AU2003303639A1 - Anti-cancer medicaments - Google Patents

Description

WO 2004/060305 PCT/US2003/041425 ANTI-CANCER MEDICAMENTS BACKGROUND OF THE INVENTION Related Applications 5 This application claims the benefit of provisional applications entitled Process For MODULATING PROTEIN FUNCTION, S/N 60/437,487 filed December 31, 2002, ANTI CANCER MEDICAMENTS, S/N 60/437,403 filed December 31, 2002, ANTI INFLAMMATORY MEDICAMENTS, S/N 60/437,415 filed December 31, 2002, ANTI INFLAMMATORY MEDICAMENTS, S/N 60/437,304 filed December 31, 2002, and 10 MEDICAMENTS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS OR DIABETES, S/N 60/463,804 filed April 18, 2003. Each of these applications is incorporated by reference herein. Field of the Invention 15 The present invention relates to novel compounds and methods ofusing those compounds to treat oncological conditions. Description of the Prior Art Basic research has recently provided the life sciences community with an unprecedented 20 volume of information on the human genetic code and the proteins that are produced by it. In 2001, the complete sequence of the human genome was reported (Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature (2001) 409:860; Venter, J.C. et al. The sequence of the human genome. Science (2001) 291:1304). Increasingly, the global research community is now classifying the 50,000+ proteins that are encoded by this genetic sequence, 25 and more importantly, it is attempting to identify those proteins that are causative of major, under-treated human diseases. Despite the wealth of information that the human genome and its proteins are providing, particularly in the area of conformational control of protein function, the methodology and strategy by which the pharmaceutical industry sets about to develop small molecule therapeutics 30 has not significantly advanced beyond using native protein active sites for binding to small molecule therapeutic agents. These native active sites are normally used by proteins to perform essential cellular functions by binding to and processing natural substrates or tranducing signals from natural ligands. Because these native pockets are used broadly by many other proteins 1 WO 2004/060305 PCT/US2003/041425 within protein families, drugs which interact with them are often plagued by lack of selectivity and, as a consequence, insufficient therapeutic windows to achieve maximum efficacy. Side effects and toxicities are revealed in such small molecules, either during preclinical discovery, clinical trials, or later in the marketplace. Side effects and toxicities continue to be a major 5 reason for the high attrition rate seen within the drug development process. For the kinase protein family of proteins, interactions at these native active sites have been recently reviewed: see J. Dumas, Protein Kinase Inhibitors: Emerging Pharmacophores 1997-2001, Expert Opinion on Therapeutic Patents (2001) 11: 405-429; J. Dumas, Editor, New challenges in Protein Kinase Inhibition, in Current Topics in Medicinal Chemistry (2002) 2: issue 9. 10 It is known that proteins are flexible, and this flexibility has been reported and utilized with the discovery of the small molecules which bind to alternative, flexible active sites with proteins. For review of this topic, see Teague, Nature Reviews/Drug Discovery, Vol. 2, pp. 527 541 (2003). See also, Wu et al., Structure, Vol. 11, pp. 399-410 (2003). However these reports focus on small molecules which bind only to proteins at the protein natural active sites. Peng et 15 al., Bio. Organic and Medicinal Chemisty Ltrs., Vol. 13, pp. 3693-3699 (2003), and Schindler, et al., Science, Vol. 289, p. 1938 (2000) describe inhibitors of abl kinase. These inhibitors are identified in WO Publication No. 2002/034727. This class ofinhibitors binds to the ATP active site while also binding in a mode that induces movement of the kinase catalytic loop. Pargellis et al., Nature StructuralBiology, Vol. 9, p. 268 (2002) reported inhibitors p38 alpha-kinase also 20 disclosed in WO Publication No. 00/43384 and Regan et al., J. Medicinal Chemistry, Vol. 45, pp. 2994-3008 (2002). This class of inhibitors also interacts with the kinase at the ATP active site involving a concomitant movement of the kinase activation loop. More recently, it has been disclosed that kinases utilize activation loops and kinase domain regulatory pockets to control their state of catalytic activity. This has been recently 25 reviewed (see, e.g., M. Huse and J. Kuriyan, Cell (2002) 109:275). SUMMARY OF THE INVENTION The present invention is broadly concerned with new compounds for use in treating anti inflammatory conditions and methods of treating such conditions. In more detail, the inventive 30 compounds have the formula 2 WO 2004/060305 PCT/US2003/041425 wherein: 5 R' is selected from the group consisting of aryls (preferably C 6

-C

3 , and more preferably

C

6

-C

12 ) and heteroaryls; each X and Y is individually selected from the group consisting of -0-, -S-, -NR 6 -,

-NR

6

SO

2 -, -NR 6 CO-, alkynyls (preferably C 1

-C

1 2 , and more preferably C 1

-C

6 ), alkenyls (preferably C 1

-C

12 , and more preferably C 1

-C

6 ), alkylenes (preferably C 1 10 C 12 , and more preferably C 1

-C

6 ), -O(CH 2 )h-, and -NR 6

(CH

2 )h-, where each h is individually selected from the group consisting of 1,2, 3, or 4, and where for each of alkylenes (preferably C 1

-C

1 2 , and more preferably C 1

-C

6 ), -O(CH 2 )h-, and

-NR

6

(CH

2 )h-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that with -O(CH 2 )h-, the 15 introduction of the side-chain oxo group does not fom an ester moiety; A is selected from the group consisting of aromatic (preferably C 6

-C

18 , and more preferably C 6

-C

12 ), monocycloheterocyclic, and bicycloheterocyclic rings; D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, 20 and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(0)-, -S(0) 2 -, -N(R 6 )CO-, -N(R 6 )SO2-,

-N(R

6

)CON(R

6 )-; j is 0 or 1; 25 m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; t is 0 or 1; 3 WO 2004/060305 PCT/US2003/041425 Q is selected from the group consisting of R4 0 R 0 ' 0 N, S _N

-S

50 "14 0 Lt< R4 Q 5 4 R Q-1 Q-2 Q- 3

R

4

Q-

4 Q-6 0 N4 R 4

R

4 0 0 0 \\ // 04 0 4 RR 4 N4 CR ZN 4 H 4 0- ' L4 Q-10 Q-1l K 10Q-8 Q-9 0 0 0R44 0S

R

4 0R 4 \N iNH

N

4 l NH N OR, N61N I N I OR, OR, OR, OR 6 0 Q-12 R, Q-15 Q-16 Q-17 15 Q-13 Q.14 0 Irv OH SH R4s

R

4 0 j 0 C0 2 H 0 N ~ 5

S-.--~A

0 N0 40 /~ / ~H 3 0 CH, 0

OR

6 * 0 C, H 2 0CH

HH

3 0 Q-18 Q-19 Q-20 Q-21 Q2 20 H_ Z3 0 0I 0 H0N 000 0. 0 N R,

SO

3 HV R4\ 4 o0 HN N 0 25 Q-24 Q-25 Q-6Q-27 Q-28 Q-29

COZR

4 0 0 0R 0 0 N,,,,OZR,

R

5 0 l" SON(R4) 2 R OR, R 4 N4 OR, 30 ''aiid Q-0Q-31 Q3Q-3Q-34 Q-35 4 WO 2004/060305 PCT/US2003/041425 each R4 group is individually selected from the group consisting of-H, alkyls (preferably CI-Cl2, and more preferably C1-C6), aminoalkyls (preferably C 1

-C

12 , and more preferably C 1

-C

6 ), alkoxyalkyls (preferably C 1

-C

1 2 , and more preferably C1-C6), aryls (preferably C6-C18, and more preferably C 6

-C

12 ), aralkyls (preferably C1-C12, 5 and more preferably C 1

-C

6 ), heterocyclyls, and heterocyclylalkyls except when the R4 substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; 10 each R5 is individually selected from the group consisting of -H, alkyls (preferably C, C12, and more preferably C1-C6), aryls (preferably C6-C18, and more preferably C 6 C12), heterocyclyls, alkylaminos (preferably C 1

-C

12 , and more preferably C1-C6), arylaminos (preferably C 6

-C,

8 , and more preferably C 6

-C

12 ), cycloalkylaminos (preferably C 3

-C

18 , and more preferably C 5

-C

1 2 and preferably Ci-C 1 2 , and more 15 preferably C-C6), heterocyclylaminos, hydroxys, alkoxys (preferably C 1

-C,

12 , and more preferably Ci-C 6 ), aryloxys (preferably C 6

-C

1 8 , and more preferably C 6 -C12), alkylthios (preferably C 1

-C

12 , and more preferably C1-C 6 ), arylthios (preferably C6-Cl, and more preferably C6-CX12), cyanos, halogens, perfluoroalkcyls (preferably C1-C12, and more preferably C1-C6), alkylcarbonyls (preferably C1-C12, and more 20 preferably C1-C6), and nitros; each R 6 is individually selected from the group consisting of -H, alkyls (preferably C C12, and more preferably C1-C6), allyls, and 3-trimethylsilylethyl; each R, is individually selected from the group consisting of alkyls (preferably C1-C12, and more preferably CI-C6), aralkyls (preferably C1-C12, and more preferably C 1 25 C6), heterocyclyls, and heterocyclylalkyls; each R, group is individually selected from the group consisting of -H, -F, and alkyls (preferably C-C12, and more preferably C-C6), wherein when two R9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; 30 G is selected from the group consisting of-O-, -S-, and -N(R 4 )-; k is 0 or 1; 5 WO 2004/060305 PCT/US2003/041425 each Z is individually selected from the group consisting of -0- and -N(R 4 )-; and each ring of formula (I) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of-H, alkyls (preferably C-C12, and more preferably C-C6), aryls (preferably C 6

-CI

8 , 5 and more preferably C6-Cl2), heterocyclyls, alkylaminos (preferably C 1

-C

12 , and more preferably C 1 -C6), arylaminos (preferably C6-C18, and more preferably C 6 C012), cycloalkylaminos (preferably C3-CI8, and more preferably C 5

-C

12 and preferably Cz-Ci2, and more preferably C 1

-C

6 ), heterocyclylaminos, hydroxys, alkoxys (preferably C1-C12, and more preferably Ca-C 6 ), aryloxys (preferably C 6 10 Cs, and more preferably C6-Cl2), alkylthios (preferably C 1

-C

1 2 , and more preferably C-C6), arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls (preferably C1-C12, and more preferably C -C 6 ), alkylsulfonyls (preferably C-C 1 2 , and more preferably CI-C 6 ), aminosulfonyls, and perfluoroalkyls (preferably C 1 C2, and more preferably C 1

-C

6 ). 15 hn a preferred embodiment, the structure is of formula (I) except that: when Q is Q-3 or Q-4, then the compound of formula (I) is not 0 Ph- H 0 N H or N h 0 N"N K NH 20 Ph N'- PI-(0 NH, 0 when Q is Q-7, then the compound of formula (I) is not 25 6 WO 2004/060305 PCT/US2003/041425 0 NH R120 = 2.3-difluoro; 2,3,6-trifluoro; 2, fluoro, 3-chloro; 2-chloro,3-fluoro; 0 3-cyano; 4-chloro A' = substituted phenyl S 1 Y'= CO; -NHCO-; -SO2-; -SO2NH-; f=0 or 1 120 NH R121= substituted phenyl; oxazolyl; pyridyl; pyrimidyl; pyrazolyl; I A' imidazolyl (Y:')f 5 R121 or 0 NH R123 =H;2.3-difluoro; 3,5-difluoro; 2-fluoro, 4-fluoro; 2-chloro, 2,4-diclioro; 3,4-dichloro;3-fluoro; 4-chloro, 2-broom; 3-bromno; 4-bromo; 4-lodo; 2-minethoxy; 3-methoxy; 4-methoxy; 3,4-dimethoxy; 10 0 2,4-diniethoxy; 2,5-dimethoxy; 3,4,5-trimethoxy; 3-CF3; 4-CF3; 3,5-di-CF3; 4-CF30-; 3-nitro; 4-nitro; 3-nitro-4-chloro; 2-methyl; 3-methyl; 4-methyl; 3.5-dihnethyl; 4-iso-propyl; 3-nimethylthiu; 3-CF3S-; 3-chloro-4-methoxy R123 NH 4-methylthio; 4-hydroxy; 4-methoxymethyl; 4-methylsulfonyl I A'= substituted phlienyl A'

Y"

= CO; f0 or I (Y) R122 = substituted phenyl; oxazolyl; pyrimidyl If

R

1 22 15 when Q is Q-7, R 5 is -OH, Y is -0-, -S-, or -CO-, m is 0, n is 0, p is 0, q is 0, and E is phenyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, then the compound of formula (I) is not 20 0 Me 0 ,Me O NH NH O N HNO O4 Oi I1 S HN , or R80 is H, MeR82 is substituted phenyl 25 RS 1 e R82 is substituted phenyl 25 R 81 is t when Q is Q-9, then the compound of formula (I) is not 7 WO 2004/060305 PCT/US2003/041425 O Ph 0 N-Me O N Ph O 6NP

H

2 N.(CH2)4 I. h, or NC R16 = H, methyl 5 Ro7 010 when Q is Q-10, then the compound of formula (I) is not HO NA N i RO 7, Rl 00=almeklyl R1 9 = H-, alkyl 10 when Q is Q-l 10, then the compound of formula (1) is not 0 0_ RlOOmetbyl, ethyl 15 X RI01 = alkyl, aminoalkyl, aryl, arylalkyl, RImo'X' N 'NH thienylalkyl, pyridinylalkyl, N S ORo o phthalimidylalkyl, alkoxycarbonylalkyl, alkoxycarbonylamninoalkyl, N arylalkenylalkyl, alkoxyalky, hydroxyalkyl, Rio arylaminocarbonyl, arylalkoxycarbonylaminoalkyl 0 RI 02 = phenyl, indolylphenyl v=0orl I X' = O,NH or 20 OMe N 0N O 0 R103 = furyl, thienyl, phenyl MeO N N N () a X" = C or S H H [ X"-Rea a= 1 or2 25 wherein there is a bond between Q and 30 (R X D L E Y 8 WO 2004/060305 PCT/US2003/041425 of formula (I), and when Q is Q-11, t is 0, and E is phenyl, then any R 7 on E is not an o-alkoxy in relation to said bond; when Q is Q-11, then the compound of formula (1) is not 5 S NH- -- NH - --0 0 Pr - i Ph 10 or 0, 0 0 R1o05-N N 1E N H RIO4 = methyl, ethIyl H H R105 = alkyl, phenyl 15

OR

10 4 R 106= fluorine-substituted phenyl H Ri 06 O 20 20 when Q is Q-15, then the compound of formula (I) is not 0 0 25 O -- R 107 or OIN H H H I CH3% / R 107 = phenyl N2CH 3

N

2 9 WO 2004/060305 PCT/US2003/041425 when Q is Q-16, then the compound of fonnula (I) is not O 5 H 3 c N, N 0 N 00 H 2 N N HN NH NH R1m1N N HH R11= Me, OH N - O OHH HO o 11 H H C-Ph N 0 N N NH NH N Oy 0 0 o0 H H N HN-C-Ph O N I H NN O HN S HN N 0 0 Ph NH 0 Ph HN 0 0)NH 0 10 WO 2004/060305 PCT/US2003/041425 H Ph O N H NNC R N 00 0 /0 0O 0 OON N ~ N "R N Hn'H.NaO N RION/ OH, SH, NH2 RIO, - hydrogen or one or more methoxy, hydroxy, halogen, nitro, dimeth~ylaminlo, or furanyl Rlto = substituted phenyl, furanyl Ril I = OH or Cl X3= , NH 5 when Q is Q-17, then the compound of formula (I) is not = O // 'NR3 R O H HN H N N R29 N 0 N NH R29 = alkyl RR3oIS= H, t-Bu, benzoylSH, N142 R 11 hydrogen or one or mre oxy, hydroxy, halogen, nifto, dimetliylanlino, or furanyl

R

110 = substituted phonyl, furanyl R, I = OHor C1 X3 0, NH 5 when Q is Q-l17, then the compound of formula (I) is not n-Bu o N0 =s "" OS R 3 0 IN 10 R29 R 29 00 H R9= alkyl

R

3 0 =H, t-Bu, benzoyl 11 WO 2004/060305 PCT/US2003/041425 when Q is Q-21, then the compound of formula (I) is not

HO

2 C\ (R) 5 Ho2C 9 0 N Ph 10 when Q is Q-22, then the compound of fon-nula (I) is selected from the group consisting of

R

4 N NH-L-(NH)p-D-(NH)p-(A)q-[(X)-Ri]m R4 15 1 11 1NH-Ly-(NH)p-D-(NH)p-(A),-[(X)j-Rylm 15 SNH X 0 NH W W | W IH W OH OH 20 L, - C(O) or S(0 2 ) SCO-(NH)p-D-(NH)p-(A)q

-[

(X)j-RI )]m D-(NH)p-(A)q-[(X)-R1)]m 25 O NH O NH W W WX w ~-w ,w ~-w OH OH R4 CO-(NH)p-D-(NH)-(A)q-[(X)j-R )]m R I D-(NH)p-(A)q-((X)j-R )]m O NH °0 NH , and 12 - 1W W OH WO 2004/060305 PCT/US2003/041425 but excluding H'q RO 00 R41 0 N N.R 6 HN N R 3 7 O R R37 R37 = N(Me)2, N R 35 N R 39 morpholino, OMe, OH, H H R34 = Me, Cl H R38 = H, CN, OMe, OH, 5 R34 R35 = -N(Me)2, morpholino Me benzyloxy, phenyl, nitro H metaorpara- R36= H, F HO meta or para- R3940= H, OH R40 = H, F R41 = H, Cl 0 0 i~ 0 0 OMe N N H, Me HN~ ~ HN 10 0N N N. -. ON'-0 N N SMe Me and HO HOO meta or para- OH meta or para MeO , N NHMe N MeO 0oo - I 15 H HO meta or para 13 WO 2004/060305 PCT/US2003/041425 when Q is Q-23, then the compound of formula (I) is not . R42 (CH 2

)

9 Me H N HSHN R, N Me0 N H HS R 42 =H,Me HS O\,O / N Cl t-Bu N Cl 15 HSO HNB u NH - ,or O 10 H I HS 20 when Q is Q-24, Q-25, Q-26, or Q-31, then is selected from the group consisting of C t-B14 H N N1 15 K 0 0HN.. t-Bu4 \ N - = - H HS\ -- - a H/ C S Hor 00 0 HS"- S 20 when Q is Q-24, Q-25, Q-26, or Q-3 1, then is selected from the group consisting of 14 WO 2004/060305 PCT/US2003/041425 R7 R7 R7 w 0 w W o W W 0o A(-mI HY * H H N A(X-RI)m ' N 'A(X-Ri)m * H * H W H H OZT , N A-(X-R1)m 0 ,N W , A-(X-Ri) O N-(X-R)m * R 7 I ,and HN W:"-"R 7 10 wherein each W is individually selected from the group consisting of -CH- and -N-; and 000 ooo0 O0 0 0 00 II~~~~~~( 0" R \%,o,/o J )// .4 O SR4 O SR 4 HN , R4OZR4 0's, ZRoR4 H ' N'N H HN N N 4 H R4 HR 15 , . , or. , Y YY Q-24 Q-25 Q-26 or Q-31 where * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31; 20 when Q is Q-31, then the compound of fonmnula (1) is not N HN H SN 25 \cl N or 10\\0 0 30 N N H H H N.. N, 15 WO 2004/060305 PCT/US2003/041425 when Q is Q-28, then the compound of fonnrmula (I) is not 5 H II-! ' or H M. - S NH- NHCM O S R It II - CM. R2"N - N_",,S l R ; 0 0(CMy) 3 NMO (C 2) 3-" o2 H 0 10 16 WO 2004/060305 PCT/US2003/041425 when Q is Q-32, then 5 (R, X A) -N D - E4Y1 10 is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; 17 WO 2004/060305 PCT/US2003011425 when Q is Q-32, then the compound of forml-ula (1) is not E

EO-P-CH

2 OCEI 0l 4 Oj N la,40 0R3 H HI R,4/ / H / 1 4 0 HH1~ ~

R

130 = benzoyl, substituted plienylaminocarbonyl R3i= Cl, Br, SPh, ljeizoyl, plienylsulfronyl

R

132 = subsituted plienylarninocarbonyl Me R,,, 1-I, Cl OEt Ph

R

134 = H, alkyl, allyl, 1-tdmiethylsilylcthyl HI-- CH=CH-C 0N ElC PhN C-P-GEt

H

2 I GEt/ ,or Ph KI' 18 WO 2004/060305 PCT/US2003/041425 when Q is Q-35 as shown 0 0 5 ZR 4

ZR

4 k ( 5 N Q-35 (para) Q-35 (meta) wherein G is selected from the group consisting of-O-, -S-, and -NR 4 -, k is 0 or 1, and u is 1, 2, 3, or 4, then 10 (RI+X~A) D-L EY 15 is selected from the group consisting of H RO W 'A-[(X)j-R",m 20 0 W o N N0 A-[(X)j-R]m W R7 H H H 0 H W N~A(~ i WR7O , N A-[(X)j-R ]m 7 W~ 0 R N HH NA-[(X)I-R]m H * H H w N . 25 ON A-[(X)j-R 1 ]m Wv o -"" R7 HN WJ R7 , N I .A-[(X)j-R

-

]m * H 30 19 WO 2004/060305 PCT/US2003/04 1425

R

7 R 7 R W-~ 'll w w w * -(~jRj A-[(X)j-R 1 ]m W an * A (X)jRlJm 20n WO 2004/060305 PCT/US2003011425 except that the compound of formula (I) is not C0 2

R

71 C0HR3P N )C 2 Meal INR 3 P -(CH )C 2 7 5 ~72 RU miet,para

W

4 '> NR7 28.1 R73 - OCH2CO2H R 7 6 j R75- H, Et

W

4 H R71 = H, Me R72 = thiazolyl, isoxazolyl R74 =oxazolyl, mi zl yl R76 H, NH2, N02 WX4 = IN, CH jrnidazolyl. furyl 28.2 R73= CO2-Me R74= clrloroplienylCF S 3 X ~ C 2 77 / 2R7 0 - h RN, Ph0mea pr NH C2 0 R77 H, alkyl o.P 5 MeC H HH X3 -0r CH, HH R78 =Halkyl 0 H CO Me NH '

O

2 M Me

R

66 0 0

R

6 6 H I N "IC0 2 Me C3 0 2 Rr 5 MeO 7 Meo meta0, para OMe 0R65-H, Et R66-ly 21 WO 2004/060305 PCT/US2003/04 1425 Me 1 0 0 MoOo = H, CH, C~CI MeO NN N"Oe Y H N ~ N. N ' H N NOMe

H

3 C N N

H

NH

2 I 0 R7 H -, Me C0 2

R

79 ,or :11 N 'N C H 0, 22 WO 2004/060305 PCT/US2003/041425 In a preferred embodiment, R , is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls. In a particularly preferred embodiment, R, is selected from the group consisting of 5w w ,w w N 5 R 2 L, N n O R '

R

2 H 0, 0, sRN Y 1 TS' R, O 10

R

5 WN- R2 N ~-R, ( H'R ' R2R R2 15 each R 2 is individually selected from the group consisting of-H, alkyls (preferably C, Cl 2 , and more preferably C 1

-C

6 ), aminos, alkylaminos (preferably C -C12, and more preferably C 1

-C

6 ), arylaminos (preferably C 6

-C

8 , and more preferably C6

C

12 ), cycloalkylaminos (preferably Cz-C 8 , and more preferably C 5 -Cl 2 and preferably C 1 -Cl 2 , and more preferably C 1

-C

6 ), heterocyclylaminos, halogens, 20 alkoxys (preferably C 1 -Cl 2 , and more preferably C,-C 6 ), and hydroxys; and each R 3 is individually selected from the group consisting of-H, alkyls (preferably C Cl 2 , and more preferably C 1

-C

6 ), alkylaminos (preferably C 1 -Cl 2 , and more preferably C 1

-C

6 ), arylaminos (preferably C 6

-C

8 , and more preferably C 6 -Cl 2 ), cycloalkylaminos (preferably C-C 1 z, and more preferably Cz-C 6 ), 25 heterocyclylaminos, alkoxys (preferably CI-Cl 2 , and more preferably Cz-C 6 ), hydroxys, cyanos, halogens, perfluoroalkyls (preferably Cz-C 1 2 , and more preferably C 1

-C

6 ), alkylsulfinyls (preferably C 1

-C

12 , and more preferably C 1

-C

6 ), alkylsulfonyls (preferably C 1 -Cl 2 , and more preferably C 1

-C

6 ), R 4

NHSO

2 -, and

-NHSO

2

R

4 . 30 In another embodiment, A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, 23 WO 2004/060305 PCT/US2003/041425 benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, and purinyl. With respect to the methods of the invention, the activation state ofa kinase is deternnined by the interaction of switch control ligands and complemental switch control pockets. One 5 conformation of the kinase may result from the switch control ligand's interaction with a particular switch control pocket while another conformation may result from the ligand's interaction with a different switch control pocket. Generally interaction of the ligand with one pocket, such as the "on" pocket, results in the kinase assuming an active conformation wherein the kinase is biologically active. Similarly, an inactive conformation (wherein the kinase is not 10 biologically active) is assumed when the ligand interacts with another of the switch control pockets, such as the "off' pocket. The switch control pocket can be selected from the group consisting of simple, composite and combined switch control pockets. Interaction between the switch control ligand and the switch control pockets is dynamic and therefore, the ligand is not always interacting with a switch control pocket. In some instances, the ligand is not in a switch 15 control pocket (such as occurs when the protein is changing from an active conformation to an inactive conformation). In other instances, such as when the ligand is interacting with the environment surrounding the protein in order to determine with which switch control pocket to interact, the ligand is not in a switch control pocket. Interaction of the ligand with particular switch control pockets is controlled in part by the charge status of the amino acid residues of the 20 switch control ligand. When the ligand is in a neutral charge state, it interacts with one of the switch control pockets and when it is in a charged state, it interacts with the other of the switch control pockets.' For example, the switch control ligand may have a plurality of OH groups and be in a neutral charge state. This neutral charge state results in a ligand that is more likely to interact with one of the switch control pockets through hydrogen boding between the OH groups 25 and selected residues of the pocket, thereby resulting in whichever protein conformation results from that interaction. However, if the OH groups of the switch control ligand become charged through phosphorylation or some other means, the propensity of the ligand to interact with the other of the switch control pockets will increase and the ligand will interact with this other switch control pocket through complementary covalent binding between the negatively or positively 30 charged residues of the pocket and ligand. This will result in the protein assuming the opposite confomation assumed when the ligand was in a neutral charge state and interacting with the 24 WO 2004/060305 PCT/US2003/041425 other switch control pocket. Of course, the conformation of the protein detennines the activation state of the protein and can therefore play a.role in protein-related diseases, processes, and conditions. For example, if a metabolic process requires a biologically active protein but the protein's switch control ligand 5 remains in the switch control pocket (i.e. the "off' pocket) that results in a biologically inactive protein, that metabolic process cannot occur at a normal rate. Similarly, if a disease is exacerbated by a biologically active protein and the protein's switch control ligand remains in the switch control pocket (i.e. the "on" pocket) that results in the biologically active protein conformation, the disease condition will be worsened. Accordingly, as demonstrated by the 10 present invention, selective modulation of the switch control pocket and switch control ligand by the selective administration of a molecule will play an important role in the treatment and control of protein-related diseases, processes, and conditions. One aspect of the invention provides a method of modulating the activation state of a kinase, preferably abl or bcr-abl alpha-kinase and including both the consensus wild type 15 sequence and disease polymorphs thereof. The activation state is generally selected from an upregulated or downregulated state. The method generally comprises the step of contacting the kinase with a molecule having the general formula (I). When such contact occurs, the molecule will bind to a particular switch control pocket and the switch control ligand will have a greater propensity to interact with the other of the switch control pockets (i.e., the unoccupied one) and 20 a lesser propensity to interact with the occupied switch control pocket. As a result, the protein will have a greater propensity to assume either an active or inactive conformation (and consequently be upregulated or downregulated), depending upon which of the switch control pockets is occupied by the molecule. Thus, contacting the kinase with a molecule modulates that protein's activation state. The molecule can act as an antagonist or an agonist of either switch 25 control pocket. The contact between the molecule and the kinase preferably occurs at a region of a switch control pocket of the kinase and more preferably in an interlobe oxyanion pocket of the kinase. In some instances, the contact between the molecule and the pocket also results in the alteration of the conformation of other adjacent sites and pockets, such as an ATP active site. Such an alteration can also effect regulation and modulation of the active state of the protein. 30 Preferably, the region of the switch control pocket ofthe kinase comprises an amino acid residue sequence operable for binding to the Formula I molecule. Such binding can occur between the 25 WO 2004/060305 PCT/US2003/041425 molecule and a specific region of the switch control pocket with preferred regions including the a-C helix, the c-D helix, the catalytic loop, the activation loop, and the C-terminal residues or C-lobe residues (all residues located downstream (toward the C-end) from the Activation loop), and combinations thereof. When the binding region is the c-C helix, one preferred binding 5 sequence in this helix is the sequence VEEFLKEAAVM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is HRDLAARNXL (SEQ ID NO. 3). When the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLSRLMT (SEQ ID NO.4), GDTYTAH (SEQ ID NO. 5), and combinations thereof. When the binding region is in the C 10 lobe residues, one preferred binding residue is F, found at position 416 relative to the full length sequence (residue 194 in SEQ ID NO. 1). When a biologically inactive protein conformation is desired, molecules which interact with the switch control pocket that normally results in a biologically active protein conformation (when interacting with the switch control ligand) will be selected. Similarly, when a biologically active protein conformation is desired, molecules 15 which interact with the switch control pocket that normally results in a biologically inactive protein confomnation (when interacting with the switch control ligand) will be selected. Thus, the propensity of the protein to assume a desired conformation will be modulated by administration of the molecule. In preferred forms, the molecule will be administered to an individual undergoing treatment for cancer including but not limited to chronic myelogeneous 20 leukemia and stromal gastrointestinal tumors. In such forms, it will be desired to select molecules that interact with the switch control pocket that generally leads to a biologically active protein conformation so that the protein will have the propensity to assume the biologically inactive form and thereby alleviate the condition. It is contemplated that the molecules of the present invention will be administerable in any conventional form including oral, parenteral, 25 inhalation, and subcutaneous. It is preferred for the administration to be in the oral form. Preferred molecules include the preferred formula (I) compounds discussed above. Another aspect of the present invention provides a method of treating cancer comprising the step of administering a molecule having the structure of the formula (I) compounds to the individual. Such conditions are often the result of an overproduction of the biologically active 30 form of a protein, including kinases. For example, a hallmark feature of chronic myelogeneous leukemia involves areciprocal chromosomal translocation involving human chromosomes 9 and 26 WO 2004/060305 PCT/US2003/041425 22. This mutation fuses a segment of the bcr gene upstream of the second exon of the c-abl nonreceptor tyrosine kinase gene. This fusion protein is called ber-abl. While the normal c-abl gene and its protein are tightly controlled in normal cells, the fusion protein product bcr-abl presents with elevated, constitutive kinase activity. It is this activity that enables ber-abl fusion 5 protein to transform cells and cause malignancy. Thus, the invention discloses and utilizes small molecule inhibitors of bcr-abl kinase. These inhibitors contain functionality which enable them to bind to an binding region, preferably an interlobe oxyanion regulator pocket in abl kinase. The inhibitors may also contain functionality which bind to the ATP pocket or other kinase amino acid residues taken from the N-lobe or C-lobe of the kinase. 10 The administering step generally includes the step of causing said molecule to contact a kinase involved with elevated kinase activity such as that found in cancer. A particularly preferred kinase to contact is bcr-abl kinase. When the contact is between the molecule and a kinase, the contact preferably occurs in a binding region (preferably an interlobe oxyanionpocket of the kinase) that includes an amino acid residue sequence operable for binding to the Formnnula 15 I molecule. Preferred binding regions of the interlobe oxyanion pocket include the M-C helix region, the catalytic loop, the activation loop, the C-termnninal lobe or residues, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence VEEFLKEAAVM (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is HRDLAARNXL (SEQ ID NO. 3). When 20 the binding region is the activation loop, one preferred binding sequence in this loop is a sequence selected from the group consisting of DFGLSRLMT (SEQ ID NO.4), GDTYTAH (SEQ ID NO. 5), and combinations thereof. A preferred residue with which to bind in the C terminal lobe is F. Such a method pennits treatment of cancer by virtue of the modulation of the activation 25 state of a kinase by contacting the kinase with a molecule that associates with the switch control pocket that normally leads to a biologically active form of the kinase when interacting with the switch control ligand. Because the ligand cannot easily interact with the switch control pocket associated with or occupied by the molecule, the ligand tends to interact with the switch control pocket leading to the biologically inactive form of the protein, with the attendant result of a 30 decrease in the amount of biologically active protein. Preferably, the cancer is selected from the group consisting of chronic mylogeneous leukemia and stromal gastrointestinal tumors. As with 27 WO 2004/060305 PCT/US2003/041425 the other methods of the invention, the molecules may be administered in any conventional form, with any conventional excipients or ingredients. However, it is preferred to administer the molecule in an oral dosage form. Preferred molecules are again selected from the group consisting of the preferred formula (I) compounds as discussed above. 5 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic representation of a naturally occurring mammalian protein in accordance with the invention including "on" and "off' switch control pockets, a transiently 10 modifiable switch control ligand, and an active ATP site; Fig. 2 is a schematic representation of the protein of Fig. 1, wherein the switch control ligand is illustrated in a binding relationship with the off switch control pocket, thereby causing the protein to assume a first biologically downregulated conformation; Fig. 3 is a view similar to that of Fig. 1, but illustrating the switch control ligand in its 15 charged-modified condition wherein the OH groups of certain amino acid residues have been phosphorylated; Fig. 4 is a view similar to that of Fig. 2, but depicting the protein wherein the switch control ligand is in a binding relationship with the on switch control pocket, thereby causing the protein to assume a second biologically-active confirmation different than the first conformation 20 of Fig. 2; Fig. 4a is an enlarged schematic view illustrating a representative binding between the phosphorylated residues of the switch control ligand, and complemental residues from the on switch control pocket; Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic form possible small 25 molecule compounds in a binding relationship with the on and off switch control pockets; Fig. 6 is a schematic view of the protein in a situation where a composite switch control pocket is formed with portions of the switch control ligand and the on switch control pocket, and with a small molecule in binding relationship with the composite pocket; and Fig. 7 is a schematic view of the protein in a situation where a combined switch control 30 pocket is formed with portions of the on switch control pocket, the switch control ligand sequence, and the active ATP site, and with a small molecule in binding relationship with the 28 WO 2004/060305 PCT/US2003/041425 combined switch control pocket. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides a way of rationally developing new small molecule 5 modulators which interact with naturally occurring proteins (e.g., mammalian, and especially human proteins) in order to modulate the activity of the proteins. Novel protein-small molecule adducts are also provided. The invention preferably makes use of naturally occurring proteins having a conformational property whereby the proteins change their conformations in vivo with a corresponding change in protein activity. For example, a given enzyme protein in one 10 conformation maybe biologically upregulated, while in another conformnnation, the same protein may be biologically downregulated. The invention preferably makes use of one mechanism of conformation change utilized by naturally occurring proteins, through the interaction of what are termed "switch control ligands" and "switch control pockets" within the protein. As used herein, "switch control ligand" means a region or domain within a naturally 15 occurring protein and having one or more amino acid residues therein which are transiently modified in vivo between individual states by biochemical modification, typically phosphorylation, sulfation, acylation or oxidation. Similarly, "switch control pocket" means a plurality of contiguous or non-contiguous amino acid residues within a naturally occurring protein and comprising residues capable of binding in vivo with transiently modified residues of 20 a switch control ligand in one of the individual states thereof in order to induce or restrict the conformation of the protein and thereby modulate the biological activity of the protein, and/or which is capable of binding with a non-naturally occurring switch control modulator molecule to induce or restrict a protein conformation and thereby modulate the biological activity of the protein. 25 A protein-modulator adduct in accordance with the invention comprises a naturally occurring protein having a switch control pocket with a non-naturally occurring molecule bound to the protein at the region of said switch control pocket, said molecule serving to at least partially regulate the biological activity of said protein by inducing or restricting the conformation of the protein. Preferably, the protein also has a corresponding switch control 30 ligand, the ligand interacting in vivo with the pocket to regulate the conformation and biological activity of the protein such that the protein will assume a first conformation and a first biological 29 WO 2004/060305 PCT/US2003/041425 activity upon the ligand-pocket interaction, and will assume a second, different conformation and biological activity in the absence of the ligand-pocket interaction. The nature of the switch control ligand/switch control pocket interaction may be understood from a consideration of schematic Figs. 1-4. Specifically, in Fig. 1, a protein 100 is 5 illustrated in schematic form to include an "on" switch control pocket 102, and "off" switch control pocket 104, and a switch control ligand 106. In addition, the schematically depicted protein also includes an ATP active site 108. In the exemplary protein of Fig. 1, the ligand 106 has three amino acid residues with side chain OH groups 110. The off pocket 104 contains corresponding X residues 112 and the on pocket 102 has Z residues 114. In the exemplary 10 instance, the protein 100 will change its conformation depending upon the charge status of the OH groups 110 on ligand 106, i.e., when the OH groups are unmodified, a neutral charge is presented, but when these groups are phosphorylated a negative charge is presented. The functionality of the pockets 102, 104 and ligand 106 can be understood from a consideration of Figs. 2-4. In Fig. 2, the ligand 106 is shown operatively interacted with the off 15 pocket 104 such that the OH groups 110 interact with the X residues 112 formnning a part of the pocket 104. Such interaction is primarily by virtue of hydrogen bonding between the OH groups 110 and the residues 112. As seen, this ligand/pocket interaction causes the protein 100 to assume a conformation different from that seen in Fig. 1 and corresponding to the off or biologically downregulated conformation of the protein. 20 Fig. 3 illustrates the situation where the ligand 106 has shifted from the off pocket interaction conformation of Fig. 2 and the OH groups 110 have been phosphorylated, giving a negative charge to the ligand. In this condition, the ligand has a strong propensity to interact with on pocket 102, to thereby change the protein conformation to the on or biologically upregulated state (Fig. 4). Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted 25 to positively charged residues 114 to achieve an ionic-like stabilizing bond. Note that in the on conformation of Fig. 4, the protein conformation is different than the off confonrmation of Fig. 2, and that the ATP active site is available and the protein is functional as a kinase enzyme. Figs. 1-4 illustrate a simple situation where the protein exhibits discrete pockets 102 and 104 and ligand 106. However, in many cases a more complex switch control pocket pattern is 30 observed. Fig. 6 illustrates a situation where an appropriate pocket for small molecule interaction is formed from amino acid residues taken both from ligand 106 and, for example, from pocket 30 WO 2004/060305 PCT/US2003/041425 102. This is termed a "composite switch control pocket" made up of residues from both the ligand 106 and a pocket, and is referred to by the numeral 120. A small molecule 122 is illustrated which interacts with the pocket 120 for protein modulation purposes. Another more complex switch pocket is depicted in Fig. 7 wherein the pocket includes 5 residues from on pocket 102, and ATP site 108 to create what is tended a "combined switch control pocket." Such a combined pocket is referred to as mnmeral 124 and may also include residues from ligand 106. An appropriate small molecule 126 is illustrated with pocket 124 for protein modulation purposes. It will thus be appreciated that while in the simple pocket situation of Figs. 1-4, the small 10 molecule will interact with the simple pocket 102 or 104, in the more complex situations ofFigs. 6 and 7 the interactive pockets are in the regions of the pockets 120 or124. Thus, broadly the the small molecules interact "at the region" of the respective switch control pocket. 31 WO 2004/060305 PCT/US2003/041425 GENERAL SYNTHESIS OF COMPOUNDS In the synthetic schemes of this section, q is 0 or 1. When q = 0, the substituent is replaced by a synthetically non-interfering group R 7 . Compounds of Formula I wherein D is taken from D-1 or D-2 and Y is alkylene are 5 prepared according to the synthetic route shown in Scheme 1.1. Reaction of isothiocyanate 1 with chlorine, followed by addition of isocyanate 2 affords 3-oxo-thiadiazolium salt 3. Quenching of the reaction with air affords compounds of Formula I-4. Alternatively, reaction of isothiocyanate 1 with isothiocyanate 5 under the reaction conditions gives rise to compounds of Fonrmula 1-7. See A. Martinez et al, Journal ofMedicinal Chemistry (2002) 10 45: 1292. Intermediates 1, 2 and 5 are commercially available or prepared according to Scheme 1.2. Reaction of amine 8 with phosgene or a phosgene equivalent affords isocyanate 2. Similarly, reaction of amine 8 with thiophosgene affords isothiocyanate 5. Amine 8 is prepared by palladium(0) catalyzed amination of 9, wherein Q is a group capable of oxidative 15 insertion into palladium(0), according to methodology reported by S. Buchwald. See M. Wolter et al, Organic Letters (2002) 4:973; B.H. Yang and S. Buchwald, Journal of Organometallic Chemistry (1999) 576(1-2):125. In this reaction sequence, P is a suitable amine protecting group. Use of and removal of amine protecting groups is accomplished by methodology reported in the literature (Protective Groups in Organic Synthesis, Peter G.M. 20 Wutts, Theodora Greene (Editors) 3rd edition (April 1999) Wiley, John & Sons, Incorporated; ISBN: 0471160199). Starting compounds 9 are commercially available or readily prepared by one of ordinary skill in the art: See March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith & Jerry March (Editors) 5th edition (January 2001) Wiley John & Sons; ISBN: 0471585890. 25 32 WO 2004/060305 PCT/US2003/041425 Scheme 1.2

,NH

2 phosgene ,N-C=O 'AH2 phsgene - [R 6 0 2 C-(NH)p]q-E-Y C=

[R

6 0 2 C-(NH)p]q-E-Y Base [R2C(NH)p]qEY 8 2

NH

2 thiophosgene ,N=C= S

[R

6 0 2 C-(NH)p]q-E-Y Base [ReO2C-(NH)p]q-E-Y 5 Re02C-NH 2 R 6 0 2 ReO2NHEYNHP deprotection M-E-Y-NHP 10 R 6 0 2 C-NH-E-Y-NHP Pd(0) catalysis II 9

R

6 0 2

C-NH-E-Y-NH

2 8 Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are also available via the synthetic route shown in Scheme 1.3. Reaction of amine 8 with isocyanate or isothiocyanate 2a yields the urea/thiourea 8a which can be cyclized by the 5 addition of chlorocarbonyl sulfenyl chloride. See GB 1115350 and US3818024, Revankar et. al US Patent 4,093,624, and Klayman et. al JOC 1972, 37(10), 1532 for further details. Where R 4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of I-4 (X=O) and I-7 (X=S). 10 33 WO 2004/060305 PCT/US2003/041425 Scheme 1.3 X

R

4 NCX

NH

2 X=0, S HN N R4

[R

6 02C-(NH)p]q-E-Y 2a [ R 6 0 2 C-(NH)p]q-E-Y' H 8a, X=O, S O X CI 'S N N R4 Deprotection S [R 6 0 2 C-(NH)p]q-E-Y' S-k 1-4 X=O 1-7 X=S X N NH

[R

6 02C-(NH)p]q-E-Y S 1-4 X=O O 1-7 X=S Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are also available as shown in Scheme 1.4. Condensation of isocyanate or isothiocyanate 2a with 5 amine RsNH 2 yields urea/thiourea 2b, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2c. VWhere R 4 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic deprotection conditions such as CAN or TFA will reveal the parent ring system of 2d. Reaction of 2d with NaH in DMF, and displacement wherein M is a suitable leaving group 10 such as chlr&ide, bromide or iodide yields I-4 (X=O) and I-7 (X=S). Scheme 1.4 0 0 RCINH2 R 4 lSHNl N N Deprotection of R 4 R4NCX R4-N N-R5 X=O, S x X X 2a X=O, S X=0, S 2b 2c NaH/DMF HN.NN R5 ,.N N

R

e HN YN-R [R 6 0 2 C-(NH)p]q-E-Y X [R 6 0eO 2 C-(NH)p]q-E- Y ' c X X=O, S 1-4 X=O 2d 8a 1-7 X=S 34 WO 2004/060305 PCT/US2003/041425 Compounds of Formula I wherein Q is taken from Q-1' or Q-2' and Y is alkylene are available via the synthetic route shown in Scheme 1.5. Condensation of isocyanate or isothiocyanate 2a with ammonia yields urea/thiourea 2e, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2f. 5 Reaction of 2f with NaH in DMF, and displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields yields I-4' .(X=O) and I-7' (X=S). Scheme 1.5 0 o R 3 NC R 4 HN NH C, R4ci RNx -cis

R

4 -KN~ x=o, s x x 2a X=0, S X=0, S 2e 2f NaH/DMF S ,N N'R Cl [R5O2C-(NH)p]q-E-Y N R4

[R

6 0 2 C.(NH)p]q-E-Y X 1-4' X=O 8a 17-T X=S 10 Compounds of Formula I wherein Q is taken from Q-3 or Q-4 and Y is alkylene, are prepared according to the synthetic route shown in Schemes 2.1 and 2.2, respectively. Reaction of 12, wherein M is a suitable leaving group, with the carbamate-protected hydrazine 13 affords intermediate 14. Reaction of 14 with an isocyanate gives rise to 15 intermediate 15. Thermal cyclization of 15 affords 1,2,4-triazolidinedione of Formula 1-16. By analogy, scheme 2.2 illustrates the preparation of 3-thio-5-oxo-l,2,4-triazolidines of Formula 1-18 by reaction of intermediate 14 with an isothiocyanate and subsequent thermal cyclization. 35 WO 2004/060305 PCT/US2003/041425 Scheme 2.1 0 OR ORIO

H

2 N-N R4 13 [R 6

O

2 C'(NH)p]q xpY N O i o

[R

6

O

2 C-(NH)p]q- -E M H 12 14 o R4

R

4

-N

=

C=O [R0 2 C(NH)pq heat S [RO2C E N, N Y ORo 0 O NH I 15 R4 R4 [R60 2 C-(NH)p]q E NI E N 0 1-16 N R4 Scheme 2.2 R4

R

4 -N=C=S [RO 6 2 C(NH)p]q-E N N OR10 heat 1o4 17 S NH R4 R4

[R

6

O

2 C(NH)p]q E NN N O 1-18 S N 0 R4 Intermediates 12 wherein p is 1 are readily available or are prepared by reaction of 19 5 with carbamates 10 under palladium (0)-catalyzed conditions. M 1 is a group which oxidatively inserts palladium(0) over group M. M 1 is preferably iodo or bromo. Compounds 19 are either commercially available or prepared by one of ordinary skill in the art. 36 WO 2004/060305 PCT/US2003/041425 Scheme 2.3

R

6 0 2

C-NH

2 10 E M /E / yReO2CNH Y M Y Pd(0) catalysis;

R

6 2 CNH Y Base 12 Compounds of Formula I wherein Q is taken from Q-3 or Q-4 and Y is alkylene are also prepared according to the synthetic route shown in Scheme 2.4. Oxidation of amine 5 R 4

NH

2 to the corresponding hydrazine, condensation with ethyl chloroformate subsequent heating yieldsl,2,4-triazolidinedione 15a. After the action of Nal in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16 (X=0) and 1-18 (X=S). 10 Scheme 2.4 1. NaNO 2 O O RsNCX 2. SnCI 2 CI OEt X=0, S heat

R

4

NH

2

R

4

NHNH

2

R

4 NHNH OEt 2a HN • NaH/DMF [R 6 0 2 C-(NH)p]q-E-YN O R4 ' RI R4 - N R X [R60 2 C-(NH)p]q-E-Y CIRN

NR

5 X 15a 8a 1-16 X=O 1-18 X=S HN-O NaH/DMF O N H R R4--N x]N H " [ReO2C-(N H)p~q-E-Y-N N' R4 Deprotection of R 5 R4N NH [R 6 0 2 C-(NH)p]q-E-Y

R

6 2 C(NH)pEYN

R

4 X 8a X 15b 1-16' X=O 15b 1-18' X=S Compounds of Formula I wherein Q is taken from Q-3' or Q-4' and Y is alkylene are also prepared according to the synthetic route shown in Scheme 2.4. When R 5 is a readily removable protecting group (e.g. R = 3,4-d-methoxybenzyl amine), the action of mild, acidic 15 deprotection conditions such as CAN or TFA on 15a will reveal 1,2,4-triazolidinedione 15b. After deprotonation of 15b by NaH in DMF, displacement wherein M is a suitable leaving group such as chloride, bromide or iodide yields 1-16' (X=O) and 1-18' (X=S). Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y is alkylene arc prepared according to the synthetic route shown in Scheme 3. Reaction of hydrazine 20 with 37 WO 2004/060305 PCT/US2003/041425 chlorosulfonylisocyanate and base, such as triethylamine, gives rise to a mixture of intermediates 21A and 21B which are not isolated but undergo cyclization in situ to afford compounds of Formnulae I-22A and I-22B. Compounds I-22A and I-22B are separated by chromatography or fractional crystallization. Optionally, compounds I-22A and I-22B can 5 undergo Mitsunobu reaction with alcohols R 4 0H to give compounds of Formulae I-23A and I-23B. Compounds 20 are prepared by acid-catalyzed deprotection of t-butyl carbamates of structure 14, wherein R 1 0 is t-butyl. Scheme 3

R

4

CISO

2 -N=C=O

[R

6

O

2 C-(HN)p]q-E-Y, NNH 20 H Base R4 R4

[R

6 2 C-(HN)p]q-E-Y_ NNH [R60 2 C-(HN)p]q-E-Y N ~N O H O " NH C /NH OwS'Cl /S I OO O 218 21 A 0 21 R4 R4 [ReO2C-(HN)p]q-E-Y' N, NSO [RG0 2 C-(HN)p]q-E-Y- N 0 O NHO O=S-NH 1-22A I-22B Ph 3 P Ph 3 P Diethyl azodicarboxylate Diethyl azodicarboxylate

R

4 OH R 4 OH R4 4 [R602C-(HN)p]q-E-Y-N NS0~ [R 6 0eO 2 C-(HN)pq-E-Y_. N O N O=S-N R4 0 R4 1-23A 1-23B 10 38 WO 2004/060305 PCT/US2003/041425 Compounds of Formula I wherein Q is Q-7 and Y is alkylene are prepared as shown in Scheme 4. Reaction of amine 8 with maleimide 24, wherein M is a suitable leaving group, affords compounds of Formula 1-25. Reaction of compound 26, wherein M is a group which can oxidatively insert Pd(0), can participate in a Heck reaction with maleimide 27, affording 5 compounds of Formula 1-28. Maleimides 24 and 27 are commercially available or prepared by one of ordinary skill in the art. Scheme 4 R4 O N 0 ,R 4

[R

6 0 2 C-(NH)p]q-E-Y NH 2 4 R 5 [R602C(NH)Pq-E-Y

NH

2 _______ [R 6

O

2 C0(NH)p]q-E-Y. N 8 Base H R5 1-25 OO O O 0 0 N R

[R.

2 C-(NH)p]q E M 27 R 5

[R

6 0 2 C-(NH)p]q E) R5 26 Pd(0), Base 1-28 Heck Reaction 10 Compounds of Formula I wherein Q is Q-8 and Y is alkylene are prepared as shown in Scheme 5, according to methods reported by M. Tremblay et al, Journal of Combinatorial Chemnisty (2002) 4:429. Reaction of polymer-bound activated ester 29 (polymer linkage is oxime activated-ester) with chlorosulfonylisocyante and t-butanol affords N-BOC sulfonylurea 30. Subjection of 30 to the Mitsunobu reaction with R 4 0H gives rise to 31. 15 BOC-group removal with acid, preferably trifluoroacetic acid, and then treatment with base, preferably triethylamine, provides the desired sulfahydantoin I-32. Optionally, intermediate 30 is treated with acid, preferably trifluoroacetic acid, to afford the N-unsubstituted sulfahydantoin 1-33. 39 WO 2004/060305 PCT/US2003/041425 Scheme 5

R

4

R

4

CISO

2

-N

=

C

= O

[R

6 0 2 C-(NH)p]q-E-Y' NHWO t-BuOH 29 0 2 O R R 4

[R

6 02C-(NH)p]q-E-Y- O3- Ph 3 P N diethyl azodicarboxylate 30 0 0 -?, O R 4 OH -- o NH 0'60 BOC R4 R4 R 4

R

4 1) H+ R4 R4

[R

6 0 2 C-(NH)p]q-E-Y' N 02 [RO2C-(NH)p]q-E-YN H 2) Triethylamine 0 31 S 1-32 / N BOC O R4 R4

R

4

[R

6 0e2C-(NH)p]q-E-Y N H+ Ozz:-.. / 30 H 1-33 Compounds of Formula I wherein Q is Q-8 and Y is alkylene are also prepared as shown in Scheme 5.1. Amine 8 is condensed with the glyoxal hemiester to yield 31a. Reaction of chlorosulphonyl isocyanate first with benzyl alcohol then 31a yields 31b, which 5 after heating yields 1-32. 40 WO 2004/060305 PCT/US2003/041425 Scheme 5.1 O @OEt H HOEt O

[R

6 0 2 C-(NH)p]q-E-Y O[ReO 2 C-(NH)pq-E-Y N OEt NaCHBH 3 31a 8 31b 0 [R OC-(NH)p]q-E-Y R0 CNH E N OEt

CISO

2 NCO - t62- Pq 2. H O1

[R

6 0 2 C-(NH)p]q-E-Y OEt 31a 3. 5% Pd/C 0 H \ N 1 0 heat [R 6

O

2 C-(NH)p]q-E-Y i N 1-32 Compounds of Formula I wherein Q is taken from Q-8', are prepared according to the 5 synthetic route shown in Scheme 5.2. Fonrmation of 31c by the method of Muller and DuBois JOC 1989, 54, 4471 and its deprotonation with NaH/DMF or NaH/DMF and subsequently alkylation wherein M is a suitable leaving group such as chloride, bromide or iodide yields I 32'. Alternatively, 1-32' is also available as shown in Scheme 5.3. Mitsunobu reaction of boc-sulfamide amino ethyl ester with alcohol 8b (made by methods analogous to that for 10 amine 8) yields 31c, which after Boc removal with 2N HCI in dioxane is cyclized by the action of NaHi on 31d results in 1-32'. Scheme 5.2 0 0"11 S -NH NaN O NH -? S-NH 31c [R 6 0 2 C-(NH)pq-E-Y R 6 0 2 C-(NH)pq-EY 8a 3 1-32' 15 41 WO 2004/060305 PCT/US2003/041425 Scheme 5.3 H O [RO2C-(NH)plq-E- Y ' O H H O Boc-N O O [ C(Hq[R 6 0 2 C-(NH)p]q-E-Y-N... IO SB N 0 8b S 0 HN HN JoEt HNJ OEt DEADCAT, PhaP 31d 0 Oi OS-NH heat

[R

6 0sO 2 C-(NH)p]q-E-YN O 1-32' 5 Compounds of Formula I wherein Q is Q-9 and Y is alkylene are prepared as shown in Scheme 6. Reaction of polymer-bound amino acid ester 34 with an isocyanate affords intermediate urea 35. Treatment of 35 with base, preferably pyridine or triethylamine, with optional heating, gives rise to compounds of Formnula I-36. Scheme 6

R

4

R

4 , R4-N= C=--O [R0O 2 C-(NH)p]q-E-Y

.

O 4 NH 34 o

R

4

R

4 [ReO 2 C-(NH)p]q-E-Y., Base SO NH R4 R4 R4 [R602C-(NH)p]q-E-Y" N

-

=0 -3_-6 / N R4 10 Compounds of Formula I wherein Q is Q-9 and Y is alkylene are also prepared as shown in Scheme 6.1. Reaction of aldehyde 8c (available by methods similar to that shown for Sa by anyone skilled in the art) with the t-butyl ester of glycine under reductive amination conditions yields 35a. Isocyanate 2a is condensed with p-nitrophenol (or the corresponding

R

4

NH

2 amine is condensed with p-nitrophenyl chloroformate) to yield the carbamic acid p 15 nitrophenyl ester, which when reacted with deprotonated 35a and yields the urea that when 42 WO 2004/060305 PCT/US2003/041425 deprotected with acid yields 35b. Fonnula 1-36 is directly available from 35b by the action of NaH and heat. Scheme 6.1 0 o0 O HN,),tB H Ot-Bu

[R

6 0 2 C-(NH)p]q-E-Y H [R 6 0 2 C-(NH)p]q-E-Y Ot-BU 8c NaCHBH 3 35a 0' N02 1. R 4 HN 0 N 2. 2N HCI/DIloxane R R 0 N 0 NH iY 0o

[R

6 0 2 C-(NH)p]q-E-Y 0 [R 6 0 2 C-(NH)p]q-E-Y' N2 OH 5 1-36 35b Compounds of Fonnula I wherein Q is taken from Q-9', are prepared according to the synthetic route shown in Scheme 6.2. Fonnrmation of 35c by the method described in JP10007804A2 and Zvilichovsky and Zucker, Israel Journal of Chemistry, 1969, 7(4), 547 10 54 and its deprotonation with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or iodide, yields 1-36'. Scheme 6.2 0 ONH NaN O N H i-NH

[R

6 0 2 C-(NH)p]q-CE-Y' M O [R 6 0 2 C-(NH)p]q-E-Y N 35c O 8a 1-36' 15 Compounds of Formula 1-39 wherein Q is Q-10 or Q-11, and Y is alkylene are prepared as shown in Schemes 7.1 and 7.2, respectively. Treatment of alcohol 37 (Z = O) or amine 37 (Z = NH) with chlorosulfonylisocyanate affords intermediate carbamate or urea of 20 structure 38. Treatment of 38 with an amine of structure HN(R 4

)R

4 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-39. Reaction of chlorosulonylisocyanate with an alcohol (Z = O) or amine (Z= NR 4 ) 40 affords intermnnediate 43 WO 2004/060305 PCT/US2003/041425 41. Treatment of 41 with an amine 8 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-42. Scheme 7.1 CIS0 2 -N=C=0 [R6O2C-(NH)p]q-E-Y'ZH > [R 6 0 2 C-(NH)p]q-E-Y- z NSO 2 cI 37 38 H R4 0 0 0 H-N O S O

R

4

[RO

6 0 2 C-(NH)p]q-E-YZ A N N R 4 H I Base H R4 I-39 5 Scheme 7.2 R4 H-Z 0 40 R 4 .SO2

CISO

2 -N=C0 L4Z- N H 41 [ReO 2 C-(NH)p]q-E-Y NR5 O O N R4Z NSN Y-E-q[(NH)pCO 2 R6 H Base R5 1-42 Compounds of Formula I wherein Q is taken from Q-12 are prepared according to the synthetic route shown in Scheme 8. Readily available pyridine 43, wherein TIPS is tri-iso propylsilyl, is alkylated under standard conditions (K 2

CO

3 , DMF, R 4 -I or Mitsunobu 10 conditions employing R 4 -OH) to give pyridine derivative 44 which is reacted with compound 12, wherein M is a suitable leaving group, to afford pyridones of formula I-45. 44 WO 2004/060305 PCT/US2003/041425 Scheme 8 OH 0 / R 4 OHO

R

4 Q, KiC0 3 DMFor Acetone TIPS R or TIPS 0 N R 4 OH, Ph 3 P Diethyl azodicarboxylate 43 44 OR4 [R60 2 C-(NH)p]q-E-Y.. 12 -" 0 N BaseI Base Y-E-[(NH)pCO 2

R

6 ]q 1-45 Compounds of Fonrmula I wherein Q is taken from Q-13 are prepared according to the synthetic route shown in Scheme 9. Readily available pyridine 46 is alkylated under standard conditions (K 2 C0 3 , DMF, R 4 -I or Mitsunobu conditions employing R 4 -OH) to give pyridine 5 derivative 47. N-alkylation with K 2 C0 3 , DMF, R 4 -I affords pyridones of formula 48. Intermediate 48 is partitioned to undergo a Heck reaction, giving I-49; a Buchwald amination reaction, giving I-51; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give I-52. The Heck reaction product I-49 may be optionally hydrogenated to afford the saturated compound I-50. Wherein the phenyl ether R 4 is methyl, compounds of formula 1-49, 1-50, 1-51, or 1-52 10 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-53, wherein R 4 is hydrogen. 45 WO 2004/060305 PCT/US2003/041425 Scheme 9 OH OR 4

R

5

R

4 Q, K 2 CO3 R5 DMFor Acetone R R41, K2CO3 OR 4 5 TIPSO N Cl or TIPS O C DMF or Acetone 0 N C R 4 OH, Ph 3 P 0 N C O N CI 46 Diethyl azodicarboxylate 47 1 R4

OR

4 48 E-[(NH)pCO 2

R

6 ]q R NR 4 4 n Hydrogenation R 5 4..8 " E-[(NH)pCO2Re] q Heck reaction 0 N E-[(NH)PC 2

R

6 q E-[(NH)pCR]q Pd(O) R 4 1-49 R 4 E(NH)pCO 2

R

6 ]q2 Base

R

4 n+2

OR

4 1-50

H

2 N E-[(NH)pCO 2

R

6 ]q boron tribromide

R

5 or lithium chloride boron tribromide 48 n'E-[(NH)PC 2 R]q or lithium chloride Buchwald amination R 4 H nE H)pCO2Rd]q Pd(0) R4 boron tribromide OH Base 1- or lithium chloride R 5 HO E-[(NH)pCO2Re]q OR4 HO E-[(NH)PC 2

R

6 ]q OR boron tribromide , E-[(NH)pCO 2

R

6

]

q 48 n R 5 or lithiul chloride 0 N Y -- > R4 Buchwald arylation ]q3 Cu(l) 0 N E-[(NH)CR6]q 1-53 Base

R

4 1-52 Compounds of Formula I wherein Q is taken from Q-14 are prepared according to the 5 synthetic route shown in Scheme 10. Starting from readily available pyridine 54, alkylation under standard conditions (K 2

CO

3 , DMF, R 4 -I or Mitsunobu conditions employing R 4 -OH) yields pyridine derivative 55. N-alkylation with K 2

CO

3 , DMF, R 4 -I affords pyridones of formula 56. Intermediate 56, wherein M is a suitable leaving group, preferably bromine or chlorine, is partitioned to undergo a Heck reaction, giving I-57; a Buchwald amination 10 reaction, giving I-59; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give 1-60. The Heck reaction product 1-57 may be optionally hydrogenated to afford the saturated compound I-58. Wherein the phenyl ether R 4 is methyl, compounds of formula 1-57, I-58, I-59, or I-60 are treated with boron tribromide or lithium chloride to afford compounds of Formula I-61, wherein R4 is hydrogen. 15 46 WO 2004/060305 PCT/US2003/041425 Scheme 10 OH OR 4 Q R 4

Q,K

2 CO QOR4 DMFor Acetone R41, K2CO, Q TIPS DMF or Acetone TIPS N R 4 OH, Ph 3 P TIP O Rs Diethyl azodicarboxylate 0 N R 54 55 R4

OR

4 / E-[(NH)pCR]q E-[(NH)pO 2 Re]q Hydrogenation n 56 --- E-[(NH)pCO 2 R]q Heck reaction 0 4 N R5 R Pd(0) 1-57 B R4 Base 1-58 OR4 HO -[(NH)pCR]qH BBr 3 or LiC 56 n 0 Rs B iOH Buchwald animation N R4 BBrorLiCl Pd(O) 1-59 Base O 6 Y0

OR

4 HO WE-[(NH)pCO2R6q 0 N R 5 SOrE-[(NH)pCO 2 Rjq BBr 3 or LiCI R4 56I 6 Buchwald arylation R-61 Cu(1) R4 Base 1-60 5 Compounds of Formula I wherein Q is taken from Q-15 are prepared according to the synthetic routes shown in Schemes 11 and 12. Starting esters 62 are available from the corresponding secoacids via TBS-ether and ester formation under standard conditions. Reaction of protected secoester 62 with Meerwin's salt produces the vinyl ether 63 as a pair of regioisomers. Alternatively, reaction of 62 with dimiethylamine affords the vinylogous 10 carbamnate 64. Formation of the dihydropyrimnidinedione 66 proceeds by condensation with urea 65 with azeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione 66 may optionally be further substituted by Mitsunobu reaction with alcohols R 4 OH to give rise to compounds 67. Scheme 12 illustrates the further synthetic elaboration of intermediates 67. Removal 15 of the silyl protecting group (TBS) is accomplished by treatment of 67 with flouride (tetra-n butylammonium fluoride or cesium flouride) to give primary alcohols 68. Reaction of 68 with isocyanates 2 gives rise to compounds of Formula I-69. Alternatively, reaction of 68 with [RO 6 0 2 C(NH)p]q-E-M, wherein M is a suitable leaving group, affords compounds of 47 WO 2004/060305 PCT/US2003/041425 Formula 1-70. Oxidation of 68 using the Dess-Martin periodinane (D. Dess, J. Martin, J. Am. Chem. Soc. (1991) 113:7277) or tetra-n-alkyl peruthenate (W. Griffith, S. Ley, Aldrichimica Acta (1990) 23:13) gives the aldehydes 71. Reductive amination of 71 with amines 8 gives rise to compounds of Formula I-72. Alternatively, aldehydes 71 may be reacted with 5 ammonium acetate under reductive alkylation conditions to give rise to the primary amine 73. Reaction of 73 with isocyanates 2 affords compounds of Formula I-74. Scheme 11

'

0 0 0 a Meerwin's TBSO R4HN0 NH 2 OBe Reagent OMe R4 NH TBSO 3 R 65 NN NH R5N(Me) 2 0 TBSO o Dimethylamile TBSO 62 4A sieves - TBSO OMe R5 64 R 5 66 0

R

4 OH R4N k NR4 66 ph3p TBSO0 diethyl azodicarboxylate n R5 67 10 48 WO 2004/060305 PCT/US2003/041425 Scheme 12 0 0 0 o O O R4- ' NR4 R4N I [R 6 0 2 C-(NH)p]q-E-N=C=O R4-N NH N N N NH 2 TBSO HO [R 6

O

2 C-(NH)p]q-CNH O O IOY R [R 6 2 C-(NH)p]q-E-M 68 R -69 0 Oxidation R4-N ' NH O O

[R

6 O2C-(NH)p R 4 .N J NH [R 6 0 2 zC-(NH)p]q-E-NH 2 R4, .N NH R OHC O Reductive amination [R2C-(NH)pq-E NH I-7._ 0 [R 6

O

2 C-(NH)p]q,-E 0U) T "

R

s R 71 R, ammonium acetate 1-72 (reductive amination) 0 O Ra N,,,H

[R

6 0 2 C-(NH)p]q-E-N=C=0 R4,,~ NHJ N NH H

H

2 \ 0 [R 6 02C-(NH)pjq-E O - 0 R, 73 1-74 Compounds of Formula I wherein Q is taken from Q-16 are prepared according to the 5 synthetic routes shown in Schemes 13 and 14. Starting esters 75 are available from the corresponding secoacids via TBS-ether and ester fonmnation under standard conditions. Reaction of protected secoester 75 with Meerwin's salt produces the vinyl ether 76 as a pair of regioisomers. Alternatively, reaction of 75 with dimethylamine affords the vinylogous carbamate 77. Formation of the dihydropyrimidinedione 78 proceeds by condensation with 10 urea 65 with azeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione 78 may optionally be further substituted by Mitsunobu reaction with alcohols R 4 OH to give rise to compounds 79. Compounds of Fonmnulae 1-81, 1-82, I-84, and I-86 are prepared as shown in Scheme 14 by analogy to the sequence previously described in Scheme 12. 49 WO 2004/060305 PCT/US2003104 1425 Scheme 13 0 o o 0 erinsR OMe00 RaetTBSO )n R 4 HN jNH 2

R

5 OMe 76 65'4N NH TBSO n4A sievesR 75

R

5 N OMe TBS n ITY)SOS

R

4 0H R4'N N I 4 Ph 3 PR diethyl azodicar-boxylate R 5 0 TBSO 79 Schemne 14 0 R4,NiKN'R4 4NIKN R4 [R6O 2 C-(NH)p]q-E-NC=O R5- 02 0.R0 OTBS -81 NH-E-[(NH)PCO 2 Re]q 0O N911 N(H ~ IR0C(H~~--H 04 R4, N 0)I Reductive aminlationl R ' 0 R 5 : 0 -8 NH-E-[(NH)PC0 2 R6]q ( nO0E-[(NH)PCO 2 Rs]q 83 ( CHO 0 1-2ammronium acetate R4,N ) N (reductive ainination) R4, I 4 [R 6 0 2 C-(NH)p]q-E-N=C=O (NH ' NH-E+[NH)PCO 2 R61q R 5--' 0 / 1-86 n NH 2 5 85 50 WO 2004/060305 PCT/US2003/041425 Alkyl acetoacetates 87 are commercially available and are directly converted into the esters 88 as shown in Scheme 15. Treatment of 87 with NaHMDS in THIF, followed by quench with formaldehyde and TBSC1 (n = 1) or M-(CH2)n-OTBS (n 2-4) to give rise to 5 compounds 88. Scheme 15 0 0 0 0 1. NaHMDS, THF Re OMe 2- R OMe 2. CHO quenIIch; 87 or Q-(CH2)n-OTBS ( OTBS 8, n > 1 0 0 (for n= 1) R5OMe TBS-Cl, pyridine, OTBS

CH

2 C1 2 88, n I 10 Compounds of Formula I wherein Q is taken from Q-17 are prepared according to the synthetic routes shown in Schemes 16.1 and 16.2, and starts with the BOC-protected hydrazine 13, which is converted to the 1,2-disubstituted hydrazine 89 by a reductive alkylation with a glyoxal derivative mediated by sodium cyanoborohydride and acidic workup. Condensation of 89 with diethyl malonate in benzene under reflux yields the 15 heterocycle 90. Oxidation with N 2 0 4 in benzene (see Cardillo, Merlini and Boeri Gazz. Chimn. Ital. (1966) 9:8) to the nitromalonohydrazide 91 and further treatment with P 2 0s in benzene (see: Cardillo,G. et al, Gazz. Chim.Ital. (1966) 9:973-985) yields the tricarbonyl 92. Alternatively, treatment of 90 with Brederick's reagent (t-BuOCH(N(Me 2

)

2 , gives rise to 93, which is subjected to ozonolysis, with a DMS and methanol workup, to afford the protected 20 tricarbonyl 92. Compound 92 is readily deprotected by the action of CsF in THF to yield the primary alcohol 94. Alcohol 94 is optionally converted into the primary amine 95 by a sequence involving tosylate formation, azide displacement, and hydrogenation. 51 WO 2004/060305 PCT/US2003/041425 Scheme 16.1 0 NO 2 B O OTBS EtO OEt 0 O N204 O BOC NacNBi 3 , CHICN ,/OTBS N 2 0 4

R

4

N-NH

2

R

4 HN-N R 4 N-N R 4 N-N 13 2) H+ H 89 9 0 \Z"OTBS 91 St-BuO-CH(NMe)2)2 P205 (Me) 2 N (Me~N, MeO .OMec o 0 oxonolysis o /~y o MeOH/DMSO 0

R

4 N-N \ OTBS

R

4 N-N \'OTBS 93 92 CsF, THF 1MeO OMe ) tosyl chloride, base MeO OMe 0 0 2) NaN' O

R

4 N-N , . 3) hydrogenation RNN " NHg R4N-N o H 9.5 94 Reaction of 94 with (hetero)aryl halide 26, wherein M is iodo, bromo, or chloro, under copper(I) catalysis affords compounds 1-96. Optional deprotection of the di-methyl keta] with aqueous acid gives rise to compounds of Formula I-98. By analogy, reaction of 5 amine 95 with 26 under palladium(0) catalysis affords compounds of Formula 1-97. Optional deprotection of the di-mnethyl ketal with aqueous acid gives rise to compounds of Formula I 99. 10 52 WO 2004/060305 PCT/US2003/041425 Scheme 16.2 MeO OMe [R 6

O

2 C-(NH)p]q-E M O H , H 0 0 " 26 H , H 2 0 0 O 4 N- R 4 N-N E Cu(1), base R4N- ' ,E-[(NH)pCO 2 R6]q \,-O,[(NH)pCO 2

R]

q R4N-N\-OH 1-96 -98 94 MeO OMe HO OH MeO Ome [R602C-(NH)pJq-EM H

+

, H 0 O 026 R4N-N Pd(O), base R 4 N- NH E-[(NH)pCOR 6 ]q R4N-- NH E-[(NH)pCO 2 R6]q VNH2 1-97 1-99 95 Compounds of Fonrmnula I wherein Q is taken from Q-17 are also prepared according 5 to the synthetic route shown in Scheme 16.3. Deprotonation of 4,4-dimethyl-3,5-dioxo pyrazolidine (95a, prepared according to the method described in Zinner and Boese, D. Pharmazie 1970, 25(5-6), 309-12 and Bausch, M. J.et.al J. Org. Chem. 1991, 56(19), 5643) with NaH/DMF or NaH/DMF and with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein M is a suitable leaving group such as chloride, bromide or 10 iodide yields I-99a. Scheme 16.3 0 0 O HN 'CI HN-NHN

[RO

6 2 C-(NH)pJq-E-YC I HN-NH [RsO 2 C.(NH)p]q-E-Y N 95a O 8a I-99a 15 Compounds of Formnula I wherein Q is taken from Q-18 are prepared as shown in Schemes 17.1 and 17.2. Aminoesters 100 are subjected to reductive alkylation conditions to give rise to intermediates 101. Condensation of amrnines 101 with carboxylic acids using an acid activating reagent such as dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOBt) affords intermediate amides 102. Cyclization of amides 102 to tetramic acids 104 is 20 mediated by Amberlyst A-26 hydroxide resin after trapping of the in situ generated alkoxide 103 and submitting 103 to an acetic acid-mediated resin-release. 53 WO 2004/060305 PCT/US2003/041425 Scheme 17.1 R 5 0 0 R 4 CHO O R 5

CH

2

CO

H O O

R

6 0 NH 2 O R 6 0 NH R 4 DCC, HOBt R 6 0 N R4 RM NaBH(OAc)3 MOM' Ne OH ( (NMe O R4 H+, R40H 40 __ N, I---R4 N R4 M 104 M' is t-BuOCH 2 -, BOCNH(CH 2

)

3 BOCNH(CH 2

)

4 -, HC=-C-CH2- 103 M is HOCH 2 -; H 2

N-(CH

2

)

3 -;

H

2

N-(CH

2 )4-; HC=-C-CH 2 Scheme 17.2 illustrates the synthetic sequences for converting intennrmediates 104 to 5 compounds of Formula I. Reaction of alcohol 104.1 with aryl or heteroaryl halide 26 (Q = halogen) under copper(I) catalysis gives rise to compounds of Formula 1-105.1. Reaction of amines 104.2 and 104.3 with 26 under Buchwald palladium(0) catalyzed amination conditions affords compounds of Formulae 1-105.2 and 1-105.3. Reaction of acetylene 104.4 with 26 under Sonogashira coupling conditions affords compounds of Formula 1-105.4. 10 Compounds 1-105.4 may optionally be reduced to the corresponding saturated analogs I 105.5 by standard hydrogenation. 54 WO 2004/060305 PCT/US2003/041425 Scheme 17.2 Re Rs 0 O R,0 /[R 6 0eO 2 C-(NH)p

]

q-E' R40 26 R 4 0 N 4-R N R4 Cu(I), base .. E-(NH)pCOR OH

O

- E [( NH )pC 02

R

6 ] q 104.1 1-105.1 Re Rs _ 0 [R 6 0 2 C-(NH)p]q-E M R 4 , /

R

4 0R40 R40 N N

R

4 R4 Pd(o), base )n_ SnNH E-[(NH)pCO 2

R

6 ]q NH2 1-105.2, n = 3 104.2, n = 3 1-105.3, n = 4 104.3, n= 4 MRe

[R

6 0 2 C-(NH)p]q-E M R, . Rs 0 0 26 Hydrogenation R 4 0 ' R- R40 N N9R 4

R

4 0 N R PdCl 2 (Ph 3 P)2, CUI R4 Base Base q[R6O2Cp(HN)j-E (Sonogashira Coupling) E-[(NH)pCO 2

R

6 ]q q[RCp(HN)E 104.4 1-105.4 1-105.5 Compounds of Formula I wherein Q is taken from Q-19, Q-20, or Q-21 are prepared 5 as illustrated in Scheme 18. Commercially available Kemp's acid 106 is converted to its anhydride 107 using a dehydrating reagent, preferably di-isopropylcarbodiimide (DIC) or 1 (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Reaction of 107 with an amines

R

4

NH

2 affords the intermediate amides which are cyclized to the imides 108 by reaction with DIC or EDC. Alternatively, 107 is reacted with amines 8 to afford amides of Formula 1-110. 10 Amides 1-110 may optionally be further reacted with DIC or EDC to give rise to compounds of Formula I-111. Acid 108 is further reacted with amines 8 to give compounds of Formula 1-109. 55 WO 2004/060305 PCT/US2003/041425 Scheme 18 S C02H O 4 O OCO DI or ED H 1) R 4

NH

2 HO- "O N

H

3 C 00 OH, 0 01CH

H

3 C CH 3

H

3

H

3 ac 2) DIC or EDC

H

3 C H 3 C 106 107 108

[R

6 0 2 C-(NH)p]q-E R 4 0

[R

6 0 2 C-(NH)p]q-ENH 2 HN

O

N 108 8

H

3 CO CH 3 DIC, HOAt 1-109 H 3 C 1Cp[R602C-(NH)p]q-E [R 6 02C-(NH)p]q-E O

[RO

2 C-(NH)p]q-E NH CO 2 H DIC or EDC HO- - / 107 8 HaC CH 3 HaC CH 3 3C H 3 C 1-110 1-111 Compounds of Formula I wherein Q is taken from Q-22 or Q-23 are prepared as 5 shown in Schemes 19.1 through 19.3. Preparation of intermediates 113 and 114 are prepared as shown in Scheme 19.1 fiom di-halo(hetero)aryls 112, wherein M 2 is a more robust leaving group than Mi. Reaction of 112 with amines 37 (Z = NH) either thermally in the presence of base or by palladium(0) catalysis in the presence of base and phosphine ligand affords compounds 113. Alternatively, reaction of 112 with alcohols 37 (X = O) either thermally in 10 the presence of base or by copper(I) catalysis in the presence of base affords compounds 114. 56 WO 2004/060305 PCT/US2003/041425 Scheme 19.1

[R

6 02C-(NH)p]q-E-YzH

ZHMM

1 W3_W 7, Z = NH W W 2Base [R60 2 C-(NH)p]q-E-Y N H 112 113 M, [R602C-(NH)p]q-E-Yz H L. W 327,Z= O Z [R602C-(NH)p]q-E-Y-. O'k," 112__ Base 114 Scheme 19.2 illustrates the conversion of intermediates 113 into compounds of Formula 1-115, 1-118, or 117. Treatment of 113 with aqueous copper oxide or an alkaline 5 hydroxide affords compounds of Formula 1-115. Alternatively, treatment of 113 with t butylmercaptan under copper(I) catalysis in the presence of ethylene glycol and potassium carbonate gives rise to 116 (see F.Y. Kwong and S. L. Buchwald, Organic Letters (2002) 4:3517. Treatment of the t-butyl sulfide 116 with acid affords the desired thiols of Formula 1-118. Alternatively, 113 may be treated with excess ammonia under pressurized conditions 10 to afford compound 117. 57 WO 2004/060305 PCT/US2003/041425 Mi Scheme 19.2 w

[R

6

O

2 C-(NH)p]q-E-Y-. N. H 113 aq CuO t-BuSH excess NH 3 , or Cul, K2CO 3 base KOH ethylene glycol OH StBu NH 2 w NW W W W W

[R

6 0 2 C-(NH)p]q-E-Y, - [R 6 0 2 C-(NH)p]q-E-Y [R6O 2 C-(NH)p]q-E-YN H H H 1-115 116 117

H

+ SH

[R

6 0 2 C-(NH)p]q-E-Y'.N H 1-118 Scheme 19.3 illustrates the conversion of intermediate 114 into compounds of Fonrmula 1-119, 1-122, and 121, by analogy to the sequence described in Scheme 19.2. 5 58 WO 2004/060305 PCT/US2003/041425 M, Scheme 19.3 wLw

R

6 0 2 C-(NH)p]q-E-YO, , C 114 aq CuO t-BuSH excess NH 3 , or Cul base KOH K 2

CO

3 ethylene glycol OH StBu NH 2 W WWW W W

R

6

O

2 C-(NH)p]q-E-Y O

R

6

O

2 C-(NH)p]q-E-Y O

R

6

O

2 C-(NH)p]q-E-Y j' 1-119 120 121

H

+ SH W W

R

e

O

2 C-(NH)p]q-E-Y O 1-122 Compounds of Formula I wherein Q is taken from Q-24, Q-25, or Q-26 are prepared 5 as shown in Scheme 20. Reaction of compounds 1-115 or I-119 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R 4

)

2 gives rise to compounds of Fommlae 1-123 or 1-124. Reaction of compounds 1-118 or 1-122 with a peracid, preferably peracetic acid or trifluoroperacetic acid, affords compounds of Formula I 125 or 1-126. Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followed by 10 in situ reaction with amines HN(R 4

)

2 or alcohols R 4 OH, affords compounds of Formulae I 127, 1-128, 1-129, or 1-130. 59 WO 2004/060305 PCT/US2003/041425 Scheme 20 OH SH

NH

2 W )IW W IW W 1"W w -kw w,- w w--Nw R602C-(NH)p]q-E-YZ L R602C-(NH)p]q-E-YZ) R6O2C-(NH)p]q-E-ZY I 1-115, Z= NH 1-118,Z=NH 117, Z= NH 1-119, Z= O 1-122,Z = O 121, Z = O 1) Chlorosulfonyl- I) Chlorosulfonyl isocyanate Peracetic acid isocyanate 2) HN(R 4

)

2 2) HN(R 4

)

2 or R 4 OH 0000 O. o %, R ,I R SNS ,N R4 S O 3 H HN N N H IW- W W .W R 4 W,' W R4 ReO2C-(NH)p]q--wZ W R602C-(NH)p]q-E-YZk ReOgC-(NH)p]q-E-yZ 1-127, Z= NH 1-123, Z = NH 1-125, Z = NH 2-128, Z= O 1-124, Z = O -126, Z = O HN NOIN S 'R W.,W H W ,W R6O2C-(NH)p]q-E-Y-Z J 1-129, Z = NH 1-130, Z = O Compounds of Formula I wherein Q is taken from Q-27 are prepared as illustrated in Scheme 21. Reductive alkylation of thiomorpholine with aldehydes 131 affords benzylic 5 amines 132, which are then subjected to peracid oxidation to give rise to the thiomorpholine sulfones 133 (see C. R. Johnson et al, Tetrahedron (1969) 25: 5649). Intermediates 133 are reacted with amines 8 (Z = NH2) under Buchwald palladium-catalyzed amination conditions to give rise to compounds of Formula 1-134. Alternatively, compounds 133 are reacted with alcohols 8 (Z = OH) under Buchwald copper(I) catalyzed conditions to afford compounds of 10 Formula 1-135. Alternatively, intermediates 133 are reacted with alkenes under palladium(0)-catalyzed Heck reaction conditions to give compounds of Formula 1-136. Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide. 60 WO 2004/060305 PCT/US2003/041425 0 S (" S SOO NNr Scheme 21 CHO S peracid N peacd NaBH(OAc) 3 oxidation M M M 131 132 133 0

[R

6 0 2 C-(NH)p]q-E-YNH 2 O [Re02C-(NH)plq-E k N. 133 0 133 Pd(0), Ph 3 P, Pd(O), phosphine, base base [R 6 02C-(NH)p]q-E ) 1-136 / n

[R

6 0e 2 C-(NH)p]q-E-Y-NH 1-134 reduction (hydrogenation or diimide) [RO02C-(NH)p]q-E-Y 'oH / S O / 133 E N ( Cu(l), base N

[R

6 0 2 C-(NH)p]q-E-Y-O 1-135

[R

6 0 2 C-(NH)p]q-E) I-137 Compounds of Formula I whereinQ is taken from Q-27 are also prepared as illustrated 5 in Scheme 21.1. Aldehyde 8c is reductively aminated with ammonia, and the resultant amine condensed with divinyl sulphone to yield 1-134. Intermediate 134a is also available by reduction of amide 8d under a variety of standard conditions. Scheme 21.1 O [R620(N~pq Y ' NH 3

[R

6 0 2 C-(NH)p]q-E-Y H NH , [R 6 0 2 C-(NH)plq-E-Y ANH 2 8c NaCHBH 3 134a Amide reduction O\ i.e. LAHr s, [RsO 2 C-(NH)p]q-E-Y NH 2 [ReO 6 2 C-(NH)p]q-E-Y N 8d S0 10 134 61 WO 2004/060305 PCT/US2003/041425 More generally, amines 134c are available via the reduction of amides 134b as shown in Scheme 21.2 The morpholine amide analogues 134d and morpholine analogues 134e are also available as shown in Scheme 21.2 5 Scheme 21.2 o o [RB0 2 C-(NH)p]q-E-Y -OH RR2NH [R 6 eO2C-(NH)p]q-E-Y NR 1

R

2 DIC coupling Be 134b H N Amide reduction S DIC coupling i.e. LAH O [R02C-(NHP]q-E-Y --- [R 6 0 2 C-(NH)p]q-E-Y 'NR 1

R

2

[R

6

O

2 C-(NH)p]q-E-Y N O 134c 134d Amide reduction i.e. LAH

[R

6 0 2 C-(NH)p]q-E-Y' N 134e Compounds of Formula I wherein Q is taken from Q-28 or Q-29 are prepared according to the sequences illustrated in Scheme 22. Readily available amides 138 are 10 reacted with chlorosulfonylisocyanate to give intermediates 140, which are reacted in situ with amines HN(R 4 )2 or alcohols R 4 OH to afford compounds of Formulae 1-141 or 1-142, respectively. Alternatively, amides 138 are reacted with sulfonyl chlorides to give compounds of Formula 1-139. 62 WO 2004/060305 PCT/US2003/041425 H H N ,Cl O0 . Scheme 22 CONH 2 0 0 HN(R 4

)

2 or C1SO 2 -N=C=-O

R

4 0H //>- base

[R

6 0 2 C-(NH)p]q-E -. y [RsO 2 C-(N H)p]q-E--.. 138 140 H 0 R4 R4I H N /"R ,0 0 N>( N 0 00 00 [Reo 2 C-(NH)p]q-E-... /[R62C-(NH)pq-E 1-141 1-142

R

9 O HN-Sz-O RqSO 2 CI 8 base 138 -/

[R

6 0 2 C-(NH)p]q-E-... / 1-139 5 Compounds of Formula I wherein Q is taken from Q-30 are prepared as shown in Scheme 23. Readily available N-BOC anhydride 143 (see S. Chen et al, J. Am. Chem. Soc. (1996) 118:2567) is reacted with amines I-IN(R 4

)

2 or alcohols R 6 0H to afford acids 144 or 145 respectively. Intemaediates 144 or 145 are further reacted with amines HN(R 4

)

2 in the presence of an acid-activating reagent, preferably PyBOP and di-isopropylethylamine, to give 10 diamides 146 or ester-amides 147. Intermediate 145 is converted to the diesters 148 by reaction with an alkyl iodide in the presence of base, preferably potassium carbonate. Intermediates 146-148 are treated with HCl/dioxane to give the secondary amines 149-151, which are then condensed with acids 152 in the presence of PyBOP and di isopropylethylamine to give compounds of Formula 1-153. 63 WO 2004/060305 PCT/US2003/041425 Scheme 23 HO2C 0 N( R 4)2 2(R)NCO N(R 4

)

2 0 H2(RN E )N l O .. O HN(4)2 OC141) PyBOP, i-PrN~t 6o- E C 146 BOC 144 N or R60H 2) HN(R 4

)

2 BOC HO2C O ORe 2(R4)NC OO OR, 143 N 145 "N 147 BOc Boc

R

6 1, base RC OR N 148 BOC HC1, dioxane

CO-X

1 O N(R 4

)

2 2(R4)NCO 0 OH N-- PyBOP, i-Pr2NEt N04

CO-X

2 H // 2(R 4 )NCO [R602C-(NH)p]q- .E- 2/4NO [R602C-(NH)p]q-E (N H)p]qE- N 150 I-153 H 152 X I, X 2 are N(R 4

)

2 ROa c OR X, is N(R 4

)

2 , X 2 is ORe 6 LN X 1 , X 2 are OR 6 N 151 H Compounds of Formula I wherein Q is taken from Q-31 or Q-32 are prepared according to the sequences illustrated in Scheme 24. Treatment of readily available 5 sulfenamides 154 with amines 37 (Z = NH), alcohols 37 (Z = 0), or alkenes 37 (Z = CH=CH 2 ), gives rise to compounds of Formula 1-155. Treatment of sulfenamides 1-155 with iodosobenzene in the presence of alcohols R 6 OH gives rise to the sulf6nimidates of Formula 1-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively, compounds 1-155 (Z = -CH=CH) may be optionally reduced to the saturated analogs 1-156 (Z= CH 2

-CH

2 -), which 10 are converted to the corresponding sulfonimidates 1-157. Treatment of readily available sulfonylchlorides 154.1 with amines HN(R 4

)

2 and base gives rise to compounds of Formula 1-154.2. 64 WO 2004/060305 PCT/US2003/041425 Scheme 24

[R

6 0 2 C-(NH)pIq-E-Y.ZH ZH 7, Z =NH Pd(0), phosphine, NH base Os/ NH 2 i "ORs

SONH

2 PlI=0 [R O 2 C-(NH[R2C(NH)p]qEyp]q-E-Yz 3,MZCN [RaO 2 C-(NH)p]q-E-Y-Z M6 Cu(I), base [RsO 2 C-(NH)plq-D-E-Y-Z 1-157 154 1-155 Phi=O

[R

6 0 2 zC-(NH)p]q-E-Y ZH R 6 OH, ZH MeCN 37, Z = CH=CH2 MeCN Pd(0), phosphine, 0S/NH 2 base Z= CH=CH Hydrogenation [R 6 0 2 C-(NH)p]q-E-Y-(CH 2

)

2 Hydrogenation 1-156

SO

2

NH

2

SO

2

N(R

4

)

2 HN(R 4

)

2 4

[R

6 0 2 C-(NH)p]q-E-Y [R 6 0 2 C-(NH)p]q-E-Y 154.1 1-154.2 Compounds of Formula I wherein Q is taken from Q-33 are prepared as shown in 5 Scheme 25. Readily available nitriles 158 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH 2 ) to afford compounds of Formula 1-159. Compounds 1-159 (wherein Z = CH=CH-) are optionally reduced to their saturated analogs 1-160 by standard catalytic hydrogenation conditions. Treatment of compounds 1-159 or 1-160 with a metal azide (preferably sodium azide or zinc azide) gives rise to tetrazoles of Formula 1-161. 10 65 WO 2004/060305 PCT/US2003/041425 Scheme 25

[R

6

O

2 C-(NH)p]q-E-Y- ZH 37, Z = NH NaN Pd(0), phosphine, N NH base CN

MN

3 CN [R60 2 C-(NH)p]q-E-Y,, 3A ZH 37, Z = 0 [R60 2 C-(NH)p]q-E-Y-Z M) [ReO 2 C-(NH)p]q-E-Y-Z 1-159 1-161 M 6Cu(I), base 158 MN 3 158 [R 6

O

2 C-(NH)p]q-E-YzH

MN

3 37, Z= CH=CH2 , CN Z = CH=CH Pd(0), phosphine, base Hydrogenation

[R

6 0 2 C-(NH)p]q-E-Y-(CH 2

)

2 1-160 Compounds of Formula I wherein Q is taken from Q-34 are prepared as shown in Scheme 26. Readily available esters 162 are reacted with amines 37 (Z = NH), alcohols 37 5 (Z = 0), or alkenes 37 (Z = -CH=CH 2 ) to afford compounds of Formula 1-163. Compounds 1-163 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-164 by standard hydrogenation conditions. Compounds 1-163 or 1-164 are converted to the desired phosphonates 1-165 by an Arbuzov reaction sequence involving reduction of the esters to benzylic alcohols, conversion of the alcohols to the benzylic bromides, and treatment of the 10 bromides with a tri-alkylphosphite. Optionally, phosphonates 1-165 are converted to the fluorinated analogs 1-166 by treatment with diethylaminosulfur trifluoride (DAST). 66 WO 2004/060305 PCT/US2003/041425 Scheme 26 C0 2

R

6 Z = CH=CH Hydrogenation [RsO 2 C-(NH)p]q-E-Y-(CH 2 )Z [RsO 2 C.(NH)p]q-E-Y Z H I-164 37, Z= NH 1) reduction to alcohol (LiBH 4 ) Pd(0), phosphine, 2) CBr 4 , Ph 3 P base 3) P(OR 6

)

3

CO

2

R

6

OR

6 C0 2

R

6 1) reduction to alcohol O / [RaO 2 C-(NH)p]q-E-Y.2H (LiBH 4 ) P-ORB 37, Z = O 2 H [RZC(H-p q 2) CBr 4 , P1 3 P M Cu(I), base [R 6

O

2 C(NH)p]q-EY-Z 3) P(OR 6

)

3 1612 -163 [R 6 0s 2 C-(NH)p]q-E-Y-Z [R6O 2 C-(NH)p]q-E-YgzH 1-165 37, Z= CH=CH2 DAST Pd(0), phosphine, base / OR 6 F P-OR 6 F

[R

6 0s 2 C-(NH)p]q-E-Y-Z 1-166 Compounds of Formula I wherein Q is taken from Q-34 are also prepared as illustrated in Scheme 26.1. Intermediate 8a, wherein M is a suitable leaving group such as 5 chloride, bromide or iodide, is refluxed with triethyl phosphite and the resulting phosphoryl intermediate saponified under mild conditions to yield 1-165. Scheme 26.1 O IOH

[R

6 0 2 C-(NH)p]q-E-Y M 1. P(OEt) 3

[R

6 0 2 C-(NH)p]q-E-Y \OH 602C OH 8a 2. saponification 1-165 10 Compounds of Formula I wherein Q is taken from Q-35 are prepared according to Scheme 27. Readily available acid chlorides 167 are reacted with oxazolidones in the presence of base to afford the N-acyl oxazolidinones 168. Intermediate 168 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CH 2 ) to afford the N-acyl 67 WO 2004/060305 PCT/US2003/041425 oxazolidinones of Fonnula 1-169. Compounds 1-169 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs 1-170 under standard hydrogenation conditions. Scheme 27 [RsO 2 C-(NH)p]q-E-Y. ZH 37, Z= NH H Pd(0), phosphine, 0-0 oo-o 0 O base COO N COGI

R

4 HN

[R

6

O

2 C-(NH)p]q-E-Y, R4 R4 \37, Z= O ZH base / Cu(I), base [R 6 0e2C-(NH)p]q-E-Y-Z M M I-169 167 168 [ReO 2 C-(NH)p]q-E-Y.ZH hydrogenation 37, Z = CH=CHz (ZH= H=CH Pd(O), phosphine, (Z= CH=CH) base 0 0 N R4

[R

5 0 2 C-(NH)p]q-E-Y-(CH 2

)

2 1-170 5 Compounds of Fonnula I wherein Q is taken from Q-36 are prepared as illustrated in Schemes 28.1 and 28.2. Reductive alkylation of the t-butylsulfide substituted piperazines with the readily available aldehydes 131 gives rise to the benzylic piperazines 171. Intermediates 171 are reacted with amines 37 (Z = NH), alcohols 37 (Z = O), or alkenes 37 (Z = -CH=CHz) to give compounds 172, 173, or 174, respectively. Optionally, intermediates 10 174 are converted to the saturated analogs 175 under standard hydrogenation conditions. 68 WO 2004/060305 PCT/US2003/041425 HN N CHO HN N2St-Bu N N-St-Bu Scheme 28.1 NaBH(OAc) 3 M M 131 171 / \NL St-Bu .N N -- _

[RO

2 C-(NH)p]q-E-Y St-Bu 37, Z = NH ZH , 37 Z= CH=CH 2 171 _____________ 171 Pd(0), phosphine, Pd(0), phosphine, 174 base [R 6 0 2 C-(NH)pq-E-Y-NH 17 base [R60 2 C-(NH)p]q-E-Y reduction (hydrogenation or diimide) N N St-Bu \__/ t-Bu [R6O2C-(NH)p]q-E-Y ZH 171 37,Z= O Z St-Bu Cu(1), base [RO 2 C-(NH)p]q-E-Y-d 173 17 ,17 [RO0 2 C-(NH)p]q-E-Y Scheme 28.2 illustrates the conversion of intermediate t-butylsulfides 172-175 to the 5 sulfonic acids, employing a two step process involving acid-catalyzed deprotection of the t butyl sulfide to the corresponding mercaptans, and subsequent peracid oxidation (preferably with peracetic acid or trifluoroperacetic acid) of the mercaptans to the desired sulfonic acids of Fomnnula 1-176. Scheme 28.2 N N \SO3H NL_/N St-Bu 1) H-' / I2) peracid oxidation [ReO 2 C-(NH)p]q-E-Y-Z [ReO 2 C-(NH)p]q-E-Y-Z 172-175 1-176 10 Z = NH, O, CH=CH, CH2-CH2 In some instances a hybrid bcr-abl kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety Ri-X-A-D. The synthesis 69 WO 2004/060305 PCT/US2003/041425 of moieties R-X-A-D are conducted as shown in Scheme 29. Readily available intermediates 177, which contain a group M capable of oxidative addition to palladium(0), are reacted with amines 178 (X = NH) under Buchwald Pd(0) amination conditions to afford 179. Alternatively amines or alcohols 178 (X = NH or O) are reacted thermally with 177 in 5 the presence of base under nuclear aromatic substitution reaction conditions to afford 179. Alternatively, alcohols 178 (X = O) are reacted with with 177 under Buchwald copper(I) catalyzed conditions to afford 179. In cases where p = 1, the carbamate of 179 is removed, preferably under acidic conditions when R 6 is t-butyl, to afford amines 180. In cases where p = 0, the esters 179 are converted to the acids 181 preferably under acidic conditions when R 6 10 is t-butyl. Scheme 29

R

1 -XH M-A-(NH)p-D-(NH)p'-CO 2

R

6 178 R 1 X-A-(NH)p-D-(NH)p'-CO 2

R

6 heat or 177 Pd(0) catalysis 179 H+H

R

1 X-A-(NH)p-D-NH 2

R

1 X-A-(NH)p-D-CO 2 H 180 181 Another sequence for preparing amines or alcohols 180 is illustrated in Scheme 30. Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 wherein M is a leaving 15 group, preferably M is fluoride, or M is a group capable of oxidative insertion into palladium(0), preferably M is bromo, chloro, or iodo, gives intermediates 183. Reduction of the nitro group under standard hydrogenation conditions or treatment with a reducing metal, such as stannous chloride, gives amines 180. Scheme 30

R

1 -XH 178 reduction M-A-(NH)p-D-NO 2 18. RX-A-(NH)p-D-NO 2 reduce RX-A-(NH)p-D-NH 2 heat or 183 180 182 Pd(0) catalysis 20 70 WO 2004/060305 PCT/US2003/041425 In instances when hybrid bcr-abl kinase inhibitors are prepared, compounds of Formula 1-184 wherein q is 1 may be converted to amines 1-185 (p = 1) or acids 1-186 (p = 0) by analogy to the conditions described in Scheme 29. Compounds of Formula 1-184 are prepared as illustrated in previous schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10, 12, 14, 5 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, or 28.2. Scheme 31

[R

6 0 2 C-(NH)p]q

"

E YQ q=1 1-184 p= 1 p= 0

H

2 N E Y Q

HO

2 C E Y Q 1-185 1-186 Compounds 1-184 are taken from schemes 1.1, 2.1, 2.2, 3, 4, 5, 6, 7.1, 7.2, 8, 9, 10 12, 14, 16.2, 17.2, 18, 19.1, 19.2, 19.3, 20, 21, 22, 23, 24, 25, 26, 27, 28.2 The preparation of inhibitors of Fonnula I which contain an amide linkage -CO-NH connecting the oxyanion pocket binding moieties and the RI-X-A-D moieties are shown in 10 Scheme 32. Treatment of acids 181 with an activating agent, preferably PyBOP in the presence of di-iso-propylethylamine, and amines 1-185 gives compounds of Formula I. Alternatively, retroamides of Formula I are formed by treatment of acids 1-186 with PyBOP in the presence of di-iso-propylethylamine and amines 180. 71 WO 2004/060305 PCT/US2003/041425 Scheme 32 D H NHj - y

'

Q + (R 1 X)m-A-(NH)p-D-CO 2 H PyBop, i-Pr 2 NEt (RX)m-(NH)p D N E Yk Q 0 Compounds 1-185 taken Compounds 181 taken from scheme 31 from scheme 29 Amides of Formula I (hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety R 1 -X-A-(NH)p-D) H H , E Q (R4X)m-A (NH)p,DI N .) E -y Q 0 2 C" "Y + (R 1 X)m-A-(NH)p-D-NH 2 PyBop, i-Pr 2 NEt 0 Compounds 1-I 86 taken Compounds 180 taken from from scheme 31 schemes 29 or 30 Retroamides ofFormula I (hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety R,-X-A-(NH)p-D) 5 The preparation of inhibitors of Fomtula I which contain an urea linkage NH-CO NH- connecting the oxyanion pocket binding moieties and RI-X-A-D moieties are shown in Scheme 33. Treatment of amines 1-185 with p-nitrophenyl chloroformate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I. Scheme 33 NH2- E yQ p-nitropenyl chloroformate 0 HN E Y (RIX)m-A-(NH)p-D-NH 2 base I Compounds 180 taken from Compounds 1-185 taken 02N schemes 29 or 30 from scheme 31 187 0 (RX)m AND N NEq yQ 1 H/ H H p Formula I (hybrid inhibitors, possessing oxyanion 10 pocket-binding moiety D and moiety R 1 -X-A-(NH)p-B) 72 WO 2004/060305 PCT/US2003/041425 Alternatively, inhibitors of Formula I which contain an urea linkage NH--CO-NH connecting the oxyanion pocket binding moieties and the R 1 -X-A-D moieties are prepared as shown in Scheme 34. Treatment of amines 180 with p-nitrophenyl chloroformate and base affords carbamrnates 188. Reaction of 188 with amines 1-185 gives ureas of Formula I. 5 Scheme 34

(R

1 X)m-A-(NH)p-D-NH z p-nitrophenyl ehloroformate HH'E N (XR)m NHE YQ Compounds 180 taken from bas Com ds taken from base O Compounds 1-185 taken schemes or 30 02N from scheme 31 188 .'AE',N YHN' D IN (XRI)m 0 Formula I (hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety R 1 -X-A-(NH)p-D) 10 V. Biological assessment of ab] and bcr-abl kinase inhibiton. A continuous spectrophotometric kinase assay is used, wherein the production of adenosine diphosphate is coupled to the oxidation of NADH and measured as a reduction in absorbance at 340nM. For details see: Barker, S.C. et al, Biochemistry (1995) 34:14843; and 15 Schindler, T. et al, Science (2000) 289:1938. Abi kinase assay Activity of nonphosphorylated AbI kinase was determined by following the 20 production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A 34 0nn) was continuous measured spectrophometrically. The reaction mixture (200 Il) contained Abl kinase (3.7 nM. Abl-2 from deCode), peptide substrate (EAIYAAPFAKKK, 0.5 mM), ATP (0.5 mM), MgC1 2 (5 25 mM), pyruvate kinase (16 units), lactate dehydrogenase (26 units), phosphoenol pyruvate (1 73 WO 2004/060305 PCT/US2003/041425 mM), and NADH (0.28 mM) in 100 mM Tris buffer, pH 7.5. The reaction was initiated by adding ATP. The absorption at 340 nm was monitored continuously for 3 to 4 hours at 30 oC on Polarstar Optima plate reader (BMG). Under these conditions, a turn over number (kcat) of 1.4 s 1 was obtained for the preparation of Abi kinase, which is similar to that (1.7 s-) 5 reported for the nonphosphorylated enzyme (Brasher and Van Etten, JBC (2000) 275, 35631 35637). No autophosphorylation of Abl was observed under these conditions since the rate is constant throughout the entire reaction time and presumably because the concentration of the enzyme used is below the critical level (- 10 nM) needed for the autophosphorylation (Brasher and Van Etten, JBC (2000) 275, 35631-35637). These results ensure what we 10 monitored was the activity of nonphosphorylated Abl kinase. Percentage of inhibition in the presence of an inhibitor was obtained by comparison of reaction rate (or slope) with that of a control. IC 50 value was calculated from a series of % inhibition values determined at a range of concentrations of the inhibitor using Prism. The IC50 values for Gleveec and PD 180970 were found to be 76 and 24 nM, respectively, which 15 are close to that reported (Schindler, et al. Science (2000) 289, 1938-1942). % Inhi Example # @ 10 uM IC50, uM 1 10 2 9 3 15 4 24 5 9 6 13 7 9 8 20 9 42 10 16 11 19 12 52 13 31 15 7 16 9 17 18 18 70 3 19 75 4 20 77 3 21 12 23 10 29 12 35 1 36 20 37 10 74 WO 2004/060305 PCT/US2003/04 1425 38 21 _____ 39 13 __ __ 40 16 42 33 _____ 43 28 _____ 75 WO 2004/060305 PCT/US2003/041425 EXAMPLES The following examples set forth preferred methods in accordance with the invention. It is to be understood, however, that these examples are provided by way of illustration and 5 nothing therein should be taken as a limitation upon the overall scope of the invention. Reagents 6-methyl-N'-(4-phenylpyrimidin-2-yl)benzene-1,3-diamine hydrochloride (Reagent AA) and 6-methyl-N'-(4-phenylpyrimidin-2-yl)benzene-l1,3-diamine hydrochloride (Reagent BB), N-Methyl-2-(methlylcarbamoylmethlyl-amino)-acetamide (Reagent CC), terephthalic acid monobenzyl ester (Reagent DD), 4-formyl-benzoic acid methyl ester 10 (Reagent EE), 4-methyl-N-3-(4-(3-pyridyl)-pyrimidin-2-yl)-benzene-1,3-diamine hydrochloride (Reagent FF), [Boc-sulfamide] aminoester (Reagent GG) and 6-methyl-N' -(4 morpholinopyrimidin-2-yl)benzene-1,3-diamine hydrochloride (Reagent HH) were synthesized according to literature procedures. 15 REAGENTAA N~ NH 2 HOI -N To a solution of N-(3-amino-4-methyl-phenyl)acetamide (5g, 25 mmol) in DMF (5 ml) was added 2-chloro-4-phenyl-pyrimidine (4g, 35 mmol) and KI (0.5g, 3 mmol), which was stirred at 100 'C overnight, cooled to 100 C and added to H 2 0 (100mL). The resulting 20 mixture was extracted with CH2C1 2 (2x100 mL), the combined organic layers dried (NazSO 4 ) and concentrated in vacuo. The residue was dissolved in cone. HCI (10 mL), stirred at 80 0 C for 2h and concentrated in vacuo to yield 6-methyl-N'-(4-phenylpyrimidin-2-yl)benzene-1,3 diamine hydrochloride (4.5g, 65%). 'H NMR (CDC13): 7.96 (m, 2H), 7.50-7.47 (in, 1H1), 7.47-7.41 (m, 5H), 7.26 (m, 2H), 2.21(s, 3H); MS (ESI) nim/e: 277 (M++l) 25 REAGENT BB N 0 NH HCI To a solution of N-(3-amino-4-methyl-phenyl) acetamide (5g, 25 mmol) in DMF (5 mL) was added 2-chloro-pyrimidine (3.8g, 33 mmol) and KI (0.5g), which was stirred at 100 30 'C overnight, cooled to 100 C and added to H20 (100mL). The resulting mixture was 76 WO 2004/060305 PCT/US2003/041425 extracted with CH 2 Cl 2 (2x100 mL), the combined organic layers dried (Na 2

SO

4 ) and concentrated in vacuo. The residue was dissolved in conc. HCI (10 mL), stirred at 80 0 C for 2h and concentrated in vacuo to yield 6-methyl-N'-(4-phenylpyrimidin-2-yl)benzene-1,3 diamine hydrochloride (3.75g, 75%). 1 H NMR (CDCl3): 8.36 (dd, J = 15.2 & 4.8 Hz, 2H), 5 7.46 (d, J = 2.4 Hz, 1H11), 6.97 (d, J = 8.0 Hz, 1H11), 7.26 (s, 1H), 6.67 (t, J = 4.8 Hz, 1H), 6.39 (dd, J= 8.0, 2.4, Hz, 1H), 2.20 (s, 3H); MS (ESI) m/e:. 201 (M +1). REAGENT CC 0 H 0 HH H H 10 To a solution of benzyl amine (16.5g, 154 mmol) and ethyl bromoacetate (51.5 g, 308 mmol) in ethanol (500 mL) was added K 2

CO

3 (127.5 g, 924 mmol). The mixture was stirred at RT for 3h, was filtered, washed with EtOH, concentrated in vacuo and chromatographed to yield benzyl-methoxycarbonylmethyl-amino)-acetic acid ethyl ester (29.02g, 67%). 1 H NMR CDC1 3 ) 6 7.39-7.23 (min, 5H11), 4.16 (q, J= 7.2 Hz, 4H), 3.91(s, 2H), 3.54 (s, 4H), 1.26 (t, J= 15 7.2 Hz, 6H); MS (ESI): m/e: 280 (Me+H). A solution of (benzyl-methoxycarbonylmethyl-amino)-acetic acid methyl ester (7.70g, 27.6 mmol) in methylamine alcohol solution (25-30%, 50 mL) was heated to 50 0 C in a sealed tube for 3h, cooled to RT and concentrated in vacuo to yield 2-(benzyl methylcarbamoylmethyl-amino)N-methyl-acetamide in quantitative yield (7.63 g). 1HNMR 20 (CDCl 3 ) 6 7.35-7.28 (min, 5H), 6.75(br s, 2H), 3.71(s, 2H11), 3.20 (s, 4H), 2.81(d, J= 5.6 Hz, 6H); MS (ESI) m/e 250(M+H ) The mixture of 2-(benzyl-methylcarbamoylmethyl-amino)N-methyl-acetamnid (3.09g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40 0 C under 40 psi H2 for 1 Oh, filtered and concentrated in vacuo to yield N-methyl 25 2-(methylcarbamoylmethyl-amino)-acetamide in quantitative yield (1.76 g). 'HNMR(CDCl 3 ) 8 6.95(brs, 2H), 3.23(s, 4H11), 2.79(d, J=4.8Hz, 6H), 2.25(brs, 1H11); MS (ESI) m/e 160(M+H +) REAGENT DD O OH 0 770" 77 WO 2004/060305 PCT/US2003/041425 REAGENT EE oo 0 H REAGENT FF H N N NH2 N z" N 5 REAGENT HH H N N NH 2 . HCI N . To a solution of N-(3-amino-4-methyl-phenyl) acetamide (5g, 41 mmol) in DMF (5 ml) was added 4-(2-chloro-pyrimidin-4-yl)-morpholine (8.1g, 40 mmol) and KI (0.5g, 3 mmol), which was stirred at 100 'C overnight, cooled to 100 C and added to H 2 0 (100mL). 10 The resulting mixture was extracted with CH 2 Cl 2 (2x100 mL), the combined organic layers dried (Na 2

SO

4 ) and concentrated in vacuo. The residue was dissolved in conc. HCI (10 mL), stirred at 80 0 C for 2h and concentrated in vacuo to yield 6-methyl-N 1 -(4 morpholinopyrimidin-2-yl)benzene-1,3-diamine hydrochloride (5.0g, 65%). 1 H NMR (DMSO-d6): 8.00 (d, J= 7.2 Hz, IH), 7.57 (brs, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.14 (dd, J= 15 8.4, 1.6 Hz, 1H), 6.65 (d, J= 7.2 Hz, 1H), 3.69 (s, 4H), 3.66 (s, 4H), 2.25 (s, 3H). MS (ESI) m/e: 286 (M +1). EXAMPLE A MeO N 0 20 To a stirred solution of chlorosulfonyl isocyanate (3g, 21 mmol) in of CH 2 Cl 2 (50 mL) at 0 oC was slowly added pyrrolidine (1.5g, 21 mmol) while the reaction temperature was controlled between 0-5 oC. After being stirred for 1.5h, a solution of 4-Aminomethyl-benzoic acid methyl ester hydrochloride (4.7 g, 23 mmol) and triethylamine (6.4g, 63 mmol) in 78 WO 2004/060305 PCT/US2003/041425 CH11 2 C1 2 (120 mL) was slowly added while the reaction temperature was controlled between 0-5 oC. When the addition was completed, the reaction solution was awarmed to RT, stirred overnight, then poured into of 10% HCI (130 mL) saturated with NaCL. The organic layer was separated and the aqueous layer was extracted with Et 2 0 (3x80 mL). The combined organic 5 layers were dried (Na 2

SO

4 ) and concentrated in vacuo to yield the crude product, which was purified by column chromatography on a silica gel to yield pure pyrolidine carboxamide, N [(4-carbomethoxybenzyl)amino]sulfonyl (3 g, 43% yield). 1H NMR (DMSO-d6) 87.70 (d, J = 2.1 Hz, 2H), 7.28 (d, J= 2.1 Hz, 2H), 4.84 (s, 2H), 3.83 (s, 3H), 315 (m, 4H), 1.67 (inm, 4H11); MS (ESI) r/e: 342 (M++l). 10 EXAMPLE B HO CO 0 o A solution of Example A (60 mg, 0.18 mmol) in THF (10 mL) was added to 3N LiOH (10 mL) at RT, stirred overnight, acidified with 1 N HC1, and extracted with EtOAc. The 15 organic layer was dried (Na 2

SO

4 ) and concentrated to yield pyrolidine carboxamide, N-[(4 carboxybenzyl)amino]sulfonyl (40 rng, 70% yield). 1 H NMR (DMSO-d6) 612.87 (s, IH), 10.01 (s, 1H), 7.88 (d, J=2.0 Hz, 2H), 7.33 (d, J=2.0 Hz, 2H), 6.90 (min, 1H ), 4.28 (s, 2H), 3.28 (m, 4H), 1.75 (min, 4H); MS (ESI) m/e: 327 (M+ 1). 20 EXAMPLE 1 0, 0o 811-e X- 0 To a solution of Reagent AA (14 mg, 0.048 mmol) in anhydrous DMF (1 mL) was added Et 3 N (26 piL, 0.18 mmol) at RT. The reaction mixture was stirred for 5 min, followed by addition of Example B (12 mg, 0.038 mmol), EDCI (14 mg, 0.055 mmol) and HOBt (7.4 25 mg, 0.055 mml). The reaction mixture was stirred over night at RT. Removal of solvent in vacuo followed by preparative HPLC yielded pure Example 1 (16 mg, 76%). 1H NMR

(CD

3 OD) 6 8.32 (d, J= 5.6 Hz, 1H), 8.24 (d, J= 7.2 Hz, 2H), 8.09 (d, J= 2.0 Hz, 1H), 7.92 79 WO 2004/060305 PCT/US2003/041425 (d, J = 8.0 Hz, 2H), 7.60-7.40 (min, 5H), 7.44 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 4.43 (s, 2H), 3.41 (in, 4H), 2.34 (s, 3H), 1.89 (min 4H); MS (ESI) m/e: 586 (M++1). EXAMPLE 2 0 0 0 N' N No .N N, N 5 The title compound was synthesized following the procedure for the preparation of Example 1, utilizing Example B and Reagent BB. 'H NMR (CD 3 OD) 8 8.46 (d, J= 5.2 Hz, 2H), 7.97 (dd, J 8.0, 2.0 Hz, 1H), 7.91 (d, J 8.0 Hz, 2H), 7.50 (dd,. J= 8.0, 2.0 Hz, 1H), 7.44 (d, J= 8.0 Hz, 2H1), 7.33 (d, J= 8.0 Hz, 1H), 6.92 (t, J 4.2 Hz, 1H), 4.43 (s, 2H), 3.41 10 (m, 4H), 2.28 (s, 3H), 1.89 (min, 4H); MS (ESI) m/e: 509 (M++1). EXAMPLE C 000 MeO 0 To a stirred solution of chlorosulfonyl isocyanate (3g, 21 mmol) in 50 mL of CH 2

CI

2 15 (50 mL) at 0 'C was slowly added a solution of 4-aminomethyl-benzoic acid methyl ester hydrochloride (4.7g, 23 mmol) and triethylamine (6.4g, 63 mmol) in CH 2 C1 2 (120 mL) while the reaction temperature was controlled between 0-5 'C. After being stirred for 1.5h, pyrrolidine (1.5 g, 21 mmol) was slowly added while the reaction temperature was controlled between 0-5 'C. When the addition was completed, the reaction solution was allowed to 20 warm to RT, stirred overnight, then poured into of 10% HC1 (130 mL) saturated with NaC1. The organic layer was separated and the aqueous layer was extracted with EtzO (3x80 mL). The combined organic layers were dried (Na 2

SO

4 ) and concentrated to yield the crude product, which was purified by column chromatography on a silica gel to yield pure Example C (2.5 g, 35% yield). 'H NMR (DMSO-d6) 87.87 (d, J=2.1 Hz, 2 H), 7.28 (d, J=2.1 Hz, 2 H), 25 4.89 (s, 2 H) 3.82 (s, 3 H), 3.15 (min, 4 H), 1.68 (min, 4 H); MS (ESI) m/e: 342 (M +1). 80 WO 2004/060305 PCT/US2003/041425 EXAMPLE D oN 00 HO0 The title compound using synthesized following the procedure for Example B utilizing Example C. 'H NMR (CD 3 OD) 57.98 (d, J=2.0 Hz, 2 H), 7.38 (d, J=2.0 Hz, 2 H), 5 4.41 (s, 2 H), 3.39 (min, 4 H), 1.87 (min, 4 H); MS (ESI) m/e: 327 (M+I). EXAMPLE 3 o o H H HH I NyNj~ N" LD -~-~ N 0 The title compound was synthesized following the procedure for the preparation of 10 Example 1 utilizing Example D and Reagent AA. 1H NMR (CD 3 OD) 68.31 (min, 1H11), 8.23 (d, J= 2.1 Hz, 2H), 8.06 (s, 1H), 7.81 (d, J= 2.1 Hz, 2H), 7.62 (min, 1H), 7.54 (min, 4H), 7.43 (d, J = 2.1 Hz, 2H), 7.37 (d, J= 2.1 Hz, 1H), 4.43 (s, 2H), 3.40 (in, 4 H), 2.33 (s, 3H), 1.89 (inm 4H); MS (ESI) m/e: 586 (M++I). 15 EXAMPLE 4 o o ,if- N-Y N N N\ H H N 0 The title compound was synthesized following the procedure of the preparation of Example 1 utilizing Example D and Reagent BB. 1H NMR (CD 3 OD) 88.45 (br s, 2H), 7.96 (d, J= 4.0 Hz, 1H11), 7.90 (d, J=8.0 Hz, 2H), 7.50 dd, J= 8.0, 2.0 Hz, 1H), 7.62 (m, 1H), 7.43 20 (d, J= 8.4 Hz, 2H), 7.29 (d, J= 8.4 Hz, 1H ), 6.87 (t, J= 4.8 Hz, 1H), 4.43 (s, 2H11), 3.40 (min, 4 H), 2.27 (s, 3H), 1.89 (m, 4H); MS (ESI) mi/e: 510 (M +l). EXAMPLE D MeO N 0 81 WO 2004/060305 PCT/US2003/041425 To a suspension of glycine ethyl ester hydrochloride (6.0g, 34 mmol) in anhydrous

CH

2

C

2 (34 mL) was added triethylamine (3.4g, 34 mmol) followed by anhydrous magnesium sulfate (12.2g, 102 mmol) and Reagent EE (6.0g, 34 mmol). After refluxing for 2h, the solid was filtered, washed with brine, dried (MgSO 4 ) and concentrated in vacuo to 5 produce methyl 4-((E)-((t-butoxycarbonyl)methylimino)methyl)benzoate which was used without further purification (8.2g, 97% yield). 'H NMR (CDC1 3 ) 8 8.30 (s, IH), 8.07 (d, J= 8.4 Hz, 2H) 7.84 (d, J= 8.4 Hz, 2H) 4.34 (s, 2H) 3.91 (s, 3H) 1.49 (s, 9H). EXAMPLE E o 0 MeO Y - 0 10 0 To a solution of Example D (8.5g, 30 mmol) in MeOH (80 mL) was slowly added solid NaBH 4 (3.42g, 90 mmol) while the reaction temperature was controlled below 20 oC. After stirring for 2h, the reaction was quenched with H20, extracted with EtOAc (3x100 mL) and the combined organic layers were washed with brine, dried (Na 2

SO

4 ), concentrated in 15 vacuo. The residue was purified via flash column chromatography to yield methyl 4-(((t butoxycarbonyl)methylamino)methyl)benzoate (6.55g, 77% yield). 'H NMR (CDCl 3 ) 5 7.98 (d, J = 8.4 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 3.90 (s, 3H,) 3.84 (s, 2H) 3.29 (s, 2H) 1.46 (s, 9H). 20 EXAMPLE F Meo 0 o 01 To a solution of Example E (5.1g, 18 mmol) in THF (80 mL) was added K 2

CO

3 (4.2g, 30 mmol) and methyl-carbamic acid 4-nitro-phenyl ester (3.6g, 18 mmol). After being stirred overnight, the resulting solid was filtered. After adding H 2 0zO and EtOAc to the filtrate, the 25 organic layer was separated and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried (Na 2

SO

4 ), concentrated in vacuo and purified by flash chromatography to yield Example F (4.4g, 73%). 'H NMR (CDCl 3 ) 8.01 (d, J= 8.4 Hz, 2H) 7.35 (d, J= 8.4 Hz, 2H) 4.59 (m, 1H) 4.57 (s, 2H) 3.91 (s, 3H) 3.90 (s, 2H) 2.79 (d, J= 4.4 Hz, 3H) 1.43 (s, 9H). 30 82 WO 2004/060305 PCT/US2003/041425 EXAMPLE G 0 MeO 0 To a suspension of NaH (0.28g, 7 mmol) in THF (80 mL) at RT was slowly added a solution of Example F (1.85g, 5.5 mmol) in THF (50 mL). After stirring for 2h, the resulting 5 solid was filtered. After adding water and EtOAc to the filtrate, the organic layer was separated and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried (Na 2

SO

4 ), and concentrated in vacuo to yield methyl 4-((3-methyl-2,4-dioxoimidazolidin-l1-yl)methyl)benzoate (1.3g, 90%). 1 H NMR

(CDCI

3 ) 8.03 (d, J= 8.4 Hz, 2H) 7.32 (d, J= 8.4 Hz, 2H) 4.62 (s, 2H) 3.90 (s, 3H) 3.73 (s, 10 2H) 3.08 (s, 3H). EXAMPLE H 0 HO N 00 To the solution of Example G (900 mg, 3.44 rmmol) in MeOH (30 mL) was added 15 conc. HCI (10 mL). The resulting solution was heated to reflux for lh, quenched with saturated Na 2

CO

3 (100 mL), and extracted with CH 2 C12 (100 mL). After separation, the organic layer was washed with brine, dried (Na 2

SO

4 ), and concentrated in vacuo to yield 4 ((3-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzoic acid as a yellow solid. The crude product was used without further purification. 20 EXAMPLE 5 0 To a solution of Example H (200 mg, 0.81 mmol) in DMF (10 mL) were added EDCI (200 mg, 1.0 mmol), HOBt (150 mg, 1.5mmol), NMM (0.5 mL) and Reagent BB (300 mg, 25 1.5 mmol). After being stirred at RT overnight, the solvent was removed under vacuum. The resulting residue was purified by preparative HPLC to yield pure 4-((3-methyl-2,4 dioxoimidazolidin- 1 -yl)methyl)-N-(4-methyl-3-(pyrimidin-2-ylanmino)phenyl)benzamide (20 mg). 1 H NMR (DMSO-d) 8:10.14 (s, 1H), 8.87 (s, 1H),8.35 (d, J= 4.8 Hz, 2H), 7.91 (d, J= 83 WO 2004/060305 PCT/US2003/041425 8 Hz, 2 H), 7.84 (d, J= 1.6 Hz, 1H), 7.45 (dd, J= 8.4, 2.0 Hz, 1H), 7.41 (d, J= 7.6 Hz, 2H), 7.15 (d, J= 8.0 Hz, 1H), 6.75 (t, J= 4.8 Hz, 1H), 4.56 (s, 2H), 3.89 (s, 2H), 2.87 (s, 3H), 2.15 (s, 3H); MS (ESI) m/e: 431 (M +1). 5 EXAMPLE 6 0 NN N -N z 00 The title compound was synthesized following the procedure for the preparation of Example 5 utilizing Example H and Reagent AA to yield N-(3-(4-phenylpyrimidin-2 ylamino)-4-methylphenyl)-4-((3-methyl-2,4-dioxoimidazolidin-1-yl)methyl)benzamide. IH 10 NMR (CDCl 3 -d) 5:8.45 (s, 1H), 8.39 (d, J= 5.6 Hz, 2H), 8.19 (s, 1H), 8.08 (dd, J= 7.2 Hz, 2 H), 7.84 (d, J= 8.4 Hz, 2H), 7.32-7.46 (m, 5 H), 7.25-7.29 (m, 2H), 7.13-7.17 (m, 2H), 4.56 (s, 2H), 3.70 (s, 2H), 3.03 (s, 3H), 2.30 (s, 3H). Ms (ESI) m/e: 507 (M++1). EXAMPLE I -NH O 0 No NH '~ 0 - 0 15 To a solution of Reagent CC (0.68g, 4.30 mmol) in dry CH 2

C

2 (20 mL) under N 2 were added NMM (2.70g, 27.2 mnol), HOBt (0.91g, 6.7 mmol), EDCI (1.26g, 6.6 nmol) and reagent DD (1.5g, 5.90 mmol). After being stirred at RT overnight, the solvent was removed under reduced pressure. The residual was washed with H20, saturated aqueous 20 K 2 C0 3 and H 2 0 to yield the white solid, which was dried in vacuo to yield benzyl 4 (bis((methylcarbamoyl)methyl)carbamoyl)benzoate (0.72 g, 42% yield). 'H NMR(CDC1 3 ) 68.74 (s, 1H), 8.10 (d, J = 8.4 Hz, 211), 7.50 (d, J= 8.4Hz, 2H), 7.46 (m, 5H), 6.35 (s,1H), 5.37 (s,2H), 3.94 (d, J= 10.8 Hz, 4H) 2.89 (m, 6H); MS (ESI) m/e: 398 (M++1). 25 84 WO 2004/060305 PCT/US2003/041425 EXAMPLE J -NH 0 0 N / NH HO > 00 To a solution of Example I (0.73g, 1.84 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg). The reaction mixture was then stirred at ambient temperature under 1 5 atmosphere of H 2 for 45 min. The reaction mixture was filtered, the solid washed with EtOH, and the combined organics concentrated in vacuo to yield 4 (bis((methylcarbamoyl)methyl)carbamoyl)benzoic acid (0.52g, 92% yield). 1H NMR (CDC1 3 ) 89.16 (s, 1H), 8.05 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 4.04 (d, J= 6 Hz, 4H), 2.94 (m, 6H); MS (ESI) m/e: 308 (M++1). 10 EXAMPLE 7 N 01~ S00 The title compound was synthesized following the procedure for the preparation of Example 1 utilizing Example J and Reagent BB to yield N',N' l 15 bis((methylcarbamoyl)methyl)-N 4 -(4-methyl-3-(pyrimidin-2 ylamino)phenyl)terephthalamide. 'H NMR (CD 3 OD) 5 8.43 (d, J = 5.2 Hz, 2H), 7.98 (d, J= 8.4 Hz, 1H), 7.97 (s, 1H), 7.58 (d, J= 8.4 Hz, 2H), 7.50 (dd, J= 8.0, 2.0 Hz, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.86 (t, J = 5.2 Hz, 1H), 4.18 (s, 2H), 4.04 (s, 2H), 2.81 (s, 3H), 2.73 (s, 3H), 2.28 (s, 3H). MS (ESI) m/e: 490 (M+1). 20 EXAMPLE 8 H H H I N) NNN N"N N - 0 0 The title compound was synthesized following the procedure for the preparation of Example 1 utilizing Example J and Reagent AA to yield N',N l 85 WO 2004/060305 PCT/US2003/041425 bis((methylcarbamoyl)methyl)-N 4 -(3-(4-phenylpyrimidin-2-ylamino)-4 methylphenyl)terephthalamide. 1 H NMR (DMSO-d 6 ) 6 10.26 (br s, 1H), 8.85 (br s,, 1H), 8.44 (d, J= 4.8 Hz, 1H), 8.40 (d, J= 3.2 Hz, 1H), 8.19 (m, 1H), 8.11 (d, J= 5.8 Hz, 1H), 8.06 (s, 1H), 7.97 (d, J= 8.4 Hz, 2H), 7.50-7.45 (m, 5H), 7.32 (d, J= 5.2 Hz, 1H), 7.18 (d, J= 8.0 5 Hz, 1H), 4.00 (s, 2H), 3.87 (s, 2H), 2.63 (d, J= 4.0 Hz, 1H), 2.58 (d, J= 4.0 Hz, 1H11), 2.21 (s, 3H); MS (ESI) m/e: 566 (M'+I). EXAMPLE K N, H HjOH N x 0 10 To the solution of Reagent AA (840 mg, 2.72 mmol) and 4-hydroxymethyl-benzoic acid (490 mg, 3.20 mmol) in dry DMF (20 mL) was added EDCl (700 mg, 3.62 mmol), HOBt (500 mg, 3.73 mmol), and NMM (0.5 mL, 3.95 mmol). The resulting mixture was stirred at RT overnight, into H 2 0 and extracted with CH 2 C1 2 . The organic layer was washed with saturated Na 2

CO

3 , purified by column chromatography on silica gel yielded N-(3-(4 15 phenylpyrimidin-2-ylamino)-4-methylphenyl)-4-(hydroxymethyl)benzamide (410 mg, 36.8%). 'H NMR (DMSO-d 6 ) 8:10.12 (s, 1H), 8.84 (s,1H), 8.44(d, J= 5.2 Hz, 1H), 8.11(d, J = 4.0Hz, 2H), 8.05 (s, 1H), 7.91(d, J= 8.0Hz, 2H) 7.45(m,5H), 7.32(d, J= 5.2 Hz, 1H), 7.19(d, J= 7.8 Hz, 1H), 4.56(d, J= 5.6 Hz, 2H), 2.30(s, 3H); MS(ESI) nm/e: 411.20(M++1). 20 EXAMPLE L ,y.ci H H!, N. 0 To the solution of Example K (410 mg, 0.99 mmol) in 1,4-dioxane (40 mL) was slowly added SOC1 2 (650 ig, 5.50 mmol) at RT. After being stirred at RT for 3h, the solvent and excessive SOC1 2 was removed in vacuo to yield N-(3-(4-phenylpyrimidin-2-ylamino)-4 25 methylphenyl)-4-(chloromethyl)benzamide as a yellow solid (460 mg), which was used without further purification. 1 H NMR (CDC1 3 -d 6 ) 8:8.42(s, 1H), 8.22(d, J = 6.0Hz, 3H), 86 WO 2004/060305 PCT/US2003/041425 8.05(m, 1H), 7.94(d, J= 1.0 Hz, 2H) 7.53-7.62(m,5H), 7.26(s,2H), 4.63(d, J= 5.4 Hz, 2H), 2.44(s, 3H); MS(ESI) n/e: 429.20(M+1) EXAMPLE M O NH 5 To the solution of phenyl-urea (13.0g, 95.48 mol) in THF (100 mL) was slowly added chlorocarbonyl sulfenylchloride (13 mL, 148.85 mmol) at RT. The reaction mixture was refluxed overnight, the volatiles removed in vacuo yielded 2-phenyl-l1,2,4-thiadiazolidine 3,5-dione as a white solid (4.0g, yield 20%). 'H NMR (DMSO-d 6 ) 6: 12.49 (s, 1H), 7.51 (d, 10 J= 8.0 Hz, 2H), 7.43(t, J= 7.6 Hz, 2H11), 7.27 (t, J= 7.2 Hz, 1 H). EXAMPLE 9 o -N - 0 To a solution of Example M (400 mng, 2.06 mmol) in anhydrous DMF and THF (1:1) 15 under N 2 at 0 oC was slowly added NaH (165 mg, 4.24 mmol). After stirring at 0 oC for 0.5h, Example L (300 mg, 0.70 mmol) was added. The solution was heated to 40 C, stirred for 3h and quenched with AcOH (0.5 mL). Removal of the solvent followed by purification via preparative HPLC yielded N-(3-(4-phlenylpyrimidin-2-ylamino)-4-methylphenyl)- 4

-((

3 ,5 dioxo-4-phenyl-l1,2,4-thiadiazolidin-2-yl)methlayl)benzamide (50 mg, yield 12 %). 'I-INMR 20 (DMSO-d 6 ) 8: 10.18(s, 1 H), 8.88(s, 1 H), 8.43(d, J= 5.2 Hz, 1H), 8.12(dd, J= 7.6 1.6 Hz, 2H), 8.05(s, 1 H), 7.92(d, J= 8.4 Hz, 2H), 7.58(d, J = 9.2 1.6 Hz, 2H), 7.44-7.50(m, 8 H), 7.34(t, J= 6.0 Hz, 2H), 7.18(d, J= 8.8 Hz, 111), 4.91(s, 2 H), 2.20(s, 3 H); MS (ESI) (m/e): 587.18(M++1). 25 EXAMPLE N MeO 2 C- NH"C'02Et Glycine ethyl ester hydrochloride (11.1g, 79 rmmol), and Reagent EE (10Og, 61 mmol) were dissolved in absolute EtOH (300 mL). NaCNBH 3 (8.4g, 134mmol) was added in 4 87 WO 2004/060305 PCT/US2003/041425 portions and the reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with IN HCI solution, saturated NaHCO 3 and brine, and dried and concentrated in vacuo to yield methyl 4-(((ethoxycarbonyl)methylamino)methyl)benzoate (8g). 'H-NMR 5 (CDC13): 7.97 (d, J= 6.8 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 4.16 (q, J= 7.2 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 2H1), 3.37 (s, 2H), 1.94 (s, 1H), 1.24 (t, J= 7.2 Hz, 3H). EXAMPLE O MeO 2 C/ 0' N---\ Ojd"OZ C02Et HN Cbz 10 To a stirred solution of chlorosulfonyl isocyanate (2.2g, 15.2 mmol) in CH 2

CI

2 (40 mL) was added benzyl alcohol (1.64g, 15.2 mmol) at 0OC. And the reaction temperature was kept not to rise above 5 0 C. After stirred for lh, a solution of Example N (4.2g, 16.7 mmol) and triethylamine (6 mL, 4.3g, 42. 6 mmol) in CH 2 Cl 2 (40 mL) was added at a rate to keep the reaction temperature not to rise above 5 0 C. When the addition was completed, the 15 reaction solution was allowed to warm to RT and stirred overnight. The reaction mixture was poured into IN HC1 saturated with NaC1 (300 mL). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (2x100 mL). The combined organic layers were dried with Na 2

SO

4 , and concentrated. The crude product was recrystallized from CH 2

C

2 /n hexane to afford desired Example O (5.9g, 76.6% yield). 1 H-NMR (CDC1 3 ): 8.00 (d, J = 8. 4 20 Hz, 2H), 7.87 (s, 1H11), 7.36 (m, 5H), 5.29 (s, 2H), 4.65 (s, 2H11), 4.15 (q, J= 7.2 Hz, 2H11), 3.98 (s, 2H), 3.92 (s, 3H), 1.24 (t, 3H). EXAMPLE P Me0 2 C / .. So co 2 Et

H

2 N 25 To a solution of Example O (5.5 g, 118 mmol) in solvent of MeOH (50 mL) and EtOAc (50 mL ) was added 10% Pd/C (0.8 g ) under N 2 . Then the resulting mixture was stirred at RT under H2 (60 psi) overnight. The solvent was removed to afford white solid Example P (3.4 g, 85% yield). 1'H-NMR (CDC1 3 ): 8.02 (d, J= 8. 4 Hz, 2H11), 7.41 (d, J= 8.4 Hz, 2H11), 5.20 (s, 2H), 4.44 (s, 2H), 4.19 (q, J= 7.2 Hz, 2H), 3.91 (s, 3H11), 3.90 (s, 2H), 1.25 30 (t, J= 7.2 Hz, 3H) 88 WO 2004/060305 PCT/US2003/041425 EXAMPLE Q ?0 MeO 2 C - N-S: 0 NH O A NaOMe solution was prepared by adding NaH (60%, dispersion in mineral oil, 43.5 5 mg, 1.1 mmol) to MeOH (30 mL). Example P (300 mng, 0.9 mmol) was added to the NaOMe MeOH solution and the reaction was stirred at RT overnight. The solution was concentrated in vacuo and the residue was dissolved in H 2 0 (30 mL). The aqueous solution was acidified with 3N HC1 and the precipitate was filtered and collected to yield methyl 4-(1,1,4-trioxo [1,2,5]thiadiazolidin-2-ylmethyl)-benzoate (120 mg, 40% yield). 1 H-NMR (DMSO-d): 7.92 10 (d, J= 8. 4 Hz, 2H), 7.49 (d, J= 8 Hz, 2H), 4.35 (s, 2H), 3.99 (s, 2H), 3.83 (s, 3H11). EXAMPLE R HooC \ o NH O Example Q (100 mg, 0.35 mmol) in THF (4 mL) and 1.5 mL of 2N aq. LiOH solution 15 was stirred at RT for 3h. The solvent was removed under reduced pressure and the residue was dissolved in H20 (20 mL) and acidified with aqueous 3N HC1. The precipitate was filtered and collected to yield 4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzoic acid (85 mg). 'H-NMR (DMSO-d): 7.90 (d, J= 8 Hz, 2H), 7.46 (d, J= 8.4Hz, 2H), 4.27-4.22 (br, 2H). 20 EXAMPLE 10 N N The title compound was prepared following the procedure of Example 1 utilizing Example R and Reagent FF to yield N-[4-methyl-3-(4-phenyl-pyrimidin-2-ylamino)-phenyl] 25 4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzamide (48% yield). 'H-NMR (DMSO) 89 WO 2004/060305 PCT/US2003/041425 610.19 (s, 1H1), 9.30 (s, 1H), 9.00 (d, 1H), 8.72 (d, J= 5.2 Hz, 2H), 8.59 (d, J=9.2 Hz, 1H), 8.52 (d, J= 5.2 Hz, 2H), 8.08 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H11), 7.62 (m, 1H), 7.50-7.43 (m, 4H), 7.19(d, J = 8.4 Hz, 2H), 4.27(s, 2H), 3.86 (s, 2H), 2.20 (s, 3H). MS (ESI) nm/e: 530.1(M+1). 5 EXAMPLE 11 %\ o H H NH N N N '. -N .- 0 The title compound was prepared following the procedure of Example 1 utilizing Example R and Reagent AA to yield N-[4-methyl-3-(4-phenyl-pyrimidin-2-ylamino)-phenyl] 10 -4-(1,1,4- trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzamide (56% yield). 'H-NMR (DMSO-d):10.18 (s, 1H11), 8 89 (s, 1H1), 8.44 (d, J= 4.8 Hz 1H11), 8.12 (d, J= 7.6 Hz, 2H), 8.05 (s, 1H), 7.92 (d, J= 8.0 Hz, 2H1), 7.50-7.44 (m, 6H11), 7.33 (d, J= 5.2 Hz, 1H), 7.18 (d, J= 8.4 Hz, 1H), 4.28 (s, 2H11), 3.81 (s, 2H), 2.20 (s, 3H). MS (ESI) m/e: 529.1(M+1). 15 EXAMPLE S o,.. o S N CO 2 Et MeO- ocH 0 A solution of Reagent GG (10g, 35.4m mol) and diisopropyl azodicarboxylate (7.2 g, 35.4 mmol) in THF (60 mL) was added dropwise (15min, 5 0 C) to a solution of equal molar quantities of triphenylphosphine (9.3g, 35.4mmol) and 4-hydroxymethyl-benzoic acid methyl 20 ester (6g, 35.4m mol) in THF (50 mL). The resulting mixture was stirred under N 2 atmosphere for 2h. The solvent was removed and the residual was chromatographed to yield ethyl-[N-(N'-tert-butyloxycarbonyl,N'-benzoic methyl ester)-sulfamoyl]-glycinate as a white powder (8g, 53.3% yield). 1 H-NMR (CDC1 3 ): 7.99 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 5.80 (t, J= 5.6 Hz, 1H), 4.85 (s, 2H), 4,12 (q, J= 7.2 Hz, 2H), 3.90(s, 3H), 3.65 (d, J 25 5.6 Hz, 2H11), 1.49 (s, 9H1), 1.24 (t, 3H11). 90 WO 2004/060305 PCT/US2003/041425 EXAMPLE T MeO / H H 0o' O The solution of Example S (3g, 7m mol) in 2N HCI/dioxane 1,4-dioxane (60 mL) was heated to 50 0 C for 15 min. Then the solvent was removed under reduced pressure to yield 5 ethyl-[N-(N'-benzonic methyl ester)-sulfamoyl]-glycinate as a white solid (2g, 86.9% yield). 1 H-NMR (CDCl 3 ): 8.01 (d, J= 8.4,2H), 7.41 (d, J= 8.4,2H), 4.86 (t, J = 4.8 Hz, 1H), 4.70 (t, J = 5.6 Hz,lH), 4.32 (d, J = 6.4 Hz, 2H), 4.21 (q, J= 7.2 Hz,2H), 3.91(s,3H), 3.82 (d, J = 5.6 Hz, 2H), 1.28 (t, 3H). 10 EXAMPLE U 0 K , oNH Meo YOC 0 A solution of Example T (1g, 30.3 mmol) and NaH (0.32g, 78.7m mol) in THF (120 mL) was heated to reflux for 8h. The mixture was cooled to RT, then quenched with 1N aq. HC1 (100 mL) and extracted with CH 2 Cl 2 (3 x 100 mL). The combined organic layers were 15 dried (Na 2

SO

4 ), and concentrated in vacuo and purified by flash chromatography to yield 4 (1,1,3-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzoic acid methyl ester as a white powder (200mg, 23% yield). H-NMR (CDC1 3 ) 8.02 (d, J = 8.4, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.02 (br s, 1H), 4.77 (s, 2H), 4.10 (d, J = 7.2 Hz, 2H), 3.90 (s, 3H) 20 EXAMPLE V 9,Q0 HO ySNH 0 0 Example U (200mg, 0.8m mol) in THF (3 mL) and 2N aq. LiOH (1.5 mL) was stirred at RT for 3h. The solvent was removed under reduced pressure, and the aqueous layer was acidified with 3N aq. HC1 solution to yield 4-(1,1,3-trioxo6-[1,2,5]thiadiazolidin-2 25 ylmethyl)-benzoic acid a white powder (120 mg, 63%). 'H-NMR (DMSO-d): 7.90 (d, J = 8.4 Hz, 2H), 7.43 (min, 2H), 4.10 (d, J = .6.0 Hz, 2H), 3.56 (d, J= 6.0 Hz, 2H). 91 WO 2004/060305 PCT/US2003/041425 EXAMPLE 11 op Nf N'NH ' N The title compound was prepared following the procedure of Example 1 utilizing Example V and Reagent FF to yield N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino) 5 phenyl]-4-(1,1, 3-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzamnide (65% yield). 'H-NMR (DMSO-d): 10.19 (s, 1H), 9.27 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 6.4 Hz, 2H), 8.52 (min, 1H), 8.06 (s, 1H),7.89 (d, J = 7.6 Hz, 5H), 7.55 (d, 1H11), 7.47-7.41 (inm, 4H), 7.18 (d, J = 7.4 Hz, 2H), 4.76 (s, 2H), 4.15 (d, J = 6.4 Hz, 2H), 2.20 (s, 3H); MS (ESI) m/e: 530.1 (M+I). 10 EXAMPLE 12 9,0o ' 'NH .N Y The title compound was prepared following the procedure of Example 1 utilizing Example V and Reagent AA to yield N-[4-Methyl-3-(4-phenyl-pyrimidin-2-ylamino) 15 phenyl]-4-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl)-benzamide (67% yield). 'H-NMR ( DMSO): 10.18 (s,1H), 8.85 (s, 1H), 8.61(m, 1H), 8.43 (d, J= 5.2 Hz, 2H), 8.10 (d, J= 6.2 Hz, 2H), 8.04 (s, 1H), 7.90 (d, J= 8.0 Hz , 2H), 7.4 (min, 5H), 7.32 (d, J= 5.2 Hz, 1H) ,7.18 (d, J= 8Hz, 1H), 7.05 (s, 1H), 6.93 (s, 1H), 4.76 (s, 2H), 4.16 (d, J= 6.4 Hz, 2H); Ms (ESI) nm/e: 529.1 (M+1) 20 EXAMPLE W OS,=o HOOC O To a solution of 4-bromomethyl-benzic acid methyl ester (5.0g, 0.02 mol) and 4 thiomorpholine (2.02g, 0.02 mol) in acetonitrile (50mL) was added K 2 C0 3 (5.52g, 0.04 mol). 25 The mixture was stirred under reflux for two days. After filtration of inorganic salt and 92 WO 2004/060305 PCT/US2003/041425 removal of solvent, the residue was added to conc. HCI. The mixture was stirred at RT for 30 min, concentrated, dissolved in acetic acid (30 mL) and 30% hydrogen peroxide (10 mL), stirred at 100 'C for overnight and then cooled to 0 0 C. Zinc powder (1,5 g) was added to the reaction solution. After being stirred for 30 min, the resulting mixture was filtered and solid 5 was washed with MeOH. The filtrate was concentrated. The residue was neutralized by 2N solution of K 2

CO

3 and adjust to PH= 8-9. The solution was extracted with CH 2 C1 2 twice. The combined organic layers were dried over Mg 2

SO

4 , and concentrated. The residue was added conc. HC1 (O10mL). The resulted solution was stirred at 80 oC for 2h and concentrated to yield 4-(4,4-dioxothiomorpholinomethyl)benzoic acid (1.02 g, 18%). 1H NMR (D 2 0) 10 87.98 (d, J= 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 4.45 (s, 2H), 3.79 (s, 4H), 3.53 (s, 4H); MS (ESI) m/e: 270 (M +1). EXAMPLE 13 sro (N, N y), 0 N.. 0 15 To a solution of Reagent BB (100 mg, 0.5 mmol) in the anhydrous DMF (3 mL) at RT was added Example W (200 mg, 0.77 mmol) followed by EDCI (200 mg, 1.20 mmol), HOBt (200 mg, 1.15 mmol) and NMM (0.5 mL). After being stirred at RT overnight., the mixture was added to H 2 0 (100 mL) and extracted with CH 2 Cl 2 (2x100 mL). The combined organic layers were washed with brine, dried (Na2SO 4 ) and concentrated. The residue was purified by 20 preparative HPLC to yield 4-(((4,4-dioxothiomorpholinomethyl)l)methyl)-N-(4-methyl-3 (pyrimidin-2-ylamino)phenyl)benzamide (100 mg, 44%). 'H NMR (DMSO-d6): 8.43 (d, J = 4.8 Hz, 2H), 8.29 (s, 1H1), 7.86 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.46 (d, J= 7.6 Hz, 3H), 7.21 (d, J= 8.4 Hz, 2H), 6.75 (t, J= 4.8 Hz, 1H), 3.72 (s, 2H), 3.10 (s, 4H), 3.03 (s, 4H), 2.32 (s, 3H); MS (ESI) m/e: 452 (M ++1). 25 EXAMPLE 14 00 -E-21 The title compound was prepared following the procedure of Example 13 utilizing Example W and Example AA to yield 4-(((4,4-dioxothiomorpholinomethyl)l)methyl)-N-(4 93 WO 2004/060305 PCT/US2003/041425 methyl-3-(4-phenylpyrimidin-2-ylamino)phenyl)benzamide. 'H NMR (CDC13): 8.54-8.52 (in, 2H), 8.49-8.11 (min, 2H), 7..88-7.83 (m, 2H), 7.80 (s, 1H), 7.50-7.39 (min, 6H), 7.23-7.15 (m, 2H), 7.02 (s, 1H), 3.73 (s, 2H), 3.12 (s, 4H), 3.01 (s, 4H), 2.38 (s, 3H); MS (ESI) m/e: 528 (M +1). 5 EXAMPLE 15 H H N / 0 N N N . ~N 0 No (0 The title compound was prepared following the procedure of Example 13 utilizing Example W and Example HH to yield 4-(((4,4-dioxothiomorpholinomethyl)1)methyl)-N-(4 10 methyl-3-(4-morpholinopyrimidin-2-ylamino)phenyl)benzamide. 'H NMR (CDCl3): 8.63 (s, 1H), 8.00 (d, J= 6.0 Hz, 1H), 7.82 (d, J= 8.0 Hz, 2H), 7.77 (s, 1H), 7.43 (d, J= 8.4 Hz, 2H), 7.16-7.09 (min, 2H), 6.72 (s, 1H), 6.02 (d, J= 6.4 Hz, 1H), 3.80-3.77 (m, 4H), 3.66 (s, 2H), 3.58 (s, 4H), 3.07 (s, 4H), 3.00-2.88 (in, 4H), 2.30 (s, 3H); MS (ESI) mn/e: 537 (M++1). 15 EXAMPLE X o o HO NAO 0 To a solution of D-4-phenyl-oxazolidin-2-one (1g, 6 mmol) in anhydrous THF (40 mL) under nitrogen protection at -78 0 C was added BuLi (2.5 M in hexane, 1.8 mL, 4.5 mmol). After one hour, the mixture was transferred to a solution of terephthalic acid chloride 20 monobenzyl ester (prepared from Reagent DD (1.2 g, 4.5 nimmol) and thionyl chloride (10 mL) at reflux for 2h), in anhydrous THF. After being stirred at -78 'C for 30 min, the reaction mixture was wanned to RT for 2h. After being quenched by adding saturate solution of ammonium chloride (1 mL), the reaction solution was extracted with CH2C1 2 (3 x 50 minL). The combined organic layers were dried (Na 2

SO

4 ) and concentrated. The residue was 25 dissolved in MeOH (20 mL) and 5% Pd/C (0.1 g) and stirred under 1 atm H2 for 5h. The suspension was filtered and filtrate was concentrated to yield D-4-(2-oxo-4-phenyl oxazolidine-3-carbonyl)-benzoic acid (0.65 g, 46%). 'H NMR (CDC13): 8.15-8.11 (m, 2H), 7.70 (dd, J= 6.8, 1.6 Hz, 2H), 7.44-7.33 (min, 5H), 5.63 (dd, J= 8.8, 6.8 Hz, 1H), 4.78 (dd, J= 94 WO 2004/060305 PCT/US2003/041425 18, 9.2 Hz, 1H), 4.36 (dd, J 9.2, 6.8 Hz, 1H); MS (ESI) m/e: 312 (M++I1). EXAMPLE Y 0 o N O HO I .L 5 The title compound was prepared following the procedure of Example X utilizing L 4-phenyl-oxazolidin-2-one to yield L-4-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-benzoic acid (0.65 g, 46%). 'H NMR (CDC13): 8.15-8.11 (m, 2H), 7.70 (dd, J= 6.8, 1.6 Hz, 2H11), 7.44-7.33 (m, 5H), 5.63 (dd, J= 8.8, 6.8 Hz, 1H), 4.78 (dd, 1J= 18, 9.2 Hz, 1H), 4.36 (dd, J 9.2, 6.8 Hz, 1H); MS (ESI) m/e: 312 (M++1). 10 EXAMPLE 16 o o H H N A N z rN N ~ N 0 o The title compound was prepared following the procedure of Example 13 utilizing Example X and Reagent AA to yield D-4-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-N-( 4 15 methyl-3-(4-phenylpyrimidin-2-ylamino)phenyl)benzamide. 'H NMR (DMSO-d6) : 10.34 (s, 1H), 8.87 (s, 1H), 8.44 (d, J= 5.2 Hz, 1H), 8.12-8.10 (m, 2H), 7.96 ( d, J= 8.4 Hz, 2H), 7.84 (d, J= 8.4 Hz, 2H), 7.54-7.30 (m, 8H), 7.19 (d, J= 8.4 Hz, 1H), 5.63 (dd, J=8.0 & 8.0, 1H11), 4.84 (t, J=8.0, 1H), 4.23 (dd, J=8.0 & 8.0, 1H), 2.21 (s. 3H). MS (ESI) m/e: 570 (M++1) 20 EXAMPLE 17 O 0 The title compound was prepared following the procedure of Example 13 utilizing Example Y and Reagent AA to yield L-4-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-N-(4 95 WO 2004/060305 PCT/US2003/041425 methyl-3-(4-phenylpyrimidin-2-ylamino)phenyl)benzamide. 'H NMR (DMSO-d6) : 10.34 (s, 1H), 8.87 (s, 1H), 8.44 (d, J= 5.2 Hz, 1H), 8.12-8.10 (min, 2H), 7.96 ( d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.54-7.30 (min, 8H), 7.19 (d, J= 8.4 Hz, 1H), 5.63 (dd, J=8.0 & 8.0, 1H), 4.84 (t, J-8.0, 1H), 4.23 (dd, J=8.0 & 8.0, 1H11), 2.21 (s. 3H). MS (ESI) m/e: 570 (M+1) 5 EXAMPLE 18 0 o N ~ NkN N 0- a I N.. N The title compound was prepared following the procedure of Example 13 utilizing Example X and Reagent FF to yield D-4-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-N-[4 10 methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamnino)-phenyl]benzamide.'H NMR (DMSO-d 6 ): 10.34 (s, 1H), 8.95 (s, 1H), 8.66 (min, 1H), 8.48 (m, 2H), 8.07 (s, 111), 7.96 ( d, J= 8.4 Hz, 2H), 7.84 ( d, J= 8.0 Hz, 2H), 7.58-7.42 (min, 4H), 7.41-7.36 (m, 3H), 7.32 (d, J= 6.8 Hz, 1H1), 7.20 (d, J= 8.4 Hz, 1H), 5.63 (t, J= 7.6 Hz, 1H), 4.84 (t, J= 7.6 Hz, 1H11), 4.23 (t, J 7.6 Hz, 1H), 2.21 (s, 3H.); MS (ESI) m/e: 571 (M++I). 15 EXAMPLE 19 o o N 0a \N The title compound was prepared following the procedure of Example 13 utilizing Example Y and Reagent FF to yield L-4-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-N-[4 20 methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]benzamide.'H NMR (DMSO-d 6 ): 10.34 (s, 1H11), 8.95 (s, 1H), 8.66 (min, 1H), 8.48 (m, 2H), 8.07 (s, 1H11), 7.96 ( d, J = 8.4 Hz, 2H), 7.84 ( d, J= 8.0 Hz, 2H), 7.58-7.42 (m, 4H), 7.41-7.36 (m, 3H), 7.32 (d, J= 6.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.63 (t, J = 7.6 Hz, 1H), 4.84 (t, J= 7.6 Hz, 1H), 4.23 (t, J= 7.6 Hz, 1H), 2.21 (s, 3H.); MS (ESI) nie: 571 (M++1). 25 96 WO 2004/060305 PCT/US2003/041425 EXAMPLE Z 0

NH

0 To a solution of 1-methyl-[1,2,4]triazolidine-3,5-dione (1.886g, 0.0164 mol) and sodium hyhride (200 mg) in DMSO (5 mL) was added 4-chloromethyl-benzoic acid methyl 5 ester (1.0 g, 0.0054 mol). The mixture was stirred at RT for overnight, quenched with H 2 0 (100 mL), and extracted by CH 2 C1 2 . The organic layer was washed with H 2 0, dried (Na 2

SO

4 ) and concentrated in vacuo to yield methyl 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin-4 yl)methyl)benzoate (1.02g, 72%). 1 H NMR (CDC1 3 ) :7.93 (d, J = 8.4 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H11), 4.68 (s, 2H), 3.83 (s, 3H), 3.27 (s, 3H). MS (ESI) nm/e: 264 (M+1) 10 EXAMPLE AA 0 HO ,)N o A solution of Example Z (1.0g, 0.0038 mol) and lithium hydroxide (0.950g) in MeOH (10 mL) was stirred at RT for overnight. The mixture was acidified by 2N HC1 to pH=5- 6 15 and extracted by CH 2

CI

2 (3x50 mL). The combined organic layers were washed with H20, dried (MgSO 4 ) and concentrated in vacuo to yield 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin-4 yl)methyl)benzoic acid (0.6 g, 64%). 'H NMR (CDCI 3 ): 7.71 (d, J= 8.4 Hz, 2H), 7.17 (d, J= 8.4 Hz, 2H), 4.68 (s, 2H), 2.90 (s, 3H), 2.6 (s, 3H); MS (ESI) m/e: 249 (M++I). 20 EXAMPLE 20 0

NA

N N. 00 SN The title temperature was prepared following the procedure of Example 1 utilizing Example AA and Reagent FF to yield N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4 methylphenyl)-4-((1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl)benzamide. 'H NMR 25 (CD 3 OD) 89.44 (s, 1H), 8.79 (d, J= 8.0 Hz, 2H), 8.50 (d, J= 4.0 Hz, 1H), 8.25 (s, 1H), 7.93 (d, J= 8.0 Hz, 2H), 7.73 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.40 (d, J= 5.2 Hz, 1H), 7.35 (d, J 97 WO 2004/060305 PCT/US2003/041425 = 8.4 Hz, 1H), 7.25 (d, J 8.4 Hz, 1H), 4.87 (s, 2H), 3.07 (s, 3H), 2.31 (s, 3H). MS (ESI) m/e: 509(M++1). EXAMPLE 20 0 o 5 The title temperature was prepared following the procedure of Example 1 utilizing Example AA and Reagent AA to yield N-(3-(4-phenylpyrimidin-2-ylamino)-4 methylphenyl)-4-((1-methyl-3,5-dioxo-l1,2,4-triazolidin-4-yl)methyl)benzamide. 'H NMR

(CD

3 OD) : 8.39 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.13 (mn, 2H), 7.93 (d, J= 8.4 Hz, 2H), 7.47 10 (m, 6H), 7.27 (m, 2H), 4.59 (s, 2H), 3.08 (s, 3H), 2.31 (s, 3H). MS (ESI) m/e: 508 (M++1). EXAMPLE 21 0 H H NH N N 0 The title temperature was prepared following the procedure of Example 1 utilizing 15 Example AA and Reagent BB to yield 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl) N-(4-methyl-3-(pyrimidin-2-ylamino)phenyl)benzamide. 'H NMR (CDCl 3 ) : 11.31 (s, 1H), 10.15 (s, 1H), 8.77 (s, 1H), 8.33 (mn, 2H), 7.87 (m, 3H), 7.40 (mn, 3H), 7.14 (d, J = 8.4 Hz, 1H), 6.71 (m, 1H), 4.73 (s, 21-H), 2.97 (s, 3H), 2.14 (s, 3H); MS (ESI) m/e: 432 (M++l). 20 EXAMPLE BB N 'CO 2 Et O=S=O MeO 2 C I NHCbz 2 To a stirred solution of chlorosulfonyl isocyanate (2.2 g, 15.2 mmol) in CH 2

C

2 (40 mnL) was added benzyl alcohol (1.64 g, 15.2 mnmol) at O'C. After being stirred for lh, a solution of Example N (4.2 g, 16.7 minmol) and triethylamine (6 mL, 4. 3 g, 42.6 mmol) in 25 . CH2Cl2 (40 mL) was added at a rate so that the reaction temperature did not rise above 5 0 C. 98 WO 2004/060305 PCT/US2003/041425 When the addition was completed, the reaction solution was allowed to warm to RT and stirred overnight. The reaction mixture was then poured into 1 N HCI saturated with NaCl (300 mL). The organic layer was separated and the aqueous layer extracted with CH 2 Cl 2 . The combined organic layers were dried over Na 2

SO

4 , and concentrated to yield the crude 5 compound. Recrystallization from CH 2 C1 2 /n-hexane yielded Example BB (5.9 g, 76.6% yield). 'H-NMR (CDCI3) 8 8.00 (d, J= 8. 4 Hz, 2H), 7.87 (s, 1H), 7.36 (min, 5H), 5.29 (s, 2H), 4.65 (s, 2H), 4.15 (q, J= 7.2 Hz, 2H), 3.98 (s, 2H), 3.92 (s, 3H), 1.24 (t, 3H). EXAMPLE CC MeO 2 C N oS O C02Et 10

HN

0 To a solution of Example BB (5.5 g, 118 mmol) in MeOH (50 mL ) and EtOAc (50 mL ) was added 10% Pd/C (0.8 g ) under nitrogen atmosphere. Then the result mixture was stirred at ambient temperature under H 2 (60 psi) overnight. The solvent was removed to yield Example CC (3.4 g, 85%) as a white solid. 'H-NMR (CDC3, 8) 8.02 (d, J = 8. 4 Hz, 2H), 15 7.41 (d, J= 8.4 Hz, 2H), 5.20 (s, 2H), 4.44 (s, 2H), 4.19 (q, J= 7.2 Hz, 2H), 3.91 (s, 3H), 3.90 (s, 2H), 1. 25 (t, J= 7.2 Hz, 3H) EXAMPLE DD o - N-S -c NH 0 20 A NaOMe solution was first prepared by adding NaH (60%, dispersion in mineral oil, 43.5 mg, 1.1 mmol) to MeOH (30 mL). Example CC (300 rng, 0.9 mmol) was added to the NaOMe-MeOH solution and the reaction was stirred at RT overnight. The solution was concentrated to dryness in vacuum and the residue was dissolved in H20 (30 mL). The aqueous solution was acidified with 3 N HCI (aq.) and the result precipitate was filtered and 25 collected to yield Example DD (120 mg, 40% yield). 1 H-NMR (DMSO-d 6 ) 7.92 (d, J= 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.35 (s, 2H), 3.99 (s, 2H), 3.83 (s, 3H). 99 WO 2004/060305 PCT/US2003/041425 EXAMPLE EE N-SsO NH 0 The solution of Example DD (100 mg, 0.35 mmol) in THF (4 mL) and 1.5 mL of 2 N aq. LiOH solution was stirred at RT for 3h. Then the solvent was removed under reduced 5 pressure and the residue was dissolved in water (20 mL) and acidified with aqueous 3 N HCl. The result precipitate was filtered to yield Example EE (85 mg). 'H-NMR ( DMSO-d)8 7.90 (d, J= 8 Hz, 2H), 7.46 (d, J= 8.4Hz, 2H), 4.27-4.22 (br, 2H). EXAMPLE 22 0 H H N SNH N .,~ 0 0 10 The title compound was prepared following the procedure of Example 1 utilizing Example EE and Reagent FF to yield Example 22. 'H-NMR (DMSO-d 6 ) 610.19 (s, 1H1), 9.30 (s, 1H), 9.00 (d, 1H), 8.72 (d, J= 5.2 Hz, 2H), 8.59 (d, J= 9.2 Hz, 1H), 8.52 (d, J= 5.2 Hz, 2H), 8.08 (s, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.62 (min, 1H1), 7.50-7.43 (min, 4H), 7.19(d, J 8.4 15 Hz, 2H), 4.27(s, 2H), 3.86 (s, 21H), 2.20 (s, 3H). MS (ESI) m/e: 530(M++1). EXAMPLE 23 0 N N 0O0 N Z The title compound was prepared following the procedure of Example 1 utilizing 20 Example EE and Reagent AA to yield Example 22. 'H NMR (DMSO-d 6 ) 810.18 (s, 1H), 8 89 (s, 1H14), 8.44 (d, J= 4.8 Hz 1H), 8.12 (d, J= 7.6 Hz, 2H), 8.05 (s, 1H), 7.92 (d, J= 8.0 Hz, 2H), 7.50-7.44 (min, 6H), 7.33 (d, J= 5.2 Hz, 1H), 7.18 (d, J= 8.4 Hz, 1H), 4.28 (s, 2H), 3.81 (s, 2H), 2.20 (s, 3H1). MS (ESI) mn/e:529(M +l). 100 WO 2004/060305 PCT/US2003/041425 EXAMPLE FF s ^'COEt MeOa Boc 0 A solution of [Boc-sulfamide] amino ester (10g, 35.4m mol) min) to a solution of triphenylphosphine (9.3g, 35.4mmol) and 4-hydroxymethyl-benzoic acid methyl ester (6g, 5 35.4m mol) in THF (50 mL) at 0-5 0 C. The result mixture was stirred under N2 for 2h. The solvent was removed and the residual was purified by column chromatography to yield Example FF as a white powder (8g, 53.3% yield). 1 H-NMR (CDCL 3 ) 7.99 (d, J= 8.4 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 5.80 (t, J= 5.6 Hz, 1H), 4.85 (s, 2H), 4,12 (q, J= 7.2 Hz, 2H), 3.90(s, 3H), 3.65 (d, J= 5.6 Hz, 2H), 1.49 (s, 9H), 1.24 (t, 3H11). 10 EXAMPLE GG MeO NICO 2 Et 0 The solution of Example FF (3g, 7m mol) in 2N HCI/dioxane 1,4-dioxane (60 mL) was heated to 50'C for 15 min. The solvent was removedin vacuo to yield Example GG as a 15 white solid (2g, 86.9% yield). 1 H-NMR ( CDC1 3 ,8) 8.01 (d, J= 8.4,2H11), 7.41 (d, J = 8.4,2H), 4.86 (t, J = 4.8 Hz,1H), 4.70 (t, J = 5.6 Hz,IH), 4.32 (d, J = 6.4 Hz, 2H), 4.21 (q, J = 7.2 Hz ,2H), 3.91(s,3H), 3.82 (d, J= 5.6 Hz, 2H), 1.28 (t, 3H). EXAMPLE HH 0L MeO YO >NH 20 0 A solution of Example GG (1g, 30.3 mmol) and NaH (0.32g, 78.7m mol) in THF (120 mL) was heated to reflux for 8h. The mixture was cool to RT, quenched with 1N aq. HCI solution (100 mL) and extracted with CH 2 Cl 2 (3x100 mL). The combined organic phases were dried (Na 2

SO

4 ), and concentrated in vacuo and purified by flash chromatography to 25 yield Example HH as a white powder (200mg, 23% yield). 'H-NMR (CDCl 3 , 5) 8.02 (d, J = 8.4, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.02 (br s, 1H), 4.77 (s, 2H), 4.10 (d, J = 7.2 Hz, 2H), 3.90 (s, 3H) 101 WO 2004/060305 PCT/US2003/041425 EXAMPLE II O' HO yK:r N- NH o Example HH (200mg, 0.8m mol) was dissolved in THF (3 mL), and 1.5 mL solution of 2N aq. LiOH was added to the reaction solution. The mixture was stirred at RT for 3h. The 5 solvent was removed in vacuo, and the aqueous layer was acidified with 3N aq. HCI solution, and filtered to yield Example II as a white powder (120mg, 63%). 'H-NMR (DMSO-d) 87.90 (d, J= 8.4 Hz, 2H), 7.43 (m, 2H), 4.10 (d, J= 6.0 Hz, 2H), 3.56 (d, J= 6.0 Hz, 2H). EXAMPLE 24 N0

N>

1 1 ~ N 'NH 10 The title compound was prepared following the procedure of Example 1 utilizing Example II and Reagent FF (65% yield). 'H-NMR (DMSO-d) 810.19 (s, 1H), 9.27 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 4.8 Hz, 2H), 8.60 (d, J = 6.4 Hz , 2H), 8.52 (m, 1H), 8.06 (s, 1H),7.89 (d, J= 7.6 Hz, 5H), 7.55 (d, 1H), 7.47-7.41 (mn, 4H), 7.18 (d, J= 7.4 Hz, 2H), 4.76 15 (s, 2H), 4.15 (d,J= 6.4 Hz, 2H), 2.20 (s, 3H); MS (ESI) m/e: 530 (M+1). EXAMPLE 25 9 "0 H H N ' 'NH .N .

The title temperature was prepared following the procedure of Example 1 utilizing 20 Example II and Reagent AA. (67% yield). 'H-NMR ( DMSO-d), 810.18 (s,IH), 8.85 (s, 1H), 8.61(m, 1H), 8.43 (d, J= 5.2 Hz, 2H), 8.10 (d, J= 6.2 Hz, 2H), 8.04 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.4 (m, 5H), 7.32 (d, J= 5.2 Hz, 1H) ,7.18 (d, J= 8Hz, 1H), 7.05 (s, 1H), 6.93 (s, 1H), 4.76 (s, 2H), 4.16 (d, J= 6.4 Hz, 2H); Ms (ESI) m/e: 529 (M+I) 102 WO 2004/060305 PCT/US2003/041425 Specific embodiments are additionally illustrated below which are intended to represent more clearly, but without limitation to the generic scope, the present invention: 5 Example 1 H H OS Example 2 N N N N N NH3CN 0 Example 3 NrN N N .N . I NN SH Example 4 N H H N N N N. S10 1103 16 WO 2004/060305 PCT/US2003/041425 Example 5 00 HH \ NH Example 6 C N HNC N Example 7 0 0 NNH Example 8 H H Ns N N N N c N0

H

3 0k N N N Example 7 H H N N HC NH 5 S104 N N 02 H 3 0 104 WO 2004/060305 PCT/US2003/041425 Example 9 H H j , rj OH N N N IN-_ OH Example 10 NN.. OH N N N IHC H N N I OH N N Example 11 0 H H N OH N N OH

H

3 4 oH -0 Example 12 N H H H NI ' HCHaC 0 5 OH H3/N - OH 0 H 0C 5 105 WO 2004/060305 PCT/US2003/041425 Example 13 H O 01 H H HN H O N t N C Example 14 N N N OCH y HC 3H N Example 15 H H NYJ::, 0 0 O OCHz H3C H SExample 16 H HH H H N N N N N H0C CNH 0' 33 0 ExampleC16 N 106H 100 WO 2004/060305 PCT/US2003/041425 Example 17 N H H f: N S-O Example 18 N C O1 N SO N Example 19 H H N SOExample 20 0 N H3C NH NN N N H N 0 N N N o00 5H 0\\ 107 WO 2004/060305 PCT/US2003/041425 Example 21. 0/ NH Example 22 NH NaH H t OEt N N H N N NN NHC0 30,~c N N Example 23 NH Example 24 / OEt H H H N N N N N N O .1 0 S 30 : NH 0 OEt 5 108 WO 2004/060305 PCT/US2003/041425 Example 25 H H2 N N N N N0 \ Example 26 0 K N H H N N N NO N 00 N Example 27 H HN N Example 28 H H H 0 N N N N

H

3 0 -0 0 N 0 5 109 WO 2004/060305 PCT/US2003/041425 Example 29 -~ N N N N 'rN N H O NHC Example 30 H H " N N N N Example 31 " N 3CC S03H ExampleExample 3231 N H H N N C N N

SSSOH

3 H 1Example 32 co) H H H NN N 0 N S0 3 H 5 110 WO 2004/060305 PCT/US2003/041425 Example 33 HH N 's N zrN N oAN O Example 34 N O Example 35 -S> HH0 N N N N~ 'H~ Example 36 H H H N N, NN N-S 5 111 WO 2004/060305 PCT/US2003/041425 Example 37 0 0 N - CN, 0HC 0

NH

3 C Example 38 00 H HN N IzrN N ~ H

H

3 C NH Example 39 00 h 3C / H3C NH Example 40 HH HH NH N N N NH ~O HNC N H'C HaC NH 112 N N '-N 0 H,0 N sk;rO HC NH 0 112 WO 2004/060305 PCT/US2003/041425 Example 41 H H N OH N N N YN(rN OH Example 42 0 I OH N N N N OH 3CC 0 Example 43 0 H H N OH H X~CC OH N N N eIN 0O Example 44 H H H N N--.O N

H

3 C-N 0 OH 113 WO 2004/060305 PCT/US2003/041425 Example 45 HOH H N OCH H H HN:X 0 N N N H 3 C Ot H, N 30 Example 46 H O H H HN 0 N N N 0 H H 3 C O O HC 3 0 0 C Example 47 HO0 H ~ H HJ: H H 0H N 'NN H 0OH N 3C Example 48 H H H N N N N 30 114 HH0OH OH 50 114 WO 2004/060305 PCT/US2003/041425 Example 49 NO N %N N 0 b 0C 0 Example 50 H H N N S N N 1 C 00 II Ni Example 51 H H rjr :z N N N N ( C' 0 Example 52 H H H N N N N XN 0 N N 115 115 WO 2004/060305 PCT/US2003/041425 Example 53 S NH "H HOEt N N N o NH H 0 Example 54 Os NH H H'OEt N N Example 55NH NH H H OEt N N NO Example 56 H H H N N N SC =NH I OEt 5 116 WO 2004/060305 PCT/US2003/041425 Example 57 H H I N SN N 0 c H 3 C Example 58 Example 59 0 Example 60 H H N N N 0O 0O IN 117 Examplee 59 H H N N N N~ N N, 0 117 WO 2004/060305 PCT/US2003/041425 Example 61 HO^H N NN N N Example 63 NN H H :r N~ NN ' N N<N ,HC 0 SO3H Example 64 H H N N NN y N SOH 5 118 WO 2004/060305 PCT/US2003/041425 Example 65 H 0 N N > O 0O cI Example 66 Example 67 N N~ NS O

H

3 0 K a N" Example 68 H H H N N N NN Et o N 'S 1190 119 WO 2004/060305 PCT/US2003/041425 Example 69 OO H N H H NH N __ HC CI Example 70 Co \I, H NH N N _ -r H0

H

3 C o O- s 0 Example 71 00 H NH N ' H7 3 C

H

3 C Example 72 H H H 0 = -N N <rN Et 0

H

3 C N , 0

H

3 C NH 0 120 WO 2004/060305 PCT/US2003/041425 Example 73 Example 74 CI R CI R4/0R 0 Example 75 Example 76 0 HN OH H mc o Et' R4 d' H8 O H 0 HOOH 5 121 WO 2004/060305 PCT/US2003/041425 Example 77 H O Cl-,NN O H cl Example 78 N N H 3 0C CH, K9 \s 0 3 Example 79 H O H HN OCH N y H0 30C OH 3

H

3 C Example 80 H H H N N N 00 Et 0 H

H

3 C

CH

3 C3 122 WO 2004/060305 PCT/US2003/041425 Example 81 Cl NN S H rfX :N: N 0 Cl Example 82 N N s - \s 0 Example 83 1H N N 0O

H

3 0 :: 0 Example 84 H H H N= N N IrNC Et N) 1so 123 WO 2004/060305 PCT/US2003/041425 Example 85 /NH OEt N 0 Cl Example 86 NH 0 NH H / OEt / : Nr N )a \\ \s 0 0--C8 Example 87 NH \OEt 0 HC Example 88 H H H N N N 0+a 0 Et / NH EtO 124 124 WO 2004/060305 PCT/US2003/041425 Example 89 HO N~~N Ph C, Example 90 0 H N NN Ph NrYO OO Example 91 0 HI N -N Ph HaC/ 0 Example 92 H H H N N N Et 0 O2 Ph 0 125 WO 2004/060305 PCT/US2003/041425 Example 93 H Ni 0 O N ' S O 3 H Cl Example 94 H N N \ S S

SO

3 H Example 95 H N N HQC

-SO

3 H Example 96 H H H N

SO

3 H 5 All of the references above identified are incorporated by reference herein. In addition, two simultaneously applications are also incorporated by reference, namely Modulation of Protein Functionalities, S/N _ , filed December ., 2003, and Anti-Inflammatory Medicaments, S/N filed December __ , 2003. 10 126

Claims (32)

1. A compound having the formula 5 R XANH-DL -E Q wherein: R 1 is selected from the group consisting of aryls and heteroaryls; 10 each X and Y is individually selected from the group consisting of -0-, -S-, -NR 6 -, -NR 6 SO 2 -, -NR 6 CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR 6 (CH 2 ) 1 h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH 2 ),-, and -NR 6 (CH 2 ) 1 ,-, one of the methylene groups present therein may be 15 optionally double-bonded to a side-chain oxo group except that with -O(CH 2 ) 1 1 -, the introduction of the side-chain oxo group does not form an ester moiety; A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; 20 D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(0)-, -S(0) 2 -, -N(R 6 )CO-, 25 -N(R 6 )SO 2 -, -N(R 6 )CON(R 6 )-; j is 0 or 1; m is 0 or 1; n is 0 or 1; p is 0 or 1; 30 q is 0 or 1; t is 0 or 1; 127 WO 2004/060305 PCT/US2003011425 Q is selected from the group consisting of o NR4 S N,4 R4 M, N, N 0 0 R4 a 0S11 0 N 0 N 0 N Q-1 Q-2 Q- 3 4 Q- 4 Q-6 4 o R R R 4 4 0 3 0 0 0 0 0 0 4 HR R4 z N 'N c~N N R Z AH Q-7R,0O Q-1 I Q-8 Q-9 0o 0 R\RR4 0 SI\R 4 R 4 \N \N NH N N H NI OR, N N OR, OR 6 , R, 6 05 0 5 0

2 Q-12 R5 Q-1 -1 Q-13 Q-14Q16Q7 0 v-~' OH SH /4 R4 0 00 CH 3 0 1 0 N OR 6 HC0 H

3 ,C H H 8 c0 CH, HCH3 HC Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 0000 H HH R 5 4( o Nl R H RH S0 3 H N 00 w wjhii w Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 COZR S0 3 R, 00 OR 6 I andi Q-30 Q-31 Q-32 Q3 -4Q3 128 WO 2004/060305 PCT/US2003/041425 each R 4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on 5 an alpha-carbon directly attached to a ring nitrogen on Q; when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R 5 is individually selected from the group consisting of -IH, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, 10 heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R 6 is individually selected from the group consisting of -H, alkyls, allyls, and 3-trimethylsilylethyl; each R, is individually selected from the group consisting of alkyls, aralkyls, 15 heterocyclyls, and heterocyclylalkyls; each R 9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R 9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; G is selected from the group consisting of-O-, -S-, and -N(R 4 )-; 20 k is 0 or 1; each Z is individually selected from the group consisting of-O- and -N(R 4 )-; and each ring of formula (I) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, 25 cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; except that: when Q is Q-3 or Q-4, then the compound of formula (I) is not 129 WO 2004/060305 PCT/US2003/041425 0 Ph or O 0 %Ph O < N\ or -N NH . N 0__ Ph /N- Ph' O NH 2 5 when Q is Q-7, then the compound of formula (I) is not 10 O NH R120= 2.3-difluoro; 2,3,6-trifluoro; 2, fluoro, 3-chloro; 2-chloro,3-fluoro; O 3-cyano; 4-chloro A'= substituted phenyl R120 NH Y'= CO; -NHCO-; -SO2-; -SO2NH-; f=0 or 1 I .R121 = substituted phenyl; oxazolyl; pyridyl; pyrimidyl; pyrazolyl; A' imidazolyl R 121 15 or 0 OO NH RI23 -H; 2.3-difluoro; 3,5-difluoro; 2-fluoro, 4-fluoro; 2-chloro, 2,4-diehloero; 3,4-dichloro; 3-fluoro;

4-chloro, 2-bromo; 3-bromo; 4-bromo; 4-iodo; 2-methoxy; 3-methoxy; 4-methoxy; 3,4-dimnethoxy; 0 2,4-dimethoxy; 2,5-dimethoxy; 3,4,5-trimethoxy; 3-CF3; 4-CF3; 3,5-di-CF3; 4-CF30-; 3-nitro; 4-nitro; 3-nitro-4-chloro; 2-methyl; 3-methyl; 4-methyl; 3,5-dimethyl; 4-iso-propyl; 3-methylthio; 3-CF3S-; 3-chiloro-4-methoxy 20 R 1 2 3 NH 4-methiylthio; 4-hydroxy; 4-methoxymethyl; 4-methylsulfonyl I A'= substituted phenyl A' Y" = CO; f- or (,) fR122 - substituted phenyl; oxazolyl; pyrbiidyl R 122 when Q is Q-7, R 5 is -OH, Y is -0-, -S-, or -CO-, m is 0, n is 0, p is 0, q is 0, and 25 E is phenyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, then the compound of formula (I) is not 130 WO 2004/060305 PCT/US2003/04 1425 0 ,M 'M e NH NH rN N' a 0 0 N N H H I $ K 81 H HN 0 0 5 ,or R80 is H, MeR8issbttedpny RS I is substituted phenyl R8isubtuedhey when Q is Q-9, then the compound of formula (T) is not 10 Ph 0 Me 0 Me NM N 0 N-M0 IR 16 0 H 2 N-(CH2)4 Ph NC p 16=Hneblor 15 HO H N - RE "N >IN R 1 0 R17, R18 = alkyl R19 =H-, alkyl 20 when Q is Q- 10, then the compound of formula (I) is not 0 0 0P RIOO= nethyl, ethyl Riot-A S, RIO I= ilkyl, aminoalkyl, aryi, iylalkyl, H' NH tbienylalkyl, pyridinylolkyl, N H ~t plihlfinidylalkyl, alkoxycarbonylslkyl, I alkoxycabonylauiinorlkyl, I arylalkciylalkyl, alkoxyalky, hydroxyalkyl, R, N arylaianocarboityl, arylslkoxycsrboniylaiuioalky 25 0v R 02 = phienyl, indolylphenyl V = 0 orI X'=0, NH or 0 NC e R 103 = furyl, thienyl, phenyl 30MeO<lN A NI. A (0) V XC or S H H'& Ra a=lIor2 131 WO 2004/060305 PCT/US2003/041425 wherein there is a bond between Q and 5 10 of formula (I), and when Q is Q-11, t is 0, and E is phenyl, then anyR 7 on E is not an o-alkoxy in relation to said bond; when Q is Q-11, then the compound of formula (I) is not 15 iN--P Ph OO NHS- -NHC - O 0 Pr - i Ph 20 or 00 0 R105N N NH R104= methyl, ethyl H H R 105= alkyl, phenyl OR 104 R 106 = fluorine-substituted phenyl H 25 HN 0 O 30 when Q is Q-15, then the compound of formula (I) is not 132 WO 2004/060305 PCT/US2003/041425 0 0 O +-R107 or ON 0% N 0 N N H H H I CH3 5 R107 = phenyl 3 NO 2 133 WO 2004/060305 PCT/US2003/041425 when Q is Q-16, then the compound of formula (I) is not 0 R 3 C K 0 C N O N H 2 N /S NH NH R 112 O N 0 R 12 = Me,OH N OH H H OH O 0 0 0 H O N HC-Ph HNCO HN S NN 0 o0 Ph -MeO H 1 H 0 N NCP NN N HN 0 00 5 134 WO 2004/060305 PCT/US2003/041425 HNC HNN RoN C H O RN N H oo/ 0H N 0 H O H O O Ph- N ORO O N' ' / NH HN N 0 , or 0 N N NH R og= OH, SH, NH2H Rl 09 = hydrogen or one or more methoxy, hydroxy, halogen, nitro, dimethylamino, or furanyl Rilo= substituted phenyl, furanyl RPh =OH or CI X 3 = O, NH 5 when Q is Q-17, then the compound of formula (I) is not 10 NN H 29 I/ I, R 2 9 = alkyl R 3 o= H, t-Bu, benzoyl 135 WO 2004/060305 PCT/US2003/041425 when Q is Q-21, then the compound of formula (I) is not 5 HO 2 C (R) 0 N 0 Ph 10 when Q is Q-22, then the compound of formula (I) is selected from the group consisting of R4 R 15 R4INH-LI - (NH)p - D- (NH) p- (A)q -[( X) j-R ]m R4 NH-LI(NH)p - D - (NH)p(A)q [( X)jR]m 0 NH O NH X 0 NH W W W W OH OH 20 L 1 - C(O) or S(0 2 ) SCO-(NH)p-D-(NH)p-(A)q-[(X)j-Ri)]m D-(NH)-(A),-[(X)j-R)]m 0 NH 0 NH 25 oo WY W W OH 4 3CO-(NH)p-D-(NH)d-(A)q-[(X)-R)]m R4 H 30 D-(NH),-(A)q-[{X)]-Ri)]m O NH W NH ,and KO W OH 136 w W OH WO 2004/060305 PCT/US2003/041425 but excluding o H 0 a N H R 3 O R 4 1 0'NqHN 'R 37 R R37 = N(Me)2, N as N R 3 9 morpholino, OMe, OH, H H R34 = Me, Cl H R38 = H, CN, OMe, OH, R3 4 R35= -N(Me)2, morpholino Me benzyloxy, phenyl, nitro HO meta or para- R36= H, F HO meta or para- R39= H, OH R40 = H, F R41 = H, CI O 0 OMe N 'N~: N''N N' N Nl 'N Me Me ,and HO HO meta or para- OH meta or para MeO N NHMe MeO 0 ,N O HH HO meta or para when Q is Q-23, then the compound of formula (I) is not R 42 ( C H 2 ) 9 Me N N--. HS NN H' HS R 42 = H, Me HS c ~N S0 N1 N. N 'I H HS HS 5 137 WO 2004/060305 PCT/US2003/041425 CI t-Bu H Cl HS- N N t-Bu N C= O I I / / SNo HSX S HS when Q is Q-24, Q-25, Q-26, or Q-31, then 5 (RyXAND L E is selected from the group consisting of R7 R7 R7 SW -x- lm W 0 WW A A-(X-R)m I Y )7 0 * H H N A-(X-Ri)m 'N A-(X-R)m H H H H H H H N W N ,A-(X-R)n 0H W N N W N O N AA(XXRR)m 0 Hy R -(X-R)m @R 7 W R 7 ,and HN W,. R7.; * I I 10 wherein each W is individually selected from the group consisting of -CH- and -N-; and 138 WO 2004/060305 PCT/US2003/041425 000 o 00 o00 o z 0 O R 4 0 HN S NR 4 RS OONR4 O 0 NSNR4 - 011I H 0 N'NHH H 4 H R4 ,O 5 Q-24 Q-25 Q-26 or Q-31 where * denotes the point of attacluhment to Q-24, Q-25, Q-26, or 10 Q-31; when Q is Q-31, then the compound of fonnula (I) is not ,0 0 . Nl C HN' H 15 N N or 20 N .N.N H H HI No~ NS 25 when Q is Q-28, then the compound of formula (I) is not 139 WO 2004/060305 PCT/US2003/04 1425 H o N 0 R , N , I II or H CH C 2 ) 3 - NM- 20 5 140 WO 2004/060305 PCT/US2003/041425 when Q is Q-32, then 5 (R X9-(A)-N D L E 10 is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; 141 WO 2004/060305 PCT/US2003011425 when Q is Q-32, then the compound of formula (D) is not OEI Et0- P CH 2 '- N N R1340~ H R 130 0tO R 132 R 1 "O 7 / R1340 NA H NH N I 1 4 ~ H H R 130 = benzoyl, substituted phenylaminocarbonyl R11= C), Br, SPh, benzoyl, plienylsulfonyl R 1 3 2 = subsituted phenylarninocarboiyl Me R13=H, Cl Ot Ph R14= H, alkyl, ally], B-trimethylsilylethyl I H 2 E9-P 0 CH=CHCHH 0 Et Ph 2 Na -C C-P-0Et H 2 II OEt E0~J ~~ CH-PO 2 Et H H N Ph ' ,or 5 142 WO 2004/060305 PCT/US2003/041425 when Q is Q-35 as shown 0 0 ( ZR 4 ZR 4 5 Q-35 (para) Q-35 Oneta) wherein G is selected from the group consisting of-O-, -S-, and -NR 4 -, k is 0 or 1, and u is 1, 2, 3, or 4, then 10 15 is selected from the group consisting of H R7 H N 2W IJwOK WH H '-N A - [(X)j - R 1]m 20 W * W R 7 * H H ' H 7 O N-W N "A-[(X)]-R1]m ' N A-(~-1Jm ,H 25 0 W N ' A -[(X)j-R 1] m R7 WJW 0W 'R ,N A-[(X)j-R]m H H H 25 N W A[XjRl R7 HN W R NS A-[(X)j-Rl]m * H 30 143 WO 2004/060305 PCT/US2003/04 1425 W R7 R 7 R

5- ( ~ j R ] N ' [ ( X ) j -R l m a n d * A [ ( X ) j -R l m 144 WO 2004/060305 PCT/US2003/04 1425 except that the compound of formula (I) is not Me~ C0 2 R 71 Me NC0 2 H P Me I73 P -(CH 2 )nCO 2 R 75 IrW , , metaPara W 4 N ' 28.1 R73 =-OCH2CC2H R 7

6 R75 =H, Et _W 4 H R71 H, Me R72 -thiazolyl, iso xazolyl R74 =oxazolyll, imidazolyl R76 - H, NH2, N02 5W4 =N, CH irnidazolyl, furyl 28.2 R73- CO2Me n1 0-1 R74- chlorophenyl CF3 X/- ~ C02R7O R - N. Ph 0: & , . R77 = H, alkyl 0 meta, pa MeNHC2 RN X3 Oor CHI RN R78 =H, lkyl I 0 0 NH N N 0O Me N 10 HN0R Me p I H H C0 2 Me 00 2 R 6 5 MeO , M F 3 C 0 a N R6 0 meta, Para OMe 0R6S-H.Et R66 -alkyl 145 WO 2004/060305 PCT/US2003/04 1425 Me MeO 5 meta, pama R, H, t-Bu MeC ~a MeC CO.Me CH, 0 N OMe N NN H 2 NyN OMe H H NI H 3 C N_ N NH 2 N N or H N C0 2 H R79 1-I, Me C0 2 R 79 ,o ~ N 0 146 WO 2004/060305 PCT/US2003/041425 2. The compound of claim 1, wherein R 1 is selected from the group consisting of 6-5 fused heteroaryls, 6-5 fusedheterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls. 5 3. The compound of claim 2, where R 1 is selected from the group consisting of W'Lw W IW __ V R , R 2 0 ' R 3 R 2 R2 H 10 yS, Ny R 4 N N-R 4 , 15 R 2 R 2 0 R 5 q R2 N N <N -N LNw~jr j- 27 'r \>-R 15 R2 H' and R each R2 is individually selected from the group consisting of-H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, 20 halogens, alkoxys, and hydroxys; and each R 3 is individually selected from the group consisting of -H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R 4 NHSO 2 -, and -NHSO 2 R 4 . 25 4. The compound of claim 1, wherein A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, benzothienyl, pyrazolylpyrimidinyl, imidazopyrimidinyl, 30 and purinyl. 147 WO 2004/060305 PCT/US2003/041425 5. A method of modulating the activation state of abl or bcr-abl a-kinriase comprising the step of contacting said kinase with a molecule having the formula 5 (RF-XjYA DL EYQ wherein: 10 R 1 is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -0-, -S-, -NR 6 -, -NR 6 SO 2 -, -NR 6 CO-, alkynyls, alkenyls, alkylenes,-O(CH 2 )1,-, and -NR 6 (CH 2 )h-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH2)h-, and -NR 6 (CH 2 )h-, one of the 15 methylene groups present therein may be optionally double-bonded to a side chain oxo group except that with -O(CH 2 )h- , the introduction of the side-chain oxo group does not form an ester moiety; A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; 20 D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(0)-, -S(0) 2 -, -N(R 6 )CO-, -N(R 6 )SO 2 -, 25 -N(R 6 )CON(R 6 )-; j is 0 or 1; m is 0 or 1; n is 0 or 1; p is 0 or 1; 30 q is 0 or 1; t is 0 or 1; 148 WO 2004/060305 PCT/US200304I1425 Q is selected from the group consisting of R4 R 4 0 R 0 N S N 10 N N N S IR IR \ 4 -5R4R Q-1 Q-2 Q- 3 R4 Q- 4 Q-6 R4R 4 0 R 4 0 0 0 0 0 O 0 N R4R 4 R 4 -K )S< R 4 S R 4 0R NR 4 z N N~ /2'ZN N 0H N -7 Rs0 0 0 Q- - Q-8 Q-9 00 0 R4oR R4 \ 4 3I RS)I N OR, N4 NOR N NN OR 6 ,2 R6 OR, R 5 R5 0, R O, 0 Q-13 Q-1 Q-15 Q-16 Q-17 o OH SH R4* 0 0oi NHR 0 COH 3 0 H 3 0 H OR 6 ,, H 3 0 I 3 HC Q-2 -2 .Q-18 Q-1]9 Q-20 Q-21Q-2-3 000 H H H ZR4 0' 0 4 0 0 /1N R, 0 N N- . 0NN' HN N Z N 000 H H SOH 0 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 COZR 4 0 S0R 00 OR, 0is Q-30 Q-1Q-32 Q-33Q-4-3 149 WO 2004/060305 PCT/US2003/041425 each R 4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly 5 attached to a ring nitrogen on Q; when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R 5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, 10 hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R 6 is individually selected from the group consisting of -H, alkyls, allyls, and 3 trimethylsilylethyl; each R 8 is individually selected from the group consisting of alkyls, aralkyls, 15 heterocyclyls, and heterocyclylalkyls; each R 9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R 9 groups are gemrninal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; G is selected from the group consisting of-O-, -S-, and -N(R 4 )-; 20 k is 0 or 1; each Z is individually selected from the group consisting of-O- and -N(R 4 )-; and each ring of formula (I) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of-H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, 25 heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; and thereby causing modulation of said activation state. 30 6. The method of claim 5, said contacting step occurring at the region of a switch control pocket of said kinase. 150 WO 2004/060305 PCT/US2003/041425

7. The method of claim 6, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (II) molecule.

8. The method of claim 6, said switch control pocket selected from the group 5 consisting of simple, composite and combined switch control pockets.

9. The method of claim 8, said region being selected from the group consisting of the ox-C helix, the catalytic loop, the switch control ligand sequence, and the C-terminal lobe and combinations thereof. 10

10. The method of claim 9, said c-C helix including SEQ ID NO. 2.

11. The method of claim 9, said catalytic loop including SEQ ID NO. 3. 15

12. The method of claim 9, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof..

13. The method of claim 9, said C-lobe residues including F. 20

14. The method of claim 5, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.

15. The method of claim 5, said activation state being selected from the group consisting of the upregulated and dowmnregulated states. 25

16. The method of claim 5, said molecule being an antagonist of the on switch control pocket for said kinase.

17. The method of claim 5, said molecule being an agonist of the off switch control 30 pocket for said kinase. 151 WO 2004/060305 PCT/US2003/041425

18. The method of claim 5, said method including the step of administering said molecule to an individual undergoing treatment for cancer.

19. The method of claim 18, said molecule being administered by a method selected 5 from the group consisting of oral, parenteral, inhalation, and subcutaneous.

20. The method of claim 5, said molecule having the structure of the compound of claim 1. 10

21. An adduct comprising a molecule binding with a kinase, said molecule having the formula (R,-XWAN DLE4Y Q 15 wherein: R' is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -0-, -S-, -NR 6 -, -NR 6 SO2-, -NR 6 CO-, alkynyls, alkenyls, alkylenes, -O(CH2)h-, and -NR 6 (CH 2 )h-, 20 where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH 2 )h-, and -NR6(CH 2 )h-, one of the methylene groups present therein may be optionally double-bonded to a side chain oxo group except that with -O(CH 2 ) 11 -, the introduction of the side-chain oxo group does not form an ester moiety; 25 A is selected from the group consisting of aromatic, monocycloheterocyclic, and bicycloheterocyclic rings; D is phenyl or a five- or six-membered heterocyclic ring selected from the group consisting of pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, furyl, pyridyl, and pyrimidyl; 30 E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; L is selected from the group consisting of -C(O)-, -S(O) 2 -, -N(R 6 )CO-, -N(R 6 )SO2-, 152 WO 2004/060305 PCT/US2003/041425 -N(R 6 )CON(R)-; j is 0 or 1; m is 0 or 1; n is 0 or 1; 5 pis 0 or 1; q is 0 or 1; t is 0 or 1; 153 WO 2004/060305 PCT/US2003104 1425 Q is selected from the group consisting of 4 4 0 R i ~ 0 N 0 S N> 0 N> \~ //N /N~~S :N\ :L-\ 0~~ I 4 R4R 4 ~~ NR R 4 Q- N, N- H4 Q1Q-2 Q-39 000 0 00 0 0 0 N R 4 F 4R -1 5 ~~N ~ N R 4 \)~ R~l R R //\OR 0 5 OR Q7Q-83 Q-94QI -6Q1 R 4 S 0R 0A O H S Q R1 002, 0H H 3 C CH 3 H 3 C 0CH 5 OR, HC H 3 C HC Q-18 Q-19 Q-20 Q-21 Q-22 Q-23 0 0 0 H H- H R SR 4 R4. o s 0 N 'N HN W' Z' N a N R H I H SO 3 H 7 Q-24 Q-25 Q-26 Q-27 Q-28 Q-29 COZR 4 0 0S0 3 R6 0 N G-,.,OZR 4 O1,, 7Q' S0 2 N(R 4 ) 2 R, I'OR, 0 R NJ OR, /-~, /~,and Q-30 Q-1Q-32 Q-3Q-34 Q-35 154 WO 2004/060305 PCT/US2003/041425 each R 4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R 4 substituent places a heteroatom on an alpha-carbon directly 5 attached to a ring nitrogen on Q; when two R 4 groups are bonded with the same atom, the two R 4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each R 5 is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, 10 hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each R 6 is individually selected from the group consisting of -H, alkyls, allyls, and 3 trimethylsilylethyl; each R 8 is individually selected from the group consisting of alkyls, aralkyls, 15 heterocyclyls, and heterocyclylalkyls; each R 9 group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two R 9 groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; G is selected from the group consisting of -0-, -S-, and -N(R 4 )-; 20 k is 0or 1; each Z is individually selected from the group consisting of -0- and -N(R 4 )-; and each ring of formula (I) optionally includes one or more of R 7 , where R 7 is a noninterfering substituent individually selected from the group consisting of-H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, 25 heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls.

22. The adduct of claim 21, said molecule binding at the region of a switch control 30 pocket of said kinase. 155 WO 2004/060305 PCT/US2003/041425

23. The adduct of claim 22, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (Ill) molecule.

24. The adduct of claim 22, said switch control pocket selected from the group 5 consisting of simple, composite and combined switch control pockets.

25. The adduct of claim 24, said region being selected from the group consisting of the c-C helix, the catalytic loop, the switch control ligand sequence, and the C-lobe, and combinations thereof. 10

26. The adduct of claim 25, said a-C helix including the sequence SEQ ID NO. 2.

27. The adduct of claim 25, said catalytic loop including SEQ ID NO. 3. 15

28. The adduct of claim 25, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.

29. The adduct of claim 25, said C-lobe residues including F. 20

30. The adduct of claim 21, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof.

31. The adduct of claim 21 said molecule having the structure of the compound of claim 1. 25

32. The method of claim 5, said molecule further binding to other sites on said kinase. 156