hz), 8.9 (1H, dd, J =
7.3, 0.8 Hz), 7.8 (1H, dd, J = 4.7, 0.8 Hz).
4-(3-Chloroanilino) wridQl3' 2'~4 Slthienof3.2-
dlovrimidine. A mixture of.4-chloropyrido[3',2';
4,5]thieno[3,2-d]pyrimidine (0.12 g, 0.54 mmol), 3-
chloroaniline (O. D6 mL, 0.5 mmol) and 2-ethoxyethanol
(5 mL) is heated under N~ with stirring at 135C for 3
h. Upon cooling a solid precipitates. The solid is
collected by filtration, washed with acetone and dried
in a vacuum oven at -80C to give 4-(3- -
chloroanilino}pyrido[3',2';4,5]thieno[3,2-d]pyrimidine
(46 mg, 27%). 'H NMR (DMSO) d 9.97 (1H, s), 8.88 (1H, -
dd, J = 4.6, 1.7 Hz), 8.85 (1H, s), 8.72 (1H, dd, J =

~O 95/19970 217 7 .~ ~ 2 pCT~S95100911
-85-
8.0, 1.7 Hz), 8.08 (2H, t, J = 2.0 Hz), 7.79 (1H, ddd,
J = 8.3, 2.0, 0.8 Hz), 7.69 (1H, dd, J = 8.0, 4.6 Hz),
7.43 (1H, t, J = 8.0 Hz), 7.19 (1H, ddd, J = 8.0, 2.0,
0.8 Hz).
Example 21 -
~-(3-bromoanilino)ovridof3' 2'- 4 5lthienof3 2-
5~] wrimidine
A mixture of 4-chloropyrido[3',2';
4,5]thieno[3,2-d]pyrimidine (72 mg, 0.32 mmol) (see
previous experimental), 3-bromoaniline (0.04 mL, 0.37
mmol) and 2-ethoxyethanol (5 mL) is heated under Nz
with stirring at 135C for 3 h. Upon cooling a solid
precipitates. The solid is collected by filtration,
washed with acetone and dried in a vacuum oven at -80C
to give 4-(3-bromoanilino)pyrido[3',2';
4,5]thieno[3,2-d]pyrimidine (45 mg, 39.4%). 'H NMR
(DMSO) d 9.96 (1H, s), 8.88 (1H, dd, J = 4.6, 1.7
Hz), 8.85 (1H, s), 8.72 (1H, dd, J = 8.0, 1.7 Hz),
8.20 (1H, t, J = 2.0 Hz), 7.84 (1H, ddd, J = 8.0,
2.D, 1.3 Hz), 7.69 (1H, dd, J = 8.0, 4.7 Hz), 7.39-
7.31 (2H, m).
Example 22
4-Anilinoindolof3.2-dlDVrimidine
A solution of 4-chloroindolo[3,2-
d]pyrimidinehydrochloride (240 mg, 1.0 mmol) [ Monge,
A.; Palop, J. A.; Goni, T.; Martinet-Crespo, F.;
Recalde, I.. J. Het. Chem., 1986, 23, 647-9. ],
and aniline (0.273 mL, 3 mmol) in ethanol (1 mL) is
heated at reflux for 3 h, during which time the
reaction becomes a thick suspension. After cooling to

WO 95119970 PCTIUS95100911
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25C and diluting with ethanol (4 ml) the mixture is ,
filtered, and the crude product washed with water (15
mL), and ethanol (IS mL), giving 274 mg tan solid,
which is recrystallized from DMF / water affording
pure 4-anilinoindolo[3,2-d]pyrimidine hydrochloride
(82 mg, 27%). 1H NMR (DMSO) : d 12.79 (1H, brs),
11.04- (1H, brs), 8.94 (1H, s), 8.27 (1H, d, J = 8.2
Hz), 7.96 (2H, d, J = 7.5 Hz), 7.85 (1H, d, J = 8.4
Hz), 7.71 (1H, t, J = 7.7 Hz), 7.49 (2H, t, J = 8.0
Hz), 7.41 (1H, t, J = 7.6 Hz), 7.24 (1H, t, J = 7.4
Hz) .
Example 23
4-Benzvlaminoindolo(3.2-dlpYrimidine
4-Chloroindolo(3,2-d)pyrimidine
hydrochloride (240 mg, 1 mmol, and benzylamine (1 mL)
are stirred under a dry nitrogen atmosphere at 150 C
for 6 hours, and then concentrated under reduced
pressure to give an oily soft solid which is dissolved
in EtOAc (20 mL), and washed with saturated sodium
bicarbonate solution (20 mL), water (3 X 15 mL), and
brine (20 mL). The solution is dried (MgS04) and the
solvent is removed under reduced pressure.
Trituration of the residue with dichloromethane, gives
4-benzylaminoindolo[3,2-d]pyrimidine (190 mg, 69%).
1H NMR (CDC1~): d 10.58 (1H, brs), 8.60 (1H, s), 8.08
(1H, d, J=8.0 Hz), 7.47-7.14 (8H, m), 4.82 (2H, d,
J=5.6 Hz), 2.41 (1H, brs).
SUBSTITUTE SHEET (RULE 26)

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Examx~le 24
4-(fRl-1-Phenvlethvlamino)indolo(3 2-dlpvrimidine
hvdrochloride
4-Chloroindolo[3,2-d]pyrimidine
hydrochloride 240 mg, 1 mmol) and (R)-(+)--
methylbenzylamine (1 ml) are stirred under a dry
nitrogen atmosphere at 150 for 5 hours, and then
concentrated under reduced pressure to an oil. This
oil is dissolved in EtOAC (20 ml), and stirred for
16 h. The precipitate which forms is collected by
filtration, washed with EtOAc, and dried at 90 in
vacuo to give 4-([R]-1-phenylethylamino)indolo[3,2-
d]pyrimidine hydrochloride (37 mg, 11%). 1H NMR (DMSO):
3 10 (1H, s), 9.14 (1H, brs), 8.64 (1H, s), 8.16 (1H,
d, J = 8.0 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.63-7.59
(1H, m), 7.50 (2H, d, J = 7.2 Hz), 7.38-7.24 (4H, m),
5.59 (1H, p, J = 7.0 Hz); 1.64 (3H, d, J = 7.0 Hz).
Example 25
4-(3-Bromoanilino)indolo 3.2-dlpvrimidine
~rdrochloride
4-Chloroindolo[3,2-d]pyrimidine
hydrochloride (240 mg, 1 mmol) and 3-bromoaniline
(0.33 mL, 3 mmol) in ethanol (3 mL) are heated at
reflux under a nitrogen atmosphere for 2h. Filtration
and washing of the collected solids with ethanol,
followed by recrystallization from DMF gives 4-(3-
bromoanilino)indolo(3,2-d]pyrimidine hydrochloride
(288 mg, 77%). 1H NMR (DMSO) d 12.73 (1H, s), 11.42
(1H, s), 9.02 (1H, s), 8.41 (1H, s), 8.28 (1H, d, J =
7.9 Hz), 7.95-7.92 (1H, m), 7.84-7.82 (1H, d, J = 8.6
Hz), 7.74-7.69 (1H, m), 7.40-7.47 (3H, m).
SUBSTITUTE SHEET (RULE 26)

PCTlUS951D0911
WO 95/19970
-88-
N
~~ Br
N
Example 26
4 (3 Bromoanilino)-5 N-methvlindolo[3 2-d7AVr~midine
hvdrochloride
A solution of 4-chloro-S,N-methylindolo(3,2-
d]pyrimidine (Kadushkin, A.V.; Nesterova, I.N.;
Golovko, T.V.; Nikolaeva, I.S.; Pushkina, T.V.;
Fomina, A.N.; Sokolova, A.S.; Chernov, V.A.; Granik,
V.G. Khim. -Farm. Zh. 1990 , 24, 18-22) (218 mg, 1
mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in 2-
propanol (7 mL) containing 0.5% HC1 gas is heated at
reflux for 3 hr, cooled to 25C, and the solids are
filtered and washed with 2-propanol and dried
affording 4-(3-bromoanilino)-5,N-methylindolo[3,2-
d]pyrimidine hydrochloride (379 mg, 97%), as a bright
yellow solid. 'H NMR (DMSO) d 9.80 (1H, s), 8.83 (1H,
s), 8.34 (1H, d, J = 8.0 Hz), 7.95-7.90 (2H, m), 7.79-
7.68 (3H, m), 7.45-7.41 (3H, m), 4.27 (3H,.s).
Example 27
a-an;i;nn;ndolo(2 3-dl wrimidine
4-Chloroindolo[2,3-d]pyrimidine
hydrochloride (R. G. Glushkov et. al., Khim.-Farm.
Zh., 1967, I(9), 25-32) (240 mg, 1 mmol) and aniline
(0.27 mL, 3 mmol) in ethanol (1 mL) are heated under

W O 95/19970 PCT/US95f009I I
-89-
reflux for-6h. The solvent is evaporated under
reduced pressure, and the residue triturated with
EtOAc to afford a tan powder which is filtered, and
washed with cold ethanol. Recrystallization from
acetone / pet. ether gives 4-anilinoindolo[2,3-
d]pyrimidine (49 mg, 19 %). 1H NMR (DMSO) d 1H, s),
8.84 (1H, s), 8.43 (1H, s), 8.37 (1H, d, J = 8.0 Hz),
7.74 (2H, d, J = 7.7 Hz), 7.52-7.D8 (6H, m).
Example 28
4-(3-Bromoax~ilino)indolof2 3-dlpvrimidine
hydrochloride __ ,
4-Chloroindolo[2,3-d]pyrimidine
hydrochloride (240 mg, 1 mmol) and 3-bromoaniline
(0.33 mL, 3 mmol) in ethanol (3 mL) are heated under
reflux for-2h. The solids are collected by suction
filtration, washed with ethanol and dried to give 4-
(3-bromoanilino)indolo[2,3-d]pyrimidine hydrochloride
(248 mg, 73%). 1H NMR (DMSO) d 1H, s), 9.02 (1H,
x),8.51 (1H, s), 8.42 (1H, d, J=7.7 Hz), 8.08 (IH, t,
J = 1.9 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.53 (1H, d,
J=7.9 Hz), 7.46 (1H, dt,-Jd = 1.0 Hz, Jt = 7.6 Hz),
7.36-7.27 (3H, m).
NH
N Br
0
' H
SUBSTITUTE SHEET (RULE 26)

WO 95!19970 PCTIUS95/00911
-90-
Example 29
g-(3-Bromoanilino)-9,N-methylindolof2,3-dlpvrimidine.
4-Chloro-9,N-methylindolo[2,3-d]pyrimidine (Portriov,
Yu. N.; Bulaga, S.N.; Zabrodnyaya, V.G.; Smirnov, L.
D. Khim. Geterotsikl. Soedin., 1991 , 3, 400-2 )
(220 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol)
in 2-propanol, containing 0.5% (w : w) HCl gas, (7 mL)
is heated under reflux for 6h. After removal of
solvent under reduced pressure, the residue is
suspended in CHC13 (50 mL), and washed with 1% aqueous
NaOH solution (25 mL), and H20 (2 X 20 mL), dried
(MgSO,), and concentrated under reduced pressure.
Column chromatography (SiO~) with CHC1, gives the
product as a light tan foam, which slowly crystallizes
upon standing at 25 C. Recrystalliaation from
diisopropyl ether (-30 ml ) affords 4-(3-
bromoanilino)-9,N-methylindolo[2,3-d]pyrimidine (220
mg, 65%)as a fluffy white solid. 1H NMR (CDC13) d
s,s,m, 3.96 (3H, s).
NH
N Br
OOJ
Examy~le 30
4-(3-Bromoanilino)-9N-(2-N,N-diethvlaminoethvl)pyri-
midof2,3-dlindole bis hydrochloride
4-Chloro-9N-(2-(N,N-diethylamino)eth3rl)-
indolof2,3-dlpvrimidine. A suspension of 4-chloroin-
SUBSTITUTE SHEET (RULE 26)

~O 95119970 PCf/US9510091 I
-91-
dolo[2,3-d]pyrimidine hydrochloride (407 mg, 2 mmol),
2-N,N-diethylaminoethyl chloride hydrochloride (413
. mg, 2.4 mmol), anhydrous cesium carbonate (1.95 g, 6
mmol) and 4 molecular sieves (1.5 g) in acetone (6 mL)
are heated at reflux under a nitrogen atmosphere for
1.5 h. The mixture is filtered through celite,
washing the filter cake with acetone (4X10 ml),
followed by concentration of the filtrate under
reduced pressure affording a viscous amber oil, which
is dissolved in CHzCl2, (20 ml), and washed with water
(2 X 25 mL), dried (MgS04), and the solvent is removed
in vacuo. The crude product is chromatographed on
silica,,eluting with 4% methanol/chloroform to give 4-
chloro-9N-(2-(N,N-diethylamino)ethyl)indolo[2,3-
d]pyrimidine (495 mg, 82%), as a pale yellow oil. 1H
NMR (DMSO) d 8.79 (1H, s), 8.41 (1H, d, J = 8.0 Hz),
7.66-7.58 (2H, m), 7.46-7.42 (1H, m), 4.57 (2H, t, J =
6.8 Hz), 2.90 (2H, t, J = 7.1 Hz), 2.63 (4H, d, J =
7.0 Hz), 0.99 (6H, t, J = 7.0 Hz).
4-(3-Bromoanilino)-9N-(2-N.N-diethylamino-
ethvl)pvrimidof2,3-dlindole bis hydrochloride. A
suspension of 4-chloro-9N-(2-(N,N-diethylamino)ethyl)-
indolo[2,3-d]pyrimidine (240 mg, 1 mmol) and 3-bromo-
aniline (0.33 mL, 3 mmol) in 2-propanol (7 mL), which
contains 0.5% HC1 gas, is heated under reflux for 6
hr, and then concentrated to a viscous brown oil which
is dissolved in chloroform (75 mL) and washed with 1 %
aqueous NaOH solution (50 mL), water (50 mL), and
dried (MgS04). The solvent is removed under reduced
pressure, and the residue is chromatographed on Si02
_ eluting with 2 % MeOH in CHCL3 to obtain the free
base of the product as a pale yellow oil (411 mg,
93%). The free base is dissolved in warm ethanol (5
SUBSTITUTE SHEET (RULE 26)

W0 95/19970 PCflITS95100911
~~~T,392
-92-
mL), and is treated with ethanol (2 mL) which had been
saturated with HC1 gas, affording 4-(3-bromoanilino)-
9N-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyrimidine
bis hydrochloride. IH NMR (DMSO) d 10.64 (1H, brs),
9.17 (1H, s), 8.60 (1H, s), 8.52 (1H, d, J = 8.0 Hz),
8.07 (1H, s), 7.93 (1H, d), 7.80 (1H, d, J = 7.7 Hz),
7.58 (1H, t, J = 7.7 Hz), 7.41 (1H, t, J = 7.2 Hz),
7.37 -7.39 (2H, m), 4.90 (2H, t, J = 7.0 Hz), 3.51
(2H, dd, J = 12.8, 6.5 Hz) 3.31-3.28 (4H, m), 1.25
(6H, t, J = 7.2 Hz).
Example 31
4-(3-Bromoanilino)6-methoxvindolof2 3-dlpvrimidine
Drano-f5-methoxy-2-nitro~henvl)acetic acid
ethyl ester. To an ice-cold solution ofethyl
cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF
(170 mL) under Nz is added of potassium tert-butoxide
(12.07 g, 107.5 mmol). The formed white suspension is
stirred for 15 min then treated with 3-fluoro-4-
nitroanisole [Halfpenny, P. R.; Horwell, D. C.;
Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chem.
(1990), 33, 286-91] (8.86 g, 51.2 mmol). The
suspension is heated at-reflux for 1.5 h. The
solution is poured into HBO, and the aqueous mixture is
acidified to pH 2 with concentrated HC1. The mixture
is extracted three times with ether then the combined
organic phases are dried (MgS04) and concentrated to an
oil that is pumped at 0.3 mm for 2 days. The oil is
dissolved in.dichloromethane and purified by flash
silica gel chromatography eluting with
dichloromethane. The product fractions are combined
and concentrated to leave cyano-(5-methoxy-2-
,nitrophenyl)acetic acid ethyl ester (14.5-g) as a
SUBSTITUTE SHEET (RULE ~~)

2171392
~O 95119970 PCTIUS95/00911
-93-
light yellow oil that is about 93-95% pure. iH NMR
(CDC13) : d 8.29 (1H, d, J = 9.2 Hz) , 7.22 (1H, d, J =
2.7 Hz), 7.04 (1H, dd, J = 9.2, 2.7 Hz), 5.69 (1H, s),
4.31 (2H, q, J = 7.0 Hz), 1.34 (3H, t, J ~ 7.2 Hz).
S a-Ammo-5-methoxv-1H-indole-3-carboxylic
acid ethvl ester. A solution of cyano-(5-methoxy-2-
nitrophenyl)acetic acid ethyl ester (13.2 g, 46.3
. mmol, 93-95% pure) in glacial acetic acid (185 mL) is
treated with a single charge of zinc dust (12.1 g, 185
mmol). The mixture is heated at 55 °C for 45 min,
then treated with more zinc (4 g). After heating for
another 105 min, the brown mixture is filtered through
a pad of flash silica gel. The pad is washed well
with acetic acid and the filtrate is concentrated to a
residue that is distributed between dichloromethane
and H=O. The organic phase is washed with 5% aqueous
sodium bicarbonate and concentrated to a residue that
shows about a 1:1 mixture of products by silica gel
thin layer chromatography (dichoromethane:EtOAc, 3:1).
The residue is purified by flash silica gel
chromatography eluting sequentially with 100:0, 95:5,
and 90:10 dichloromethane:EtOAc. The fractions
containing the pure higher R= product are combined and
concentrated to a solid that. is sonicated in tert-
butyl methyl ether. The solids are collected by
filtration to give pure 2-amino-5-methoxy-1H-indole-3-
carboxylic acid ethyl ester (2.07 g) as an off-white
solid. Further chromatography of the combined mother
liquor and impure fractions affords 120 mg of
additional product. Total yield = 2.19 g (20%). 1H
NMR (DMSO) : d 10.44 (1H, br s, exchanges with DZO),
' 7.11 (1H, d, J = 2.2 Hz), 6.98 (1H, d, J = 8.4 Hz),
6.61 (2H, b. s, exchanges with D20), 6.48 (1H, dd, J =

WO 95119970 PCTYUS95/00911
-94_
8.4, 2.7 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.71 (3H, s),
1.32 (3H, t, J = 7.2 Hz).
6-Methoxv-3H-indolo(2.3-d7DVrimidine-4-one.
A solution of 2-amino-5-methoxy-1H-indole-3-carboxy-
lic acid ethyl ester (2.15 g (9.2 mmol), sodium meth-
oxide (0.5 g (9.3 mmol), and formamide (200 mL), is
heated under N2 at 220'C for 1.5 h. The solution is
cooled to room temperature, stored for 2.5 days, and
filtered. The solvent is evaporated by FCugelrohr
distillation at 95 °C/0.8 mm. The residual solids are
washed with HBO, then heated in 35 mL of boiling N,N-
dimethylformamide. The hot suspension is filtered hot
over a pad of flash silica gel. The cooled filtrate
is concentrated in vacuo to a solid that is sonicated
in about 30 mL of MeOH. The solids are filtered,
washed with MeOH, and dried to leave 6-methoxy-3H-
indolo[2,3-d]pyrimidine-4-one (1.71 g,72%) that is
about 83 % pure. 'H NMR (DMSO) : d 12.16 (1H, br
s, exchanges with D20), 12.04 (1H, br s, exchanges with
Da0), 8.08 (1H, d, J = 3.4 Hz, exchanges to s with
D,O), 7.46 (1H, d, J = 1.9 Hz), 7.37 (1H, d, J = 8.7
Hz), 6.95 (1H, dd, J = B.B, 2.5 Hz), 3.81 (3 H, s).
4-Chloro-6-methoxvindolof2,3-dlpvrimidine. A suspen-
sion of 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one
(800 mg, 3.08 mmol, -83-% pure) and POC13 (7 mL) is
heated at 90 °C for 6 h. The suspension is concen-
trated to a solid that is evacuated at 1 mm for 1 h.
The solids are cooled in a -78 °C bath then treated
dropwise with cold H:o. :he bath is removed and the
frozen solids are allowed to gradually melt. The
solids are filtered, washed well with cold HZO, and
dried to leave 4-chlora-6-methoxyindolo[2,3-d]pyrimi-

~V0 95119970 PCT'/US95100911
-95-
dine (733 mg, 81%) that is about 80% pure. 1H NMR
(DMSO) : d 12.64 (1H, br s, exchanges with Dz0), 8.74
(lFi, s) , 7.74 (1H, d, J = 2.4 Hz) , 7.57 (1H, d, J =
8.9 Hz), 7.28 (iH, dd, J = 8.9, 2.4 Hz), 3.88 (3H,
s) .
4-(3-Bromoanilino)-6-methoxvindolof2,3-d1-
pyrimidine. A mixture of 4-chloro-6-methoxyindolo-
[2,3-d]pyrimidine (107 mg, 0.37 mmol, 80% pure), 3-
bromoaniline (0.15 mL, 1.4 mmol), N,N-dimethylaceta-
mide (1 mL), and 1 drop of a solution of 2-propanol
that is 8.5 molar in HC1 is heated under N~ at 120 °C
for 5 h. The solution is concentrated in vacuo to an
oily solid that is triturated in 5% aqueous sodium
bicarbonate. The solids are collected by filtration,
- then washed successively with Hz0 and EtOAC. The
solids are warmed in a small volume of N,N-
dimethylformamide and filtered. The filtrate is
purified by thick layer silica gel chromatography
eluting with 3:2 dichloromethane:EtOAc. The product
band is collected and sonicated in EtOAc. The mixture
is filtered and the filtrate is concentrated to a
solid that is sonicated in MeOH. The solids are
collected, washed with MeOH, and dried to give pure 4-
(3-bromoanilino)-6-methoxyindolo[2,3-d]pyrimidine (39
mg, 28%) hydrated with 0.7'equivalent of,H=O. 'H NMR
(DMSO) : d 11.99 (1H, br s, exchanges with D20),, 8.97
(1H, br s, exchanges with Dz0), 8.44 (1H, s), 8.02
(1H, s), 7.91 (1H, d, J=2.4 Hz), 7.76 (1H, d, J= B.0
Hz), 7.42 (1H, d, J=8.7 Hz), 7.36 - 7.24 (2H, m), 7.08
(lH,dd, J = 8.7, 2.2 Hz), 3.87 (3H, s).

W 0 95119970 PCTIUS95/00911
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Example 32
2-Aminp-4-(3-bromoanilino) wrimido(2 3-dlindole
ndole-3-carboxylic acid ethyl
A suspension of 2 aminoindole-3-
carboxylic acid ethyl ester ( 2.04 g, 10.0 mmol),
cyanamide (534 mg, 12.7 mmol), and concentrated
hydrochloric acid (1 mL) in dioxane ( 91 mL), are
heated under reflux for 48 hr. After the reaction
mixture has cooled to 25 C it is filtered and the
1D solids washed well with dry diethyl ether, and then
air dried to give 2-guanidinoindole-3- carboxylic acid
ethyl ester hydrochloride (l.OSg, 38 %) 2-
guanidinoindole-3-carboxylic acid ethyl ester
hydrochloride as an off-white solid, mp >250 C.
2-Amino-4-oxo-3H-indolo(2,3-dl~yrimidine. A
mixture of 2-guanidinoindole-3-carboxylic acid ethyl
ester hydrochloride (1.00 g, 3.5 mmol) and sodium
hydroxide (1.5 g) in water (50 mL) is heated to gentle
reflux for 6 hr followed by the addition-of sufficient
5 % HC1 to adjust the solution to pH 1, and filtration
of the resulting mixture through celite, washing the
pad with water. The filtrate is extracted with ethyl
acetate (3 X 25 mL), and then basified with solid sodium
carbonate. The tan precipitate which slowly forms is
collected by filtration, washed with water, and dried in
vacuo affording2-amino-4-oxo-3H-indolo[2,3-d]pyrimidine
(561 mg, 78%) as light tan crystals, mp> 275 C.
2-Amino-4-chioroindolo[2 3-dlDVrimidine
hydrochloride. A suspension of 2-amino-4-oxo-3H-
indolo[2,3-d]pyrimidine (490 mg, 2.5 mmol) and
phosphoryl chloride (7 ml, 75 mmol) in dioxane (13 ml)
is heated under reflux for 4 hr, then concentrated in

~O 95/19970 ~ PCTIITS95/00911
-97-
vacuo. The residue is triturated with ethanol,
filtered, and the solids washed with 10 : 1 Ethanol
Ethyl Acetate to give 170 mg (27 %) 2-amino-4-
chloroindolo[2,3-dJpyrimidine hydrochloride as a grey
solid, mp >250 C.
2-Amino-4-(3-bromoanilino)indolo(2.3-
dlpvrimidine. A mixture of 2-amino-4-chloroindolo(2,3-
d)pyrimidine hydrochloride (123 mg, 0.6 mmol) and 3-
bromoaniline (0.3 mL, 2.8 mmol) in 2-propanol (6 mL) is
heated at reflux for 4 hr, filtered through a celite
pad, and concentrated in vacuo. The residue is
partitioned between ethyl acetate (25 mL) and water (25
mL). The aqueous phase is extracted With further ethyl
acetate (2 x 20 mL), followed by washing the combined
extracts with 1% aqueous sodium hydroxide (25 mL), water
(2 x 40 mL), saturated brine (40 mL), and drying
(Na2S09). The solution is evaporated to dryness under
reduced pressure to afford 105 mg crude product as a tan
powder. The solid is dissolved in a minimum amount of
methanol, filtered, and further purified by preparative
plate chromatography (SiO,; .1 : 1, EtOAc : CH2C1~; Rt =
.40 ). After extraction of the product from the silica
gel with ethyl acetate, the volume of the warm solution
is reduced to minimum, and it is filtered through
celite, and the solvent is removed under reduced
pressure. The oily solid thus obtained is dissolved in
a minimum amount of 2-propanol and allowed to
crystallize at 3 C over an 18 h period. The crystals
are collected by suction filtration, washed with a small
amount of cold 2-propanol, and dried in vacuo to give 2-
amino-4-(3-bromoaailino)indolo(2,3-d)pyrimidine (34 mg,
17%). 1HNMR, (DMSO): dbrs), 8.57 (1H, s), 8.11 (1H, d, J

W0 95/19970 PCTIUS95100911
_98_
= 8.0 Hz), 8.01 (1H, s), 7.94 (1H, d, J = 8.2 Hz), 7.34-
7.12 (SH, m), 6.41 (2H, bra).
Example 33
4-(3-Bromoanilino)-9N-(2-N.N-diethylaminoethvll-6-
methoxvindolof2.3-dlpvrimidine bishydrochloride
4 - C h 1 o r o - 6 - m a t h o x v - 9 H - f 2 - N , N -
diethvlaminoethvl)indolof2.3-dlpvrimidine. A suspension
of 4-chloro-6-methoxyindolo[2,3-d]pyrimidine (773 mg,
2.5 mmol, -80% pure), 2-diethylaminoethyl chloride
hydrochloride (582 mg, 3.4 mmol), anhydrous cesium
carbonate (2.3 g, 7.1 mmol), 4 molecular sieves (2.1
g), and acetone:N,N-dimethylformamide (12 mL, 2:1) is
heated at reflux under N= for 16.5 h The mixture is
filtered over Celitem and the filter pad is washed well
with acetone. The filtrate is concentrated in vacuo to
a viscous oil that is distributed between
dichloromethane and HZO. The organic phase is dried
(Mg50,) and concentrated to an oil that is purified by
flash silica gel chromatography eluting first with
dichloromethane, then with dichloromethane:MeOH (98:2).
The product fractions are combined and concentrated in
vacuo to leave 4-chloro-6-methoxy-9H-(2-N,N-
diethylaminoethyl)indolo[2,3-d]pyrimidine (667 mg, 80
%) as 'a yellow oil. 1H NMR (CDC13) : d 8.75 (1H, s) ,
7.87 (1H, d, J=2.4 Hz), 7.47 (1H, d, J = 8.9 Hz), 7.25
(1H, dd, J = 8.9, 2.4 Hz), 4.50 (2H, t, J=7.2 Hz), 3.96
(3H, s), 2.86 (2H,t, J=7.1 Hz), 2.59 (4H, q, J=7.1 Hz),
0.96 (6H, t, J=7.1 Hz).
4-(3-Bromoanilino)-6-methoxv-9H-(2-N.N-
diethylaminoethvl)indolo(2,3-dlpvrimidine bishvdrochlor-
y~e_. A solution of 4-chloro-6-methoxy-9H-(2-N,N-

~0 95/19970 PGTIU595100911
-99_
diethylaminoethyl)indolo[2,3-d]pyrimidine (660 mg, 1.98
mmol), 3-bromoaniline (D.52 mL, 4.8 mmol, 0.25 mL of a
solution of 2-propanol that is 8.5 molar in HC1, and
N,N-dimethylacetamide (4 mL) is heated at 120 °C under
Nz for 2 h. The solution is concentrated in vacuo and
the residue is distributed between dichloromethane and
1% aqueous sodium hydroxide. The dichloromethane phase
is washed with Hzo, dried (MgSO,), and concentrated to an
oil that is purified by flash silica gel chromatography
eluting first with EtOAC, then EtOAc:MeOH:triethylamine
(95:5:1). The product fractions are combined and
concentrated to leave an oil that is stored at room
temperature overnight. The semisolid is treated with an
excess of a solution of 2-propanol that is 8.5 molar in
HC1. After storage for several hours at room tempera-
ture, the solids are collected by filtration, washed
with 2-propanol, and dried to leave 4-(3-bromoanilino)-
6-methoxy-9H-(2-N,N-diethylaminoethyl)indolo[2,3-d]pyri-
midine (727 mg, 65%) as a salt with 2.1 equivalents of
HC1 and solvated with 0.9 equivalent of H20. 'H NMR
(DMSO) : d 1D.55 (1H, br s, exchanges with D20), 9.28
(1H, br exchanges with Da0), 8.55 (1H, s), 8.02 (1H,
s,
d, J=2.2 (1H, s), 7.84 (1H, d, 8.7 Hz),
Hz}, 7.99 J=
7.74 (1H, d, J=7.2 Hz), 7.39 - 7.32 (2H, 7.21
m),
(lH,dd, = 8.9, 2.2 exchanges
J Hz), .
5.30 (3H,
br s,
.
with Di0 4.85 (2H, t, J = s), 3.48
), 7.2 Hz), 3.90 (3H,
(2H, dd, 6.4 Hz); 3.35-3.21 (4H, m); 1.23
J
=
12.2,
(6H, t, = 7.2 Hz).
J
Example 34
4-(3-Bromoanilino)benzofuranof3.2-dlpvrimidine
Methyl 2-(2-cvano~henoxv)ethanoate. Methyl
bromoacetate (1.95 mL, 20 mmol} is added dropwise to a

W0 95119970 PCTIUS95100911
2~~~~9~
-loo-
solution of 2-cyanophenol (2.38 g, 20 mmol) , and KzC03
(2.78 g, 20.1 mmol) in acetone (100 mL) stirred under N~
at 25°C.- After 24 h, the solid is filtered off and the
filtrate is concentrated is vacuo and the residue is
dried in a vacuum oven to give methyl 2-(2-
cyanophenoxy)ethanoate (3.82 g, 100%) as a beige solid.
'H NMR (DMSO) d 7.76 (1H, dd, J = 7.6, 1.7 Hz), 7.64 (1H,
dt, Jd = 1.6 Hz, Jt = 8.0 Hz), 7.20-7.10 (2H, m), 5.04
(2H, brs), 3.70 (3H, s).
Methyl 3-aminobenzofblfuran-2-carboxvlate. A
solution of methyl 2-(2-cyanophenoxy)ethanoate (3.82 g,
mmol) in DMSO (40 mL) is added dropwise to a
suspension of NaH (0.84 g, 21 mmol) and DMSO (10 mL)
stirred under Na at 25°C. After 10 min the mixture is
15 poured onto ice water and extracted with ether. The
combined extracts are washed with water, saturated brine
and dried (MgSO,). After removal of the solvent under
reduced pressure, methyl 3-aminobenzo[b7furan-2-
carboxylate (2.15 g, 56%) is obtained as a yellow solid.
20 1H NMR (DMSO) d 7.95 (1H, d, J = 7.7 Hz), 7.48 (2H, d, J
= 3.4 Hz), 7.29-7.22 (1H, m), 6.40 (2H, brs), 3.80 (3H,
s).
3H-Benzofurano(3.2-dl wrimid-4-one. A
solution of methyl 3-aminobenzo(b]furan-2-carboxylate
(0.28 g, 1.36 mmol) in formamide (5 mL) is heated at
135C for 4 h, then the temperature is raised to 170C.
After 4 h the reaction is cooled to 25°C and a dark
purple solid precipitates. The solid is collected by
vacuum filtration and air dried to give 3H-
benzafurano[3,2-djpyrimid-4-one (118 mg, 46.6%). 1H NMR
(DMSO) d 13.0 (1H, brs), 8.25 (1H, s), 8.05 (1H, d, J

~O 95119970 PCTlUS95100911
-101-
= 8.1 Hz), 7.84 (1H, d, J = 8.3 Hz), 7.68 (1H, t, J =
7.7 Hz), 7.51 (1H, t, J = 7.7 Hz).
- 4-Chlorobenzofuranof3.2-dlavrimidine. DMF
(0.23 mL, 3.1 mmol) is added dropwise to a solution of
(COC1)2 (0.28 mL, 3.1 mmol) in 1,2-dichloroethane (15 mL)
at 25'C. After gas evolution ceases, 3H-benzofurano[3,2-
d]pyrimid-4-one (113 mg, 0.61 mmol) is added. The
resulting mixture is heated at reflux for 1 h. After the
reaction has cooled to 25°C, water is added and the
resulting mixture is extracted with CHC1; . The combined
extracts are washed with water, saturated brine and
dried (MgSO,). The solvent is removed under reduced
pressure to give 4-chlorobenzofurano(3,2-d]pyrimidine
(116mg, 93k) as a yellow solid. 'H NMR (DMSO) d 9.08
(1H, s), 8.30 (1H, d. J = 8.1 Hz), 8.02 (1H, d, J = 8.5
Hz), 7.90, (1H, dt, Jd = 1.3 Hz, JL = 7.1 Hz), 7.64 (1H,
dt, J° = 1.0 Hz, J~ = 7.8 Hz).
4-(3-Bromoanilino)benzofurano(3,2-
dlavrimidine. A mixture of 4-chlorobenzofurano[3,2-
d]pyrimidine (116mg, 0.57 mmol) and 3-bromoaniline (0.07
mL, 0.6 mmol) is heated at 135°C under N2 in stirred 2-
ethoxyethanol for 3 h. The mixture precipitates upon
cooling, and the solid is cpllected and recrystallized
from EtOH to give 4-(3-bromoanilino)benzofurano[3,2-
d]pyrimidine (15.7 mg, 8%). 'H NMR (DMSO) d 10.35 (1H,
s), 8.73 (1H, s), 8.34 (1H, t, J = 1.9 Hz), 8.17 (1H,
ddd, J = 7.2, 1.2, 0.7 Hz), 7.93 (1H, ddd, J = 8.2, 2.2,
1.0 Hz), 7.88 (1H, d, J = 8.4 Hz), 7.77 (1H, dt, Jd = 1.4
~ Hz, J~ = 7.2 Hz) , 7.56 (1H, dt, Jd = 0.8 Hz, J~ = B.0
Hz), 7.34 (1H, t. J = 8.0 Hz), 7.27 (1H, ddd, J = 8.0,
2.0, 1.0 Hz).

WO 95119970 PGTIUS95100911
-102-
The pharmaceutical compositions of the
invention can take any of a wide variety of oral and
parenteral dosage forms. The dosage forms comprise as
the active components an inhibitor as defined
previously.
For preparing pharmaceutical compositions, one
uses inert, pharmaceutically acceptable carriers that
can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules,
capsules, cachets, and suppositories. A solid carrier
can be one or more substances which may also act as
dilutents, flavoring agents, solubilizers, lubricants,
suspending agents, binders, or tablet disintegrating
agents; it can also be an encapsulating material. In
powders, the carrier is a finely divided solid which is
in admixture with the finely divided active compounds.
In the tablet, the active compounds are mixed with
carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size
desired. The powders and tablets preferably contain
from 5% or 10% to about 70% of active ingredients.
Suitable solid carriers are magnesium carbonate,
magnesium stearate, talc, sugar, lactose, pectin,
dextrin, starch, gelatin, tragacanth, methyl cellulose,
sodium carboxymethyl cellulose, a low melting wax, cocoa
butter, and the like. The term "preparation" is
intended to include the formulation of the active
compounds with encapsulating materials as carrier,
providing a capsule in which the active components (with
or without other carriers) are surrounded by carrier,
which are thus in association with it. Similarly,
cachets are included. Tablets, powders, cachets, and

~O 95119970 ~ ~ ~ pCT/LTS95/00911
-103-
capsules can beuaed as solid dosage forms suitable for
oral administration.
Liquid form preparations include solutions,
suspensions, and emulsions. As an example may be
mentioned water or water-propylene glycol solutions for
parenteral injection. Liquid preparations can also be
formulated in solution in aqueous polyethylene glycol
solution. Aqueous solutions suitable for oral use can
be prepared by dissolving the active component in water
and adding suitable colorants, flavors, stabilizing, and
thickening agents as desired. Aqueous suspensions
suitable for oral use can be made by dispersing the
finely divided active components in water with viscous
material, i.e., natural or synthetic gums, resins,
methyl cellulose, sodium carboxymethyl cellulose, and
other well-known suspending agents.
Preferably, the pharmaceutical preparation is
in unit dosage form. In such form, the preparation may
be subdivided into unit doses containing appropriate
2o quantities of inhibitor and other anti-cancer materials
individually o_~ as a combination, i.e., in a mixture.
The unit dosage form can be a packaged preparation, the
package containing discrete_quantities of preparation,
for example, packeted tablets, capsules, and powders in
vials or ampoules. The unit dosage form can also be a
capsule, cachet, o_~ tablet itself or it can be the
appropriate number of any of these in packaged form.
Additionally, the unit dosage form may be a dividable
form having an inhibitor in one part and other anti-
cancer materials in the other part, such as, a dividable
capsule, a dividable package, or a two-part ampoule,
vial or the like.

W 0 95119970 PCT/U595I00911
-104-
The quantity of an inhibitor in unit dosages
of preparation may be varied or adjusted from about 0.01
mg/kg to 100.0 mg/kg, preferably 0.03 mg/kg to less than
1.0 mg/kg of inhibitor.
The pharmaceutical compositions preferably are
constituted so that they can be administered
parenterally or orally. Solutions of the active
compounds as free bases and free acids or
pharmaceutically acceptable salts can be prepared in
water suitable mixed with a surfactant such as
hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols, and
mixtures thereof and in oils. Under ordinary conditions
of storage and uae, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for
injectable use include sterile aqueous solutions or
dispersions and sterile-powders for the extemporaneous
preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and
must be fluid to the extent that easy syringability
exists. It must be stable under the conditions of
manufacture and storage and. must be preserved against
the contaminating action of the microorganisms such as
bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like),
suitable mixtures thereof, and vegetable oils. The ,
proper fluidity can be maintained, for example, by the
use of a coating such as lecithin, by the maintenance of _
the required particle size in the case of dispersion,

~0 95119970 ~ PCTIUS95100911
-105-
and by the use of surfactants. The prevention of the
action of microorganisms can be brought about by various
antibacterial and antifungal agents, for example,
paragens, chlorobutanol, phenol, sorbic acid,
thimerosal, and the like. In many cases, it will be
preferred to include isotonic agents, for example,
sugars or sodium chloride. Prolonged absorption of the
injectable compositions of agents delaying absorption,
for example, gelatin.
l0 Sterile injectable solutions are prepared by
incorporating the active compounds in the required
amount in the appropriate solvent with various other
ingredients enumerated above, as required, followed by
filtered sterilization. Generally, dispersions are
prepared by incorporating the various sterilized active
ingredients, into a sterile vehicle which contains the
basic dispersion medium and the required other
ingredients from those enumerated above. In the case of
the sterile powders for -the preparation of sterile
injectable solutions, the preferred methods of
preparation are vacuum drying and the freeze-drying
technique which yields a powder of active ingredients
plus an additional desired ingredient from a previously
sterile-filtered solution thereof.
As used herein, "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion
media, coatings, antibacterial and antifungal agents,
isotonic and absorption delaying agents and the like.
The use of such media and agents for pharmaceutically
active substances is well known in the art. Except
insofar as any conventional media or agent is
incompatible with the active ingredient, its use in the

W 0 95119970 PCT/US95100911
-106-
therapeutic compositions is contemplated. Supplementary
active ingredients can also be incorporated into the
compositions.
It is especially advantageous to formulate
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit
form as used herein refers to physically discrete units
suitable as unitary dosages for the mammalian subjects
to be treated; each unit containing a predetermined
quantity of active materials calculated to produce the
desired therapeutic effect in association with the
required pharmaceutical carrier. The specification for
the novel dosage unit forms of the invention are
dictated by and directly dependent on (a) the unique
characteristics of the active materials and the
particular therapeutic effect to be achieved, and (b)
the limitation inherent in the art of compounding such
active materials for the treatment of disease in living
subjects having a diseased condition in which bodily
health is impaired as herein disclosed in detail.
The principal active ingredients are
compounded for convenient and effective administration
in effective amounts with a suitable pharmaceutically
acceptable carrier in dosage unit form as hereinbefore
disclosed. A unit pazenteral dosage form can, for
example, contain the principal active compound, i.e. an
inhibitor, in amounts ranging from about 0.5 to about
100 mg, with from about 0.1 to 50 mg being preferred.
The daily parenteral doses for mammalian subjects to be ,
treated ranges from 0.01 mg/kg to 10 mg/kg of the
inhibitor. The preferred daily dosage range is 0.1 _
mg/kg to 1.0 mg/kg.

~O 95/19970 ~ PCTIU595/00911
-1D?-
For oral dosages, the daily amount may range
from 0.01 mg of active compound/kg of mammalian subject
to 1D0 mg/kg, preferably 0.1 to 10 mg/kg of subject.
The inhibitor described above may form
commonly known, pharmaceutically acceptable salts such
as alkali metal and other common basic salts or acid
addition salts, etc. References to the base substances
are therefore intended to include those common salts
known to be substantially equivalent to the parent
compound and hydrates thereof.
The active compounds described herein are
capable of further forming both pharmaceutically
acceptable acid addition and/or base salts. All of
these forms are within the scope of the present
invention.
Pharmaceutically acceptable acid addition
salts of the active compounds include salts derived from
nontoxic inorganic acids such as hydrochloric, nitric,
phosphoric, sulfuric, hydrobromic, hydriodic,
hydrofluoric, phosphorous, and the like, as well as the
salts derived from nontoxic organic acids, such as
aliphatic mono- and dicarboxylic .acids, phenyl-
substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and
aromatic sulfonic acids, etc. Such salts thus include
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,
nitrate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate,
chloride, bromide, io3ide, acetate, trifluoroacetate,
_ 30 propionate, caprylate, isobutyrate, oxalate, malonate,
succinate, suberate, sebacate, fumarate, maleate,

WO 95/19970 PCT/US95/00911
-108-
mandelate, benzoate, chlorobenzoate, methylbenzoate,
dinitrobenzoate, phthalate, benzenesulfonate,
toluenesulfonate, phenylacetate, citrate, lactate,
maleate, tartrate, methanesulfonate, and the like. Also
contemplated are salts of amino acids such as arginate
and the like and gluconate, galacturonate (see, for
example, Berge, S.M. et al, "Pharmaceutical Salts",
JOURNAL of PHARMACEUTICAL Scmcs, 66, pp. 1-19 (1977) ) .
The acid addition salts of said basic
compounds are prepared by contacting the free base form
with a sufficient amount of the desired acid to produce
the salt in the conventional manner. Preferably, an
active compound can be converted to an acidic salt by
treating with an aqueous solution of the desired acid,
such that the resulting pH is less than 4. The solution
can be passed through a C18 cartridge to absorb the
compound, washed with copious amounts of water, the
compound eluted with a polar organic solvent such as,
for example, methanol, acetonitrile, and the like, and
isolated by concentrating under reduced pressure
followed by lyophilization. The free base farm may be
regenerated by contacting the salt form with a base and
isolating the free base in the conventional manner. The
free base forms differ from their respective salt forms
somewhat in certain physical properties such as
solubility in polar solvents, but otherwise the salts
are equivalent to their respective free base for
purposes of the present invention.
Pharmaceutically acceptable base addition ,
salts are formed with metals or amines, such as alkali
and alkaline earth metals or organic amines. Examples ,
of metals used as cations are sodium, potassium,

~WO 95119970 ~ ~ l ~ ~ ~ ~ PCT/US95100911
-109-
magnesium, calcium, and the like. Examples of suitable
amines are N,N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, dicyclohexylamine,
ethylenediamine, N-methylglucamine, and procaine (see,
for example, Berge, S.M. et al, "Pharmaceutical Salts",
Jouxrsal, of Pxatuvac>:vxical, SCIENCE, 66, pp. 1-19 (1977) ) .
The base addition salts of said acidic
compounds are prepared by contacting the free acid form
with a-sufficient amount of the desired base to produce
the salt in the conventional manner. Preferably, an
actiue-compound can be converted to a base salt by
treating with an aqueous solution of the desired base,
such that the resulting pH is greater than 9. The
solution can be passed through a C18 cartridge to absorb
the compound, washed with copious amounts of water, the
compound eluted with a polar organic solvent such as,
for example, methanol, acetonitrile and the like, and
isolated by concentrating under reduced pressure
followed by lyophilization. The free acid form may be
regenerated by contacting the salt form with an acid and
isolating the free acid in the conventional manner. The
free acid forms differ from their respective salt forms
somewhat in certain physical properties such as
solubility in polar solvents, but otherwise the salts
are equivalent to their respective free acids for
purposes of the present invention.
Certain of the compounds of the present
invention can exist in unsolvated forms as well as
solvated forms, including hydrated forms. In general,
3Q the solvated forms, including hydrated forms are
equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention.

WO 95/19970 ~ ~ ~ 7 ~ 9 2 PCT/US95/00911
-110-
Certain of the compounds of the present
invention possess one or more chiral centers and such
center may exist in the R(D) or S(L) configuration. The
present invention includes all enantiomeric and epimeric
forms as well as the appropriate mixtures thereof.
While the forms of the invention herein
constitute presently preferred embodiments, many others
are possible. It is not intended herein to mention all
of the possible equivalent forms or ramifications of the
to invention. It is understood that the terms used herein
are merely descriptive rather than limiting and that
various changes may be made without departing from the
spirit or scope of-the invention.

~17139~
~WO 95119970 PCT/US95100911
-111-
H N1 l'Ar
COOH ~ Nn
1. HCONH, ~
~NHy 2. (COCI)a/DMF ~~s~
3. Ar(CHa)nNHa
Sche._,_,_P t . Synthesis of Preferred Grouy~l.
0 0
Ma OMQ I. HNO3/HaSO4 M° i NH, I. HCNMea(OBu')aheat
2. Separate ~ 2. RaNi H
Nos 3. NH3 o,N No, a
O H N~Ar
H 1. POCK /
N 2. Ar(CHa)nNHa H N
Sche.r,_P 2. Synthesis of Preferred Group 4: 13.2-gl ring fusion.
0
'eooH I, HCONHa o,N~NH 1. Py.HCI heat
2. HzS04/HN03 J~~'~ ~ 2. RaNi Ha
CI NHq 3. MeONa nneo N 3, HCOOH
O HN1 /'Ar
N NH I. PISS N~ Nn
2. MeI base
o N 3. Ar(CH=)"NHa o N
Scheme 3 Sy~thecic of Preferred Grouts 5: f4.5-gl ring fu ion.
SUBSTITUTE SHEET (RULE 26)

W 0 95119970 PCT/US95I00911
-112-
CI
CI CONHz HO CONHy O
1. KOH ~ 1. HC(OEt)3 ' I ~ N
NOp NOx 2. RaN1 HZ HpN NHy 2. POCig ~N ~ N
HN1 /'Ar
Ar(CH~"NHz o Nn
N N
CrhPmP a Synthetic of Preferred Groun 5: f5.4~1 ring fusion.
0
cooH I, HCONHZ o,N ~, NH 1. NaSH
2. HZS04/HN03 ~ , ~l 2. HC(OEt)3
CI NHy g. MeSNa (3 equ) Hs N
O NN'C TAr
N ~ NH I. PzSS N \ 'Nn
2. MeI base
s N 3. Ar(CH~"NHZ s N
o
CI ~ CONHy I. NBSH ~ ~ CONHp I, RaNI Hz _ ~~ ~ ~ H
NO ~NO 2' N~~ N "' NOy 2~ HC(OEt)g N
2 2
3. HCOOH
H N~Ar
I . POCI3 <s I ~ N n
2. Ar(CHZ)nNH?
N
Crhr.r,P (, Cvnthrcic of Preferred GfOUn 6: 5.4-gl ring fusion.
SUBSTITUTE SHEET (RULE 26)

~O 95/19970 ~ ~ 7 7 3 9 2 PCTIUS95100911
-lI3-
O
'cooH I. HCONHz °zN~NH 1. RaNi HZ
2. HzS04/HN03 ~~~ ~, J 2. HCOOH
CI '~ NHp 3. ~ HyN N
3
O HN1 rAr
N NH I. PzSS N~ Nn
2. MeI base
N 3. Ar(CHZ)nNHz H N
Scheme 7 ~ynthesic of Preferred Grou~7
HZN COOH
'' I I. HNOZ N r ( 1. RaNi H2
2. H2S04 HN03 ~N Nox 2. HC(NH)NHZ
3. Cr03 H
O HN1 /'Ar
N H I. POCI3 / ~ H
N~N~ Z. Ar(CHy)nNH2 N~N/
H H
H
AeNH N COOH
1. HNO; N 1. Pd/C HZ
2. NaOH ~ I Noz Z. HC(NH)NH~
3. HNOZ
4. Cr03 (~
O H N'1 /'Ar
H ~ H n
N N N H I. POCIZ N N ~ ~i ~ H
I Ns~ 2. Ar(CHZ)nNH, ~
N
~~hama 9 Synthe~;c of Preferred Group 10' f'~.-1-Jl rin~fusion.
SUBSTITUTE SHEET (RULE 28)

W 0 95119970 PC1'/US95I00911
-114-
0
cooH I. HCONHZ oZN NH I. RaNi Hz
2. H2S04/HN03 ~J 2. HNOz
CI NHq 3, NHg HyN N
O H N1 l'Ar
N I. PzSS N
N° ~~ H 2. MeI base N~ ~~
N N 3. Ar(CHg)"NHy 'H N
H
O
~ COOH I. HCONHZ ~?N~NH i. RaNi H2
2. HzSO4/HN03 II~~I ~l 2. Ho 0
CI NHy 3_ NHg HyN N
~O~OH
O HN1 /'Ar
N~NH I. P2S5 N _ 1 n
J 2. MeI base ~ ~~~~y~~/~~
N N 3. Ar(CHz)"NH2 N N
o 0
I. CC13CHO H~O2 Hooc , COOH
HpN ~ ~ NHq NH2OH o=~o N3OH H N ~. ~ NH
2. H.,SO4 H H = '
CI CI RS HN1 l'Ar
1. HC(NH)NH, N ~ I '~ N 1. Ar(CH=)"NH= N ~ I ~. Nn
2. POCI 'N N~ 2. R orH,/Pd ~N ~ N°J
Scheme 1~ Synthesis of Preferred Groun 13' B & E are Nitro~~
SUBSTITUTE SHEET {RULE 26)

2177392
~0 95/19970 PC1'IUS95100911
-115-
O
o,N COOH I. HCONHZ ANH I. HNO, H,SOd
NH
~
~ 2~ HZ RaNi I ~l 2. dil HCI
NHp 3. Ac20 3. Hz Pd/C
NHZ O I, HCOOH /=N HN~Ar
H N ~ H 2. PISS H N .~ N
3. MeI
4. Ar(CH~"NHz
0
cooH i, HCONH2 NH 1. HZPd/C
~ 2. HZS04/HN03 y HpN I N~ 2. HCOOH
CI~NHy
3. separate No2 3. piss
4. NH3 4. MeI base
SMe HN1 /'Ar
n
Ar(CH2)nNH2
N N N N
~NH ~-NH
scheme 14. Synthesis of Preferred Group 33: f4.5-hl ring fusion
O H N~Ar
C N I. HSCH,COOEt \ s N H I. (COCI)'/DMF_ R\ ' N H
F NEt3 DMSO 100°C ~ ~ ~ NyJ Z. Ar(CH~nNH_ - ~ ~ N~l
2. HCONHZ
SUBSTITUTE SHEET (RULE 26)

WO 95/19970 2 ~ 7 7 3 9 2 1'C'1'IUS95100911
-116-
I 1. LDA R/\' CHO I, NH,OH Rrl' cN
F 2. DMF ~~~ F 2. MsCI/ NEt3 w~I F
O H N~Ar
I. HSCH~COOEI R~ s N H I. (COCI).,/DMF R~ s N H
NEL3 DMSO I00°C I I N~ 2. Ar(CH2)nNHz
2. HCONH2 N
ci ci
H + Br I. NEtz s,sn ~. N 1. St;_lle coupli~
Ct~J ~sH 2. LDA ~ I sJ.2NJ 2. Ar(CHZ)nNHZ
3. Me SnCI
(~ Br
H N~Ar
n
C~~J
S N
OII OII
Br I. BuLiEt20 s~oMe I. (COCI)2 s~onn~
2. Ss ~ ~ PhN(Me)CHO ~
3. BrCHZCOOMe s 2. NHZOH s cN
3. MsCI/ NEL3
I. NEtg DMSO o HNC TAr
o S
100 C ,\ I ~ H 1. (COCI)~/DMF s I ''N
2. HCONH= I N ?. Ar(CH=)nNH= ~ ~ N%~
s s
scheme 18. Synthecic of Preferred Grou~a 41 ~ 13'''w X114 5-dl rin; cion
SUBSTITUTE SHEET (RiiL~ 26j

~O 95/19970 2 I 7 l 3 9 2 PC17US95100911
-lI7-
OI CI
Br 1. LDA EtzO Br N 1. LDA
/1 /1 ~ N
2. SR ~J 2. Me,SnCl
s 3.4,6-dichloro s s N 3_ Stillecoupling s s NJ
-pyrimidine
HN~Ar
Ar(CH2)"NH2 Nn
s s N
Scheme 19 Svmt_hecis of Preferred Grog 41 ~ ! ' 3'~ 11 4 dl ring scion
1. POC13/ DMF N cl 1. BuLi cl HSCH CONH
2. (CHZOH)2 H+cWs~~ 2. H30+ ~~cN Na0Et2 z
s
0 3. NHZOH
4. MsCI/ NEt3
s 1. CH(OEt)g HN~Ar
/ CONHz 2. PGCI~ N s N
g NHp 3. Ar(CHp)nNH2 s ~
N
Scheme 20 Symthecic of Preferred ro ~~[4' S'~ 1!4 dl ring scion
Br Br s
Br~~ 1. BuLi oHC~~ I. NH,OH ~ 1 / co2Et HCONH~
N 2. DMF N 2. MsCI/NEt3 N NH,
B" 3_ H* B" 3. HSCH~COzEt e"
NaH DMSO
O HN'1 /'Ar
N s I. H=/Rh N s n
NH 2. P=S5 ~ I ~ N
B"N--~ - NH~
N~ 3. MeI base N
4. Ar(CH=)~NH=
Scheme' l Synthetic of Preferred Croup 45~ f4' S'w '~lia 5 dl rin; ~cinn
SUBSTITUTE SHEET (RULE 26)

211392
WO 95119970 PCTIITS95I00911
-118-
p H N1 l'Ar
C N 1, HSCH2COOEt ".N S N H 1. (COCI)~/DMF N S N H
ci NEt3 DMSO 100°C ~ ~ NUJ 2. Ar(CHZ)nNH2 ~ ~ I N~'~
2. HCONHz
Scheme 22. Synthesis of Preferred Group 49: f2'.3': 2.4.5-dl ring »ion
NHa 1. BrCH2CO2Me / N 1. HCONHy N HN'C TAr
R~ 2. KOBU~ ~ ~ ~ coxMe 2, pOCIg r I I NH
~CN
3. Ar(CHZ)nNH2 ~%~~J
R
H N~Ar
1.NCCHZCOzMe co2Me 1. HCONHZ _ NH
KOBUt ' ~ ~ NH, 2. POC13
NOq 2. RaNi HZ R/ H 3. Ar(CHZ)nNH2 R/ H N J
~'oH 1. BrCHZCO~Me ~. 0 1. HCONHZ HN~Ar
I/ cN 2~ NaH DMSO ~, ~ ~ cozMa 2. POC13 ~' I o ( ~NH
R R NHp 3. Ar(CH2)nNH2 % !J
R
Srhr~mP ~s cynthecic of PrefPmed Grou~~ 61: (3?-d) rin~fusion
SUBSTITUTE SHEET (RULE 26)

Representative Drawing