ZA200504625B

ZA200504625B - 2,4,6-Trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in the treatment of cancer

Info

Publication number: ZA200504625B
Application number: ZA200504625A
Authority: ZA
Inventors: John M Nuss; Paul A Renhowe; Sabina Pecchi
Original assignee: Chiron Corp
Priority date: 2002-11-21
Filing date: 2005-06-06
Publication date: 2006-09-27
Also published as: CN1735607A; CN1735607B; SI2316831T1

Description

/ ’ 2,4, 6-TRISUBSTITUTED PYRIMIDINES AS PHOSPHOTIDYLINOSITOL (PI) 3-KINASE

INHIBITORS AND THEIR USE IN THE TREATMENT OF CANCER

FIELD OF THE INVENTION

. This invention pertains generally to the treatment of diseases, such as cancer, characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases. In other aspects, the present invention provides small molecule inhibitors of phosphotidylinositol (PI) 3-kinase, pharmaceutical formulations containing such inhibitors, methods of treating patients with such pharmaceutical formulations, and to methods of preparing such pharmaceutical formulations and inhibitors. .

BACKGROUND OF THE INVENTION :

Phosphotidylinositol 3-kinase (PI3K) is both a phospholipid kinase, and a protein serine/threonine kinase as described in Carpenter et al, Mol. Cell. Biol. 13:1657-1665 (1993). PI3K is an enzyme stimulated by growth factors that is responsible for phosphorylating phosphotidylinositol (PI) at the D-3' position of the inositol ring as described in Whitman et al, Nature 332:644-646 (1988). PI3K association with Src-like or receptor tyrosine kinases also implicates PI3K in the oncogenic or mitogenic responses induced by these protein kinases, as described in Cantley ez al, Cell 64:281-302 (1991),

Escobedo and Williams, Nature 335:85-87 (1988), and Fantl et al, Cell 69:413-423 (1992).

Previously, studies to elucidate the downstream effects of PI 3-kinase activation have been conducted with receptor mutants constructed to alter the signal transduction of

PI3K, or by constructing mutant oncogenes to study a PI3K inducible oncogenic response. The failure of receptor mutants of platelet derived growth factor (PDGF) receptor to activate PI3K has been correlated with deficiency of the receptor mutants in triggering a mitogenic response. Similarly, mutants of certain oncogenes have failed to trigger the oncogenic transformation inducible by the parent oncogene. A method was subsequently constructed to facilitate downstream effects of PI3K directly, without growth factor activation to determine whether PI3K was distinctly involved oncogenesis ] and mitogenesis. The results elucidated that PI3K can be directly or indirectly responsible for many cellular processes, such as mitogenesis and oncogenesis, as well as histamine secretion, neutrophil activation, platelet activation, cell migration, glucose transport, antilipolysis, and vesicle sorting. -1-

CL py

With the many regulatory responses associated with PI3-kinase, which is known to be involved in signal cascades involving other well known oncogenic proteins, such as receptor tyrosine kinases (e.g., VEGF-RTK), it would be highly desirable to produce . small molecules capable of modulating, e.g. inhibiting, the activity of PI3-kinase.

It is an object of this invention to provide potent inhibitors of PI3K. It is further an object of the instant invention to provide compounds alone or in combination with other known agents to modulate cellular proliferation in patients in need thereof.

Additionally, it is an object of this invention to provide medicaments for use in the treatment cancer.

SUMMARY OF THE INVENTION

The present invention provides novel pyrimidine based compounds, pharmaceutical formulations comprising the compounds, methods of inhibiting phosphotidylinositol 3-kinase (PI3K), and methods of treating cancer.

In one aspect, the present invention provides compounds of formula (I):

R, +X NR

N.__N ¥ -@ its stereoisomers, tautomers, pharmaceutically acceptable salts, esters, and prodrugs, wherein

Y is selected from the groups consisting of 1) substituted or unsubstituted C,-Cg-alkyl, (2) substituted or unsubstituted C,-C¢-alkenyl, (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, . 25 (5) substituted or unsubstituted heterocyclyl, and (6) substituted or unsubstituted heteroaryl; . X is selected from the group consisting of (1) adirect link, 2) -NRIX)- (3) ~(CHp)py-CR?*, R3X)-NRI¥)-, 2-

Fl

“@ -o, © 5, (6) -SO-, (7) -S0p, (8) -C(R2x,R3X)., and ® — wherein RIX, RX, and R3x are selected from the group consisting of (a) H, (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted C,-Cg¢-alkenyl, (d) substituted or unsubstituted C,-Cg-alkynyl, (e) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis 0,1,2,3,or4;

R; is selected from the group consisting of (I) H (2) substituted or unsubstituted C,-Cg-alkyl, (3) -COOH, (4) halo, (5) -ORIt and (6) -NHRI, wherein R1t is H or C;-Cg-alkyl;

Rj is selected from the group consisting of (1) substituted or unsubstituted aryl, 2) substituted or unsubstituted heteroaryl, and . 3) substituted or unsubstituted heterocyclyl; and

W is selected from the group consisting of . €)) substituted or unsubstituted C;-Cg-alkyl, (2) -NRIW, R2W), and k

CA

: 3) Ng (Cx wherein RIW and R2W are selected from the group consisting of @ HK (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl, (d) substituted or unsubstituted heterocyclyl, and (e) substituted or unsubstituted heteroaryl, wherein R!W and

R2W are not both H;

Z is selected from the group consisting of @ -O- ®) NR~, (OTE ES (d -80-, (¢) -SOy-, and ® -CHy-, wherein RZ is H or substituted or unsubstituted alkyl group; and

R4W is selected from the group consisting of (a H (b) substituted or unsubstituted C,-Cg-alkyl, (c) —COOR5V, (d —CONH, (e) -OR5V¥, and ® -NHRSv, wherein R3W is H or C;-C¢-alkyl; and ris 0, 1, or 2; with the proviso that when X is O, then Y is substituted or unsubstituted aryl, . substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; with the proviso that when W is morpholino, thiomorpholino, 1-oxido- thiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R; is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N'-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is NH, then

Y is not hydrogen, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, chloro-phenyl, - carboxy-phenyl, carbomethoxy-phenyl, or pyridyl; with the proviso that when W is morpholino, thiomorpholino, 1-oxido- . thiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R; is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N'-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is a direct link, then Y is not phenyl, substituted or unsubstituted C1-C6-alkyl, or 1-oxidothiomorpholino; and with the proviso that when R; is phenyl independently substituted with one to five substituents selected from hydrogen, cycloalkyl, heterocycloalkyl, halo, nitro, amino, sulphonamido, or alkylsulphonylamino, R; is hydrogen, haloalkyl, alkyl, or halo, and X is

NR, then Y is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

In one embodiment, the invention provides compounds of formula (I), wherein

Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heterocyclyl, and (4) substituted or unsubstituted heteroaryl;

X is selected from the group consisting of (1) adirect link, (2) NRE), (3) -(CH)yn-C(R?*, R3X)-N(R1¥)-, and

C)) ~~ wherein R1¥, R2X, R3X are independently H or substituted or unsubstituted

C,-Cg-alkyl; and ; W is selected from the group consisting of \ 0)

Z ’ wherein Z is -O- or NRZ-, wherein R4W is H or substituted or unsubstituted

Cy-Cgalkyl.

In another embodiment, the invention provides compounds of formula @, wherein

Y is selected from the groups consisting of . ¢)) substituted or unsubstituted heterocyclyl, 2) substituted or unsubstituted heteroaryl,

X is selected from the group consisting of (1) adirect link, (2) NRX), (3) «(CHp)y-CR?*, R3%)-N(RI¥)-, and 4) — wherein RIX, R2X, R3X are independently H or substituted or unsubstituted

C,-Cs-alkyl; and

W is selected from the group consisting of x ,) z H wherein Z is -O- or -NRZ-, wherein R4¥ is H or substituted or unsubstituted

C;-Cg-alkyl.

In another embodiment, the invention provides compounds of formula (I), wherein

Y is substituted or unsubstituted aryl;

X is selected from the group consisting of (1) adirect link, 2? NR), (3) ~(CHp)u-C(RZ*, R3X)-N(RI¥)-, and “4 ~~ wherein R1X, R2X, R3X are independently H or substituted or unsubstituted

C,-Cg-alkyl; and

W is selected from the group consisting of y “J 4 H]

wherein Z is -O- or -NRZ-, wherein R4¥ is H or substituted or unsubstituted

C-Cg-alkyl.

In another embodiment, the invention provides compounds of formula, (I), . wherein

Y is substituted or unsubstituted alkyl;

X is selected from the group consisting of (1) adirect link, @ NR", (3) -(CHp)p-CR¥ R¥-NR™-, and 10 .@ — wherein R1¥, R2x, R3X are independently H or substituted or unsubstituted

C,.Cg.alkyl; and

W is selected from the group consisting of

N

“rg,

Z ’ wherein Z is -O- or -NRZ-, wherein R4Y is H or substituted or unsubstituted

C;-Cg-atkyl.

In another embodiment, the invention provides compounds of formula (I), wherein

Y is selected from the group consisting of 4) substituted or unsubstituted heterocyclyl, (2) substituted or unsubstituted heteroaryl;

X is selected from the group consisting of (1) adirect link, (2) NRX), (3) -(CHy)p-C(R2X, R3%)-N(RI¥)-, and : 4) — wherein R1X, R2X, R3X are independently H or substituted or unsubstituted

C,-Ce-alkyl;

Rj is substituted or unsubstituted aryl; and

Wis )

Z bd wherein Z is -O- or -NH-.

In another embodiment, the invention provides compounds of formula (I), 5S wherein

Y is substituted or unsubstituted aryl;

X is selected from the group consisting of (1) adirect link, @ NR™-, 3) ~(CHpmCR™ R¥-NR"-, and 4) ~— wherein R™, R%, R* are independently H or substituted or unsubstituted

C;.Cg.alkyl;

R, is substituted or unsubstituted aryl; and

Wis )

Z Hi wherein Z is -O- or -NH-.

In another embodiment, the invention provides compounds of formula (I), wherein

Y is substituted or unsubstituted alkyl;

X is selected from the group consisting of (1) adirect link, oo 2 -NRM-, (3) -(CHYp-CR™ R™-NR™)-, and

TN

. —N N— 4) ~— wherein R', R*, R* are independently H or substituted or unsubstituted

C;-Cg-alkyl;

Rj is substituted or unsubstituted aryl; and rs

Wis () . z Hd wherein Z is -O- or -NH-.

In another embodiment, the invention provides compounds of formula (I) having structure (II):

Ry rN a () (0) (II) wherein Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heterocyclyl, and (4) substituted or unsubstituted heteroaryl; and

X is selected from the group consisting of (1) adirectlink, 2) NR). (3) -(CHp)u-CR2X, R3X)-N(RI)-, and @ n—~ .

In another embodiment, the invention provides compounds of formula (I) having structure (I), wherein Y and X, taken together, are selected from the group consisting of ’ H p) 3

COT eA

N h N { H

H H H CH,

Ac H H H H H 0 H

A ooh CY pi Sr C T pi 0 O 0)

H ‘ H

N re Shh Cy RA is ~

N=~/ ZZ

HaCO™ NF N~# Z H

H NT

N ~

N ~ EN ~ = N

NT ~ NX ON OR Sh ~ NA

H IN

Si Sl: > ND \

NZ OL = CL NZ NO 0

CHa HO 0 OCH

LO, WO & NH— OJ SN, HO N— ~~ rd oN ON NT re

SS CD

IT Sonn

Cl ON re (ON - ~ HaC.

NON rN (NT Ha NT

J dN

P Oh 0)

In another embodiment, the invention provides compounds of formula (I) having structure (II), wherein Y and X, taken together, are selected from the group consisting of

HO MeO HyCO

H H H H

Or NOR BORRCH

HaCO HO H,CO

H H H H

HsC I )

HsCO "0 HsC HO

H CH; H oor aot

H

HC "0

HC. H ® H 30 4 HCO N_ (ID / MS a J

OC es

OH N OCH

H H " H

N

NON OANe SO

CLT vo 0 0 HCO

In another embodiment, the invention provides compounds of formula (I) having structure (II), wherein Y and X, taken together, are selected from the group consisting of : H

H H HN N__

He Hao Ms HOT ers oN

OH and 2

Rs Re yg Ri

E N._-N

Hol RT

R, \'4 (IID wherein R3, Ry, Rs, Rg are selected from the group consisting of (1) H, (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COORt!l, (4) -COONHj,, (5) -ORlt and (6) -NHR!t,

In another embodiment, the invention provides compounds of formula (I) having structure (IV):

Rs Re um Ri 5 N. __N

N

H Re 1

CQ

0

Iv) wherein R3, Ry, Rs, Rg are selected from the group consisting of a HH (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COORI!t, (4) -COONH,,

(5) -ORlt and (6) -NHRI,

In another embodiment, the invention provides compounds of formula (I) having . structure (V):

R, Re Hg Ri 7 SL R% RY)

N 7 Ry he (J

Vv) wherein R3, Ry, Rs, Rg are selected from the group consisting of

I) H, (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COOR1M, (4) -COONH,, (5) -ORIt and (6) -NHRIt; and

R22 and R2b are selected from the group consisting of

I Hh (2) substituted or unsubstituted alkyl, (3) halo, 4) -(CHpyN(R2e, R29), 5) -(CHy)¢- N(R, R2d)CORZ2e, (6) -(CHy)q OR, (7) -(CH,);-OCORZe, 8 -(CHp){-OCOOR?, (9) -(CH,)-COORZe, (10) -(CH,)4-CONRZ, (11) -CN, (12) NO, (13) -SO,NH, (14) -NHSO,CHj3, and

(15) -SO,RZf wherein R2¢, R24, R2¢, and R?f are selected from the group consisting of (@ H, i (b) substituted or unsubstituted alkyl, and (©) substituted or unsubstituted phenyl; and qis0,1,2,3,or4.

In another embodiment, the invention provides compounds of formula (I) having structure (VI):

H

N R,

EY

OY

N ZZ

S$ 0 (VD)

wherein R is selected from the group consisting of } pe OH Jl OH OCHjs OCH,CHj3 2, OL, Die OF

OCF, 0” “CH, oy CH 0 c(h, CHs

QA Og, OL oN cy ee a-— o) OCH,

NH,

JOT JONNY Longs

Cl

JOR jal jou JO j “TL

O Cl OH OH OW OH

F i x Ig JON ~ ~ ~ LL ~ 9 “NO, 9 ~S0,CH; JON ~ “CHy

Tea. OL OD OY

CHa

In another embodiment, the invention provides compounds of formula (I) having structure (VII):

Rog Ri

NY

N._2N

RY Ry OY

Rg \'4 (VID wherein Ry, Rg, Rg, and Rj are selected from the group consisting of

I HH

(2) substituted or unsubstituted C;-Cg-alkyl, (3) —COORIt, (4) —COONH,, (5) —ORIt and (6) -NHRIt,

In another embodiment, the invention provides compounds of formula (I) having structure (VIII): :

Rio g ki

SOS

:

N.__N

Ry Rg Y

Se 0 (VII) wherein Ry, Rg, Rg, Ry are selected from the group consisting of 1) KH (2) substituted or unsubstituted C;-Cg-alkyl, (3) —COORL, (4) —CONH,, (5) —ORlt and (6) -NHRIt

In another embodiment, the invention provides compounds of formula (I) having structure (IX):

H ~ ®'2 RY) pe ae

N

(J

Xx) wherein R12 and RIV are selected from the group consisting of 1) HK (2) substituted or unsubstituted alkyl, (3) halo, (4) (CH NR, RZ, 3) -(CHp)-N(R?®, R2d)COR2e, (6) -(CHp),OR?, 7 -(CH,)-OCORZe, 8) -(CH,)-OCOOR?e, 9) -(CH,)-COOR?e, (10) -(CHp)4-CONRZe, (11) -CN, (12) -NO,, (13) -SO,NH,, (14) -NHSO,CHj3, and (15) -SO,RZf, wherein R%¢, R2d, R2¢, and Rf are selected from the group consisting of (@ H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted phenyl; and

R7 is selected from the group consisting of (1 BH, (2) substituted or unsubstituted C;-Cg-alkyl, (3) —COORIt,

4) -COONH,, (5) -ORIt and (6) -NHRIL,

In another embodiment, the invention provides compounds of formula (I) having structure (X):

H

NYY

J

0

X)

wherein Ry is selected from the group consisting of : pe OH JO OH OCH, OCH,CH,

Oo, OA, Oa OE

OCF, 0” “CH; ony Ce occa,

CH

O48 Of, Of oe, oP, (0) OCH,

NH,

Jo JONNS Lms

Cl oO Ci OH OH POW OH

F oO 00 a, 2, LL o (0) CF; CN CO,CHj3 - 9 “NO, = ~SO,CH; JON - _ “CHy ~ eee LL, OL OO

NHSO,CH3 NH, F Cl °r

CH,

In another embodiment, the invention provides compounds of formula (I having structure (XI):

OR

Ie

N

A

NIT

N ~~ 0] 5 (XD) wherein R28 is selected from the group consisting of

I HH

(2) substituted or unsubstituted alkyl, (3) -CONHR2h (4) ~CON(R?)-(CHy)p3N(R2:, R2), (5) -CORZ, (6) -CO,RZ, (7) —COC;-Cg4-alkyl-CO,H, (8) -CH,-OC(=O)RZi, (9 -CH,-OC(=0O)NHCHR2iCO,R3, (10) -P(=0)(ORZk, OR?p),

CO,H 0

HO

OH

(11) OH and 6]

N_

AIO

1] Ne) (12) 0 ’ wherein R2b, R2i, R2i, R2k and R2P are selected from the group consisting of (@ H, (b) substituted or unsubstituted alkyl, and (©) substituted or unsubstituted aryl.

In another embodiment, the invention provides compounds of formula (I) having structure (XII):

OR?

H

NX N 7S (J

O

(XID) wherein R28 is selected from the group consisting of 1 H (2) substituted or unsubstituted alkyl, (3) -CONHRZ?h, (4) ~CON(R?)-(CHp)y 5-N(R2:, R2), (5) -COR%, (6) -CO,RZ, ¢)) ~COC,-C¢-alkyl-CO5H, (8) -CH,-OC(=0)R2i, (9) -CH,-OC(=O)NHCHRZ2ICO,RZ, (10) -P(=0)(OR2Zk, OR2p),

CoH 0]

HO

OH an OH ,and 0

AT

55 (12) 0 , wherein R2h, R21, RZ], RZK, and R2P are selected from the group consisting of (@ H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted aryl.

In another embodiment, the present invention provides compounds of the following formula (I):

R,

PR

NN

¥

I wherein W is:

A

Ra) ) 7% 'n wherein Z is selected from the group consisting of -CH,-, -NH-, -O-, -S-, and —

NRg-, where Rg is an alkyl or substituted alkyl group;

Rj is absent or selected from the group consisting of alkyl, substituted alkyl, amino, alkylamino, aminoalkyl, dialkylamino, dialkylaminoalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, carbonylamino, and alkoxycarbonyl; and . m and n are integers from 0-2;

X is a covalent bond or is selected from the group consisting of -CH,-, -CHF-, -CF>-, -NH-, -O-, -S-, and -NRs-, where Rs is an alkyl or substituted alkyl group;

Y is selected from the group consisting of heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R; is selected from the group consisting of hydrogen, halogen, carboxylic acid, and alkyl; and

R; is selected from the group consisting of heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the tautomers thereof, and the pharmaceutically acceptable salts, esters, or prodrugs thereof.

In another aspect of the compound of formula (I), W is a morpholinyl group as . shown below:

L

®t J, oo” 'n wherein, R3, m, and n are as described above,

In another more particular embodiment of compound (I), W is an unsubstituted morpholiny! group.

In another more particular embodiment of compound (I), X is -NH-. 5S In another more particular embodiment of compound (I), Y is a heteroaryl or substituted heteroaryl group selected from pyridyl, and alkoxypyridyl.

In another more particular embodiment of compound (I), R; is hydrogen.

In another more particular embodiment of compound (I), R, is an aryl or substituted aryl group.

In another more particular embodiment of compound (I), R, is selected from the group consisting of phenyl, phenol, aniline, hydroxybenzyl, phenylalkoxycarbonyl, phenylcarbonylalkoxy, phenylaminocarbonyl, and phenylcarbonylamino.

In another more particular embodiment of compound (I), Rj is absent.

In another embodiment, compounds of formula (II) are provided:

Ry dp

NN

N

) (J

II wherein X is selected from the group consisting of -NH-, -O-, and -S-;

Rj is hydrogen, halogen, or a carboxylic acid group;

R; is selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; the tautomers thereof, and the pharmaceutically acceptable salts, esters, or prodrugs thereof.

In another aspect of the compound of formula (II), X is -NH-.

In another aspect of the compound of formula (IT), Y is a heteroaryl or substituted heteroaryl group selected from pyridyl, and alkoxypyridyl.

In another aspect of the compound of formula (IT), R; is absent.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

L. A compound having the formula I: R, ENE

N.__N ¥ @ or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cs-alkyl, (2) substituted or unsubstituted C,-Cg-alkenyl, (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heterocyclyl, and (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, 2 -NRX:- (3) «(CH CR, R)-NR IY), “4 -O- 5) 5, 6) -SO- (7) -80,, (8) -C(R2X, R3X)-, and © — wherein RIX, R2%, and R3* are selected from the group consisting of @@ Hh, (b) substituted or unsubstituted C;-Cg-alkyl, (©) substituted or unsubstituted C,-Cg-alkenyl,

: | -

(d) substituted or unsubstituted C,-C¢-alkynyl, (¢) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis0,1,2,3,or4; R, is selected from the group consisting of 1) HK (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COOH, 4) halo, (5) -ORIt and 6) -NHRI, wherein R1t is H or C;-Cg-alkyl; Rj is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C,-Cg-alkyl, 2) NE R2W), and RL ™ 3) Ng Cr wherein R1W and R2W are selected from the group consisting of (@ H (b) substituted or unsubstituted Cy-Cg-alkyl, (c) substituted or unsubstituted aryl, : (d) substituted or unsubstituted heterocyclyl, and (e) substituted or unsubstituted heteroaryl, wherein R1W and R2w are not both H;

Z is selected from the group consisting of @ -O-, (b) = -NRZ, . (c) -S- (d -SO-, (e) -SO,-, and f -CHp, wherein RZ is H or substituted or unsubstituted alkyl group; and RAW is selected from the group consisting of (@ H (b) substituted or unsubstituted C;-Cg-alkyl, (c) -COOR>W, (d) -CONH,, (e) —OR3%, and (H -NHRSV, wherein ROW is H or C;-Cg-alkyl; and ris 0, 1, or 2; with the proviso that when X is O, then Y is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; with the proviso that when W is morpholino, thiomorpholino, 1-oxido- thiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, Rj is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N'-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is NH, then Y is not hydrogen, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, chloro-phenyl, carboxy-phenyl, carbomethoxy-phenyl, or pyridyl; with the proviso that when W is morpholino, thiomorpholino, 1-oxido- thiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R; is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N'-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is a direct link, then Y is not phenyl, substituted or unsubstituted C1-Cé-alkyl, or 1-oxidothiomorpholino; and with the proviso that when Rj is phenyl independently substituted with one to five substituents selected from hydrogen, cycloalkyl, heterocycloalkyl, halo, nitro, amino, sulphonamido, or alkylsulphonylamino, R; is hydrogen, haloalkyl, alkyl, or halo, and X is

NR, then Y is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

2. The compound of claim 1, wherein Y is selected from the group consisting of (1) substituted or unsubstituted C4-Cg-alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heterocyclyl, and (4) substituted or unsubstituted heteroaryl, X is selected from the group consisting of (1) adirect link, 2 NRX, (3) -(CHp)y-CR*,R3X)-NRI¥)-, and 4) — wherein R1%, R?X, R3X are independently H or substituted or unsubstituted C,-Cg-alkyl; and W is selected from the group consisting of \ “g) z ’ wherein Z is -O- or -NR2z-, wherein R4¥ is H or substituted or unsubstituted C;-Cg-alkyl.

3. The compound of claim 1, wherein Y is selected from the group consisting of ¢)) substituted or unsubstituted heterocyclyl, 2) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, 2) NRX),

(3) «(CHp)p-CR?*, R3¥)-N(RIX)-, and —N N— 4) ~ wherein RIX, R2X, R3X are independently H or substituted or unsubstituted C;-Ce-alkyl; and W is selected from the group consisting of 4 ad ) \, wherein Z is -O- or -NRZ-, wherein R4W is H or substituted or unsubstituted C,-Cg¢-alkyl.

4. The compound of claim 1, wherein Y is substituted or unsubstituted aryl; X is selected from the group consisting of (1) adirect link, 2) NRX). (3) «(CHp)p-C(R?X,R¥¥)-N(R1X)-, and : @ wherein RIX, R2%, R3X are independently H or substituted or unsubstituted C,-Cg-alkyl; and W is selected from the group consisting of 4 ead ) . \, wherein Z is -O- or -NRZ-, wherein R4W is H or substituted or unsubstituted C;-Cg-alkyl.

5. The compound of claim 1, wherein Y is substituted or unsubstituted alkyl;

- X is selected from the group consisting of ¢)) a direct link, @ NR", (3) (CHpp-CR™ R™)-NR™-, and (4) ~7 wherein R1x, R2x, R3x are independently H or substituted or unsubstituted

C;.Cg.alkyl; and W is selected from the group consisting of RW T ) Z > wherein Z is -O- or -NRZ-, wherein R4Y is H or substituted or unsubstituted C;-Cg-alkyl.

6. The compound of claim 1, wherein Y is selected from the group consisting of (1) substituted or unsubstituted heterocyclyl, (2) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, 2) NRX). (3) -(CHp-CR2Y, R*)-NR¥)-, and 4) ~~, wherein R1¥, R2X, R3X are independently H or substituted or unsubstituted C,-Cg-alkyl; Rj is substituted or unsubstituted aryl; and

Wis () 2 wherein Z is -O- or -NH-.

7. The compound of claim 1, wherein Y is substituted or unsubstituted aryl; X is selected from the group consisting of (1) adirect link, @ NR, (3) ~-(CHppCR™ R¥)-NR™)-, and /N\ (4) — wherein R™ R*, R* are independently H or substituted or unsubstituted C,-Cg-alkyl; R, is substituted or unsubstituted aryl; and Wis CO) Z ? wherein Z is -O- or -NH-.

8. The compound of claim 1, wherein Y is substituted or unsubstituted alkyl; X is selected from the group consisting of (I) adirect link, 2 NRY-, (3) -(CHpyCR™R™-NR™)-, and I (4) ~~, wherein R', R®, R™ are independently H or substituted or unsubstituted . C;-Cg-alkyl;

Rj is substituted or unsubstituted aryl; and Wis . 0 Z LH] wherein Z is -O- or -NH-,

9. The compound of claim 1, having the formula II: R PNR aa J) 0 dn wherein Y is selected from the group consisting of (1) substituted or unsubstituted C,-C¢-alkyl, (2) substituted or unsubstituted aryl, (3) substituted or unsubstituted heterocyclyl, and (4) substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (1) adirect link, (2) NRX): (3) ~(CHp-CR?%, R3)-N(RIX)-, and C)) \—/

10. The compound of claim 1, having the formula II: R YIN aa

J 8] an -107-

lL

“wherein Y and X, taken together, are selected from the group consisting of ) H 4 n N ICL NP N N N ~ 7] N ~ . ~ ~ HiC CO eID N N N { N H H H CHa H Ac H H H H H H Oo oOo aot Oot (0) 0 0) H H SOR She Ohi FINNS Or N= HaCO = NA yy =/ H % H ~ N ~ N = nN” Ny < IAN < S rd N N 1 ) A Ni N © CH, _ “CH; _ “CH; O OCH; THs HO be re SEC HNG, NH— O 7 re SONS: “or oY SUD 7 enAn Cl O,N pd oN P -

HiC. Ns N_ I$) HC () i gS (0)

11. The compound of claim 1, having the formula II: R; ON ae 0) O (In wherein Y and X, taken together, are selected from the group consisting of H H OMe H H HO MeO HaCO H H H H rr No ROARS HsCO HO HsCO H H H H H HaCO Co HaC HO H CH H oY aot H HC” "0 H ® H "oy Heo N C0 3 Oi TC re OH N OCHj H H H N H oJ 0 CTT 0 HCO

12. The compound of claim 1, having the formula II: R; NN 0 (0) dn wherein, Y and X, taken together, are selected from the group consisting of H H H HN N_ Hae Haco™ NN HOT on CL OH and 2,

13. The compound of claim 1, having the formula III: Rs Re H Ry

N._2N N H Re YT Ry Ww (IID) wherein R3, Ry, Rs, Rg are selected from the group consisting of I (2) substituted or unsubstituted C,-Cg-alkyl, (3) -COORtl, (4) -COONH,, (5) -OR!t and (6) -NHRIt -110- i

14. The compound of claim 1, having the formula IV: Re BR mw Ri ST

N.__N Ho] & 1 Ee 0) av) wherein R3, Ry, Rs, Rg are selected from the group consisting of I (2) substituted or unsubstituted C;-C¢-alkyl, (3) -COOR1t, (4) -COONH,, (5) -ORIt and (6) -NHRIt,

15. The compound of claim 1, having the formula V: Rs Rg H R; = ns ®R® rR?) esq NS | ’ N’ 3 N__N N H Rs I C0 0) ) - wherein Rj, Ry, Rs, Rg are selected from the group consisting of 1 HH (2) substituted or unsubstituted C,-C¢-alkyl, - (3) -COORIt, (4) -COONH,, ) (5) -ORl and (6) -NHRIt; and

R22 and R2D are selected from the group consisting of I KH (2) substituted or unsubstituted alkyl, . (3) halo, 4) -(CHpg NR? R29), (5) ~(CHp)N(R2, R2CORZ, (6) -(CHp)q-OR?e, (7) -(CH,)-OCORZ, (8) -(CH,);-OCOORZe, (9 ~(CHp)-COORZ, (10) -(CH,);-CONRZe, (11) CN, : (12) -NO,, (13) -SO,NH, (14) -NHSO,CHj, and (15) -SO,R2f wherein R2¢, R24, R2¢, and Rf are selected from the group consisting of @ H (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted phenyl; and qis0,1,2,3,0r4.

16. The compound of claim 1, having the formula VI: H ry ® (VD wherein Rj is selected from the group consisting of OH JO OH OCH OCH,CH,

L.A, Ofte O23 OCF, 0” “CH; oH oP c(t CH; Os, OA, Ot _— 0h, 0 OCHj, NH, Jon JOSS Loy cl 0 Cl OH OH po 2, F O00 Qo, a, 2 0 0 CF3 CN CO,CH4 JO ’ SO,CHg 7 | C(CHg3)3 CH, F soe, A, I, OD, I NHSO,CHj NH, F Cl J Jou OO CH;

17. The compound of claim 1, having the formula VII: Rio g Ri NSN

N._N RY Ry OY Rg w (VID) wherein R7, Rg, Rg, and Ry are selected from the group consisting of I KH (2) substituted or unsubstituted C;-Cg¢-alkyl, (3) -COORl, (4) -COONH,, (5) -ORIt and (6) -NHRLI,

18. The compound of claim 1, having the formula VIII: Rog Ri NYY Rg ZZ R, Mp Rg ™ Oo (VII wherein Ry, Rg, Rg, Ry are selected from the group consisting of 1 HH 2) substituted or unsubstituted C;-C¢-alkyl, (3) -COOR1t, (4) —CONH,, (5) ORI, and . (6) -NHRI,

19. The compound of claim 1, having the formula IX: = Z RY N CJ IX) wherein R12 and RIP are selected from the group consisting of I H (2) substituted or unsubstituted alkyl, 3) halo, 4) (CHp) N(R, R2d), 6) -(CHy)¢-N(R2e, R2d)COR2e, 6) -(CHy)q-OR?e, (7) -(CHy)q-OCORZe, ®) -(CH;)q-OCOOR?Ze, C)) -(CH,)q-COOR?Ze, (10) -(CH,)-CONRze, (11) -CN, (12) -NO,, (13) -SO,NH,, (14) -NHSO,CHj3, and (15) -SO,R2f, wherein R2¢, R24, R2¢, and Rf are selected from the group consisting of (@ H (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted phenyl; and - wherein Ry is selected from the group consisting of (I) H (2) substituted or unsubstituted C;-C¢-alkyl, (3) -COORIt,

“4 —CONH,, (5) -ORM and (6) —NHRIt,

20. The compound of claim 1, having the formula X: H N R SN 2 ORD = he 0) (0) X)

wherein R; is selected from the group consisting of OH Jol OH OCH; OCH,CH;4 Lr, Ot, Oto OS OCF; 0” “CH; on Ce 0” (oH, CHa CAL, Of, OL oP ety oe, 0” och, NH, Jon JOBS Los Cl ¢ ci OH OH POW OH F CO 00 a, Qa, CL o 0 CFs CN CO,CH4 JO PON JON - 3 "CH3 F Loe, 0 OL OL OY Jou Je CH

!

21. The compound of claim 1, having the formula XI: OR? ) H SORD : NN N A (0) XI) wherein R28 is selected from the group consisting of (I H (2) substituted or unsubstituted alkyl, (3) -CONHR2h, (4) -CON(R2h)-(CH,), 3-N(R2h, R2i), (5) -COR%, (6) -CO,RZ, (7) —~COC;-C4-alkyl-CO,H, (8) -CH,-OC(=0O)RZ, (9) -CH,-OC(=O)NHCHRZ2ICO,R2i, . (10) -P(=0)(ORZk, OR2p), CO,H O HO OH (11) OH , and 0] N_ / (J p 17 Ne) (12) 0 , : wherein R?h, R21, R2j, R2k and R2P are selected from the group consisting of (@ H, : (b) substituted or unsubstituted alkyl, and (©) substituted or unsubstituted aryl.

22. The compound of claim 1, having the formula XII: OR’ H NX N X = he J O XII) wherein R28 is selected from the group consisting of OH KH (2) substituted or unsubstituted alkyl, (3) -CONHR?h, (4) ~CON(RZ)-(CHy)y. N(R, R), (5) -CORZ, (6) -CO,RZ, (7) —COCy-Cg-alkyl-CO,H, (8) -CH,-OC(=O)R2i, (9) -CH,-OC(=0)NHCHRZ2ICO,R?, (10) -P(=0)(ORZ2k, OR2p), CoH Oo HO OH (11) OH , and 0] N I) In “0 (12) 0 , wherein R2h, R2i) R2), R2k, and R2P are selected from the group consisting of @ H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted aryl.

23. A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound effective to inhibit phosphotidylinositol (PI) 3-kinase activity in a human or animal subject when administered thereto, wherein the compound has the formula I:

R; SE N_-N ¥ @ or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, (2) substituted or unsubstituted C,-Cg-alkenyl, (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heterocyclyl, and (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, (2) NR), (3) ~(CHy)yrCR, REX)-NRIX)-, “4 -O- GS, (6) -SO-, (7) -80g-, (8) -C(R2X,R3X)., and 6) ~~ wherein RIX, R2X, and R3X are selected from the group consisting of : @ § (b) substituted or unsubstituted C;-C¢-alkyl, (c) substituted or unsubstituted C,-Cg-alkenyl, (d) substituted or unsubstituted C5-Cg-alkynyl,

(e) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis0,1,2,3,0r4; R; is selected from the group consisting of 1 HH (2) substituted or unsubstituted C,-Cg-alkyl, (3) - -COOH, 4) halo, (5) -ORI!t and 6) -NHRI, wherein R!t is H or C;-Cg-alkyl; R, is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, 2) NEE R2w), and ef) 3) N 2 (Cx wherein R1W and R2W are selected from the group consisting of (@ H (b) substituted or unsubstituted C;-Cg-alkyl, ©) substituted or unsubstituted aryl, (d) substituted or unsubstituted heterocyclyl, and : (¢) substituted or unsubstituted heteroaryl, wherein RY and R2w are not both H; Z is selected from the group consisting of @@ -O- (b) -NRZ, (c) -5,

CY n PCT/US2003/037294 : d -S0- . . (e) -S Oy, and ® CH, oo wherein RZ is H or substituted or unsubstituted alkyl group; and R4V is selected from the group consisting of = Co @ EH oo E (b) substituted or unsubstituted C;-Cgalkyl, =~ (c) —COORS¥, (d -CONH,, (6) —ORSW, and ® -NHRSW, : wherein R5¥ is H or C;-Cg-alkyl; and : ris 0,1,0r2. EEE oo 24. - The composition of Claim 23 further comprising at least one additional agent for the treatment of cancer. 2s The composition of Claim 24, wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, tamoxifen, CPT 11, and trastuzumab.

26. Use of a compound having the formula I: B Ee | : . : NN w ora stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein | | | : : A122 : AMENDED SHEET

® Co | PCT/US2003/037294 : Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg4-alkyl, © (2) substituted or unsubstituted C,-Cq-alkenyl, Co : (3) substituted or unsubstituted C,-Cg-alkynyl, - GC) substituted or unsubstituted aryl, : oo (5) substituted or unsubstituted heterocyclyl, and : (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, : @ NRW, (3) ~(CHp)y-CR*, RIXN(RIY)-, @ 0, oo A ONE oo oo 6) -SO-, - (0 -S0,, . (8) -C(R2X,R3X)-, and oN | oo © ~~, wherein RX, R2X, and R3X are selected from the group consisting of @ H oo (b) substituted or unsubstituted C;-Cg-alkyl, Co oo (c) substituted or unsubstituted C,-Cg-alkenyl, © (d) substituted or unsubstituted C-Cg-alkynyl, : ~ (e) substituted or unsubstituted aryl, . i oo : ® substituted or unsubstituted heterocyclyl, _. (2) substituted or unsubstituted heteroaryl; and B © mis0,1,2,3,or4; SE R, is selected from the group consisting of 1) H : (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COOH, 4 halo, EE (5) -ORI!t, and -123- oo AMENDED: SHEET i

C PCT/US2003/037294 6) -NHRY, : ‘wherein R1t is H or C-Cg-alkyl; : R, is selected from the group consisting of (1) substituted or unsubstituted aryl, - (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of . (1) substituted or unsubstituted C;-Cg-alkyl, @ Ne ROW), and ct™ ) 3) \(CHa)r | co : wherein RW and R2W are selected from the group consisting of @ B&H ‘(b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl,

r. : (d) substituted or unsubstituted heterocyclyl, and (¢) substituted or unsubstituted heteroaryl, wherein R1% and R2w are not both H; : oo Z is selected from the group consisting of : : : @ 0, : ®) NRE, | B © @ -SO-, | oo : (e) -SO5-, and ® CH, : : | Co ! wherein RZ is H or substituted or unsubstituted alkyl group; and : Réwis selected from the group consisting of @ H (b) substituted or unsubstituted C;-Cg-alkyl, (c) —COORSW, oo oo (dy —CONHy, : (6) —~ORSY,and ; ~124- AMENDED SHEET | :

® © PCT/US2003/037294 (fH -NHRS¥, | g wherein R3Y is H or C,-C4-alkyl; and ris 0, 1, or 2 in the manufacture of a medicament for treating a condition by modulation of phosphotidylinositol (PI) 3-kinase activity.

27. Use of Claim 26, wherein the compound has an IC50 value of less than about uM in a cell proliferation assay.

28. Use of Claim 26, wherein the condition is cancer. © 29. A method for inhibiting phosphotidylinositol (PI) 3-kinase activity ina = - human or animal subject, comprising administering to the human or animal subject a * composition comprising an amount of a compound effective to inhibit phosphotidylinositol (PI) 3-kinase activity in the human or animal subject, wherein the compound has the formula I: R, NN he ora stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug _ thereof, wherein : oo Y is selected from the group consisting of © (1) substituted or unsubstituted C;-Cg-alkyl, oo (2) substituted or unsubstituted Cy-Cg-alkenyl, (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, | : (5) substituted or unsubstituted heterocyclyl, and oo (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of oo (1) adirect link, (2) -NRIx)., : - (3) (CH)y-CR?%,R¥)-NRIX)-, : @ 0, 1s a. co - AMENDED SHEET - }

GS, (6) -SO- (7) -SOp, (8) -C(R2X,R3X)-, and ©) — wherein RIX, R2X, and R3X are selected from the group consisting of (@ H (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted C,-Cg-alkenyl, (d) substituted or unsubstituted C,-Cg-alkynyl, (¢) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis0,1,2,3,or4; Rj is selected from the group consisting of (1) H (2) substituted or unsubstituted C;-Cg-alkyl, 3) -COOH, (4) halo, (5) -ORIt and (6) -NHRI, wherein R1tis H or C;-Cg-alkyl; Rj is selected from the group consisting of (1) substituted or unsubstituted aryl, 2) substituted or unsubstituted heteroaryl, and 3) substituted or unsubstituted heterocyclyl; and : W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, 2) NE R2W), and rR ™ 3) NN 7 {Cr

® oo : © PCT/US2003/037294 Co wherein R1% and R2W are selected from the group consisting of : CL (@) B,

a . (6) substituted or unsubstituted C;-Cg-alkyl, SE : | (c) substituted or unsubstituted aryl, (d) substituted or unsubstituted heterocyclyl, and : (e) substituted or unsubstituted heteroaryl, , wherein RW and R2w are not both H; ~ Zis selected from the group consisting of oo : (a) :0-, . ®) -NRz-, . - i (©) -S-, . © @ -SO-, Co (e) -SOp~, and ® -CH, wherein RZ is H or substituted or unsubstituted alkyl group; and R4W is selected from the group consisting of (® H : - (b) substituted or unsubstituted C;-Cg-alkyl, ©) —COORS¥, SE @ -CONH, €) ~ORSW, and ® NHR, wherein RS is H or C-Cg-alkyl; and | . : ris 0, 1, or 2. : }

30. A substance or composition for use in a method for treating a cancer disorder in a human or animal subject, said substance or composition comprising a compound having the formula I: -127- AMENDED SHEET

9 : PCT/US2003/037294 Ry : - | PENN - he - Ww 0 or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug. : thereof, wherein 'Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, (2) substituted or unsubstituted C,-Cg-alkenyl, (3) substituted or unsubstituted C,-C¢-alkynyl, _ | (4) substituted or unsubstituted aryl, : 5) substituted or unsubstituted heterocyclyl, and oo ~ (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, @ NRW, (3) -(CHyur CR, RIGNRIX), @ -0, a NORE | : : ‘© -so-, (7) -50p, : (8) -C(R2X R3X)-, and : = ©) ~—~ wherein R1X, R2X and R3X are selected from the group consisting of (® H' : (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted C,-Cg-alkenyl, So © (d) substituted or unsubstituted C,-C-alkynyl, : (e) substituted or unsubstituted aryl, (fy substituted or unsubstituted heterocyclyl, : (g) substituted or unsubstituted heteroaryl; and -128- N : | : AMENDED SHEET SE

: oo ® PCT/US2003/037294 E mis0,1,2,3, 0rd; oo . © Rj is selected from the group consisting of + 1 H oo (2) substituted or unsubstituted C;-C¢-alkyl, (3) -COOH, Co (4) halo, | ] (5) -ORI and (6) NHR, wherein R1t is H or C-Cg-alkyl; : * Ry is selected from the group consisting of (1) substituted or unsubstituted aryl, Co (2) substituted or unsubstituted heteroaryl, and : EC) | substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C;-C¢-alkyl, @) Na, R2¥), and | | oo rl) - ® Lo wherein R1W and R2V are selected from the group consisting of @ H, (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl,. Co - (d) substituted or unsubstituted heterocyclyl, and oo (e) substituted or unsubstituted heteroaryl, wherein RIW and R2w are not both Hi; Z is selected from the group considing of : oo | CC @ Oo, oo oo (®) -NR%, : (© -S-, (@ -SO-, Ce (6) 80, and ®H CHp -129- Co oo : AMENDED SHEET :

® PCT/US2003/037294 wherein RZ is H or substituted or unsubstituted alkyl group; and ~~ oo R4V is selected from the group consisting of : @ KH oo (b) substituted or unsubstituted C;-Cgalkyl, oo (cy —COORSw, @ -CONH, oo (¢) —OR5V¥, and : ® “NHR5W, : oo ‘wherein RSW is H or C;-Cg-alkyl; and oo ris 0, 1, or 2, and said method comprising administering a phosphotidylinositol (PI) ’3-kinase activity inhibiting amount of said substance or composition to the : human or animal subject.

31. A substance or composition for use in a method of treatment of Claim 30 . further comprising administering to the human or animal subject at least one additional agent for the treatment of cancer.

32. A substance or composition for use in a method of treatment of Claim 31, wherein the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, tamoxifen, CPT 11, and trastuzumab. !

33. Use of a compound having the formula I: : Ry ENR

N._N | . or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein Y is selected from the group consisting of : ) - substituted or unsubstituted C,-Cg-alkyl, } (2) substituted or unsubstituted C,-Cg-alkenyl, SL -130- AMENDED SHEET

PY PCT/US2003/037294 (3) substituted or unsubstituted C,-C¢-alkynyl, oo (4) substituted or unsubstituted aryl, 6) substituted or unsubstituted heterocyclyl, and. : (6) substituted or unsubstituted heteroaryl; R X is selected from the group consisting of (1) adirect link, @ NRW, 3) (CH) CR, R3)-NRIX)., @ -O-, oo NORE © 80, @ -80p-, (8) -C(R2x,R3X)., and — © wherein RIX, Rx, and R3X are selected from the group consisting of @® §H o (b) substituted or unsubstituted C,-C¢-alkyl, (c) substituted or unsubstituted Cy-Cg-alkenyl, : (d) substituted or unsubstituted C,-Cg-alkynyl, Ce) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, : (2) substituted or unsubstituted heteroaryl; and misO,1,2,3,o0r4; : : R; is selected from the group consisting of : . OH (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COOH, (4) halo, : (5) -ORltand = : oo © NHR wherein R1t is H or C;-Cg-alkyl; oo : : R, is selected from the group consisting of . -131- : | AMENDED SHEET x

® | PCT/US2003/037294 (1) substituted or unsubstituted aryl, oo (2) substituted or unsubstituted heteroaryl, and : (3) substituted or unsubstituted heterocyclyl; and . W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, 2) Ne, R2%), and oo wy TC 0 oo @ Zz ar wherein R1¥ and R2W are selected from the group consisting of oo (a H - : (b) substituted or unsubstituted C;-Cg-alkyl, (©) substituted or unsubstituted aryl, ~ (d) substituted or unsubstituted heterocyclyl, and (¢) substituted or unsubstituted heteroaryl, wherein RIW and R2w are not both H; Z is selected from the group consisting of -@ 0, oo CC® Re, a © -S @ so . (® -S0p- and ® CHp, wherein R? is H or substituted or unsubstituted alkyl group; and RAW is selected from the group consisting of - @ H (b) substituted or unsubstituted C;-Cg-alkyl, (© -COORSw, (d) -CONH,, (6) —ORS¥,and oo © -NHRSW, : wherein RW is H or C-Cg-alkyl; and AE ris 0, 1, or 2. in the manufacture of a medicament for inhibiting tumor growth in a human or animal subject. -132- : AMEADED SHEET

C | PCT/US2003/037294

34. A method for inhibiting the proliferation of capillaries in a human or animal subject, comprising administering to the human or animal subject an effective amount of a compound having the formula I: oo 8, - . PEN

N.2N @ } : or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein - : Y is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, @) substituted or unsubstituted C,-Cg-alkenyl, (3 substituted or unsubstituted C,-C¢-alkynyl, a | (4) substituted or unsubstituted aryl, : (5) substituted or unsubstituted heterocyclyl, and : (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) adirect link, - oo @ NRX, (3) -(CHpp-CRZ, RIX)-NRI1X)-, : @ 0, 6B) -S, © -SOo-, oo : : (MH -SOy-, (8) -C(R,R3)- and a © ~~, "wherein R1X, R2X, and R3x are selected from the group consisting of . @ Ho (b): substituted or unsubstituted C 1-Ce-alkyl, (©) substituted or unsubstituted Cy-Cg-alkenyl, | oo - -133- , Cae AMENDED SHEET Co

(d) substituted or unsubstituted C,-Cg-alkynyl, (e) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis0,1,2,3,or4; R; is selected from the group consisting of I KH (2) substituted or unsubstituted C;-Cg-alkyl, (3) -COOH, (4) halo, (5) -ORIt and (6) -NHRI, wherein R1t is H or C;-Cg4-alkyl; Rj is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, 2) NEE R2W), and Ss ) 3) 2, wherein RI and R2V are selected from the group consisting of (a H, (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl, : (d) substituted or unsubstituted heterocyclyl, and (e) substituted or unsubstituted heteroaryl, wherein R!W and R2w are not both H; Z is selected from the group consisting of (@ -O- (b) -NRZ,

© 8, (d -S0O- (e) -SO,-, and (H -CHyp, wherein RZ is H or substituted or unsubstituted alkyl group; and RW is selected from the group consisting of @@ H (b) substituted or unsubstituted C;-Cg-alkyl, (cp —COOR>W, (d —CONH,, (¢) —-OR5W%, and (® -NHRSY, wherein R3V is H or C;-Cg-alkyl; and ris 0, 1, or 2.

35. A compound for use in the treatment of cancer, wherein the compound has the formula I: R,

N. _-N I! 0) or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein Y is selected from the group consisting of (1) substituted or unsubstituted C;-C¢-alkyl, (2) substituted or unsubstituted C,-C¢-alkenyl, : (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heterocyclyl, and (6) substituted or unsubstituted heteroaryl; X is selected from the group consisting of ¢)) a direct link,

@) NRX, (3) «(CHy)yr CR, RZ)NRY, 4) -O- : 6) -S 6) -SO- (7) -SOyp, (8) -C(R2x,R3x)., and ©) — wherein RIX, RZX, and R3x are selected from the group consisting of @ H, (b) substituted or unsubstituted C;-C¢-alkyl, (c) substituted or unsubstituted C,-C¢-alkenyl, (d) substituted or unsubstituted C,-C¢-alkynyl, (e) substituted or unsubstituted aryl, ® substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and mis0,1,2,3,or4; R is selected from the group consisting of 1 KH (2) substituted or unsubstituted C;-C¢-alkyl, (3) -COOH, (4) halo, (5) -ORIt and (6) -NHRI, wherein R1t is H or C;-Cg-alkyl; R, is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, : (2) NRW, R2W), and

- @ ~ PCT/US2003/037294 rv) €) pC , oo | Co - wherein R1W and R2¥ are selected from the group consisting of ® § | oo (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl, : oo (d) substituted or unsubstituted heterocyclyl, and (e) substituted or unsubstituted heteroaryl, wherein RW and R2w are not both H; : Z is selected from the group consisting of @ 0, ®) © NR%, oo Co | © -S- & -80, (e) -SO;-, and ® -CHp, wherein RZ is H or substituted or unsubstituted alkyl group; and B : R4¥ is selected from the group consisting of @ H- | | oo (b) substituted or unsubstituted C;-Cg-alkyl, (6) —COORS¥, (d) —CONH,, oo © (9 -ORW, and ® ~NHR>V, wherein R5¥ is H or C;-Cg-alkyl; and ris0,1,or2. oo

36. Use of a compound in the manufacture of a medicament for the treatment of cancer, wherein the compound has the formula I: : oo | | 137 - Bn | AMENDED SHEET =

® | PCT/US2003/037294 E : Ry YEN NN : : Co Ee a or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein . Y is selected from the group consisting of ~~ : (1) substituted or unsubstituted C;-C¢-alkyl, . (2) substituted or unsubstituted C,-Cg-alkenyl, : (3) substituted or unsubstituted C,-Cg-alkynyl, (4) substituted or unsubstituted aryl, a : (5) substituted or unsubstituted heterocyclyl, and (6) substituted or unsubstituted heteroaryl; CL X is selected from the group consisting of a (1) adirect link, @ NR, oo (3) (CHYp CER RWMNERY)-, CL @® oo, 6) 8, © so, oo Mm 80x (8) -C(R2x,R3X)., and —~ oo 6) — a. wherein R1X, R2X, and R3X are selected from the group consisting of - : @® H (b) substituted or unsubstituted C;-Cg-alkyl, oo (c) substituted or unsubstituted C,-Cg-alkenyl, CC @ substituted or unsubstituted C,-Cg-alkynyl, (e) substituted or unsubstituted aryl, 63) substituted or unsubstituted heterocyclyl, . : ’ © substituted or unsubstituted heteroaryl; and 138 AMENDED SHEET:

® : } PCT/US2003/037294 © mis0,1,2,3,0r4; : R; is selected from the group consisting of oo oo a KH (2) substituted or unsubstituted C,-Cq-alkyl, : oo (3) -COOH, (4) halo, | oo Co (5) -ORIlt and bo 6) NERY, : wherein R!t is H or C;-Cg-alkyl; oo Ry is selected from the group consisting of (1) substituted or unsubstituted aryl, | Co © (2) substituted or unsubstituted heteroaryl, and (3) substituted or unsubstituted heterocyclyl; and W is selected from the group consisting of (1) substituted or unsubstituted C;-Cg-alkyl, 2) NR, R?¥), and a “Cd 3) Z , wherein R1W and R2¥ are selected from the group consisting of ® H . (b) substituted or unsubstituted C;-Cg-alkyl, (c) substituted or unsubstituted aryl, (d) substituted or unsubstituted heterocyclyl, and Co (e)° substituted or unsubstituted heteroaryl, wherein RW and R2w are not both H; : : Z is selected from the group consisting of oo | @ -O, oo ® NRE, © @ So, (e) -SOp-,and : : ® CH, -139- AMENDED SHEET E

E 9 : PCT/US2003/037294 . . z * . . : . wherein RZ is H or substituted or unsubstituted alkyl group; and R4W is selected from the group consisting of : (@® H ~~ (b) substituted or unsubstituted C;-Cq-alkyl, : (©) ~COOR5W, : : (d -CONH,, oo (© —-OR5V, and ! ® —NHR5W, wherein RY is H or C;-Cg-alkyl; and ris 0, 1, or 2.

37. Use of a compound as defined in claim 29 or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, in the manufacture of a medicament for inhibiting phosphotidylinositol (PI) 3-kinase activity in a human or animal subject.

38. Use of a compound as defined in claim 34 a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, in the manufacture of a medicament for inhibiting the proliferation of capillaries in a human or animal subject. : 39. A substance or composition for use in a method for treating a condition by modulation of phosphotidylinositol (PI) 3-kinase activity, said substance or composition comprising a compound as defined in claim 26, or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, and said method comprising administering an : effective amount of said substance or composition to a human or animal subject in need of such treatment. : ’

40. A substance or composition for use in a method for inhibiting phosphotidylinositol (PI) 3-kinase activity in a human or animal subject, said substance or composition comprising a compound as defined in claim 29, or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, and said method comprising administering an effective amount of said substance or composition to the human or animal subject. ’ ‘ -140- : oo AMENDED SHEET Ce

Ck ~ PCT/US2003/037294 ® :

41. A substance or composition for use in a method for inhibiting tumor growth in a human or animal subject, said substance or composition comprising a compound as defined in claim 33 or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug ~ thereof, and said method comprising administering an effective amount of said substance or + composition to the human or animal subject.

42. A substance or composition for use in a method for inhibiting the proliferation of capillaries in a human or animal subject, said substance or composition comprising a compound as defined in claim 42 or a stereoisomer, tautomer, pharmaceutically acceptable salt, _ ester, or prodrug thereof, and said method comprising administering an effective amount of said : substance or composition to the human or animal subject. :

43. A compound according to claim 1, or claim 35, substantially as herein described and illustrated. 44, A composition according to claim 23, substantially as herein described and ~ illustrated.

45. Use according to any one of claims 26, or 33, or 36 to 38, substantially as herein described and illustrated.

46. A method according to claim 29, or claim 34, substantially as herein described : and illustrated.

47. A substance or composition for use in a method of treatment according to any one of claims 30, or 35, or 39 to 42, substantially as herein described and illustrated.

48. A new compound; a new composition; a new use of a compound as defined in any one of claims 26, or 29, or 33, or 34, or 36; a new non-therapeutic method of treatment; or a substance or composition for a new use in a method of treatment, substantially as herein described. -141- AMENDED SHEET :