ZA200505268B - Anti-inflammatory medicaments - Google Patents

Description

ANTHINFLAMMATORY MEDICAMENTS ~~

So BACKGROUND OF THE INVENTION ER

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

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

The present invention relates to novel compounds and methods of using those compounds to treat anti-inflammatory diseases. :

Description of the Prior Art

Basic research has recently provided the life sciences community with an unprecedented 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, 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 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 : 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, “ 5 clinical trials, or later in the marketplace. Side effects and toxicities continue to be a major reason for the high attrition rate seen within the avg development process. For the kinase protein family of proteins, interactions at these native active sites have been recently reviewed: see]. 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.

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 al., Bio. Organic and Medicinal Chemistry 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 of inhibitors binds to the ATP active : site while also binding in a mode that induces movement of the kinase catalytic loop. Pargellis etal, Nature Structural Biology, Vol. 9, p. 268 (2002) reported inhibitors p38 alpha-kinase also 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 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 . compounds have the formula :

. rib ao) fe) tvio 0 : : a 5 } : ’ } . wherein: oo

R! is selected from the group consisting of aryls (preferably CC, and more preferably

C¢-C,,) and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NR¢-, -NRSO,-, -NR(CO-, alkynyls (preferably C,-C,;, and more preferably C,-C,,), . alkenyls (preferably C,-C,s, and more preferably C-Cio)s alkylenes (preferably

C,-C,;, and more preferably C,-C,,), -O(CH,),~, and “NR(CH,),, where eachh is individually selected from the group consisting of 1, 2, 3, or 4, and where for oo each of alkylenes (preferably C,-C,s, and more preferably C;-C,,), -O(CH,),-, and

NR(CH,),-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH,),- the introduction of the side-chain oxo group does not form an ester moiety;

A is selected from the group consisting of aromatic (preferably C4-C,s, and more 20 . preferably C-C,,), 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, fury], pyridyl, and pyrimidyl;

E is selected from the group consisting of phenyl, pyridinyl, and pyrimidinyl; :

L is selected from the group consisting of -C(O)- and -S(O),-; : jisOorl; . mis Oorl; nis Oorl; a pisOorl; qisOorl; tisOorl;

Q is selected from the group consisting of . Ro. | R, o Re se a 0 N ps od : he NN T he Ho 1 Fo | =o

I} Ho : Ho Neel Ny ng ~N , Gg" N ,

CL Ce ny TS ws WN R YC Re % : ) 5 Ce Q2 Qf Q4 & , oF

Re Rf Re 4 0 9 0° °o AA

ON Ry Re CO Re NA XM A ES AAS ) Oa ah wow SL . N N wan

S CL ht IS 1 ~ : : Q7"’ 8. Qo Q-10 Ql 0 o o 1 ” 0 [eo] 4 . oY R, Rig SNP NY " “NH ki Rs \ ’ xn | f | I AA ANS N Ra

ORe x or, Ri N ors Re © , Ré , RA yo» . : Q12 - ’ o 14 Q-Is Q-16 17

Bg 2 Jp Ss CoH of? I a SN Nu . p Rs & N I 2 Wy o § . L * eS on™ = RIVE

ORs , i j R Re ’ RC : 0. a os | Cod 00 oa Q22 Q23 0 9 Ro HN oo 1 > Re Aas Ra Yo ° Nr Re © hg as

WNT TNT 2 sop Nn Je N

A Fees x

CU yO Yow hl beg a A

Qu Q-25 as So Q27 Qs Qe» . SO,Re Rk : COZR, o : - o. ~~ SOMNR,), Fe Tore © Ry Ng IE :

B | N » | ~ ~ | N N°

ENCED ZA SE TR VS nh , wi, , “a : , s aI 030 Q-31 it ’ os fhe Q34 lie Q35 each R, group is individually selected from the group consisting of -H, alkyls (preferably

C,-Cis, and more preferably C,-C,,), aminoalkyls (preferably C,-C,, and more : preferably C,-C,,), alkoxyalkyls (preferably C,-C,5, and more preferably C-Co)s : } aryls (preferably C.-C, g, and more preferably C,-C,,), aralkyls (preferably C¢-Cg, . 5 and more preferably C4-C,, and preferably C,-C,;, and more preferably C,-C,,), heterocyclyls, and heterocyclylalkyls except when the Ry, substituent places a heteroatom on an alpha-carbon directly attached to a ring nitrogen on Q; when two R, ra are bonded with the same atom, the two R,, groups optionally form : an alicyclic or heterocyclic 4-7 membered ring; : 10 each R; is individually selected from the group consisting of -H, alkyls (preferably C,-

Cs, and more preferably C,-C,,), aryls (preferably C,-C,q, and more preferably :

Cs-C,,), heterocyclyls, alkylaminos (preferably C,-C,,, and more preferably C-

Cy), arylaminos (preferably C,-C,;, and more preferably Ce-Cr2) oo : cycloalkylaminos (preferably C,-C,;, and. more preferably CC), 15 heterocyclylaminos, hydroxys, alkoxys (preferably C,-C,s, and more preferably

C,-C,,), aryloxys (preferably C-C,;, and more preferably C,-C,,), alkylthios (preferably C,-C,3, and more preferably C;-C,,), arylthios (preferably C,-C,,, and more preferably Cg-C,,), cyanos, halogens, perfluoroalkyls (preferably C,-C,, and more preferably C,-C,,), alkylcarbonyls (preferably C,-C,s, and more preferably : 20 -C,;-C,,), and nitros; : each R; is individually selected from the group consisting of -H, alkyls (preferably C,-

C,s, and more preferably C,-C,,), allyls, and B-trimethylsilylethyl; each R; is individually selected from the group consisting of alkyls (preferably C,-Cis, and more preferably C,-C,,), aralkyls (preferably CC, and more preferably Ce 25 Ci) preferably C,-C,s, and more preferably C,-C,;), heterocyclyls, and - heterocyclylalkyls (preferably C,-C,,, and more preferably C,-C,,); : each R, group is individually selected from the group consisting of -H, -F, and alkyls ’ (preferably C,-C,4, and more preferably C;-C,,), wherein when two R, groups are ] geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 30 membered ring; oo each Z is individually selected from the group consisting of -O- and -N(R,)-;and °° :

each ring of formula @ optionally includes one or more of R,, where R, is a noninterfering substituent individually selected from the group consisting of -H, EE alkyls (preferably C,-C,;, and more preferably C,-C,,), aryls (preferably C4-Cis, } and more preferably C,-C,,), heterocyclyls, alkylaminos (preferably C,-C,q, and . 5 ‘more preferably C,-C},), arylaminos (preferably C-C,g, and more preferably Ce-

Cp), cycloalkylaminos (preferably Ci Cre and more preferably C,-C)), : heterocyclylaminos, hydroxys, alkoxys (preferably C,-C,,, and more preferably . C;-Cyp), aryloxys (preferably C4-C,q, and more preferably C,-C,,), alkylthios (preferably C,-C,4, and more preferably C,-C,,), arthylthios, cyanas; halogens, nitrilos, nitros, alkylsulfinyls (preferably C,-C,;, and more preferably C,-C,,), alkylsulfonyls (preferably C,-C,q, and more preferably C,-C,,), aminosulfonyls, and perfluoroalkyls (preferably C,-C,,, and more preferably C,-C,,).

In one preferred embodiment, the compound has the structure of formula (I) except that: when Q is Q-3 or Q-4, then the compound of formula (I) is not

N a : De o y lo] Ne_ph

J! ey ae pas 8 AL a I = Jor 0 2 when Q is Q-7, qis 0, and R, and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, : pyrimidyl, pyrazolyl, or imidazolyl; : when Qis Q-7, R, is -OH, Y is -O-, -S-, or -CO-, mis 0, nis 0, pis 0, and A is phenyl, - pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, R;is -OH, mis 0, nis 0, pis 0, t is 0, and A is phenyl, pyridyl, or thiazolyl, then D is not thienyl, thiazolyl, or phenyl; when Q is Q-7, then the compound of formula (J) is not p

M ) [o] CH3 ) . : Qn TQ oe Nd o n ad CN 0 av, wy © = 0 HOT O- 0 0 :

H ne x . xy .

Ss s 7S Ly Me OFEt . ne : oJ 0 "un me . i NN —=N “0 "“O oC. “NN 0, : ’ "soc i O\_NH ' y NAH 5 ~ 0 , Roy a 0 y xy

Ne “QO

J "TC eet Me d phenyl R82 is substituted phenyl when Q is Q-8, then Y is not -CH,0-; when Q is Q-8, the compound of formula (JI) is not

H .

N oP o( $5 y o ’

Rio N AN / \ Fe

Tov

SN - ’ . " Ryo = alkyl, aryl, arylalkoxyalkyl, or arylalkyls when Q is Q-9, then the compound of formula (I) is not ) Ph 0]

Me AN 0 ° W—{ . } 11 Oss

H >s [e] NH N os ads. oO. § ) 3 HoN-(CHz2)a : Ph LIN : R R : s —N Riz N 5 Rr

N 15

Peo o. Sno o | So

Ret S N a ON~(" s J ONC TS J # [eo] B [0] Riz R [eo] ’ ‘Ris ? . . R11 =H, alkyl, alkoxy, nitro, halogen R12, RI3 = £1, alky) Ria Hay propargy! 0 $ se A 0 2

Oy pak ee 0 o nM Cx WN Ru ® Rig © ~n Ris © 0) , ar Ry7 ; .

NC R16 = H, methyl R17, R18 = alkyl

R19 = H, alkyl when Q is Q-10, tis 0, and E is phenyl, then any R, on E is not an o-alkoxy; when Q is Q-10, then the compound of formula (I) is not

NTN

RAY 1

MN SAT 0 ; teu” NH BH when Q is Q-11, tis 0, and E is phenyl, then any R, on E is not an o-alkoxy; ] when Q is Q-11, then the compound of formula (I) is not i-Pr Ph

H.R _ o fT TJ. i-Pr Ph when Q is Q-15, then the compound of formula (D is not 0 0 o ° oy Ts “. 7 ox N : —Ph

No _-N N._N SLL Y N

Oo N NN o} N = R A 3 20 /

Ho 8 Te Ho 0 Va 8 0"™N N HN \ NH

R,q = substituted phenyl, Ry; = H, alkyl when Q is Q-16 and Y is -NH-, then

R—X P| I —E oo ( : To pp of formuia () 1s not biphenyl; © 15 ~ when Qis Q-16 and Y is -S-, then :

R—X PE NP —E fs "of formula (I) is not phenylsulfonylaminophenyl or phenylcarbonylaminophenyl; when Q is Q-16 and Y is -SO,NH-, then the compound of formula (I) is not

0 . ou Ag Ji

Ph—N RA HC (Ns : . : RY N° N° H

NSN H Ty Rz ~~ H Ty

Hol No © No . N o , H Ry; = Me, OH H . Raa I

NC AN : N% N .

A 0 SD o_O

AN © YQ s 7 S$ : NF , Cw . /" N ow

R24 no , 24 ’ NSo

Ras Xs, H H ,Or ) \ PA %AF o _S

Dy

N [0] 5

Roz = OH, SH, NH2 3 R34 = hydrogen or one or more methoxy, when Q 18 hydroxy, fluoro, chloro, nitro, dimethylamino, . or furanyl

Q-16 Ras = substituted phenyl, furanyl

Ryg=OHor Cl and Xs=0,NH; :

Y is -CONH-, then :

A Bos] i, (rat) px 20 . VE ‘m A P VP i of formula (I) is not imidazophenyl; oo when Q is Q-16 and Y is -CONH-, then the compound of formula (I) is not wo

HaN NN \ NH

Rs 28 [¢ . - H ’

Ray = substituted phenyl, pyridylcarbonyl

Ray = CN, methoxycarbonyl - n=0orl when Q is Q-16 and tis 0, then :

A H

(Ri—%—A—N)—1—NyD—E - 5: : m P p of formula (I) is not phenylcarbonylphenyl, pyrimidophenyl, phenylpyrimidyl, pyrimidyl, or N-pyrolyl; oo when Q is Q-17, then the compound of formula (I) is not n-Bu C)

Wen . “N Cm N

Rel 6 H "<1

Rog ; 'e) .

Ryo = alkyl k ] n-Bu ’ Rs; = H, t-Bu, benzoyl Rj; = substituted phenyl when Q is Q-21, then the compound of formula (I) is not : : HOC. ~&) 0"

N. ; . ( ©

Ph when Q is Q-22, then the compound of formula (I) is selected from the group consisting of :

Ry r : oo lo) 4 : . . y \ lo

N A \ - (NH)p-A-(X-Ry)m ) \ : : A NH Ny NOH AR SE

Ww ho C w

Ty . 3 Won ’ . s | y

NH-L-(NH)p-A-(X-R)m Ra :

So NH-L-(NH)p-A-(X-Rq)m

Ox NH oC

X Ox NH iN &

WW SW .

Po

To » and won when Q is Q-22 and q is 0, then the compound of formula (J) is selected from the group consisting of

Rs Rs Rs Ry ’

NB B) UB) Im 0)

Non CO-(NH)p-A-(X-Ri)n ~ "N” “A-(XRym New CO-(NH)p-A-(X-Ry)m New A-(X-R;)m .

CQ [oT &

Wy ’ Y ; Woh , won

OH OH

Ra Ra oo 1 CO-(NHp-A-X-Ry)m IY ARM T _CO-(NH)p-A-(X-R)m AN ARDM

I gr ge Qn xX Og _NH Ox _NH OgNH 1 AS X . , Ly , , and & w s > ew ‘who won

OH OH : : but excluding : oo 12

H o Ra 0. N 1& Rag HN “LX Raz . Q 1 (o] Rao Ras R37 =NMe)2, 0

STON Bo , Xr ON Ras morpholino, OMe, OH, H

H - R34=Me,Cl H ‘R38 =H, CN, OMe, OH,

X H Re & Ras R3s=-N(Me)2, morpholino /~ Me . benzyloxy, phenyl nitro ‘ meta or para- R36=H,F HO meta or para- : Hie on 0

R41=H,Cl - . o o ol

OMe Q i$ Q N

AS A

HN wv Y Qo o oy" OMe Q ZN 0 0) Z ‘ =X N Xr” N

N H , | 1 H and v PZ 3 Me AP Me .

HO HO . - meta or para- OH meta or para-

MeO- Np he . ; : g N

MeO 7 8 ~ N

L :

ZF . } HO ’ meta or para-

when Q is Q-23, then the compound of formula (I) is not “) Raz (CHj)eMe ©. 0 0)

IORONe or " ye w , H > HS Ry, =H, Me HS fe EV o 9 SA 2

C ses

HS C3 > HS HS

SOzNHz cl t-Bu

SP C

5s JOEL wl OOO : HE ® Ns: u §=5 00 ’ lo) lo) cl = N ® ® S jon )

HS 0 ip SH 3

LJ or cl al when Q is Q-24, Q-25, Q-26, or.Q-31, then the compound of formula (I) is selected from the group consisting of CL

Ry Ry : Ry . 5 a TW oo Fw oo

Yo ’™ w. Dd. W \ 80

CAN (Rk Nn OTL ! , : , ! :

R, R R, -T% 0 a o T& 0g .

NA A AKRm | iv Y e N PN rin [NR . - ¥ " R wow oo X X i ww 0 ww 9

N ACR Im J Ry

Yh NN necnin Ny in ’ : oxy rn og gross os fry sei . 2 Ag, ow, and mg Fe a wherein each W is individually selected from the group consisting of -CH- and

N-; each G, is individually selected from the group consisting of -O-, -S-, and : -N(R,)-; and : * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows: 0 00 0 00 0 00

A ¥ er |W LY Rr, Y; ZR, Oz 0” "NTN LY Rr NS N° JY Re os 35r“7R

Hoh ONY CLR ROWNTREE of 2 5 3 . 0 s y O IN I 3 * ’ .

NN -— - )

Q-24 . Q-25 Q-26 or Q-31 ‘wherein each Z is individually selected from the group consisting of -O- and N(R) when Q is Q-31, then the compound of formula (I) isnot

0] 0, 0) . . \

HN H . of Joe : . ) ~N_ 0

H

. oO Cl

I's 5 ’ - Or 0 7 LL ~N N - i A Lo ~ ZZ - \vi a 5 when Q is Q-28 or Q-29 and tis 0, then the compound of formula (I) is not : . je O—N 7“ - .

Nor Sx

N a N~, sc Che fo) dg bY ;

Aan CO 00 ) ZU

Rag = hydrogen, hydroxyalkyl, alkoxyalkyloxy, hydroxy ] when Q is Q-28 or Q-29 and Y is an ether linkage, then the compound of formula Dis not

=n ores

O ) . ) ’ or - 5 / 0” ~ ; aul cl aS when Q is Q-28 or Q-29 and Y is -CONH-, then the compound of formula (I) is not i 7

Po Semae! : . ~ Me , ) pn ©

: ‘when Q is Q-32, then :

H H ) : Ri—X PF IFN . : — Pp p is not biphenyl, benzoxazolylphenyl, pyridylphenyl or bipyridyl; when Q is Q-32, Yis -CONH-,qis 0, mis 0,and

H HY |.

N—L—N

P p of formula (T) is -CONH-, then A is not phenyl; when Q is Q-32, q is 0, m is 0, and :

N7—L—N } P pi. . is -CONH-, then the compound of formula (I) is not } : ; IN 0 q Req

RO ~ 3 : Rg0” nr — Ay or - RO TL

RsO g - HH o TH Res ;

Ay = R3 ZN Tr) :

Rot MON . 2 Rs¢ s N - } Xe

Rs4 = benzoyl, phenylalkylaminocarbonyl, _ substituted phenylaminocarbonyl H, Br . Ry7 = alkyl, substituted phenyl, thienyl, phenacetyl Rss = Cl, Br, SPh, benzoyl, phenylsulfony] : naphthyl * Rs; = H, phenylsulfonyl, phenyl, benzyl

Rig =H, alkyl, Br, substituted pheny], benzoyl, Rg =Et, i-Pr : phenylsulfony! Rs; = substituted phenyl, substituted benzyl]

Rqg = H, alkyl, phenyl X; = O, N-Ph, N-alkyl, N-carbamoyl

Rsp = substituted phenyl Z, =N(R50),0 when Q is Q-32, D is thiazolyl, q is 0, tis 0, p is 0, n is 0, and m is 0, then A is not phenyl or 2-pyridone; : when Q is Q-32, D is oxazolyl or isoxazolyl, qis 0, tis 0, pis 0, nis 0, and mis 0, then

A is not phenyl; o 5 © when Q is Q-32, D is pyrimidyl q'is 0, tis 0, p is 0, n is 0, and mis 0, then A is not phenyl; when Q is Q-32 and Y is an ether linkage, then

R—X}—A—N}—L—N}/—D—FE m Pp p of formula (I) is not biphenyl or phenyloxazolyl; when Q is Q-32 and Y is -CH=CH-, then

H

R—X—A I; D—E m p Pp of formula (I) is not phenylaminophenyl; when Q is Q-32, then the compound of formula (I) is not

Rss 9 “Rez __N . : i = 0 x= ResO~1 H %

Algo —{) HM N ReaD N ~ oe AlkylO N = HH d Rs © HH b Rey © to fe) 57 0 Rg o . b=0-1 RegO—1) H N

X,=0,8 Reo” N 7

R56 = H, CF3, Cl, imidazolyl, amino, morpholino, phenylthio, HH d R cycloalkyl, benzyl, phenyl, phenoxy, thienyl, substituted alkyl, 8] 81 ' pyridylthio, pyrimidyl, benzylamino, N-benimidazolyl, 0 oN : pyridylcarbonylimino, ureido,N- thiourea, substituted alkanoylamino, RegO~1] H A " phenylsulfonyl, substituted benzoyl, phenylatkenoyl, furanoyl, Reg0” SH j [x . . thienoyl, pyridinoyl, : HH d R

R57 = substituted phenyl, substituted biphenyl o] 3

Res _ 9 Rez N 9 H RedO~1) ~

ResO nN a H d sand

HH g lo] Rso H Ret d=0-2 - . rs : ’ R60 =H, alkyl bd = subsfiuted alkylaminocarbonyl, phenylaminocarbonyl R61 = substituted phenyl, thienyl, Br ) R62= H, alkyl, phenyl ) R63 = substituted phenyl when Q is Q-35 as shown : - ZRqq ZR10 wy oy

Cs RO

Q-3 s (para) Q-35 (meta) : wherein G is selected from the group consisting of -O-, -S-, -NR,-, and -CH,-, k isOorl,anduis 1,2, 3, or 4, then 10 (rat Ns 15 is selected from the group consisting of

Rr w ¥ oH Magog 20 BN i ww Y TX

A 0 Ha Sy roa Re,

Ry. Sry’ “AOR4Im

Naw Org SRA

SA : / on {CRM IN AMeeRm . 4 ° We SAO) Im

YX

Ry wy WR, 25 Ry, BN A : ) 0 Wow og

Wl IN 1,0 SA 4 h NSA 0RIm PN AMiRm

Ry, R R

Gy 7, 7. - NZ A Axia > A NA & 30 [ HH YOON ARIm NARI

Ry Ry, W Ry W ‘ + WwW . a XX JX YULR BN Ce

NT ARM \ AI(X)-Ralm \ AX)-Rqm : 5 R Co R Ry

CTY a Ts

N ) 03 : hii Priore NP hiram . Rz . . a E R; Ry

N x oR N eieoprim sive :

H We A-[(X)-R4]m 0 Wo ATX-Rem RH We A-[(X)j-Rslm

PLT

. * W. A Ry’ , 3 WwW. A Ry ,and HN W. Ry ,

except that the compound of formula (I) is not - :

COR: ol COsH 2) ~

Me @® : We ® . Res Ph | —~(CHonCORys } : ® FZ ® Res Co meta, para ! 7 Ws ’ ’ : : We Sep : "Ru 28.1 R73=-OCH2COZH R R75 =H, Et } 5 \=w, H R71 =H, Me R72 = thiazolyl, isoxazolyl "R74 =oxazolyl, imidazolyl | 0 R76 = H, NH2,NO2 . W4=N,CH imidazoly], fury} 28.2 R73=C0O2Me n=0-1 . : R74= chlorophenyl .

E CF; — Ny cl [on R 4 [020d R & ) xg Com \ cor 3 : ‘ ' meta para Me A Ph ) NH

O R7=Halkyl - 0 a A | COzH : = HN N ha! X3=0orCH, R78 = H, alky] o om ? OL ) . 10 ad) D0 cose

HN N= HN N= 0 ' Res _N - : . =N, Me =

ND Res e XL 0 ~ 2

HN S| =TC0E, N N N Cy CO-Rer

Tw Res A H Spa 0

I; Sg meta,pan COMe ° wi HN ce

E CORss MeO @ ° R87 OI, NI, ' .

FaC ® | No Re R68=CF;, Me 1 MeO A rs R70 = 2-MeSO,-phen-i-yl, 4g (J ’ @® : 2-NH,S0;-phen-1-yl, ® meta para morpholino, imidazolyl, N(Et), : W2=CRgorN : ome © Res=HE R66 = alkyl Reg or

CHa ’ . . Oo. N Zz - OMe ~AN, x

HNN OMe H | H.

Y HC, NN =z : . N a R [e] J

LTC

COH : , or Ly

R79=H, Me CORye ® . . . Ne) . .

“Even more preferably, R, as discussed above is selected from the group consisting of 6-5 * fused heteroaryls, 6-5 fused heterocyclyls, 5-6 fused heteroaryls, and 5-6 fused heterocyclyls, and : } even more preferably, R, is selected from the group consisting of . 5 EV ~

Sod of dy SG

Lr, Na NN, 0 FE 0 Rs , ’ Rp Rz N

I A © ly FOR orl

Ayko Go hd NYE RNIN Re N : 2 Rp . 0 } Rs WwW. Rp Ng—N } HC HE FCT HE HE each R, is individually selected from.the group consisting of -H, alkyls (preferably C,-C,3, and more preferably C,-C,,), aminos, alkylaminos (preferably C,-C,,, and more preferably C,-C,,), arylaminos (preferably

C,¢-C,g, and more preferably C¢-C,,), cycloalkylaminos (preferably C,-Cg, and more preferably C,-C,,), heterocyclylaminos, halogens, alkoxys (preferably C,-C,;, and more preferably C,-C,,), and hydroxys; each R; is individually selected from the group consisting of -H, alkyls : (preferably C,-C,¢, and more preferably C,-Cp), alkylaminos (preferably

C,-Cis and more preferably C,-C,,), arylaminos (preferably C¢-C,,, and more preferably C-C,,), cycloalkylaminos (preferably C,-C,q, and more preferably C,-C,,), heterocyclylaminos, alkoxys (preferably C,-C,;, and : more preferably C,-C,,), hydroxys, cyanos, halogens, perfluoroalkyls (preferably C -C, ¢» and more preferably C,-C,,), alkylsulfinyls (preferably

C,-C,s, and more preferably C,;-C,,), alkylsulfonyls (preferably C,-C,q, and more preferably C,-C,,), R,;NHSO,-, and -NHSO,R,; and

V is selected from the group consisting of O and H,. _

: Finally, in another preferred embodiment, A as described above 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, purinyl, o 5 and oo : he Wy

Wa? Ww? , where each W, is individually selected from the group consisting of -CH- and -N-.

With respect to the method of using the novel compounds, the activation state of a kinase is determined by the interaction of switch control ligands and complemental switch control a pockets. One 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 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 notina switch a. 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 oo switch control pockets is controlled in part by the charge status of the amino acid residues of the "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 24 So interact with one of the switch control pockets through hydrogen boding between the OH groups and selected residues of the pocket, thereby resulting in whichever protein conformation results a from that interaction. However, if the OH groups of the switch control Ii gand become charged through phosphorylation or some other means, the propensity of the ligand to interact with the aE 5 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 charged residues of the pocket and ligand. This will result in the protein assuming the opposite conformation assumed when the ligand was in a neutral charge state and interacting with the other switch control pocket.

Of course, the conformation of the protein determines the activation state of the protein and can therefore play a role in protein-related diseases, processes, and conditions. For example, if ametabolic process requires a biologically active protein but the protein’s switch control ligand : 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

E 15 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 : 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 condiiions.

One aspect of the invention provides a method of modulating the activation state of a kinase, preferably p38 a-kinase and including both the consensus wild type 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 a lesser propensity to interact with the occupied switch control pocket. As aresult, the protein will have : a greater propensity to assume either an active or inactive conformation (and consequenctly 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 25 2 :

state. The molecule can act as an antagonist or an agonist of either switch 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 : 5 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, Preferably, the region of the switch control pocket of the kinase comprises an amino acid residue sequence operable for binding to the Formula I molecule. Such binding can occur between the molecule and a specific region of the switch control pocket with preferred regions including the o.-C helix, the oo o-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 o-C helix, one preferred binding sequence in this helix is the sequence IIXXKRXXREXXLLXXM, (SEQ ID NO. 2). When the binding region is the catalytic loop, one preferred binding sequence in this loop is DIIHRD (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 DFGLARHTDD (SEQ ID NOA4),

EMTGYVATRWYR (SEQ ID NO. 5), and combinations thereof. When the binding region is in the C-lobe residues, one preferred binding sequence is WMHY (SEQ ID NO. 6). When a biologically inactive protein conformation is desired, molecules which interact with the switch conirol 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 which interact with the switch control pocket that normally results in a biologically inactive protein conformation (when interacting with the switch control ligand) will be selected. Thus, the propensity of the protein to assume a desired 75 conformation will be modulated by administration of the molecule. In preferred forms, the molecule will be administered to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative . sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, : bone resorptive diseases, graft-versus-host reaction, Chron’s disease, ulcerative colitis,

inflammatory bowel disease, pyresis, and combinations thereof. In such forms, itwillbe desired ~~ to select molecules that interact with the switch control pocket that generally leads to a

X | 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 - 5 molecules of the present invention will be administerable in any conventional form including oral, parenteral, inhalation, and subcutaneous. It is preferred for the administration to be in the oral form. Preferred molecules include the preferred compounds of formula (I), as discussed above. :

Another aspect of the present invention provides a method of treating an inflammatory condition of an individual comprising the step of administering a molecule having the general oo formula (I) to the individual. Such conditions are often the result of an overproduction of the biologically active form of a protein, including kinases. The administering step generally oo includes the step of causing said molecule to contact a kinase involved with the inflammatory process, preferably p38 «-kinase. When the contact is between the molecule and a kinase, the : 15 contact preferably occurs in an interlobe oxyanion pocket of the kinase that includes anamino acid residue sequence operable for binding to the Formulal molecule. Preferred binding regions of the interlobe oxyanion pocket include the a-C helix region, the o-D-helix region, the catalytic loop, the activation loop, the C-terminal residues, and combinations thereof. When the binding region is the a-C helix, one preferred binding sequence in this helix is the sequence :

IIXXKRXXREXXLLXXM, (SEQIDNO. 2). When the binding region is the catalytic loop, one : preferred binding sequence in this loop is DIIHRD (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 DFGLARHTDD (SEQ IDNO.4), EMTGYVATRWYR (SEQIDNO. 5), and . combinations thereof. Such a method permits treatment of the condition by virtue of the modulation of the activation 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 decrease in the amount of biologically active protein. Preferably, the inflammatory condition is selected from the group consisting of human inflammation, : 27 E theumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, E septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory : . distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft-versus-host “ 5 reaction, Chron’s disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof. As with the other methods of the invention, the molecules may be administered in any conventional form, with any convention excipients oringredients. 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 discussed above.

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 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. 3is a view similar to that of Fig. 1, but illustrating the switch control ligand in its 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 conformation different than the first conformation 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; oo

Fig. 5 is a view similar to that of Fig. 1, but illustrating in schematic form possible small * 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 : 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 oC 5 combined switch control pocket.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a way of rationally developing new small molecule 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 conformation may be biologically upregulated, while in another conformation, the same protein may be biologically downregulated. The invention preferably makes use of one mechanism of conformation change utilized by naturally occurring proteins, throu gh the interaction of what are termed “switch control ligands” and “switch control pockets” within the protein.

As used herein, “switch control ligand” means a-Tegion or domain within a naturally 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 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. | oo : 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 : : 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 biolo gical 0 5 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. 1,2 protein 100 is 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 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 pocket. 104 such that the OH groups 110 interact with the X residues 1 12 forming 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 fom that seen in Fig. 1 and corresponding to the off or biologically downregulated conformation of the protein.

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 biolo gically upregulated state (Fig. 4). Fig. 4a illustrates that the phosphorylated groups on the ligand 106 are attracted v 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 conformation 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 I. 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 -- 5 102. 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 * residues from on pocket 102, and ATP site 108 to create what is termed a “combined switch control pocket.” Such a combined pocket is referred to as numeral 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 molecule will interact with the simple pocket 102 or 104, in the more complex situations of Figs. 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.

MATERIALS AND METHODS

General Synthesis of Compounds. Co :

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 Rs.

Compounds of Formula I wherein Q is taken from Q-1 or Q-2 and Y is alkylene are ’ 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 Formula I-7. See A. Martinez et al, Journal of Medicinal Chemistry (2002) 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 M is a group capable of oxidative 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.

Wutts, Theodora Greene (Editors) 3rd edition (April 1999) Wiley, John & Sons, :

Incorporated; ISBN: 0471160199). Starting compounds 2 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) Sth edition (January 2001) Wiley John & Sons; ISBN : 0471585890.

Scheme 1.1 . . nc | R © ne | : : YC . ®y © sagt 5" 0 2) [R0,C-(NH),Jg-D-E-Y-N=C=0 §._ —N, 1 d N, Y-E-D-[(NH)p-CO 2 Y-E-D-{(NH)p-CO,R¢]q {(NH}p-CO-Relq = ” 3 . 14 . . : Rs na R © N or ®p' © 3yainrr N be

Rq—N=C=§ — ON Nes Sn : ; 2) [Re0;,C-(NH)plg-D-E-Y-N=C=S $y Y-E-D-[(NH)p-CORelq :

Y-E-D-[(NH)p-CO2Rg]q = 6 7 5 } : : Scheme 1.2 . . .

NH, phosgene _N=C=0 [ReO,C~(NH)p]g-D-E-Y~~ Bae [RgO2C-(NH)plg-D-E-Y a . se 2 ’ NH, thiophosgene N=—C=S§ . [ReOLC-(NHplg-D-E-Y” . ° a [Rs02C-(NH)pjq-D-E-Y ~~ ase o -

Rg0,C-NH, Setotact ) . 10 NH_D.EY—| eprotection

M.D-E.Y—NHP 10 Rg02C-NH-D-E-Y—NHP

Pd(0) catalysis . 11 2 : Rg02C-NH-D-E-Y—NH, : : 8

Compounds of Formula I wherein Q is taken from Q1 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 ; 10 addition of chlorocarbonyl sulfenyl chloride. See GB1115350 and US3818024, Revankar et, al US Patent 4,093,624, and Klayman et. al JOC 1972, 37(1 0), 1532 for further details.

Where Ry 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 : oo system of I-4 (X=0) and I-7 (X=S). R

Scheme 1.3 FNCX | X 4 _NH, X=0, 8 AR : : : [RgO2C-(NH)plg-D-E-Y — [Rg02C-(NH)p]g-D-E-Y’ H 8 : : 8a, X=0, S

SS

_Cl R cl S _N NT Deprotection- ’ —_— [Re0.C-(NH)plg-D-E-Y" y — 0] 14 X=0 1-7 X=S . .

B 1, _N" NH : [RO2C-(NH)plg-D-E-Y |S : 0 Y N : 1-4 X=0 - } 17 X=S : 1-7 is also available as shown in Scheme 1.4. Condensation of isocyanate or : isothiocyanate 2a with amine RsNH, yields urea/thiourea 2b, which, when reacted with chlorocarbonyl sulfenyl chloride according to GB1115350 and US3818024 yields 2c. Where

Ry 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 such as chloride, bromide or iodide yields I-4 (X=0) and I-7 (X=S). i 34

Scheme 1.4 0 0] oT

H S : : RsNHy ReHN N-g. one 5 Deprotection of Ry - :

RNCX —— )[ ——————— Ry “Rs a. . X=0, S X hg 2a X=0, 8 X=0, $ : 2b So 2c

O 0) ’

S al NaH/DMF 8

HN N~r N_ N~ he 5 - 7 Rs 3 I yy [ReOC-(NH)plgrD-E-Y T :

X=0, § [RgO2C-(NH)pla-D-E-Y : 2d 4 X=0 8a 7 X=S

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 1.3. 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.

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=0) and I-7° (X=S). : Scheme 1.5 ) 0] 0)

NH; RaHN_ _N Me s—

R,NCX os hil H__C” Ss RN Ny ‘ X=0, S X } TY : ’ 2a X=0, 8 X=0, 8 2e 2f ] 0}

NaH/DME TS _— } pe ~R y [ReO,C-(NH)plgD-EY” J * [ReO2C-(NH)plq-D-E-Y~ X : i-4° X=0 8a : I7' X=S

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 intermediate 15. Thermal cyclization of 15 affords 1,2,4-triazolidinedione of Formula }-16.

By analogy; scheme 2.2 illustrates the preparation of 3-thio-5-0x0-1,2,4-triazolidines of

Co Formula I-18 by reaction of intermediate 14 with an isothiocyanate and subsequent thermal cyclization. ~~ : } . Scheme 2.1 ’ . °y-0Rig Co

HN—N_ Ra .

Re D__Y¥_ _N_ OR

D Ye 13 R.0O,C-(NH 7 ~~ ~NT 10

ReOC-NH)plg™ “ETM ——— [ReQLNHPIa N T = 14

N } © Ra -. .

Ry—N=C=0 heat

D Y- N OR

SUNN ‘N10 —— > [Rs0,C-(NH)plq E N~ hd EE

JL

) (0) NH . ] 15 Ra

Ry ' . )

Pe NGA ON uN [RsO2C-(NH)plq E N : : =o . 116 ~ N : hd \ . Rs

Scheme 2.2 Re . D Y- N OR . R4;—N=C=8 [ReO02C-(NH)plg™~ ~~ SN hd 10 heat 14 BY 5 5 — 17 s NH xy ;

Rs

DOAN oY : [RgO2C-(NH)plq E N -

Java : rs 88 . Ra

Intermediates 12 wherein p is 1 are readily available or are prepared by reaction of 19 with carbamates 10 under. palladium(0)-catalyzed conditions. My is a group which oxidatively inserts palladium(0), preferably iodo or bromo, and is of greater reactivity than . M. Compounds 19 are either commercially available or prepared by one of ordinary skill in the art. } Scheme 2.3 ’ Co

Rg0,C-NH, : in ] . M E _M rere RgO,C-NH. SUNG : “py Pd(0) catalysis; D Y co Base 19 zo

Compounds of Formula I wherein D 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 R4NH, : to the corresponding hydrazine, condensation with ethyl chloroformate subsequent heating . yields1,2,4-triazolidinedione 15a. After the action of NaH in DMF, displacement wherein M . is a suitable leaving group such as chloride, bromide or iodide yields I-16 (X=0) and I-18 (X=S). SE

Scheme 2.4 : (0) . 1. NaNO, 0 RsNCX oo. sal ox J. X05 hea

R4NHy ————m INFN _ R4NHNiH Ct —_— —— . : 2a 0 [RsO CNH) ]g-D-E-Y. 0

HN—( NaH/DMF 2 plg-D-E-Y{ N—¢ : ~N___N~ EE n

Ry Rs —N N~ hi M Rq Rs

X ReOLC-NHpIG-D-EY TY : 8 15a 2 116 X=0 1-18 X=S 0 OL : | Sed NaH/DMF N—NH

RNG NH = [RgO.C-(NH)plq-D-E-Y=N_ N-g,

Deprotection of Rg hig [RgO,C-(NH)pla-D-E-Y ’ hil

X 8a : X : 1-116' X=0 15b 1-18" X=S

Compounds of Formula I wherein D is taken from D-3’ or D-4’ and Y is alkylene, are also prepared according to the synthetic route shown in Scheme 2.4. When Rs 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 on 15a will reveal 1,2,4-triazolidinedione 15b.

After deprotonation of 15b by NaH in DMF, displacement wherein M is a suitable leaving

Co "group such as chloride, bromide or iodide yields I-16’ (X=0) and I-18’ (X=S).

Compounds of Formula I wherein Q is taken from Q-5 or Q-6 and Y is alkylene are : prepared according to the synthetic route shown in Scheme 3. Reaction of hydrazine 20 with 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 Formulae I-22A and 1-22B. Compounds I-22A and 1-22B are separated by chromatography or fractional crystallization. Optionally, compounds I-22A and I-22B can undergo Mitsunobu reaction with alcohols R4OH to give compounds of Formulae I-23A and 1-23B. Compounds 20 are prepared by acid-catalyzed deprotection of t-butyl carbamates of : structure 14, wherein Rg is t-butyl.

‘Scheme 3 . Rs CISO,~N=C=0 . : [ReO,C-(HN)pla-D-E-¥o | NH 20 H Base [ReO2C-(HN)PIG-DEYS, | NH [ReO,C-(H N)PIa-DEY- N 0 : . + ee

NH

: 0 1 NI : 7 ~C! : J No

Ry Ra [ReO2C-HNIplG- DEY NO ReOCAHNRIDE yo / Xo + 0=5—nh . NH J : 122A 1-228

PhyP PhP

Diethyl azodicarboxylate Diethy! azodicarboxylate

R,OH R,OH

Rs Ry _ [ReO2C-(HN)pla-D-E-Y~ Ng? ResC-HNRI-D-E yo / ’ N, © ¥ =F —N, 123A 1-238

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 I-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 compounds of Formula 1-28. Maleimides 24 and 27 are commercially available or prepared by one of ordinary skill in the art.

Scheme 4

Rs

ON

0 ° Rs ’ ’ Q = N ’ @

Oo [ReO5C-(NH)pla-D-E-Y. 24 Rs . s02C-(NH)p] “NH, [ReOC-{NH)pla-D-E-Yo | ~~ g Base H Rs i : 125

Ra ’ 20 0] N 4 . . ~_/ o . (2)

DM 27 R [Re0.C-(NHpla” ET _ T° I e- [ROC ET A 26 Pd(0), Base 1-28

Heck Reaction —

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

Chemistry (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 R4OH gives rise to 31. :

BOGC-group removal with acid, preferably trifluoroacetic acid, and then treatment with base, " preferably triethylamine, provides the desired sulfahydantoin I-32. Optionally, intermediate is treated with acid, preferably irifluorcacetic acid, to afford the N-unsubstituted sulfahydantoin I-33.

’ Scheme 5

R4 Rs CISO,—N=C=0

Rs0,C-(NH)pjq-D-E-Y. t-BuOH [ReO,C~(NH)plq : ave , 29 lo)

Ra R, [Re02C-(NH)plg-D-E-Y-_ 0 PhyP : diethyl azodicarboxylate 30 —_—_— = o0=S 0) °Y "NH R,OH

BOC :

Rs R [ReO;C-(NH)plq-D-E-Y DH Reg, feOaLARHpa-L- N “UO —— ROSMNHRGDEY =S_ Rs 0 2) Triethylamine ol 0 ua ZW | wm OSS

BOC o R 4

Ri gr,

Precast, X

H+ Osi © —_— 4 3 0 H 1-33 : : Compounds of Formula I wherein Q is Q-8 and Y is alkylene are also prepared as shown in Scheme 5a. Amine 8 is condensed with the glyoxal hemiester to yield 31a.

Reaction of chlorosulphonyl isocyanate first with benzyl alcohol then 31a yields 31b, which after heating yields I-32. :

oo Scheme 5.1 oo o : OEt . _NH . [ReO2C-(NH)plq-D-E-Y 2 ___. 0 ROCHE ot :

NaCHBH; 8- 31a

HaN Q Oo ; : OH N clsoNcO —m8M8Mm ————————— [ReO2C-(NH)plq-D-E-Y NE. 2. ) H Oo . [RgO,C-(NH)plg-D-E-Y 7 NA oe 31a : 3. 5% Pd/C o H 1 Oo heat AS —— = [RgO2C-(NH)plg-D-E-Y 1-32

Compounds of Formula I wherein Q is taken from Q-8’, are prepared according to the synthetic route shown in Scheme 5.2. Formation of 31c¢ by the method of Muller and DuBois

JOC 1989, 54, 4471 and its deprotonation with NaH/DMF or Nall/DMF and subsequently - alkylation wherein M is a suitable leaving group such as chloride, bromide or iodide yields I- 32°. Alternatively, I-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 amine 8) yields 31e¢, which after Boc removal with 2N HCI in dioxane is cyclized by the : 10 action of NaH on 31d results in I-32°.

Scheme 5.2 : 0)

OL ll “S—NH 0)

NaN NJ ¥ Ox SNH .

M o WN . [ReO2C-(NH)plq-D-E-Y SE — [ReO2C-(NH)pla-D-E-Y : ’ } 31c 0 da 1-32¢ oo Scheme 5.3 SE Co

H © [ReO.C-(NH)p] Dey HO _

Boc—N_,0 one pla [Re0,C-(NH)pla-D-E-Y—N. ITO

Sy _ te]

HN } HN . TOE DEADCAT, PhP 31d OFt

Lo 0

Oss _ heat ROR (ple DEY (eo 1-32' : ~ 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 Formula 1-36.

Scheme 6 :

R, R4

R4~N=C=0 : Rg02C-(NH)plg-D-E-Y- [ReO2C-(NH)plq Re 34 0

Rs Rs retest, Xo) Base : : ere J s = Oo 10] NH

R4

Re rR, [ReO-C-(NH)plq-D-E-YS

PAA

1-36 .

HE oy . Ry

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 under reductive amination conditions with , 10 the t-butyl ester of glycine yields 35a. Isocyanate 2a is condensed with p-nitrophenol (or the corresponding R4NH, amine is condensed with p-nitrophenyl chloroformate) to yield the : carbamic acid p-nitrophenyl ester, which when reacted with deprotonated 35a and yields the urea that when deprotected with acid yields 35b. Formula 1-36 is directly available from 35b by the action of NaH and heat. Co : . Scheme 6.1 o eo] . : PS HN AS, Bu PN } [ReO.C-(NH)pJG-D-E-Y” TH — = [RgO,C-(NH)plg-D-E-Y~ Ot-Bu

NaCHBH3z . 8c 35a 2 1. RHINO 2, 2N HCl/Dioxane ; ; ne OM 5

ITT — I NO 1-36 35b - -

Co Compounds of Formula I wherein Q is taken from Q-9°, are prepared according to the synthetic route shown in Scheme 6.2. Formation of 3Sc¢ by the method described in

JP10007804A2 and Zvilichovsky and Zucker, Israel Journal of Chemistry, 1969, 7(4), 547- : 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 : NH :

NaN 0)

SNH rd M Oo ” N [ReO2C-(NH)plg-D-E-Y ——— = [ReOC-(NH)plg-D-E-Y™ 35¢ oO 8a 1-36"

Compounds of Formula I 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 structure 38. Treatment of 38 with an amine of structure HN(R4); and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula 1-39. Reaction of chlorosulonylisocyanate with an alcohol (Z = O) or amine (Z = NRy) 40 affords intermediate 41. Treatment of 41 with an amine 8 and base, preferably triethylamine or pyridine, gives sulfonylureas of Formula I-42.

~ Scheme 7.1 : CIS0,—N=C=0 x [ReO:C-(NH)pIa-D-EY, ——————» [Re02C-(NH)plg-D-E-Y~,, 0 } | 37 38 H

Re | 0

HN A RV i Ry [ReO,C-(NH)p]a-D-E-Y,, NT OSNT 4 ’ Base H L " .

Scheme 7.2 Ra }

H—Z 0 a PN = SO,Cl

CSO,—N=C=0 ——————— Fiz nN” 2

B Rk 41 N = [ReO2C (NH)pla-D-E-YS, Rs 1 op 8 H Raw PS XX _Y-D-E-q[(NH)pCO,Rs 2 ya N N > } H iy } Base 3 142 s

Compounds of Formula I wherein Q is taken from Q-12 are prepared according to the synthetic route shown in Scheme 8. Alkylation of pyridine 43, wherein TIPS is tri- - isopropylsilyl, under standard conditions (K>CO3, DMF,. Rs-I or Mitsunobu conditions employing Rs-OH) yields pyridine derivative 44 which is reacted with compound 12, wherein

M is a suitable leaving group, to afford pyridones of formula 1-45.

Scheme 8

OH : oe

RQ. KoCO. ie * DMFor Acetone Is : —————————

TIPS

No N° ROH PhP BLN NG : . Diethyl azodicarboxylate - 43 . 44 : . oe

ReO2C(NHIPlG DEY jo ” —_— a (0) N

Base Y-DE-(NH)PCORslq 45

Compounds of Formula I wherein Q is taken from Q-13 are prepared according to the synthetic route shown in Scheme 9. Starting from readily available pyridine 46, alkylation under standard conditions (K,CQO;, DMF, R41 or Mitsunobu conditions employing R4-OH) a . yields pyridine derivative 47. N-alkylation with K>COs, DMF, Ry-I affords pyridones of formula 48. Intermediate 48 is partitioned to undergo a Heck reaction, giving 1-49; a :

Buchwald amination reaction, giving I-51; or a Buchwald Cu(l) 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 Ry group is methyl, compounds of formula I-49, I-50, 1-51, or I-52 are treated with boron tribromide or lithium : chloride to afford compounds of Formula I-53, wherein R4 is hydrogen.

: Scheme 9 : : OH OR4 . OR, -

R : R4Q, KaCOy R, i 4 ‘ oY ® DMForAcetone oY 5 Rl, KsCOg Rs . ———— DMF or Acet

TPS Nd ol ROH,Php TPS Ny a or Acetone . Diethyl azodicarboxylate 0 N cl “ : lL" : OR, 48 : : E__I(NH)pCORglq ‘ OR

ZN P # Rs Hyd i R 8 n | ydrogenation a 5 8 E«(NH)PCORelg —>

Heck reaction 0) N 7 pl Rela E.__[(NH)pCOzRglq

Pd(0) Ry 1-49 n lo] N 0 )

Base —= 4 CT on¥2 . : OR, I-50 :

HaN y E NH)pCO2R b ibromid ’ Avi ~p IpCOaRln 7 Rs or lihium chloride boron tribromide

JP —— : | or lithium chloride bo 1:4 Db

Buchwald amination ) N ve [(NH)pCO,Relq -

Pd(0) 4 1-51 boron tribromide OH : Base —— : or lithium chloride ] TT FF Rs

HO) E«_INHPCORla “OR,

Avil D boron tribromide _E.__[(NH)pCO.Relq 48 n Rs or lithium chloride oO N y” D rere J ~ | — Ra .

Buchwald arylati an 07 i othe PNNHipCoRela EE

Base Rs n : Compounds of Formula I wherein Q is taken from Q-14 are prepared according to the synthetic route shown in Scheme 10. Starting from readily available pyridine 54, alkylation under standard conditions (X;CQOj;, DMF, Ry4-I or Mitsunobu conditions employing R4-OH) yields pyridine derivative 55. N-alkylation with K;COs, DMF, Rs-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 reaction, giving I-59; or a Buchwald Cu(I) catalyzed O-arylation reaction, to give 1-60. The

Heck reaction product I-57 may be optionally hydrogenated to afford the saturated compound 1-58. Wherein Ry is methyl, compounds of formula I-57, 1-58, I-59, or I-60 are treated with boron tribromide or lithium chloride to afford compounds of Formula 1-61, wherein Ry is . hydrogen.

Scheme 10 -

OH OR,

OR,

RQ. KC

AN M Oar Fctome IN M _— : M —— | ovtordesne [ ] TIPS A pps TIPS yZ or Acetone © N Rs Dist azodiaonyate ~o N Rs TNT Rs 54 : 55 . Ry fre | OR ®

E-__-l(NH)p-CO2Rslq 3 4 . 7 0” 7 a A £- OS [(NH)p-COR ala Hydrogenation} n 2 R 56 x — Ff | E (NH)p-COzReld

Heck reaction ‘

Pd(0) °° KX Ro 57 0% ~N7 “Rs

Base 1-27 Rg “1-58

RG BB; or LiCl . f4 OF LA

FN Exp (NHIP-COF Hy Bop 107-00 ® Brg or LICH 56 — IL

Buchwald amination 0 N, Rs BB; or LiCl oH . . ‘Do :

HOw y Ew -I(NH)p-CORelq ~~ QR

AVA Owyy Ep INHIP-COREIA Br; or LiCl oR Fe n Z vw D 3 . ss > Lo _—

Buchwald arylation o > N Rs 61 . )

Base 4 1-60 :

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 sccoacids via TRS-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 dimethylamine affords the vinylogous carbamate 64. Formation of the dihydropyrimidinedione 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 R4OH to give rise to compounds 67. : :

Scheme 12 illustrates the further synthetic elaboration of intermediates 67. Removal 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 1-69. Alternatively, reaction of 68 with [R¢O,C(NH)plg-D-E-M, wherein M is a suitable leaving group, affords compounds of

Formula I-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, 4ldrichimica

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 : 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 © So 0 . O

Meerwin's | TBSO . 0] 0 2 Reagent Sone i PY PR . .

TBSO "s RaEIN™ NH Ra~ “OMe 63 Rs 65 : N” TNH

Dimethylamine n } 62 4A sieves reso PN one Rs ~ oo 64 Rs 66 o

R,OH SP 66 -_— diethyl azodicarboxylate ’ n : }

Rs ’ a

Scheme 12 :

SU

=) |=! Ra } NP NP osc ate D-ON=C-0 AY NH ————— eee J

UNAS NS a } .n n I xe

Fe [ReO:CNH)plg-D-E- 8 1-69 . 8 = 0 Oxidation

A fe) fe] [Re0:C-(NH)pla-D-C-NH, J : (ReOLCNHIPI-OE" VN NSN A " Ro ————————

OHC. . F— NH

Rs Hi WON Reductive umination (ReOCINHIPIG-D-E” NS

L70 n

Rs Rs kit ammonium acelute En (reductive amination) [o} [o]

PY [R¢02C-(NH)plg:D-C-N=C=0 NPN

Ry NH 2 l§ — © NH N xn

HN AS [Re02C NHIpla-D-E hi vf 0 . n 0 Rs .

Rs . n 174

Compounds of Formula I wherein Q is taken from Q-16 are prepared according to the synthetic routes shown in Schemes 13 and 14. Starting esters 75 are available from the corresponding secoacids via -TBS-ether and ester formation 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 urea 65 with azeotropic removal of dimethylamine or methanol. Dihydropyrimidinedione 78 : may optionally be further substituted by Mitsunobu reaction with alcohols R4OH to give rise . to compounds 79. Compounds of Formulae 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.

PCT/US2003/041449

Scheme 13 : ~o o o 0 Meerwin's © Rg N OMe Q fo)

Reagent PY ) co . . . - ) RHN NH, Ry A . - Rs © OMe 16850 u 65 : ~N NH } ) Dimethylami N(Me), O -_ ’

TBSO n : Libs A Rg N 0° © . 5 Rg OMe ) . ’ ’ ) . co TBSO n

TBSO n 1 8 - Oo :

R PR Ry

R4OH NN NT .

PhsP diethyl azodicarboxylate oe ’ . TBSO ), oC : 9 .

Scheme 14 . o . 0 0 PR SP ] . Ry Rs ,

Ril J Aa . ~n nN" {R¢O:C-(NH)p]q-D-EN=C=0 .

N N x . — 2 Rg” | 0 aN — O .

Rs Ny [&] Re ° ( —X . ( ( 1 NH-C-D-[(NH)pCOzRela 0188 [ReO:C-(NH)plg-D-E-M s0° OH n yi) . - rd | Oxidation 9 .

Ry BS Re 2 a ahd

Rex PR Ra JR [Re0;C-(NH)pl4-D-E-NH.

SN nN” AN No Re . 2 i ™ Reductive amination . :

Rs 0. RN 0 : . ( NH-C-O-{NHIpCOzRela ’ O-E-D-{{NH)pCO2Rglq ' . 8 n 83 2CHO . ] J ammonium acetate = AN N~ Ra . , } (reductive amination) o CS

Ry PY Rs [Re0:C-(NH)plg-D-E-N=C=0

Sw N 2 : ( "NH —_— > : j E———— } k Rs ow dg ( 1:86 :

NH, . . n } . ’ 8s -

oo 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 THF, followed by quench with formaldehyde and TBSCl (n = 1) or Q-(CH2)n-OTBS (n = 2-4), gives rise to . compounds 88. To x 5 . : Scheme 15 i 0 0] 0 0

J 1. NaHMDS, THF

Rg “OMe 3 Cryo quench so 8 or Q-(CH2)n-OTBS (

TOTBS

§,n>1 o ‘o : (forn=1) No

TEC ores pein tho : 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 : heterocycle 90. Oxidation with N,O4 in benzene (see Cardillo, Merlini and Boeri Gazz.

Chim. Ital., (1966) 9:8) to the nitromalonohydrazide 91 and further treatment with P,Os 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-BuOCHIN(Mey),, gives rise to 93, a which is subjected to ozonolysis, with a DMS and methanol workup, to afford the protected 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.

Scheme 16.1 " 0 . . NO, . 1 i .

BOC OTBS NOy . 7 NaCNBH,, CHiCN A :

RN—NH, —— > ~ 73 APINEING Ve oO © RyN—N © ReN—N } 13 H+ H go gg ~~ OTBS Notes . | t-BuO-CH(NMe),); P.0s : {Me)zN . MeO_ OMe o fo) oxonolysis a 0 ’ MeOH/DMS

RaN—N RaN—N 4 93 : 22 0 | CSF, THF

MeO. OMe 1) tosy! chloride, base 0 0 2) Nal MeQ_ OMe . R,N—N 3) hydrogenation

NH, N"oH [2

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 ketal with aqueous acid gives rise to compounds of Formula 1-98. By analogy, reaction of : 5 amine 95 with 26 under palladium(0) catalysis affords compounds of Formula I-97. Optional deprotection of the di-methyl ketal with aqueous acid gives rise to compounds of Formula I- 99. :

Scheme 162 : : yw MeO OMe HO OH

Meo. OMe [ReOC-NHPG-DE™ © o OF : : ° SF 26 HY, HO

R{N—N * Cu(T), base RINTN gr ED INHIRCOzRE AN E-D-(NHIpPCO2Rela

TNA

OH 196 1-98

AM MeO OMe Ho OH

MeO_ OMe [RgO2C-(NH)plq-D-E

RAN PAO base NTN yg BO TNHRCORAS RIN=N yr OE (NHIPCORela g C199 95 1:97 =

Compounds of Formula I wherein Q is taken from Q-17 are also prepared according to the synthetic route shown in Scheme 16.3. Deprotonation of 4 4-dimethyl-3,5-dioxo- '5 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) a. with NaH/DMF or NaH/DMF and its subsequent displacement of M, wherein Mis a suitable leaving group such as chloride, bromide or iodide yields I-99a.

Scheme 16.3 0 } 0) 0] HN cl . HN—NH ON [RgO2C-(NH)plg-D-E-Y”~ = [RgOC-(NH)plg-D-E-Y 8 95a 0 - 10 a © 1-99a

Compounds of Formula 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 amines 101 with carboxylic acids using an acid activating reagent such as dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOB?) affords intermediate amides 102. Cyclization of amides 102 to tetramic acids 104 is 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.

Scheme 17.1 : Re’

Ge 0 R.CHO 0 RsCH,CO,H 0 . . :

A BNL —_— PNP NG 4

B 5) or NaBH(O AC); M' DCC, HOBt . M' : 102 100 101 . Rs o Rg o oo Ces OH- H+, R40H : Ones © for —_— RO fo rrr J N Rs N Rs . Mm M . - 104 :

M' is t- BuOCH,-, BOCNH(CH,);-, =

BOCNH(CH,),-, HC=C-CHr 103 M is HOCH; HyN-(CHp)3-;

H,N-(CH,) HCE==C-Criz-.

Scheme 17.2 illustrates the synthetic sequences for converting intermediates 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 I-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. oo 10 Compounds 1-105.4 may optionally be reduced to the corresponding saturated analogs I- 105.5 by standard hydrogenation.

Scheme 17.2

R

0 . u Rs o ro-C 1. Re0LCNHPpI OE” rod

NR —_——————— No _ Rs ) on Cull) base ro E-D-INH)PCOZRelg 104.1 1-105.1

Rs o " Rs 0 E / {Rs02C-(NH)plg-D-E” 4 :

RO 26 RO N.__R

N Rs _—= 0 ~~ : (On PA), base ij—E-DANHIPCORela

NH; 1-105.2, n=3 104.2, n=3 105.3, n=4 } . ’ 1043, n=4 . [ReO2C-NH)plg-D-E~" Rs Ce ° 0 26 / Hydrogenation RO 4 / — RO —_— N Rs

RO No _Ry ~~

No _R, PdCl,(Ph,P),, Cul ~ ~ Base . . (Sonogashira Coupling) E-D{(NH)pCORelq a[ReO2CR(HN)}-D-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 amines R4NH, 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.

Amides I-110 may optionally be further reacted with DIC or EDC to give rise to compounds of Formula 1-111. Acid 108 is further reacted with amines 8 to give compounds of Formula - 1-109.

J

Scheme 18 : : 0 Ry © - : CO.H cop | DICorEDC Ho /° 0 DRNH; yo PON

HaC CHa le] 0 ’ ’ HiC CHs HaC CHa i o 2) DIC or EDC

H3C AaC ) [ReO2C-(NHJpla-D-§ ° Re 0O

RgO2C-(NH)plq-D-E } [RgO2C-(NH)plq “NH, HN—/ N 0 108 8 HaC CHa

DIC, HOAt : 1-109 HC ’ D- [ReO2C-(NH)pla-D-E 2 NH GOH pic or EDC Ho—y/ 8 CO, _— 0 107 — : HC CH, HaC CHa

CL aC iC

I-110 L111:

Compounds of Formula I wherein Q is taken from Q-22 or Q-23 are prepared as shown in Schemes 19.1 through 19.3. Preparation of intermediates 113 and 114 are prepared as shown in Scheme 19.1 from di-halo(hetero)aryls 112, wherein Mj; is a more robust leaving group than M;. Reaction of 112 with amines 37 (Z = NH) either thermally in the presence of

IE 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 the presence of base or by copper(I) catalysis in the presence of base affords compounds 114.

Scheme 19.1 . [RgO2C-(NH)pla-D-E-Y<_ SE . ZH

M, M, : wy ~~ 3,Z=NH wy

AS _ a 12 113 [Re02C-NHIPI-D-EY : Sw 37,2=0 Rg0,C-(NH)pla-D-E-Y. A) m2 EA [Re02C~( ~o PF : 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 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 to afford compound 117. ] :

Scheme 19:2 oo PY

Scheme 19: wo Sw [RgO2C-(NH)plg-D-E-Y<_ A :

H

. : aq CuO +~-BuSH excess NHs, or Cul, K,CO, base

KOH ethylene glycol

OH StBu bg

Sw Sw i Sw (ReOC-(NH)pla-D-E-Y, A [ReO2C-NHPIG-D-E-Y pg roc ompeoer, AJ

H H H

1-115 116 17 :

H*

A

: wo Sw reo mrpeoev AJ

H ! . : 1-118 oo Scheme 19.3 illustrates the conversion of intermediate 114 into compounds of

Formula I-119, 1-122, and 121, by analogy to the sequence described in Scheme 19.2. :

XL

AS .

Scheme 19.3 1 W

ReO2C-(NH)plg-D-E-Yo_ A or 114 .| aq CuO t-BuSH excess NH, : or Cul base :

KOH K,CO;4 ethylene glycol bid SiBu a a NH,

W Sw | wu Su roc nple nev AJ Re02C-(NH)plq-D-E-Y+_ A reosc-tplaniv NJ

L119 120 121 + .

Hen : wu

Rs02C-(NH)p]q-D-E-Y._ A : L122

Compounds of Formula I wherein q is taken from Q-24, Q-25, or Q-26 are prepared as shown in Scheme 20. Reaction of compounds I-115 or [-119 with chlorosulfonylisocyanate, followed by in situ reaction with amines HN(R4), gives rise to compounds of Formulae 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 I-126. Reaction of compounds 117 or 121 with chlorosulfonylisocyanate, followed by : in situ reaction with amines HN(Ry), or alcohols R4OH, affords compounds. of Formulae I- 127, 1-128, 1-129, or 1-130. :

Scheme 20

OH SH BY

Su ws w i Sw

Re0C-(NH)pla-D-E-Ys. A) | ROLCNHRGDEYS, A ReO2C-NH)PIG-DEYS, A ! 1-115,Z=NH 1-118,Z=NH . 117,Z=NH 1-119,2=0 1-122,Z=0 : 121,Z=0 ’ 1)-Chlorosulfonyl- 1) Chlorosulfonyl- isocyanate Perace ic acid isocyanate : 2) HN(R4), | 2)HN(Ry); or ROH 0 9 0 0 0 o , : N/

J SOgH Wo" : lo)

A ; 4 ww A Ry . ww Rg0;C-(NH)plq-D-E-Y. A hi ¥

ReOCANHIBI DEY A 602 pla ~z # ReOLC-NH)pIa-D-E-Y, AJ z 1-123, 2=NH 125, Z= I-27, Z=NH

I124,2=0 Js Z = AH oC -1-128,2=0 0 1 ) PN PP : wo No ws , reoscnrpeoev A J : 1-129, Z=NH : 1:130,Z2=0

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 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 = NH,) under Buchwald palladium-catalyzed amination conditions to give rise to compounds of Formula J-134. Alternatively, compounds 133 are reacted with alcohols 8 (Z = OH) under Buchwald copper(I) catalyzed conditions to afford compounds of

Formula 1-135. Alternatively, intermediates 133 are reacted with alkenes under : palladium(0)-catalyzed Heck reaction conditions to give compounds of Formula I-136. : Compounds 1-136 are optionally reduced to the corresponding saturated analogs 1-137 by standard hydrogenation conditions or by the action of diimide.

0

Scheme 21 CJ OO NS

CHO N peracid

JRE SY. EE a. —— . ) 0 NaBH(OAc), oxidation a d a 131 132 133 Va 0 : (3 =o [REOC-NHIPa DEY, ~~ 5 Rec NHple ER E

Pd(0), phosphine, Lo PhP, i base NN a 1-136 - [ReO,C-NH)pla-D-E-Y —NH ! : 1-134 . reduction (hydrogenation or o | diimide)

ReO,C-(NH)p]q-D-E-Y. : [ReO2C-(NH)plq on es °

NA J

B38 ($0

Cu(l), base A Nn [RsO,C-{NH)p|q-D-E-Y—C : oo oo LI3S o &

Compounds of Formula I wherein Q is taken from Q-27 are also prepared as illustrated in Scheme 21.1. Aldehyde 8c is reductively aminated with ammonia, and the _ resultant amine condensed with divinyl sulphone to yield I-134. Intermediate 134a is also available by reduction of amide 8d under a variety of standard conditions. :

Scheme 21.1 o :

Bw [ReOC-(NH)pPIG-D-E-Y”™ “H — . [RyO0,C-(NH)plg-D-E-Y” “NH,

NaCHBH gc ndiadh 134a

Amide reduction o. PO : i.e. LAH | Ng mn

X

[Rs02C-(NH)plga-D-E-Y” “NH, RaOC-NHIBIG D-EY NN 8d L_s=0 134 0

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. Co

Scheme 21.2 0) 0] . PY RyR,NH PS [RgO,C-(NH)plg-D-E-Y~ “OH ————— [Rg0,C-(NH)plg-D-EY” “NRiR; . DIC coupling ' ) 8e : 134b :

N

C ) Amide reduction 0 DIC coupling . i.e. LAH 1 ~

Rg02C-(NH)plg-D-E-Y™ - "NR4R [Re0,C-(NH)plg-D-E-Y NY [ReO: a bh :

Lo 134c. . 134d : :

Amide reduction : i.e. LAH : [RsO,C-(NH)Rla-D-E-Y”"N"™ 134e Lo

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 reacted with chlorosulfonylisocyanate to give intermediates 140, which are reacted in situ with amines HN(Ry); or alcohols R4OH to afford compounds of Formulae 1-141 or 1-142, - respectively. Alternatively, amides 138 are reacted with sulfonylchlorides to give compounds of Formula 1-139.

yo

H N.C :

Scheme 22 CONH, © I 8 ° HN(Ry), or » CISO,-N=C=0 R,OH : v yo base [ReO,C-(NH)plq-D-E~y/ - [Re02C-(NH)plg-D-E~—~ / - oo 138 140 . Ns ’ fa

H

H 0]

Ho No NR Ne Mall re Fo h Tee . . 0) [ReO,C-(NH)pla-D-E~ ,/ [Re02C-(NH)p)g-D-E~—/ : : 1-141 1-142

Re fo) HN—8=0 : : lo] :

RySO,Cl : . base 138 —_— [ReO,C-(NH)pla-D-E— / 1-139

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 HN(R4), or alcohols R¢OH to afford acids 144 or 145, respectively. Intermediates 144 or 145 are further reacted with amines HN(R4), in the presence of an acid-activating reagent, preferably PyBOP and di-isopropylethylamine, to give 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-

Cv isopropylethylamine to give compounds of Formula 1-153.

0 . Ox N(Ry)

Scheme 23 HO, ¢ yr 2RINGY Y 42 0 0 HNR N i N

XY Co (Re)z Boc 144 1) PyBOP, i-Pr,NEt goc 146 . . N or ROH o oR 2) HN(Ry), o oR

BOC HOC Y ® _ 2(R)NCO Y : : 143 “y 145 Ne 147 g : BOC BOC sc . 0 OR

Rl, base ROC Y 6 : Sw 148

BOC

. | HCI, dioxane

CO-X, lo} ( 7 2(RgNCO N(Rek oH | a Le 16 : To PyBOP, i-Pr,NEt : Ne 192

CO-Xz H 3

TT » ao 7 2(RINCO Y

Re02C-NH)pla-DE~ [R0ZC-(NHIPle-D-E—/ NY 1-153 - b 150 : 152

Xi, X; are N(Ry): OW ORs

X, 15 N(Ry)a, Xs 15 ORg : : had Y

Xn X, are OR : : N 151 : go

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 sulfenamides 154 with amines 37 (Z = NH), alcohols 37 (Z =-0), or alkenes 37 (Z = - - :

CH=CH,), gives rise to compounds of Formula [-155. Treatment of sulfenamides I-155 with : jodosobenzene in the presence of alcohols R¢OH gives rise to the sulfonimidates of Formula 1-157 (see D. Leca et al, Organic Letters (2002) 4:4093). Alternatively, compounds 1-135 (Z ~~ = .CH=CH) may be optionally reduced to the saturated analogs 1-156 (Z = CH,-CH;-), which are converted to the corresponding sulfonimidates 1-157.

Treatment of readily available sulfonylchlorides 154.1 with amines HN(R4)2 and base gives rise to compounds of Formula I-154.2.

Scheme 24 : [ReOzC-(NH)pla-D-E-Y 37,Z=NH :

Pd(0), phosphine, NH » base AV

CNL "ORs

SONH, : : =0 we’ ’ 2 [RO2C-(NH)plg-D-E-Y-_ ® PhI »

ZH _— 22-0 5 Reon [RgO2C-(NH)plq-D-E-Y—Z

M Cul), base IReOC-NHPla-D-E-Y—2Z 1-157 14 : L155 Phi=0 [ReO2C-(NHIPI- DEY | R¢OH,

MeCN 37, Z=CH=CH2

Pd(0), phosphine, os? } base : :

Z=CH=CH- (0 ’ Hydrogenation [ReQ2C-(NH)p]g-D-E-Y—(CHa)2 . 1-156

SO,NH, SON(Ry),

HN(R); es tee : [RgO2C-(NH)plg-D-E-Y [R602C-(NH)p]q-D-E-Y : 154.1 1-154.2 . © Compounds of Formula I wherein Q is taken from Q-33 are prepared as shown in

Scheme 25. Readily available nitriles 158 are reacted with amines 37 (Z = NH), alcohols 37 (Z=0), or alkenes 37 (Z = -CH=CH,) 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 I-160 with a metal azide (preferably sodium azide or zinc azide) gives rise to tetrazoles of Formula 1-161.

So Scheme 25 : ‘ [ReOZC-NHIpIa DEY : a. vw, Pd(0), phosphine, Ng \H vo base

CN

: CN MN; “ ‘ [ReO2C-(NHIpIa-D-EY EE : - 7 > 37,2=0 y; [Re02C-(NH)plq-D-E-Y—Z ——————— » [RgO2C-(NH)p]q-D-E-Y—Z :

M Cu(l), base L159 1-161 158 A ’ ’ MN; [ReOoC-(NHIplrD-EY_ : 37,Z = CH=CH2 a : CN

Pd(0), phosphine, : Z = CH=CH- } base Hydrogenation [Rg02C-(NH)p]g-D-E-Y—(CHz) 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 (Z=0), or alkenes 37 (Z = -CH=CHa) 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 bromides with a tri-alkylphosphite. Optionally, phosphonates 1-165 are converted to the flourinated analogs I-166 by treatment with diethylaminosulfur trifluoride (DAST).

: COZRg

Z=CH=CH- ) )

Scheme 26 (0 } >

Hydrogenation [RsO,C-(NH)pJg-D-E-Y—(CHa) . ROCNHPIED-EY L164 . 37, Z=NH 1) reduction to alcohol , —_— (LiBH,) ~ Paco), phosphine, 2) CBr, PhsP - we 3) PORs)s

COZRg : ORs . COsRg 1) reduction to alcohol ENV [RgO2C-(NH)plq-D-E-Y_ (LiBHy) P—ORg 31,z=0 HM —_— —— ee / / [RgO2C-(NH)p]g-D-E-Y—2Z 2) CBry, PhyP .

M Cu(I), base : 3) P(ORg)s 162 7 20s 1-163 [RgO2C-(NH)plg-D-E-Y—Z

ReO:C-NH)PIG-DE-Y. 1165 37,2=CH=CH2 —_— DAST

Pd(0), phosphine, base ’ OR : ° .

F Sore [Re02C-(NH)plg-D-E-Y—2 1-166

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) to afford the N-acyl + oxazolidinones of Formula 1-169. Compounds I-169 (wherein Z is -CH=CH-) are optionally converted to the saturated analogs I-170 under standard hydrogenation conditions.

Scheme 27 [Rs02C-(NH)plg-D-E-Yo H 37,Z=NH . .

Pd(0), phosphine, Co Q 0 . - 0 Q base a : : J 9 o. N_/ 1 coc VI ~ [RgO2C-(NH)plg-D-E-Y- . R, gal PIQ-U-E=T( » Rs i ) 37,Z=0 ZH oo > y; base ; _ Cu(l), base [ReO2C-(NH)pla-D-E-Y—2Z

M M SC

167 168 [ReO2C-(NH)pIa-D-E-Y_ | } 37,Z= CH=CH, hydrogenation

DEE —— . 7 = CH=C

P4(0), phosphine, ( 0 base . ) lo} . ha

Rs : [RO2C-(NH)p]q-D-E-Y —(CHa), 1-170

Compounds of Formula I wherein Q is taken from Q-35 are also prepared as illustrated in Scheme 27.1. 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 I-165. oo

Scheme 27.1

O

M1. POEL kor [RgO2C-(NH)plg-D-E-Y : Ja . [Re02C-(NH)pIq-D-E-Y™ \y 8a 2. saponification 1-165 _

Compounds of Formula 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 = 0), or alkenes 37 (Z = CH=CH.) to give compounds 172, 173, or 174, respectively. Optionally, intermediates 174 are converted to the saturated analogs 175 under standard hydrogenation conditions.

\ \ : cio ste NM seu : . Scheme 28.1 ) a — : . NaBH(OAc), :

M M fs 131 1m

NN

[R02C-(NH)plq-D-E-Y~, NN sve 171 wz=-Nnn 2H \—/ \—St-Bu 37,Z=CH=CH, pn —— mw —

Pd(0), phosphine, [> PA(0), phosphine, fo 174 ’ base [F base } [ReO2C-(NH)pJg-D-E-Y—NH 112 [ReOzC~(NH)p]q-D-E-Y reduction (hydrogenation or ] Ny \ diimide) : \_/ \—StBu [Re0;C-(NH)plq-D-E-Y ™\

ZH mn LZ=0 NN sem

Cu(), base [Re02C-(NH)pjq-D-E-Y—0 13 [Rg02C-(NH)p]a-D-E-Y : :

Scheme 28.2 illustrates the conversion of intermediate t-butylsulfides 172-175 to the 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 Formula I-176.

Scheme 28.2 — /\ N N

N N : w= / \—stBu NH SOs ’ : aS

AN SA

1 Ca (A

LP 2) peracid oxidation [RgO2C-(NH)p)q-D-E-Y—Z . [ReO2C-(NH)plq-D-E-Y—Z oe I 172-175 1-176

Z=NH, O, CH=CH, CH2-CH2 .

In some instances a hybrid p38-alpha kinase inhibitor is prepared which also contains an ATP-pocket binding moiety or an allosteric pocket binding moiety R;-X-A. The synthesis of functionalized intermediates of formula R;-X-A are accomplished as shown in be 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 ‘0) are reacted thermally with 177 in 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 Rg 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 Rg is t-butyl. }

Scheme 29

Ry—XH

M-A-(NH)p-CORs 178 _ RyX—=A-(NH)p-COzRs ’ heat or : 177 Pd(0) catalysis 179 . : RiX=A-NH R4X—A-CO,H oo 180 181.

B

Another sequence for preparing amines 180 is illustrated in Scheme 30. Reaction of amines or alcohols 178 with nitro(hetero)arenes 182 wherein M is a leaving 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. 71 oo

Scheme 30 : 178 reduction } ’

M-A-NO, — RiX—A-NO, | 'RX-A-NH, - - heat or 183 182 Pd(0) catalysis - 180

In instances when hybrid p38-alpha 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, 16.2,17.2,18,19.1,19.2,19.3, 20, 21, 22, 23, 24, 25, 26, 27, or 28.2.

Scheme 31 }

CL arEa, AQ ~~ [ReO2C-(NH)p]a-D Y q=1 1-184

H* 4 NT - E ~ Q

HoN-D~ Ey 8 HOL,C-D Y 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 a 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 Formula I which contain an amide linkage —CO-NH- connecting the oxyanion pocket binding moieties and R;-X-A moieties are shown in 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, . 15 retroamides of Formula I are formed by treatment of acids I-186 with PyBOP in the presence of di-iso-propylethylamine and amines 180.

Scheme 32

E Q X—A | oo | 7 : R4X—A-CO,H : : . ) HoN-D~ = Sy” 1 2 PyBop, i-Pr,NEt J Cy

Lt r=” nPop a

H

’ Compounds I-185 taken Compounds 181 taken - : from scheme 31 from scheme 29 Amides of Formula 1 } (hybrid inhibitors, possessing oxyanion ’ pocket-binding moiety Q and moiety R;-X-A)

RyX—A-NH 7

SE AQ 1 —A- 2 J -

HO,C-D Y + PyBop, i-Pr,NEt RX—A-NH py 2 ——————————

Compounds 1-186 taken Compounds 180 taken from from scheme 31 schemes 29 or 30 RetroamideFormulal = - (hybrid inhibitors, possessing oxyanion pocket-binding moiety Q and moiety Ry-X-A)

The preparation of inhibitors of Formula I which contain an urea linkage NH-CO- ‘ ~ NH- connecting the oxyanion pocket binding moieties and the R;-X-A moieties are shown in

Scheme 33. Treatment of amines I-185 with p-nitrophenyl chloroformate and base affords carbamates 187. Reaction of 187 with amines 180 gives ureas of Formula I.

Scheme 33

EE. _Q -nitrophenyl chioroformat Ry X—A-NH

HN Sy PTOPIey coro 0 HN Eny 2 CARA base or 0 Compounds 180 taken from

Compounds I-18S taken O,N ’ "schemes 29 or 30 from scheme 31 - 187 ’ oo .

A PS : } Ry ~x~'SN N-D~g-a .

H H :

Formula . . (hybrid inhibitors, possessing oxyanion - pocket-binding moiety Q and moiety R|-X-A) : . 10 :

Alternatively, inhibitors of Formula I which contain an urea linkage NH-CO-NH- connecting the oxyanion pocket binding moieties and the R;-X-A moieties are. prepared as.

shown in Scheme 33. Treatment of amines 180 with p-nitrophenyl chloroformate and base affords carbamates 188. Reaction of 188 with amines 1-185 gives ureas of Formula L . : Scheme 34 : :

Ry X—A-NH | AEA . : A 2 p-nitrophenyl chloroformate . 0. HN. _X H,N-D Y . ——————— PAR PENSS—————————

Compounds 180 taken from b ’ ' hig a Ry schemes 29 or 30 ase 0] Compounds 1-185 taken

ON from scheme 31 188 0 :

Rig AayyPog a

H H : : Formula I (hybrid inhibitors, possessing oxyanion : . pocket-binding moiety Q and moiety R;-X-A) ’

AFFINITY AND BIOLOGICAL ASSESSMENT

OF P38-ALPHA KINASE INHIBITORS :

A fluorescence binding assay is used to detect binding of inhibitors of Formula I with unphosphorylated. p38-alpha kinase as previously described: see J. Regan et al, Journal of - Medicinal Chemisiry (2002) 45.2594. 1. P38 MAP kinase binding assay

The binding affinities of small molecule modulators for p38 MAP kinase were } determined using a competition assay with SKF 86002 as a fluorescent probe, modified based on published methods (C. Pargellis, et al Nature Structural Biology (2002) 9, 268-272. J.

Regan, et al J. Med. Chem. (2002) 45, 2994-3008). Briefly, SKF 86002, a potent inhibitor of p38 kinase (Ka = 180 nM), displays an emission fluorescence around 420 nm when excitated : ~~ 20 at 340 nm upon its binding to the kinase. Thus, the binding affinity of an inhibitor for p38 kinase can be measured by its ‘ability to decrease the fluorescence from SKF 86002. The . assay was performed in a 384 plate (Greiner uclear 384 plate) on a Polarstar Optima plate _ reader (BMG). Typically, the reaction mixture contained 1 pM SKF 86002, 80 nM p38 kinase and various concentrations of an inhibitor in 20 mM Bis-Tris Propane buffer, pH 7,

containing 0.15 % (w/v) n-octylglucoside and 2 mM EDTA in a final volume of 65 ul. The reaction was initiated by addition of the enzyme. The plate was incubated at room temperature (~ 25 °C) for 2 hours before reading at emission of 420 nm and excitation at 340 ) nm. By comparison of rfu (relative fluorescence unit) values with that of a control (in the absence of an inhibitor), the percentage of inhibition at each concentration of the inhibitor was calculated. ICs, value for the inhibitor was calculated from the % inhibition values obtained at a range of concentrations of the inhibitor using Prism. When time-dependent inhibition was assessed, the plate was read at multiple reaction times such as 0.5, 1,2, 3, 4 and 6 hours. The ICs, values were calculated at the each time point. An inhibition was : assigned as time-dependent if the ICso values decrease with the reaction time (more than two- : fold in four hours). :

IC50, nM 1 | 22 | Yes [a2 [mr | No 8s. |e | ves 9 | ®® | No 2800 ii 2153 No ~ 10000 : —10000_ | No | : : 22 | ees [No 2% | es | Yes 31

Yes

46 1741 No a7 | 2458 3300 | No ’ IC50 values obtained at 2 hours reaction time ) - Biological assessment of p38-alpha kinase inhibitors of Formula I is performed in 2

THP-1 cell assay, measuring inhibition of LPS-stimulated TNF-alpha production. See see J.

Regan et al, Journal of Medicinal Chemistry (2002) 45:2994.

EXAMPLES | oo

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 nothing therein should be taken as a limitation upon the overall scope of the invention. . 5 : [Boc-sulfamide] aminoester (Reagent AA), 1,5,7,-trimethyl-2,4-dioxo-3-aza- bicyclo[3.3.1]nonane-7-carboxylic acid (Reagent BB), and Kemp acid anhydride (Reagent CC) was prepared according to literature procedures. See Askew et. al J. Am. Chem. Soc. 1989, 111, . 1082 for further details.

EXAMPLE A : “A 3. NH, oo Ne

To a solution (200 mL) of m-amino benzoic acid (200 g, 1.46 mol) in concentrated HCI was added an aqueous solution (250 mL) of NaNO, (102 g, 1.46 mol) at 0 °C. The reaction mixture was stirred for 1 h and a solution of SnCl,*2H,0 (662 g, 2.92 mol) in concentrated HCI (2 L) was then added at 0 °C, and the reaction stirred for an additional 2h at RT. The precipitate was filtered and washed with ethanol and ether to yield 3-hydrazino-benzoic acid hydrochloride as a white solid. :

The crude material from the previous reaction (200 g, 1.06 mol) and 4,4-dimethyl-3-oxo- . pentanenitrile (146 g, 1.167 mol) in ethanol (2 L) were heated to reflux overnight. The reaction solution was evaporated in vacuo and the residue purified by column chromatography to yield ethyl 3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (Example A, 116 g, 40%) as a white solid to gether with 3-(5-amino-3-terz-butyl-1H-pyrazol-1-yl)benzoic acid (93 g, 36%). "HNMR (DMSO-d): 8.09 (s, 1H), 8.05 (brd, J=8.0 Hz, 1H), 7.87 (brd, J= 8.0 Hz, 1H), 7.71 (t, J=8.0

Hz, 1H), 5.64 (s, 1H), 4.35 (q, J= 7.2 Hz, 2H), 1.34 (t, /J= 7.2 Hz, 3H), 1.28 &, oH). “ 5 EXAMPLE B : 0 . +h LA

N

‘NT ONT ONT J

H H

= Et0,C Co

To a solution of 1-naphthyl isocyanate (9.42 g, 55.7 mmol) and pyridine (44 mL)in THF (100 mL) was added a solution of Example A (8.0 g, 27.9 mmol) in THF (200 mL) at 0°C. The mixture was stirred at RT for 1h, heated until all solids were dissolved, stirred at RT for an additional 3h and quenched with H,0 (200 mL). The precipitate was filtered, washed with dilute

HCl and H,0, and dried in vacuo to yield ethyl 3-[3-z-butyl-5-(3-naphthalen-1-ylureido)-1H- pyrazol-1-ylJbenzoate(12.0 g, 95%) as a white power. '"H NMR (DMSO-d;): 9.00 (s, 1 H), 8.83 (s,1 H),825 7.42 (m, 11 H), 6.42 (s, 1 H), 4.30 (q, J=7.2 Hz, 2 H), 1.26 (s, 9 H), 1.06 (t, J= + 7.2 Hz, 3 H); MS (ESI) m/z: 457.10 (M+H"). :

: EXAMPLE C

SSUES

Co BNW

H H

. E0.C :

To a solution of Example A (10.7 g, 70.0 mmol) in a mixture of pyridine (56 mL) and

THF (30 mL) was added a solution of 4-nitrophenyl 4-chlorophenylcarbamate (10 g, 34.8 mmol) in THF (150 mL) at 0 °C. The mixture was stirred at RT for 1 h and heated until all solids were © dissolved, and stirred at RT for an additional 3 h. H,0 (200 mL) and CH,Cl, (200 mL) were a added, the aqueous phase separated and extracted with CH,CI, (2 x 100 mL). The combined organic layers were washed with 1N NaOH, and 0.1N HC, saturated brine and dried over anhydrous Na,SO,. The solvent was removed in vacuo to yield ethyl 3-{3-tert-butyl-5-[3-(4- : chlorophenyl)ureido]-1H-pyrazol-1-yi}benzoate (8.0g, 52%). "H NMR (DMSO- dg): 8 9.11 (s, : 1H), 8.47 (s, 1H), 8.06 (m, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.65 (dd, J : =8.0,7.6 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.30 (d, J= 8.8 Hz, 2H), 6.34 (s, 1H), 4.30 (q, J = 6.8 Hz 2H), 1.27 (s, 9H), 1.25 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 441 (M™+H). oo EXAMPLE D | oo “n o. {NAAR } H H a } | HO

To a stirred solution of Example B (8.20 g, 18.0 mmol) in THF (500 mL) was added

LiAlH, powder (2.66 g, 70.0 mmol) at -10 °C under N,. The mixture was stirred for 2 h at RT and excess LiAIH, destroyed by slow addition of ice. The reaction mixture was acidified to pH = 7 with dilute HC}, concentrated in vacuo and the residue extracted with EtOAc. The combined organic layers were concentrated in vacuo to yield 1-{3-tert-butyl-1-[3-(hydroxymethyl)phenyl]- 1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (7.40 g, 99%) as a white powder. 'H NMR (DMSO- . 5 dg): 9.19 (s, 1 H), 9.04 (s, 1 H), 8.80 (s, 1 H), 8.26-7.35 (m, 11 H), 6.41'(s, 1 H), 4.60 (s, 2 H), 1.28 (s, 9 H); MS (ESI) m/z: 415 (M+H"). : .

EXAMPLE E

N

PN

H H

Cl

A solution of Example C (1.66 g, 4.0 mmol) and SOCI, (0.60 mL, 8.0 mmol) in CH;Cl (100 mL) was refluxed for 3 h and concentrated in vacuo to yield 1- {3-tert-butyl-1-[3- chloromethyl)phenyl}-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (1.68 g, 97%) was obtained as white powder. '"H NMR (DMSO-d6): 6 9.26 (s, 1 H), 9.15 (s, 1 H), 8.42 - 7.41 (m, 11 H), 6.40 (s, 1 H), 4.85 (s, 2 H), 1.28 (s, 9 H). MS (ESI) m/z: 433 (M+H?"). 80 2 :

EXAMPLE

AAT h 5 New AN

H H

- HO -

To a stirred solution of Example C (1.60 g, 3.63 mmol) in THF (200 mL) was added

LiAIH, powder (413 mg, 10.9 mmol) at -10 °C under N,. The mixture was stirred for 2h and excess LiAIH, was quenched by adding ice. The solution was acidified to pH = 7 with dilute :

HCL. Solvents were slowly removed and the solid was filtered and washed with EtOAc (200 + : 100 mL). The filtrate was concentrated to yield 1-{3-tert-butyl-1-[3-hydroxymethyl)phenyl}- 1H-pyrazol-5-yl} -3-(4-chlorophenyl)urea (1.40 g, 97%). "TH NMR (DMSO- d): § 9.11 (s, 1H), 8.47 (s, 1H), 7.47-7.27 (m, 8H), 6.35 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 1.26 (s, 9H); MS (ESD) m/z: 399 (M+H").

EXAMPLEG o Cl su Nel

NN

H H :

Ne : : 25 . A solution of Example F (800 mg, 2.0 mmol) and SOC], (0.30 mL, 4 mmol) in CHCl, (30 mL) was refluxed gently for 3h. The solvent was evaporated in-vacuo and the residue was ) taken up to in CH,Cl, (2 x 20 mL). After removal of the solvent, 1-{3-tert-butyl-1-[3- (chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea (812 mg, 97%) was obtained as white powder. "HNMR (DMSO-d): § 9.57 (s, 1H), 8.75 (s, 1H), 7.63 (s, 1H), 7.50 - 7.26 (m,

7H), 6.35 (s, 1H), 4.83 (s, 2H), 1.27 (5s, 9H); MS (ESD mv/z: 417 (M+H"). } EXAMPLE H

Nn NHs

Na OO

To a suspension of LIAIH, (5.28 g, 139.2 mmol) in THF (1000 mL) was added Example

A (20.0 g, 69.6 mmol) in portions at 0 °C under N,. The reaction mixture was stirred for 5 h, quenched with 1 N HCI at 0 °C and the precipitate was filtered, washed by EtOAc and the filtrate evaporated to yield [3-(5-amino-3-tert-butyl-1 H-pyrazol-1-yl)phenyljmethanol (15.2 g, 89%). 'H NMR (DMSO-d,): 7.49 (s, 1H), 7.37 (m, 2H), 7.19 (d, J = 7.2 Hz, 1H), 5.35 (s, 1H), 5.25 +15 (t, J =5.6 Hz, 1H), 5.14 (s, 2H), 4.53 (d, J = 5.6 Hz, 2H), 1.19 (s, 9H); MS (ESI) m/z: 246.19 (M+HY).

The crude material from the previous reaction (5.0 g, 20.4 mmol) was dissolved in dry

THF (50 mL) and SOC, (4.85 g, 40.8 mmol), stirred for 2h at RT, concentrated in vacuo to yield i 3-tert-butyl-1-(3-chloromethylphenyl)-1H-pyrazol-5-amine (5.4 g), which was added to N, (3.93 g, 60.5 mmol) in DMF (50 mL). The reaction mixture was heated at 30 °C for 2 h, poured inte

H,O (50 mL), and extracted with CH,Cl,. The organic layers were combined, dried overMgSQO,, and concentrated in vacuo to yield crude 3-tert-butyl-1-[3-(azidomethyl)phenyl]-1 H-pyrazol-5- amine (1.50 g, 5.55 mmol).

EXAMPLEI -

Co VOGAL

H2N Je

Example H was dissolved in dry THF (10 mL) and added a THF solution (10 mL) of 1- isocyano naphthalene (1.13 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3h, quenched with H,O (30 mL), the resulting precipitate filtered and washed with INHCl and ether to yield 1-[2-(3-azidomethyl-phenyl)-5 -t-butyl-2H-pyrazol-3-yl}- 3-naphthalen-1-yl-urea (2.4 g, 98%) as a white solid. :

The crude material from the previous reaction and Pd/C (0.4 g) in THF (30 mL) was : 15 hydrogenated under 1 atm at RT for 2 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo to yield 1- {3-tert-butyl-1-[3-(amonomethyl)phenyl}-1 H-pyrazol-5yl)-3- (naphthalene-1-yl)urea (2.2 g, 96%) as a yellow solid. 'H NMR (DMSO-d): 9.02 (s, 1H), 7.91 (d,J=7.2 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.67-7.33 (m, 9H), 6.40 (s, 1H), 3.81 (s, 2H), 1.27 (s, 9H); MS (ESI) m/z: 414 (M+H?*). | : - © EXAMPLE] : 7 \ lr

Noy Ay .

H H : : We

To a solution of Example H (1.50 g, 5.55 mmol) in dry THF (10 mL) was added a THF . 30 solution (10 mL) of 4-chlorophenyl isocyanate (1.02 g, 6.66 mmol) and pyridine (5.27 g, 66.6 mmol) at RT. The reaction mixture was stirred for 3 h and then H,0 (30 mL) was added. The precipitate was filtered and washed with 1N HCI and ether to give 1-{3-tert-butyl-1-[3.

- (amonomethyl)phenyl} -1H-pyrazol-5yl)-3-(4-chlorophenyl)urea (2.28 g, 97%) as a white solid, which was used for-next step without further purification. MS (ESI) m/z: 424 (M+H"). :

EXAMPLE K o 4 © ~ NG : H H : :

To a solution of benzyl amine (16.5g, 154 mmol) and ethyl bromoacetate (51.5g, 308 mmol) in ethanol (500 mL) was added K,CO, (127.5g, 924 mmol). The mixture was stirred at : RT for 3h, was filtered, washed with EtOH, concentrated in vacuo and chromatographed to yield

N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (29g, 67%). '"H NMR (CDCl): 87.39-7.23 (m, 5H), 4.16 (q, /= "7.2 Hz, 4H), 3.91(s, 2H), 3.54 (s, 4H), 1.26 (t,J= 7.2 Hz, 6H);

MS (ESI): m/e: 280 (M'+H). :

A solution of N-(2-ethoxy-2-oxoethyl)-N-(phenylmethyl)-glycine ethyl ester (7.70g, 27.6 : mmol) in methylamine alcohol solution (25-30%, 50 mL) was heated to 50°C in a sealed tube for 3h, cooled fo RT and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-N- (phenylmethyl)-glycine methylamide in quantitative yield (7.63g). 'H NMR (CDCl): § 7.35- 7.28 (m, 5H), 6.75 (br s, 2H), 3.71(s, 2H), 3.20 (s, 4H), 2.81 (d, /= 5.6 Hz, 6H); MS (ESI) m/e 250(M+H"). _

The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15g). The mixture was stirred and heated to 40°C under 40 psi H, for 10h, filtered and concentrated in vacuo to yield N-(2- methylamino-2-oxoethyl)-glycine methylamide in quantitative yield (1.76g). "HNMR (CDCL,): § 6.95(br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25(br s 1H); MS (ESI) m/e 160(M-+H")

EXAMPLE 1. : : : 0

RsS¥el oo

N Se ig

To asolution of 1-methyl-[1,2,4]triazolidine-3, 5-dione (188 mg, 16.4 mmol) and sodium hydride (20 mg, 0.52 mmol) in DMSO (1 mL) was added Example E (86 mg, 0.2 mmol). The : reaction was stirred at RT overnight, quenched with H,O (10 mL), extracted with CH,Cl,, and the organic layer was separated, washed with brine, dried over Na,SO, and concentrated in vacuo. The residue was purified by preparative HPLC to yield 1-(3-tert-butyl-1-{3-[(1-methyl- 3,5-dioxo-1,2,4-triazolidin-4-yl)methyl]phenyl}-1H-pyrazol-5 _y1)-3-(naphthalene- 1-ylurea (Example 1, 14 mg). "HNMR (CD,OD): §7.88-7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, SH), 6.49 (s, 1H), 4.85 (s, 1H), 1.34 (s, 9H), 1.27 (s, 6H); MS (ESI) m/z: 525 (MHD). :

EXAMPLE 2

A JT

. N : : : | “ Wo

Oo

N— : / mn rr N ge

O

The title compound was synthesized in a manner analogous to Example 1, utilizing

Example G to yield 1-(3-tert-butyl-1-{3-[(1-methyl-3 ,5-dioxo-1,2,4-triazolidin-4- yl)methyl]phenyl} -1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea 'H NMR (CD,0D): 6 7.2~7.5 (m, 7H), 6.40 (s 1H), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1H), 1.50 (m, 1H), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 M+HY. : EXAMPLE 3 : { ~__-Cl

[0] ~~

N JQ A gl

N N N

H H

H H )

Ch ~N N

MN T

:

A mixture of compound 1,1-Dioxo-[1 ,2,5]thiadiazolidin-3-one (94 mg, 0.69 mmol) and

NaH (5.5 mg, 0.23 mmol) in THF (2 mL) was stirred at-10 °C under N, for 1h until all NaH was ’ dissolved. Example E (100 mg, 0.23 mmol) was added and the reaction was allowed to stir at RT overnight, quenched with H,0, and extracted with CH,Cl,. The combined organic layers were } 30 concentrated in vacuo and the residue was purified by preparative HPLC to yield 1-(3-tert-butyl- 1-{[3-(1,1,3 -trioxo-[1,2,5]thiadiazolidin-2-yl)methyl]phenyl} -1H-pyrazol-5-yl)-3-(naphthalen-1- yDurea (18 mg) as a white powder. "HNMR (CD,OD): 57.71 - 7.44 (m, 11 H), 6.45 (s, 1 H),

4.83 (s,2 H), 4.00 (s, 2 H), 1.30 (s, 9 H). MS (ESD m/z: 533.40 (M-+HY). . EXAMPLE 4 . 5 “ 0 cl ny 3 ’ N “ SN. 0 H H : | Mg NI 2) do” So

The title compound was obtained in a manner analogous to Example 3 utilizing Example

G. to yield 1-(3-tert-butyl-1- {[3-(1,1,3-trioxo-[1,2,5]thiadiazolidin-2-ylmethyl phenyl} -15- pyrazol-5-yl)-3-(4-chlorophenyl)urea. IH NMR (CD,0D): 8 7.38 - 7.24 (m, 8 H), 6.42 (s, 1 H), 4.83 (s, 2 H), 4.02 (s, 2H), 1.34 (5, 9 H); MS (EST) m/z: 517 (M+HY).

EXAMPLE 5

N N o sl

NAT

38

H H .

Qs a

T > :

To a stirred solution of chlorosulfonyl isocyanate (19.8 pL, 0.227 mmol) in CH,Cl, (0.5 : mL) at 0°C was added pyirolidine (18.8 pL, 0.227 mmol) at such a rate that the reaction solution temperature did not rise above 5°C. After stirring for 1.5 h, a solution of Example J (97.3 mg, © 0.25 mmol) and Et;N (95 pL, 0.678 mmol) in CH,C}, (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 °C. When the addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10%

HC], extracted with CH,Cl,, the organic layer washed with saturated NaCl, dried over MgSO,, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC . to yield l1-(3-tert-butyl-1-[[3-N-J[(1- pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4- so 5 chlorophenyl)urea. 'H NMR(CD,0D): 6 7.61 (s, 1 H), 7.43 -7.47 (m, 3 H), 7.23 - 7.25 (dd, J =6.8 Hz, 2 H), 7.44 (dd, J=6.8 Hz, 2 H), 6.52 (s, 1 H), 4.05 (s, 2 H), 3.02 (mn, 4 H), 1.75 (m, 4

H), 1.34 (s, 9 H); MS (ESI) m/z: 574.00 (M+H").

EXAMPLE 6 : 0 “h J . N N N ae

T 5%

The title compound was made in a manner analogous to Example 5 utilizing Example I to yield 1-(3-tert-butyl-1-[[3-N-[[(1-pyrrolidinylcarbonyl)amino]sulphonyl]aminomethyl]- phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yDurea. "HNMR (CDCL): 8 7.88 (m, 2 H), 7.02 - 7.39 (m, 2 H), 7.43 - 7.50 (m, 7 H), 6.48 (s, 1 H), 4.45 (5, 1 H), 3.32 3.36 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.34 (s,9 H); MS (ESD) m/z: 590.03 (M+H").

EXAMPLE 7 :

Ny AN A

H H

. H H

Ch _N__N

FY

To a stirred solution of chlorosulfonyl isocyanate (19.8 pA, 0.227 ppoA) w XHyXhy (0.5 pA) az 0°C, was added Example J (97.3 mg, 0.25 mmol) at such a rate that the reaction ’ solution temperature did not rise above 5 °C. After being stirred for 1.5 h, a solution of

N pyrrolidine (18.8 pL, 0.227 mmol) and Et,N (95 pL, 0.678 mmol) in CH,Cl, (1.5 mL) was added at such a rate that the reaction temperature didn rise above 5 °C. When addition was completed, the reaction solution was warmed to RT and stirred overnight. The reaction mixture was poured into 10% HCI, extracted with CH,CL, the organic layer was washed with saturated NaCl, dried : - over Mg,SO,, and filtered. After removal of the solvents, the crude product was purified by preparative HPLC to | yield 1-(3-rert-butyl- 1-[[3-N-[[(1- pyrrolidinylsulphonyl)amino]carbonyl]aminomethyl]phenyl]-1H-pyrazol-5-yl)-3-(4- } chlorophenyljurea. "HNMR (CDCl): 6 7.38 (m, 1H), 7.36 - 7.42 (m, 3 H), 7.23 (d, J=8.8 Hz, 2H), 7.40 (d, J= 8.8 Hz, 2 H), 6.43 (s, 1 H), 4.59 (s, 1 H), 4.43 (s, 2 H), 1.81 (s, 2 H), 1.33 (s, a. 9H); MS (ESD) m/z: 574.10 (M+H). :

EXAMPLE 8 : oo N 0 hao

NUNN 1§ § SUNS i NL - | ' ) 25%

FY

: The title compound was made in a manner analogous to Example 7 utilizing Example I to yield 1-(3-tert-butyl-1-[[3-N-{[(1-pyrrolidinylsulphonyl)amino]carbonylJaminomethyl}- oo ~ phenyl]-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea. "HNMR (CDCl,): & 7.88 (m, 2 H), 7.02 - 7.39 (m, 2H), 7.43 - 7.50 (m, 7 H), 6.48 (s, 1 H), 4.45 (s, 1 H), 3.32 - 3.36 (m, 4 H), 1.77 - 1.81 (m, 4 H), 1.34 (s,9 H); MS (ESI) m/z: 590.03 (M+H"). :

EXAMPLE 9

“nL 3 . N

SARS

. 5 Q 0 NH

O .

To asolution of Reagent BB (36 mg, 0.15 mmol), Example 1(62 mg, 0.15 mmol), HOBt (40 mg, 0.4 mmol) and NMM (0.1 mL, 0.9 mmol) in DMF (10 mL) was added EDCI (58 mg, 0.3 mmol). After being stirred overnight, the mixture was poured into water (15 mL) and extracted with EtOAc (3 5 mL). The organic layers were combined, washed with brine, dried with Na,SO,, and concentrated in vacuo. The residue was purified by preparative TLC to yield 1,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]nonane-7-carboxylic acid 3-[3-t-butyl-5-(3- naphthalen-1-yl-ureido)-pyrazol-1-yl]benzylamide (22 mg). "HNMR (CDCl): 6 8.40 (s, 1H), 8.14 (d,J=8.0 Hz, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.86 (d, J=17.2Hz, 1H),7.78 (d,J="7.6 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.57-7.40 (m, 4H), 7.34 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.32 (t, J= "5.6 Hz, 1H), 5.92 (brs, 1H), 4.31 (d, J=5.6 Hz, 2H), 2.37 (d, J = 14.8 Hz, 2H), 1.80 (d, J= 13.2 Hz, 1H), 1.35 (s. 9H), 1.21 (d, J= 13.2 Hz, 1H), 1.15 (s, 3H), 1.12 (d, J= 12.8 Hz, 2H), 1.04 (s, 6); MS (ESD) m/z: 635 (M+H". oo

EXAMPLE 10

Cs ; 0. Cl

N_ \ EN

N N

H H

. NH 0, ) TE - 15 - The title compound, was synthesized in a manner analogous to Example 9 utilizing

Example] to yield 1,5,7-trimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1Jnonane-7-carboxylic acid 3- {3- t-butyl-5-[3-(4-chloro-phenyl)-ureido]-pyrazol-1-yl}benzylamide. '"H NMR (CDCl): 5 8.48 (s, 1H), 7.78 (s, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.69 (s, 1H), 7.53 (t,/= 8.0 Hz, 1H), 7.48 (d, J= 8.8

Hz, 2H), 7.26 (m, 3H), 6.62 (s, 1H), 6.35(t, J = 6.0 Hz, 1H), 5.69 (brs, 1H), 4.26 (d,J=6.0 Hz, 2H),2.48(d,J=14.0 Hz, 2H), 1.87 (d, /= 13.6 Hz,1H), 1.35 (s, 9H), 1.25 (m, 6H), 1.15 (s, 6H);

MS (ESI) m/z: 619 (M+H™).

EXAMPLE 11

[0] .

A . :

TA

H H

. 0s Qo ox NNO

A mixture of Example I (41 mg, 0.1 mmol), Kemp acid anhydride (24 mg, 0.1 mmol) and Et;N (100 mg, 1 mmol) in anhydrous CH,Cl, (2 mL) were stirred overnight at RT, and concentrated in vacuo. Anhydrous benzene (20 mL) was added to the residue, the mixture was refluxed for 3h, concentrated in vacuo and purified by preparative HPLC to yield 3-{3-[3-t- butyl-5-(3-naphthalen-1 -yl-ureido)-pyrazol-1-yl]-benzyl}-1 ,5-di-methyl-2,4-dioxo-3-aza- bicyclo[3.3.1Inonane-7-carboxylic acid (8.8 mg, 14%). '"H NMR (CD,;0D): § 7.3 - 7.4 (m, 2H), 7.20 (m, 2H), 7.4 - 7.6 (m, 7H), 6.50 (m, 1H), 4.80 (s, 2H), 2.60 (d, J = 14 Hz, 2H), 1.90 (m, 1H), 1.40 (m, 1H), 1.30 (m, 2H), 1.20 (s, 3H), 1.15 (s, 6H); MS (ESI) m/z: 636 (M+H").

EXAMPLE 12 \/

TN Lr

NG oy

H H

0x NNO

Jl - 30 :

The title compound, was synthesized in a manner analogous to Example 11 utilizing

Example J to yield 3-{3-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-benzyl}-1,5-

dimethyl-2,4-dioxo-3-aza-bicyclo[3.3.1]nonane-7-carboxylic acid. 'H NMR (CD,OD): 672- 7.5 (m, 7H), 6.40 (s 1H), 4.70 (s, 2H), 2.60 (d, J= 14 Hz, 2H), 1.90 (m, 1H), 1.50 (m, 1H), 1.45 (s, 9H), 1.30 (m, 2H), 1.21 (s, 3H), 1.18 (s, 6H); MS (ESI) m/z: 620 (M+H"). , 5 EXAMPLE 13 0] “0. @

N

NEN

. _N

HN” r le) : * The title compound was synthesized in a manner analogous to Example 1 utilizing

Example E and 4 4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-1- {3-[(4,4-dimethyl- . 3,5-dioxopyrazolidin-1-yl)methyl]phenyl} -1 H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea. "HNMR (CD,0OD): & 7.88 - 7.86 (m, 2H), 7.71-7.68 (m, 2H), 7.58 (m, 2H), 7.60-7.42 (m, 5H), 6.49 (s, 1H), 4.85 (s, 11), 1.34 (5, 9H), 1.27 (5, 6H); MS (ESD m/z: 525 (M+HY), 93 So

EXAMPLE 14 “ . cl

ACT

" 3 Nn oy

H H

N

HN” r o)

The title compound was synthesized in a manner analogous to Example 1 utilizing

Example G and 4,4-dimethyl-3,5-dioxo-pyrazolidine to yield 1-(3-tert-butyl-1-{3-[(4.4- dimethyl-3,5-dioxopyrazolidin-1-yl)methyllphenyl}- 1 H-pyrazol-5-yl)-3-(4-chlorophenyl)urea. "HNMR (CD,;OD): 6 7.60 - 7.20 (m, 8H), 6.43 (s, 1H), 4.70 (s, 1H), 1.34 (s, 9H), 1.26 (s, 6H);

MS (ESD) m/z: 509, 511 (ME).

EXAMPLE 15 \/

Ra SSE

NNT ONT

HN N° NTN 9

AN

N

LC

—N Oo ©

H

Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (64.2 mg, : 30 0.15 mmol) were added HOB (30 mg, 0.225 mmol), Example K (24 mg, 0.15 mmol) and 4- methylmorpholine (60 mg, 0.60 mmol 4.0 equiv), DMF (3 mL) and EDCI (43 mg, 0.225 mmol).

The reaction mixture was stirred at RT overnight and poured into H,0 (3mL), and a white precipitate collected and further purified by preparative HPLC to yield 1-[1-(3- {bis[ (methylcarbamoyl)methyl]carbamoyl} phenyl)-3-terz-butyl-1 H-pyrazol-5-yl]-3-(naphthalen- ] | 1-yl)urea (40 mg). "HNMR (CDC): 8.45 (brs, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.86-7.80 (m, 2H), 7.63-7.56 (m, 2H), 7.52 (s, 1H), 7.47-7.38 (m, 3H), 7.36-7.34 (m, 1H), 7.26 (s, 1H), 7.19- ~~ 5 7.17 (m, 2H), 6.60 (s, 1H), 3.98 (s, 2H), 3.81 (s, 3H), 2.87 (5, 3H), 2.63 (s, 3H), 1.34 (5, 9H); MS (ESD m/z: 570 (M+H").

EXAMPLE 16 :

Cl

Rau e; ~~ NOY ONT ON

HN } N H H

N s Cr

SNTNo

H

The title compound was synthesized in a manner analogous to Example 15 utilizing

Example C (37 mg) and Example K to yield 1-[1-(3- {bis[( methylcarbamoyl)methyl]carbamoyl} phenyl)-3-tert-butyl-1H-pyrazol-5-yl}-3-(4- chlorophenyl)urea. 'H NMR (CD,0D): 6 8.58 (brs, 1H), 8.39 (brs, 1H), 7.64 -'7.62 (m, 3H), 7.53-7.51 (m,1H), 7.38 (d, J=9.2 Hz, 2H), 7.25 (d, J= 8.8 Hz, 2H), 6.44 (s, 1H), 4.17 (s, 2H), : 4.11 (s, 2H), 2.79 (s, 3H), 2.69 (5, 3H), 1.34-1.28 (m, 12H); MS (BSD m/z: 554 (M+H').

EXAMPLE 17 - oo Rau le or PARAS

H H oO

Oe o : Example B was saponified with 2N LiOH in MeOH, and to the resulting acid (0.642 g, 1.5 mmol) in dry THF (25 mL) at -78 °C were added freshly distilled triethylamine (0.202 g, 2.0 mmol) and pivaloyl chloride (0.216 g,1.80 mmol) with vigorous stirring. After stirring at -78 °C for 15 min and at 0 °C for 45 min, the mixture was again cooled to -78°C and then transferred : into the THF solution of lithium salt of D-4-phenyl-oxazolidin-2-one [*: The lithium salt of the -oxazolidinone regeant was previously prepared by the slow addition of n-BuLi (2.50M in hexane, 1.20 mL, 3.0 mmol) into THF solution of D- 4-phenyl-oxazoldin-2-one at -78 °C]. The reaction solution was stirred at -78 °C for 2 h and RT overnight, and then quenched with aq. ammonium chloride and extracted with dichloromethane (100 mL). The combined organic + layers were dried (Na,S0,, and concentrated in vacuo. The residue was purified by preparative : HPLC to yield D-1-{5-tert-butyl-2-[3-(2-ox0-4-phenyl-oxazolidinyl-3-carbonyl)phenyl}-2H- ~pyrazol-3-yl}-3-(naphthalen-1-yl)urea (207 mg, 24%). "HNMR (CDCL): 5 8.14- 8.09 (m, 2H), © 8.06 (s,1H), 7.86 - 7.81 (m, 4H), 7.79 (s, 1H), 7.68 - 7.61 (m, 2H), 7.51 - 7.40 (m, 9H), 6.75 (s, 1H), 5.80 (t,/=9.2, 7.6 Hz, 1H), 4.89 (t, /= 9.2 Hz, 1H), 4.42 (dd, J=9.2, 7.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H. 5d 30

EXAMPLE 18 “ . . 5 : Nin ON g

H H ge

N an (r° 0

The title compound was synthesized in a manner analogous to Example 17 utilizing

Example B and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-0x0-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2 H-pyrazol-3-yl}-3-(naphthalen-1-yljurea 'HNMR (CDCL): 58.14 - 8.09 (m, 2H), 8.06 (s,1H), 7.86 - 7.81 (m, 4H), 7.79 (s, 1H), 7.68 - 7.61 (m, 2H), 7.51 - 7.40 (m, 9H), 6.75 (5, 1H), 5.80 (t, J=9.2, 7.6 Hz, 1H), 4.89 (t, J=9.2 Hz, 1H), 4.42 (dd, /=9.2, 7.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/z: 574 (M+H")

EXAMPLE 19 \ : Ci :

Rau Ses

Nin N ‘N ’ H H re 8) ) 30

The title compound was synthesized in a manner analogous to Example 17 utilizing 97 So

Example C and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-oxo-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2 H-pyrazol-3-yl }-3-(4-chlorophenyl)urea. 'H NMR (CDCl): BE 87.91 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.71 (m, 1H), 7.65 (m, 1H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1H), 5.77 (dd, J=8.8, 8.0 Hz, 1H), 4.96 (t, 8.8

Hz 1H),4.44 (dd, J = 8.8, 8,0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H")

EXAMPLE 20 cl “A 1 0Y

No NTN : H H { ) N “Cre ©

The title compound was synthesized in a manner analogous to Example 17 utilizing

Example C and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-tert-butyl-2-[3-(2-ox0-4-phenyl- : oxazolidinyl-3-carbonyl)phenyl]-2 H-pyrazol-3-yl}-3-(4-chlorophenyl)urea. '"H NMR (CDCL): 3791s, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.71 (m, 1H), 7.65 (m, 1H), 7.49 - 7.40 (m, 8H), 7.26 - 7.24 (m, 2H), 6.68 (s, 1H), 5.77 (dd, J=8.8, 8.0 Hz, 1H), 4.96 (t, 8.8

K ~~ Hz, 1H), 4.44 (dd, J= 8.8, 8.0 Hz, 1H), 1.36 (s, 9H); MS (ESI) m/z: 558 (M+H") } 30

EXAMPLE L

| 4

NZ

Ln

I

To a stirred suspension of (3-nitro-phenyl)-acetic acid (2 g) in CH,Cl, (40 ml, with a catalytic amount of DMF) at 0 °C under N, was added oxalyl chloride (1.1 ml) drop wise. The : reaction mixture was stirred for 40 min morpholine (2.5 g) was added. After stirring for 20 min, - the reaction mixture was filtered. The filtrate was concentrated in vacuo to yield 1-morpholin-4- yl-2-(3-nitro-pheny)-ethanone asa solid (2 g). A mixtureof1 -morpholin-4-yl-2-(3-nitro-pheny)- ethanone (2 g) and 10 % Pd on activated carbon (0.2 g) in ethanol (30 ml) was hydrogenated at 30 psi for 3h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-amino- phenyl)-1-morpholin-4-yl-ethanone (1.7 g). A solution of 2-(3-amino-phenyl)-1-morpholin-4-yl- ethanone (1.7 g, 7.7 mmol) was dissolved in 6 N HCI (15 ml), cooled to 0 °C, and vigorously stirred. Sodium nitrite (0.54 g) in water (8 ml) was added. After 30 min, tin (II) chloride dihydrate (10 g) in 6 N HCI (30 ml) was added. The reaction mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with solid potassium hydroxide and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided 2-(3-hydrazin-phenyl)-1- morpholin-4-yl-ethanone (1.5 g). 2-(3-Hydrazinophenyl)-1-morpholin-4-yl-ethanone (3 g) and 4,4-dimethyl-3-oxopentanenitrile (1.9 g, 15 mmol) in ethanol (60 ml) and 6 N HCI (1 ml) were refluxed for 1h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a ’ residue that was extracted with ethyl acetate. The volatiles were removed in vacuo to provide - } 2-[3-(3 -tert-butyl-5-amino-1H-pyrazol-1-yl)phenyl]-1-morpholinoethanone (4 g), which was used without further purification. :

EXAMPLE 21 . | N= ‘ NZ oO y wr 9 5

N

0]

A mixture of Example L (0.2 g, 0.58 mmol) and 1-naphthylisocyanate (0.10 g, 0.6 mmol) in dry CH,Cl, (4 ml) was stirred at RT under N, for 18 h. The solvent was removed in vacuo and the crude product was purified by column chromatography using ethyl acetate/hexane/CH,Cl, (3/1/0.7) as the eluent (0.11 g, off-white solid) to yield 1-{3-tert-butyl-1-[3-(2-morpholino-2- oxoethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalene-1-yljurea. mp: 194 - 196 ; 'H NMR (200MHz, DMSO-d,): § 9.07 (1H, 5), 8.45 (s, 1H), 8.06 - 7.93 (m, 3H), 7.69 - 7.44 (m, 7H), 7.33 - 7.29 (d, 6.9 Hz, 1H), 6.44 (s, 1H), 3.85 (m, 2H), 3.54 - 3.45 (m, 8H), 1.31 (s, 9H); MS:

EXAMPLE 22

N=

N

°

HN yy "Oe

N cl : 0 . © 30

The title compound was synthesized in a manner analogous to Example 21 utilizing

Example L (0.2 g, 0.58 mmol) and 4-chlorophenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-

tert-butyl-1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl} -3-(4-chloropheny])urea. mp: 100 104 ; 'H NMR (200MHz, DMSO-d,): § 9.16 (s, 1H), 8.45 (s, 1H); 7.52-7.30 (m, 8H), 6.38 (s, 1H), 3.83 (m, 1H), 3.53 - 3.46 (m, SH), 1.30 (s, 9H); MS:

Cs EXAMPLE 23

NF

HN” '@ "“~() ; N lo} ’ }

The title compound is synthesized in a manner analogous to Example 21 utilizing

Example L (0.2 g, 0.58 mmol) and phenylisocyanate (0.09 g, 0.6 mmol) to yield 1-{3-zert-butyl- 1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 H-pyrazol-5-yl}-3-phenylurea. :

EXAMPLE 24 : N=

Co /

J anf C) . x @ x {

OMe - o)

The title compound is synthesized in a manner analogous to Example 21 utilizing

Example L (0.2 g, 0.58 mmol) and 1-isocyanato-4-methoxy-naphthalene to yield 1- {3-zert-butyl- 1-[3-(2-morpholino-2-oxoethyl)phenyl]-1 A-pyrazol-5-y1}-3-(1-methoxynaphthalen-4-yl)urea. . 5 EXAMPLE M “hoi 0) /

NPN

NNR

Ne

OEt } The title compound is synthesized in a manner analogous to Example 0) utilizing © Example A and phenylisocyanate to yield ethyl 3-(3-tert-butyl-5-(3-phenylureido)- 1H-pyrazol-1- yl)benzoate.

EXAMPLE N

N= . : NZ

NH, © HoN 0

A solution of (3-nitrophenyl)acetic acid (23 g, 127 mmol) in methanol (250 ml) and a catalytic amount of concentrated in vacuo H,SO, was heated to reflux for 18 h. The reaction mixture was concentrated in vacuo to a yellow oil. This was dissolved in methanol (250 ml) and stirred for 18 hin an ice bath, whereupon a slow flow of ammonia was charged into the solution. 102 So

. The volatiles were removed in vacuo. The residue was washed with diethyl ether and dried to afford 2-(3-nitrophenyl)acetamide (14 g, off-white solid). '"H NMR (CDCl): § 8.1 (s, 1H), 8.0 oo (d, 1H), 7.7 (4, 1H), 7.5 (m, 1H), 7.1 (bd s, 1H), 6.2 (brs, 1H), 3.6 (s, 2H).

The crude material from the previous reaction (8 g) and 10 % Pd on activated carbon (1 : 5 g) in ethanol (100 ml) was hydrogenated at 30 psi for 18 h and filtered over Celite. Removal of the volatiles in vacuo provided 2-(3-aminophenyl)acetamide (5.7 g). A solution of this material (7 g, 46.7 mmol) was dissolved in 6 N HCI (100 ml), cooled to 0 °C, and vigorously stirred.

Sodium nitrite (3.22 g, 46.7 mmol) in water (50 ml) was added. After 30 min, tin (I) chloride dihydrate (26 g) in 6 N HCI (100 ml) was added. The reaction mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with 50 % aqueous NaOH solution and extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo provided 2-(3- * hydrazinophenyl)acetamide.

The crude material from the previous reaction (ca. 15 mmol) and 4,4-dimethyl-3- oxopentanenitrile ( 1.85 g, 15 mmol) in ethanol (60 ml) and 6 N HCI (1.5 m1) was refluxed for 1 h and cooled to RT. The reaction mixture was neutralized by adding solid sodium hydrogen carbonate. The slurry was filtered and removal of the volatiles in vacuo provided a residue, ) which was extracted with ethyl acetate. The solvent was removed in vacuo to provide 2-[3-(3- tertbutyls -amino-1H-pyrazol-1-yhphenyllacetamide as a white solid (3.2 g), which was nsed without further purification. : EXAMPLE 25

NJ

. yb ° CY

A mixture of Example N (2 g, 0.73 mmol) and 1-naphthylisocyanate (0.124 g, 0.73 mmol) in dry CH,Cl, (4 ml) was stirred at RT under N, for 18 h.

The solvent was removed in vacuo and the crude product was washed with ethyl acetate (8 ml) and dried in vacuo to yield 1-{3-zert-butyl-1-[3-(carbamoylmethyl)phenyl)-1 H-pyrazol-5-yl} -3-(naphthalene-1-yl)urea as ‘a white solid (0.22'g). mp: 230 (dec.); 'H NMR (200MHz, DMSO-d): § 9.12 (s, 1H), 8.92 (s,

1H), 8.32 - 8.08 (m, 3H), 7.94 - 7.44 (m, 8H), 6.44 (s, 1H), 3:51 (s, 2H), 1.31 (5, 9H); MS:

EXAMPLE 26

N= oo o : HN~—¢

HAN HN

2 cl

Oo

The title compound was synthesized in a manner analogous to Example 23 utilizing

Example N (0.2 g, 0.73 mmol) and 4-chlorophenylisocyanate (0.112 g, 0.73 mmol) to yield 1- {3-tert-butyl-1-[3-(carbamoylmethyl)phenyl)-1H-pyrazol-5-y1}-3-(4-chlorophenyljurea as a. white solid (0.28 g). mp: 222 224 . (dec.); "HNMR (200MHz, DMSO-d); 8 9.15 (s, 1H), 8.46 (s, 1H), 7.55 - 7.31 (m, 8H), 6.39 (s, 1H), 3.48 (s, 2H), 1.30 (s, 9H); MS:

EXAMPLE O

. : lo) ry AL

SQ

: H

JO

OEt

The title compound is synthesized in a manner analogous to Example C utilizing

Example A and 1-isocyanato-4-methoxy-naphthaleneto yield ethyl 3-(3-tert-butyl-5-(3-(1- methoxynaphthalen-4-yl)ureido)-1H-pyrazol-1-yl)benzoate.

EXAMPLE 27 : 0 =

DSSS

} No a i Nl le

NN

{ \ Da 0)

The title compound is synthesized in a manner analogous to Example 17 utilizing . Example M and D-4-phenyl-oxazolidin-2-one to yield D-1-{5-tert-butyl-2-[3-(2-0x0-4-phenyl- oxazolidinyl-3-carbonyl)phenyl]-2 H-pyrazol-3-yl}-3-phenylurea.

EXAMPLE 28 nA

N< A, . : .

NR

Ne SE

Oho a.

J

: The title compound is synthesized in a manner analogous to Example 17 utilizing a

Example M and and L-4-phenyl-oxazolidin-2-one to yield L-1-{5-ferz-butyl-2-[3-(2-ox0-4- phenyl-oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl}-3-phenylurea.

EXAMPLE P

.. 5 NE

MeO | A mixture of 3-(3-amino-phenyl)-acrylic acid methyl ester (6 g) and 10 % Pd on activated carbon (1 g) in ethanol (50 ml) was hydrogenated at 30 psi for 18% and filtered over

Celite. Removal of the volatiles in vacuo provided 3-(3-amino-phenyl)propionic acid methyl ester (6 g). : A vigorously stirred solution of the crude material from the previous reaction (5.7 g, 31.8 mmol) dissolved in 6 N HCI (35 ml) was cooled to 0 °C, and sodium nitrite (2.2 g) in water (20 ml) was added. After 1h, tin (I) chloride dihydrate (18 g) in 6 N HCI (35 ml) was added. And the mixture was stirred at 0 °C for 3 h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided methyl 3-(3-hydrazino-phenyl)propionate (1.7 g). * A stirred solution of the crude material from the previous reaction (1.7 g, 8.8 mmol) and 4,4-dimethyl-3-oxopentanenitrile ( 1.2 g, 9.7 mmol) in ethanol (30 ml) and 6 NHC (2 ml) was : refluxed for 18 h and cooled to RT. The volatiles were removed in vacuo and the residue dissolved in EtOAc and washed with 1 N aqueous NaOH. The organic layer was dried (Na,SO,) and concentrated in vacuo and the residue was purified by column chromatography using 30 % ethyl acetate in hexane as the eluent to provide methyl 3-[3-(3-tert-butyl-5-amino-1H-pyrazol -1-yl)phenyljpropionate (3.2 g), which was used without further purification

EXAMPLE 29 E

N a— . N_ 0

HN

: 5 ~ )

HN oo »

A mixture of Example P (0.35 g, 1.1 mmol) and 1-naphthylisocyanate (0.19 g, © 1.05 mmol) in dry CH,Cl, (5 ml) was stirred at RT under N, for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) . containing lithium hydroxide (0.1 g) for 3 h at RT, and subsequently diluted with EtOAc and dilute citric acid solution. The organic layer was dried (N a,50,), and the volatiles removed in vacuo. The residue was purified by column chromatography using 3 % methanol in CH,Cl, as the eluent to yield 3-(3- {3-tert-butyl-5-[3-(naphthalen-1-yl)ureido]-1H-pyrazol-1- yDphenylpropionic acid (0.22 g, brownish solid). mp: 105-107 ; 'H NMR (200MHz, CDCl): 87.87-7.36(m, 10H), 7.18 - 7.16 (m, 1H), 6.52 (s, 1H),2.93 {t, J=6.9 Hz, 2H), 2.65 (t, J = 7.1 Hz, 2H), 1.37 (s, 9H); MS

EXAMPLE 30 . 5 N= : N_/ pe "HN

IS

HN

HO : o

SE

The title compound was synthesized in a manner analogous to Example 29 utilizing

Example P (0.30g, 0.95 mmol) and 4-chlorophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3- {3-tert-butyl-5-[3-(4-chloropnehyl)ureido]-1 H-pyrazol-1-yl)phenyl)propionic acid (0.05 g, white solid). mp:85 87 ; "HNMR (200MHz, CDCl,): § 8.21 (s, 1H), 7.44 - 7.14 (m, 7H), 6.98 (s, 1H), 6.55 (s, 1H), 2.98 (t, J= 5.2 Hz, 2H), 2.66 (t, J = 5.6 Hz, 2H), 1.40 (s, 9H); MS

EXAMPLE Q

\/

N= : / 0 . EtO HN—¢ nol oO

A mixture of ethyl 3-(4-aminophenyl)acrylate(1.5 g) and 10 % Pd on activated carbon (0.3 g) - in ethanol (20 ml) was hydrogenated at 30 psi for 18h and filtered over Celite. Removal of the volatiles in vacuo provided ethyl 3-(4-aminophenyl)propionate (1.5 g).

A solution of the crude material from the previous reaction (1.5 g, 8.4 mmol) was dissolved in 6 N HCI (9 ml), cooled to 0 °C, and vigorously stirred. Sodium nitrite (0.58 g) in - water (7 ml) was added. After 1h, tin (IT) chloride dihydrate (5 g) in 6 N HCI (10 ml) was added.

. The reaction mixture was stirred at 0 °C for 3h. The pH was adjusted to pH 14 with solid KOH and extracted with EtOAc. The combined organic extracts were concentrated in vacuo provided a ethyl 3-(4-hydrazino-phenyl)-propionate(1 g). oo

The crude material from the previous reaction (1 g, 8.8 mmol) and 4,4-dimethyl-3- ) | 5 oxopentanenitrile (0.7 g) in ethanol (8 ml) and 6 N HCI (1 ml) was refluxed for 18h and cooled to RT. The volatiles were removed in vacuo. The residue was dissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The organic layer was dried (Na,SO,) and “concentrated in vacuo. The residue was purified by column chromatography using 0.7 % ‘methanol in CH,C}, as the eluent to provide ethyl 3-{4-[3-tert-butyl-5-(3-(naphthalene-1- ylureido]-1H-pyrazol-1-yl}phenyl)prpanoate (0.57 g).

EXAMPLE 31 -

N./ g o J "oN A lr HN~¢ )

H

Ce SAGES:

A mixture of Example Q (0.25 g, 0.8 mmol) and 1-naphthylisocyanate (0.13 g, 0.8 mmol) in dry CH,C], (5 ml) was stirred at RT under N, for 20 h. The solvent was removed in vacuo and the residue was stirred in a solution of THF (3 ml)/MeOH (2 ml)/water (1.5 ml) containing lithium hydroxide (0.1 g) for 3h at RT and diluted with EtOAc and diluted citric acid solution.

The organic layer was dried (Na,SO,), and the volatiles removed in vacuo. The residue was - purified by column chromatography using 4 % methanol in CH,Cl,as the eluent to yield 3- {4-[3- . tert-butyl-5-(3-(naphthalene-1-yl)ureido]-1H-pyrazol-1-yl} phenyl)propanonic acid (0.18 g, off- white solid). mp: 120 122 ; 'H NMR (200MHz, CDCl): 8 7.89 - 7.06 (m, 11H), 6.5 (s, 1H), 2.89 (m, 2H), 2.61 (m, 2H), 1.37 (s, 9H); MS :

EXAMPLE 32

N =

NF

0 ro AT HN ~

HN

0] a P

The title compound was synthesized in a manner analogous to Example 31 utilizing

Example Q (0.16 g, 0.5 mmol) and 4-chlorophenylisocyanate (0.077 g, 0.5 mmol) to yield 3-{4- [3-tert-butyl-5-(3-(4-chlorphenyl)ureido]-1H-pyrazol-1-yl} phenyl)propanonic acid acid (0.16 g, off-white solid). mp: 112 - 114 ; 'H NMR (200MHz, CDCL,): 8 8.16 (s, 1H), 7.56 (s, 1H), 7.21 (s, 2H), 7.09 (s, 2H), 6.42 (s, LH), 2.80 (m, 2H), 2.56 (m, 2H), 1.32 (s, 9H); MS

EXAMPLE R

. s 0) NH,

N=/

A 250 mL pressure vessel (ACE Glass Teflon screw cap) was charged with 3- nitrobiphenyl! (20 g, 0.10 mol) dissolved in THF (~100 mL) and 10% Pd/C (3 g). The reaction "vessel was charged with H, (g) and purged three times. The reaction was charged with 40 psi H,

N (2) and placed on a Parr shaker hydrogenation apparatus and allowed to shake overnight at RT.

Co | "HPLC showed that the reaction was complete thus the reaction mixture was filtered through a bed of Celite and evaporated to yield the amine: 16.7g (98% yield) a In a 250 mL Erlenmeyer flask with a magnetic stir bar, the crude material from the . previous reaction (4.40 g, 0.026 mol) was added to 6 N HCI (40 mL) and cooled with an ice bath to ~ 0 °C. A solution of NaNQ, (2.11 g, 0.0306 mol, 1.18 eq.) in water (5 mL) was added drop . wise. After 30 min, SnCi,2H,0 (52.0 g, 0.23 mol, 8.86 eq.) in 6IN HCi (100 mL) was added and 20. the reaction mixture was allowed to stir for 3h, then subsequently transferred to a 500 mL round bottom flask. To this, 4,4-dimethyl-3-oxopentanenitrile (3.25 g, 0.026 mol) and EtOH (100 ml) were added and the mixture refluxed for 4h, concentrated in vacuo and the residue extracted with

EtOAc (2x100 mL). The residue was purified by column chromatograph using hexane/ . EtOACc/Et;N (8:2:0.2) to yield 0.53g of Example R. 'H NMR (CDCl): 8 7.5 (m, 18H), 5.8 (s, 1H), 1.3 (s, 9H).

EXAMPLE 33 - - £0 "os HN” ON

H oo :

So N Ny

N= 10 ; BE

In a dry vial with a magnetic stir bar, Example R (0.145 g; 0.50 mmol) was-dissolvedin 2mL CH,Cl, (anhydrous) followed by the addition of phenylisocyanate (0.0544 mL; 0.50 mmol; 1 eq.). The reaction was kept under argon and stirred for 17h. Evaporation of solvent gave a crystalline mass that was triturated with hexane/EtOAc (4:1) and filtered to yield 1-(3-tert-butyl- : 15 1-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-phenylurea (0.185 g, 90%). HPLC purity: 96%; mp: 80 84 ; "HNMR (CDCl): 8 7.3 (m, 16 H), 6.3 (s, 1H), 1.4 (s, 9H).

EXAMPLE 34 $ 0 or 2) HNN

H

~The title compound was synthesized in a manner analogous to Example 33 utilizing

Example R (0.145 g; 0.50 mmol) and p-chlorophenylisocyanate (0.0768 g, 0.50 mmol, 1 eq.) to : yield 1-(3-tert-butyl-1-(3-phenylphenyl)-1H-pyrazol-5-yl)-3-(4-chlorophenyljurea (0.205 g, -

92%). HPLC purity: 96.5%; mp: 134 136 ; 'H NMR (CDCL): 8 7.5 (m, 14H), 7.0 (s, 1H), 6.6 (s, 1H), 6.4 (s, 1H), 1.4 (s, 9H).

. EXAMPLE S ot F . ; Ney” NN

H H

WO

OFt . The title compound is synthesized in a manner analogous to Example C utilizing - .

Example A and 4-fluorophenyl isocyanate yield ethyl 3-(3-tert-butyl-5-(3-(4- flurophenyl)ureido)-1H-pyrazol-1-yl)benzoate. | :

EXAMPLE 35 } 0 | 4 OMe

NP

AT oA SI

Be 4 { J

The title compound is synthesized in a manner analogous to Example 17 utilizing ‘Example M and D-4-phenyl-oxazolidin-2-one to yield D-1- {5 -tert-butyl-2-[3-(2-oxo0-4-phenyl- , oxazolidinyl-3-carbonyl)phenyl]-2H-pyrazol-3-yl} -3--(naphthalen-1-yl)urea. 116 : Ss

EXAMPLE 36. -

NZ

0 R . HN

B!

HN

HO -

The title compound is synthesized in a manner analogous to Example 29 utilizing

Example P (0.30g, 0.95 mmol) and 4-flu0rophenylisocyanate (0.146 g, 0.95 mmol) to yield 3-(3- 5 (3-tert-butyl-5-(3-(4-fluorophenyl)ureido)-1H-pyrazol- 1-yl)phenyl)propanoic acid.

EXAMPLE T a 5 N=

N/ 4 NH, : NHBoc

To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane- methylsuifide (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6 N HCI was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na,SQ,) filtered and concentrated in vacuo to yield 3-tert-butyl-1-[3-(2-aminoethyl)phenyl]-1 H-pyrazol-S amine (0.9 g).

A mixture of the crude material from the previous reaction (0.8 g, 3.1 mmol) and di-tert- butylcarbonate (0.7 g, 3.5 mmol) and catalytically amount of DMAP in dry CH,Cl, (5 ml) was stirred at RT under N, for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography using 1% methanol in CH, Cl, as the eluent to yield tert- butyl 3-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)phenylcarbamate (0.5 g).

EXAMPLE 37 - od

N/

HG oo HN ()

NH

A mixture of Example T (0.26 g, 0.73 mmol) and 1-naphthylisocyanate (0.123 g, 0.73 ‘mmol) in dry CH,Cl, (5 ml) was stirred at RT under N, for 48 h. The solvent was removedin vacuo and the residue was purified by column chromatography using 1% methanol in CH,Cl,as the eluent (0.15 g, off-white solid). The solid was then treated with TFA (0.2ml) for 5 min and oe "15 diluted with EtOAc. The organic layer was washed with saturated NaHCO, solution and brine, dried (Na,SO,), filtered and concentrated in vacuo to yield 1-{3-tert-butyl-1-[3-(2-

Aminoethyl)phenyl]-1H-pyrazol-5-yl} -3-(naphthalen-1-yl)urea as asolid (80 mg). mp: 110-112 : "TH NMR (200MHz, DMSO-d): 59.09 (s,1H), 8.90 (s, 1H), 8.01 - 7.34 (m, 11H), 6.43 (s, 1H), 3.11 (m, 2H), 2.96 (m, 2H), 1.29 (s, 9H); MS

EXAMPLE 38 + ~~ . y HN ~

Ev . 30 Cl

NH, : 119 So

“The title compound was synthesized in a manner analogous to Example 37 utilizing

Example T (0.15 g, 0.42 mmol) and 4-chlorophenylisocyanate (0.065 g, 0.42 mmol) to yield 1- {3-tert-butyl-1-[3-(2-Aminoethyl)phenyl]- 1 H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as an off- white solid (20 mg). mp:125-127 ; 'H NMR (200MHz, CDCl,): & 8.81 (s, 1H), 8.66 (s, 1H), oo 5 7.36-7.13 (m, 8H), 6.54 (s, 1H), 3.15 (brs, 2H), 2.97 (brs, 2H), 1.32 (s, 9H); MS : EXAMPLE U “N” “NH > “OCH;

Co In a 250 mL Erlenmeyer flask with a magnetic stir bar, m-anisidine (9.84 g, 0.052 mol) was added to 6 N HCI (80 mL) and cooled with an ice bath to 0 °C. A solution of NaNO, (4.22 : 2.0.0612mol, 1.1 8 eq.) in water (10 mL) was added drop wise. After 30 min, SnCl,2H,0 (104.0 g, 0.46 mol, 8.86 eq.) in 6 N HCI (200 mL) was added and the reaction mixture was allowed to stir for 3 h., and then subsequently transferred to a 1000 mL round bottom flask. To this, 4,4- * dimethyl-3-oxopentanenitrile (8.00 g, 0.064 mol) and EtOH (200 mL) were added and the mixture refluxed for 4 h, concentrated in vacuo and the residue recrystallized from CH,CI, to yield 3-tert-butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-amine as the HCl salt (13.9 g). :

The crude material from the previous reaction (4.65 g, 0.165 mol) was dissolved in 30 mL of CH, C1, with Et;N (2.30 mL, 0.0165 mol, 1 eq.) and stirred for 30 min Extraction with water followed by drying of the organic phase with Na,SO, and concentration in vacuo yielded a brown syrup that was the free base, 3-tert-butyl-1-(3-methoxyphenyl)-1 H-pyrazol-5-amine ' (3.82 g, 94.5%), which was used without further purification.

EXAMPLE 39 :

" R : 0) oJ “N N N ’ : 5 H H .

MeO N

In a dry vial with a magnetic stir bar, Example U (2.62 g, 0.0107 mol) was dissolved in CH,CI, (5 mL, anhydrous) followed by the addition of 1-naphthylisocyanate (1.53 mL, 0.0107 mol, 1 eq.). The reaction was kept under Ar and stirred for 18 h. Evaporation of solvent followed } by column chromatography with EtOAc/hexane/EtN (7:2:0.5) as the eluent yielded 1-[3-tert- butyl-1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalen-1-yl)urea (3.4g,77%). HPLC: 97%; mp: 78 - 80; 'H NMR (CDCl;): 6 7.9 - 6.8 (m, 15H), 6.4 (s, 1H), 3.7 (s, 3H), 1.4 (s, 9H).

EXAMPLE 40 \/ 6 AC

I

Co Ra Weel } N } ’

H H : :

MeO

The title compound was synthesized in a manner analogous to Example 39 utilizing

Example U (3.82 g; 0.0156 mol) and p-chlorophenylisocyanate (2.39 g, 0.0156 mol, 1 eq.) purified by trituration with hexane/EtOAc (4:1) and filtered to yield 1-[3-zert-butyl-1-(3- methoxyphenyl)-1H-pyrazol-3 -y1]-3-(4-chlorophenyl)urea (6.1g, 98%). HPLC purity: 95%; mp: 158-160 ; 'H NMR (CDCl): & 7.7 (s, 1H); 5 7.2 6.8 (m, 8H), 6.4 (s, 1H), 3.7 (s,3H),1.3 (s,

9H).

EXAMPLE 41

BNE GN

N

Sale

HO” ° | | : : In 2 100 ml round bottom flask equipped with a magnetic stir bar, Example 39 (2.07 g) was dissolved in CH,C], (20 mL) and cooled to 0 °C with an ice bath. BBr; (1 M in CH,Cl,; 7.5 mL) was added slowly. The reaction mixture was allowed to warm warm to RT overnight.

Additional BBr, (1 M in CH,Cl,, 2 X 1 mL, 9.5 mmol total added) was added and the reaction was quenched by the addition of MeOH. Evaporation of solvent led to a crystalline material that

Co was chromatographed on silica gel (30 g) using CH,Cl,/MeOH (9.6:0.4) as the eluent to yield 1-[3-tert-butyl-1-(3-hydroxyphenyl)-1H-pyrazol-5-yl]-3-(naphthalene-1-yl)urea (0.40g, 20%). 'H NMR (DMSO-d,): 89.0 (s, 1H), 8.8 (s, 1H), 8.1 - 6.8 (m, 11H), 6.4 (s, 1H), 1.3 (s, 9H). MS (BSD m/z: 401 (M+H"). :

Co EXAMPLE 42

I.

N

. H H ’

HO :

The title compound was synthesized in a manner analogous to Example 41 utilizing

Example 40 (2.00°'g, 5 mmol) that resulted in a crystalline material that was filtered and washed with MeOH to yield 1-[3-tert-butyl-1-(3-hydroxyphenyl)- 1H-pyrazol-5-yl}-3-(4- } chiorophenyl)urea (1.14 g, 60%). HPLC purity: 96%; mp: 214 - 216 ; 'H NMR (CDCl,): & 8.4 (s, 1H), 7.7 (s, 1H), 7.4 - 6.6 (m, 9H), 1.3 (s, OH), . s Co - EXAMPLEYV “

Non NH, . 15 ou

NH

Hot

The starting material, 1-[4-(aminomethyl)phenyl]-3-terz-butyl-N-nitroso-1H-pyrazol-5- amine, was synthesized in a manner analogous to Example A utilizing 4-aminobenzamide and oe 4,4-dimethyl-3-oxopentanenitrile.

A 1 L four-necked round bottom flask was equipped with a stir bar, a source of dry Ar, a heating mantle, and a reflux condenser. The flask was flushed with Ar and charged with the crude material from the previous reaction (12 g, 46.5 mmol; 258.1 g/mol) and anhydrous THF (500 ml). This solution was treated cautiously with LiAIH, (2.65 g, 69.8 mmol) and the reaction . was stirred overnight. The reaction was heated to reflux and additional LiAIH, was added - complete (a total of 8.35 g added). The reaction was cooled to 0 and H,O (8.4 ml); 15% NaOH (8.4 ml) and H,O (24 ml) were added sequentially; The mixture was stirred for 2h, the solids filtered through Celite, and washed extensively with THF, the solution was concentrated in vacuo to yield 1-(4-(aminomethyl-3-methoxy)phenyl)-3-terz-butyl-1 H-pyrazol-5-amine (6.8 2) as an oil.

A 40 mL vial was equipped with a stir bar, a septum, and a source of Ar. The vial was charged with the crude material from the previous reaction (2 g, 8.2 mmol, 244.17 g/mol) and

CHC], (15 mL) were. cooled to 0 under Ar and di-terz-butylcarbonate (1.9 g, 9.0 mmol) dissolved in CHCl; (5 mL) was added drop wise over a 2 min period. The mixture was treated with IN KOH (2 mL), added over a 2h period. The resulting emulsion was broken with the addition of saturated NaCl solution, the layers were separated and the aqueous phase extracted with CH,Cl, (2 x 1.5 ml). The combined organic phases were dried over Na,SO4, filtered, concentrated in vacuo to yield tert-butyl [4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)-2- methoxybenzylcarbamate (2.23 g, 79%) as a light yellow solid. 'H NMR (CDC): § 7.4 (m,

SH), 5.6 (s, 1H), 4.4 (d, 2H), 1.5 (s, 9H), 1.3 (s, 9H).

EXAMPLE 43 . . Oo

PR

SARS

: : H H s

NH

A 40 mL vial was equipped with a septum, a stir bar and a source of Ar, and charged with

Example V (2 g, 5.81 mmol), flushed with Ar and dissolved in CHCl, (20 mL). The solution was treated with 2-naphthylisocyanate (984 mg, 5.81 mmol) in CHCl; (5 mL) and added over 1 min

The reaction was stirred for 8h, and additional 1-naphthylisocyanate (81 mg) was added and the reaction stirred overnight. The solid was filtered and washed with CH,Cl,to yield tert-butyl 4-[3- tert-butyl-5-(3 -naphthalen-1-ylureido)-1H-pyrazoi- 1-ylJbenzylcarbamate (1.2 g). HPLC purity: 94.4 %; "H NMR (DMSO-d): 5 9.1 (s, 1H), 8.8 (s, 1H), 8.0 (m, 3H), 7.6 (m, 9H), 6.4 (s, 1H), 42 (d, 2H), 1.4 (s, SH), 1.3 (s, 9H).

EXAMPLE 44 : . Bal o or \

NaN Noy

H H

2s s

Co o o—&

The title compound was synthesized in a manner analogous fo Example 43 utilizing

Example V 20 g, 5.81 mmol) and p-chlorophenylisocyanate (892 mg) to yield tert-butyl 4-[3- tert-butyl-5-(3-(4-chloropnehyl)ureido)-1H-pyrazol-1-yl]benzylcarbamate (1.5 g). HPLC purity: . 5 97%; '"H NMR (DMSO-d,): 89.2 (s, 1H), 8.4 (s, 1H), 7.4 (m, 8H), 6.4 (s, 1H), 4.2 (d, 2H), 1.4 (s, 9H), 1.3 (s, 9H).

EXAMPLE A45

ND NY : oo

N

H H

: PY 0) o—& : A 10 mL flask equipped with a stir bar was flushed with Ar and charged with Example 43 (770 mg, 1.5 mmol) and CH,Cl, (1 ml) and 1:1 CH,C1,:TFA (2.5 mL). After 1.5 h, reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (15 mL), washed with : saturated NaHCO; (10 mL) and saturated NaCl (10 mL). The organic layers was dried, filtered and concentrated in vacuo to yield 1-{3-zert-butyl-1-[4-(aminomethyl)phenyl]-1 H-pyrazol-5-yl}- 3-(naphthalen-1-yl)urea (710 mg). '"H NMR (DMSO-d): 8 7.4 (m, 11H), 6.4 (s, 1H), 3.7 (5, 2H), 1.3 (s, 9H).

EXAMPLE 46 . . - Cl

LO

N. \ Py

N

H H

The title compound was synthesized in a manner analogous to Example 45 utilizing

Example 44 (1.5g, 1.5 mmol) to yield 1-{3-tert-butyl-1-[4-(aminomethyl)phenyl}-1 H-pyrazol-5-

y1}-3-(4-chlorophenyl)urea (1.0 g). HPLC purity: 93.6%; mp: 100 - 102 ; 'H NMR (CDCl): 8 8.6 (s, 1H), 7.3 (m, 8H), 6.3 (s, 1H), 3.7 (brs, 2H), 1.3 (s, 9H). ~ EXAMPLE 47 . 5 Nn

Pe

N \ EN N

N e

NT

(so,

A 10 ml vial was charged with Example 45 (260 mg, 63 mmol) and absolute EtOH (3 mL) under Ar. Divinylsulfone (63 uL, 74 mg, .63 mmol) was added drop wise over 3 min and the reaction was stirred at RT for 1.5 h. and concentrated in vacuo to yield a yellow solid, which was purified via preparative TLC, developed in 5% MeOH:CH,Cl,. The predominant band was cut and eluted off the silica with 1:1 EtOAc:MeQH, filtered and concentrated in vacuo to yield 1-{3-tert-butyl-1-[4-(1,1-dioxothiomorpholin-4-yl)methylphenyl]- 1H-pyrazol-5-yl} -3- (naphthalen-1-ylurea (150 mg). HPLC purity: 96%; '"H NMR (DMSO-d): § 9.1 (s, 1H), 9.0 (s, 1H), 7.9 (m, 3H), 7.5 (m, 8H), 6.4 (s, 1H), 3.1 (brs, 4H), 2.9 (brs, 4H), 1.3 (s, 9H).

EXAMPLE 48 -

Cl 0

N

. 5 Q

NT

(so, © The title compound was synthesized in a manner analogous to Example 47 utilizing

Example 46 (260mg, 0.66 mmol) to yield 1-{3-tert-butyl-1-[4-(1,1-dioxothiomorpholin-4- yDmethylphenyl]-1H-pyrazol-5-yl} -3-(4-chlorophenyl)urea (180 mg). HPLC purity: 93%; mp: 136 - 138 ; '"H NMR (DMSO-d): 39.2 (s, 1H), 8.5 (5, 1H), 7.4 (m, 9H), 6.4 (s, 1H), 3.1 (brs, 4H), 3.0 (brs, 4H), 1.3 (s, 9H). | Co

EXAMPLE 49 : we

I.

N

H H 9 0)

S54 : i N“7N0

H

To a stirring solution of chlorosulfonyl isocyanate (0.35g , S mmol) in CH,Cl, (20 mL) ~ at 0 °C was added pyrrolidine (0.18 g, 5 mmol) at such a rate that the reaction temperature did not rise above 5°C. After stirring for 2h, a solution of Example 41 (1.10 g, 6.5 mmol) and triethylmine (0.46 g, 9 mmol) in CH,Cl, (20 mL) was added. When the addition was complete, . the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into 10% HCI (10 mL) saturated with NaCl , the organic layer was separated and the aqueous layer extracted with ether (20 mL). The combined organic layers were dried (Na,SO,) and concentrated in vacuo, purified by preparative HPLC to yield (pyrrolidine-1-carbonyl)sulfamic acid 3-[3-terz-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]phenyl ester (40 mg). 'H NMR (CDCl): 8 9.12 (brs, 1H), 8.61 (brs, 1H), 7.85 - 7.80 (m, 3H), 7.65 (d, J = 8.0 Hz, 2H), 7.53 - 7.51 (m, 1H), 7.45 - 7.25 (m, 5H), 6.89 (s, 4H), 3.36 - 3.34 (brs, 1H), 3.14 - 3.13 (brs, 2H), 1.69 (brs, 2H), 1.62 (brs, 2H), 1.39 (s, 9H); MS (ESI) m/z: 577 (M+H").

EXAMPLE 50 - cl . 0

Cs nA

H H

0

JA 0 @h N"" NO

H

| SE "The title compound was synthesized in a manner analogous to Example 49 utilizing

Example 42 to yield (pyrrolidine- 1-carbonyl)sulfamic acid 3-[3-tert-butyl-5-(4-chlorophenyl-1- Co yl-ureido)pyrazol-1-yl]phenyl ester. MS (ESI) m/z: 561 (M+H?).

EXAMPLE W

7 \

S

Y

: OMe

Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (1 00. : mL) and treated with triethylamine (20.2 g). The mixture was stirred. at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight.

The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-terz- butyl-1-(4-methoxyphenyl)-1 H-pyrazol-5-amine (25 g, 70%). 'H NMR (DMSO-d): 8 7.5 (d, . 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).

C131

EXAMPLESI oo } OMe . : 0 9 y “rd

N . : : OMe ~ Toasolution of 1-isocyanato-4-methoxy-naphthalene (996 mg) in anhydrous CH,Cl, (20 mL) of was added Example W (1.23 g). The reaction solution was stirred for 3 h, the resulting white precipitate filtered, treated with 10% HCI and recrystallized from MeOH, and dried in vacuo to yield 1-[3-zert-butyl-1-(4-methoxyphenyl)-1 H-pyrazol-5-y1]-3-(1-methoxynaphthalen- 4-yl-urea as white crystals (900 mg, 40%). HPLC purity: 96%; mp: 143 - 144 ; 'H NMR ) (DMSO-d,): 6 8.8 (s, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.6 (m, SH), 7.1 (d, 2H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H); 1.3 (5, 9H).

EXAMPLE 52 oo : : Br 0] } “ni Cr

N

: H H

The title compound was synthesized in a manner analogous to Example 51 utilizing

Example W and p-bromophenylisocyanate (990mg) to yield 1-{3-tert-butyl-1-(4-

methoxyphenyl)-1H-pyrazol-5-yl}-3-(4-bromophenyl)urea as off-white crystals (1.5g, 68%).

HPLC purity: 98%; mp: 200 - 201 ; "HNMR (DMSO-d): 59.3 (s, 1H), 8.3 (s, 1H), 7.4 (m, 6H), ] 7.0 (d,2H), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (s, 9H).

EXAMPLE 53 . Cl 0]

LLY

N

: H H

OMe

The title compound was synthesized in a manner analogous to Example 51 utilizing

Example W and p-chlorophenylisocyanate (768 mg) into yield 1-{3-tert-butyl-1-(4- methoxyphenyl)- 1H-pyrazol-5-yl}-3-(4-chlorophenyl)urea as white crystals (1.3g, 65%). HPLC purity: 98%; mp: 209 - 210 ; 'H NMR (DMSO-d,): § 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (m, 4H), 7.3 (d, 2H), 7.1 (d, 2H), 6.3 (s, 1H), 3.8 (s, 3H), 1.3 (5, 9H). _

EXAMPLE 54 : : __Ci

Oo ‘N

H H

OH

~The title compound was synthesized in a manner analogous to Example 41 utilizing

Example 53 (500 mg) to yield 1-{3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4- chlorophenyl)urea as white crystals (300 mg, 62%). HPLC purity: 94%; mp: 144 - 145 ; 'H

NMR (DMSO-d): 6 9.7 (s, 1H), 9.1 (s, 1H), 8.3 (s, 1H), 7.4 (d, 2H), 7.3 (m, 4H); 6.9 (d, 2H),

6.3 (s, 1H), 1.3 (s, 9H) Co to EXAMPLE 55 > at 0 Br . ] nD 0 H H . on

The title compound was synthesized in a manner analogous to Example 41 utilizing Example 52 (550 mg) to yield I1-{3-tert-butyl-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl}-3-(4- bromophenyl)urea as a white crystalline solid (400 mg, 70%). HPLC purity: 93%; mp: 198 200

Lo - 3 "TH NMR (DMSO-d): 8 9.7 (s, 1H), 9.2 (s, 1H), 8.3 (s, 1H), 7.4 (d, 4H), 7.2 (m, 2H), 6.9 (d, 2H),63 (s, 1H), 1.3 (s, 9H).

EXAMPLE X

I IY

5 Noy NH,

COsMe

Methyl 4-(3-tert-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared , from methyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al.,

J. Med. Chem., 45, 2994 (2002). oo

EXAMPLE 56 0 oo rot . 3 H

CO.Me - A 500mL round bottom flask was equipped with a magnetic stir bar and an ice bath. The flask was charged with Example X (1 g) and this was dissolved in CH,Cl, (100 ml). Saturated ~ sodium bicarbonate (100 mL) was added and the mixture rapidly stirred, cooled in an ice bath and treated with diphosgene (1.45 g) and the heterogeneous mixture stirred for 1 h. The layers were separated and the CH,CI, layer treated with tert-butanol (1.07 g) and the solution stirred overnight at RT. The solution was washed with H,0O (2 x150 mL), dried (Na,S0,), filtered, concentrated in vacuo, and purified by flash chromatography using 1:2 ethyl acetate: hexane as the eluent to yield zert-buthyl 1-(4-(methoxycarbonyl)phenyl)-3-tert-butyl- 1H-pyrazol-5- ylcarbamate (100 mg) as an off-white solid. "H NMR (DMSO-d): 69.2 (s, 1H), 8.1 (d, 2H), 7.7 (d,2H), 6.3 (s, 1H), 3.3 (s, 3H), 1.3 (s, 18H). :

EXAMPLE 57 ol Cl 0

Rael

L N

H H

COsMe

The title compound was synthesized in a manner analogous to Example 41 utilizing

Example X (1.37 g) and p-chlorophenylisocyanate (768 mg) to yield methyl 4- {3-tert-butyl-5-[3-(4- chlorophenyl)ureido]-1H-pyrazol-1-yl} benzoate as white crystals (1.4 g 66%). HPLC purity: 98%; mp: 160 - 161 ; 'H NMR (DMSO-d): 8 9.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.8 (d, 2H), : . 7.5(d, 2H), 7.3 (d, 2H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H). :

EXAMPLE 58

N/ Obie ped

Nd A

N

HH 9

CO,Me . : 25 The title compound was synthesized in a manner analogous to Example 41 utilizing

Example X (1.27 g) and 1-isocyanato-4-methoxy-naphthalene (996 mg) to yield methyl 4- {3- tert-butyl-5-[3-(1-methoxynaphthalen-4-yl)ureido]-1H-pyrazol-1-yl} benzoate as white crystals (845 mg, 36%). HPLC purity: 98%; mp: 278 280 ; 'H NMR (DMSO-d,): 6 8.76 (s, 1H), 8.73 ]

(s, 1H), 8.1 (m, 3H), 7.9 (d, 1H), 7.7 (4, 2H), 7.6 (m, 3H), 7.0 (d, 1H), 7.0 (d, 1H), 6.3 (s, 1H), 4.0 (s, 3H), 3.9 (s, 3H),1.3 (s, 9H). | Co ’ 5

EXAMPLE 59

H H

0

COoMe

The title compound was synthesized in a manner analogous to-Example 41 utilizing ’

Example X (1.37 g) and p-bromophenylisocyanate (990 mg) to yield methyl 4-{3-zerz-butyl-5-[3- (4-bromophenyl)ureido]-1H-pyrazol-1-yl} benzoate as white crystals (1.4 g, 59%). HPLC purity: 94%; mp: 270 272 ; 'H NMR (DMSO-d,): 89.2 (s, 1H), 8.6 (s, 1H), 8.1 (d, 2H), 7.7 (d, 2H), 7.4 (d, 4H), 6.4 (s, 1H), 3.9 (s, 3H), 1.3 (s, 9H).

EXAMPLE 60

I.

N

H H

2 OH

To a solution of Example 59 (700 mg) in 30 mL of toluene at -78 °C, was added dropwise .

a solution of diisobutylaluminum hydride in toluene (1M in toluene, 7.5 mL) over 10 min.

The reaction mixture was stirred for 30 min at -78 °C, and then 30 min at 0 °C.

The reaction mixture -

was concentrated in vacuo to dryness and treated with H,0. The solid was filtered and treated with acetonitrile.

The solution was evaporated to dryness and the residue was dissolved in ethyl

. 5 acetate, and precipitated by hexaries to afford yellow solid which was dried under vacuum to give 1-[3-tert-butyl-1-(4-hydroxymethyl)phenyl)-1H-pyrazol-5-yljurea (400 mg, 61%). HPLC purity: 95%; 'H NMR (DMSO-d,): § 9.2 (s, 1H), 8.4 (s, 1H), 7.5 (m, 8H), 6.4 (s, 1H), 5.3 (t, 1H), 4.6 (d, 2H), 1.3 (s, 9H).

Example 1 ) Example 2 . “ny hil ol : “ny 0 NPN

NN N es Nan AA

H H- : H H.

D D

. Example 3 . Example 4 lo) : sO Say, “ a

N A BW

~ N N N N g ; \

Si 3 A,

Yel Co

D : Yo :

Example 5 Example 6 E “ ee “A £00

N a N \

N” TN N” N “N HE N NTOHR OD A

Y<p p No - Wherein Y is O, S, NR6, -NR6SO2-, NR6CO-, alkylene, 0O-(CH2)n-, NR6-(CH2)n-, wherein } one of the methylene units may be substituted with an oxo group, or Y is a direct bond; D is ’ “ taken from the groups identified in Chart I © . :

oo Chart 1 :

R R R Re Ra o} Re . ~ : S NT 0 No he RE a ENP l= J Ia Wal Wl ~g Ng Ay vd SSN / N Ny

LA a Gt GE Se a

QR Q4 os

LT Coe FA Ry 2 Rq 0 0 AS 0 AS - oo ak Sa EA Reg ny SN A NaN Ny == Ne N R H ) gS A 4 ~ - IE Ru . 7 Q-8- Qo Q-10 Q-11 . 0 0 . 0 0 Q o]

R R : < A - OND (LN NL ND GA go : | | ANA AN Nw / ©Re ~ ORg N ORs Rs N ORs Rs ° Re 0 4 -

Co 12 ors “oe 1s 6 - Q-16 Q-17 o

Reg R wn OH SH

N “PSP com ol A :

To ~ S~ " re cn “L { i 0 : 3 3 x ORs HC CH, kd HiC CHg A ! vo. : FC iC i a Co

Q-18 Q-19 Q-20 Q21 Q-22 Q-23

Pe Ry 1 a Rq | NL (8) Ne Rs 0 i Reg Ze 0” “NW an NZ . o° J) T Jo

POR SS GRAN & : wo wo A I

I I IL YN, ~

A ( Py rr NO

Q-24 Q-25 - po ‘n '

Q-26 Q-27 Q-28 Q29

COZR, SO4Rs g ~

Soe IXY oP

SON(Ry), Ro Tors oN . , Hs

AN NN N ORg 4 G n S R4 “2 SZ / AF AF + F

Q31 Th Ta = es " Q-30 . Q-32 Q-34 Q-35 Co

Q-33

Example 7 Example 8 oo \. cl “ . N H H H H . B : S

S “N— .

NT = =o 0} 8) 3 H . . H . Example 9 Example 10 o ° pS) Way, “ al

N A J

N” °N . N

Sal =

IP 0 N

H ”

Example 11 Example 12 oo \ XY oO ra : 0 - oo Ba\ LOO iat LI : N x N NTN

NT N n N ] ] “N “H H - Va : S ’ ~S -

NT N

J =o A = 0”. N, | .

Example 13 Example 14 oO : Oo AN

I \ cl “ NTN

Bul, : Non Ah ’ H H H H . : ak CHa »=o I 0 073 ~N S

ON ry 0% ~N le) H

Example 15 Example 16 fo) : pS ia; | 0

N_ N nL / \ J \

N N N N—\

FH . S

N-" N . =o nT

S 0 0%) TN = : 4 H 0“ ~N - lo] HB

Example 17 TL Example 18 - 0 F } a) / aN NH

Ise g Swe

H H H H )

CHa CH

N —N . N —N . J =o | =o 0%} ~~N 0%} ~N oO H o H

Example 19 Example 20".

Lo - " Q NTN ‘ N_ ) AL) i ) A EN . N H H ) ~N N NT . H H . 0 (AN NTS

HaC le) HaC o

Example 21 Example 22 o oo

Say, | Ps peu; | dO

H NH OH ON

- . fo) ; A

Ww WW

NH © NH

HiC oy

HsC vo) HaC lo} ’ Example 23 : Example 24 o oo - o)

NAL, Ay - N H NOH OH 4

Cc

Ww VY

NN NSN

. : NH : NH

HsC . ’ HoT . .

Example 25 Example 26 : : 0 ; 0 yANy : oo

I \ Cl “ NZN ©

Bul, | DAD ; } H H H H } : fo} q AP . fo) A AP a .

PN D4 CHa PS pd Wak:

R . H CHs CHs

Example 27 Example 28 po) ay “ a : : . Ss :

N A | NAO) “N N N N - N

HoH OH NTR =, o O 0 : .

N\A . . fo) Oo Q

PN ON CHs PS \/ CH3 (o) N N o NTN

Ho Ch, Ho dn

Example 29 ’ Example 30- xX 0 XX oo

D0 DL Qs ~ N N NA N .

N H H N . N H H Va \“ X CH

ANN AH oS 3 : : | N Li, H Shy

Example 31 Example 32 ’ o 0 NPN a

IN c “

Bu, {NAGA

N OH : N OH

OH OH

AN - N

Co ) 0 :

Example 33 } Example 34 0 0 “A J =) I \ S -

N_ N nL N J A

Non ON NN 4,

P o y OH n Ov

OH

N : CON OH : © 0 . Example 35 - Example 36

CC \ | BYE : : / NH

Yee DAO oo Ny nu N : -H H 0 o) : N OH n OH : ) OH OH ' - MN : N oo 0 0

Example 37 . Example 38 : :

Nf a | 0 NA

N J : Kd \ J I : H OH MoH OH _

N~ : HNP N :

Ho pd)

HC Chis HaC : CH aC iC

Example 39 Example 40 o-

SOW SN i {

N og FNL ~ N™ °N N re ob 2 CHs © : =

HN N co ie ’ ~/ HN— N fo

HiC CH3 : [®) g

HC CHa c ? : oC : Example 41 : Example 42 0 FF 0- ;

I \ “ NH hl, \ | N_ \ A

H H. NH nH As oP CH 0

HN—/ N hv” N lo}

H3C CHjy HaC ° CHa - aC 3C 146 J

: Example 43 Example 44 o i (o] NPN ’ / . “ “At BNP y ~ on SE =0 - l_s=° ls % ‘ lo] -

Example 45 Example 46 : 0 o : “A jay; aN,

N_ N n—L4 N JL \ Lo

HOH HN / N aN CO : NT NY 0 ° he . % : Example 47 ’ Example 48 \ \/ pew CDN / Non MN Nou oH 4

NY ’ ~ sz © oC : _s° o) %

Example 49 Example 50 b. LO . LAO ~ N N— N . NOH OH H oN ’ ( ’ 2 O k 7

Vv : V 0%" NT cH, 07 “NT cH;

H H

Example 51 Example 52 o) E dro We

N_ N nL / \

N NN N Nan Hou \

Oo | Q : 0 _. \V/ V 07 “NT CH, 07 NT cH . H - H : - : Example 53 Example 54 : 0 Z . lo} }

LLCO OC

- SN N N SN NS N N

NN NOH OH 4

Oo Qo

Vv : vo 0% NT “CHa © NT cH

H H

Example 55 or Example 56 : o [os JN

NPN

. 1 \ Cl “ I : oul, Nay oy : . H H H H : 0 ee © (omen

CONHCH3 CONHCH3.

Example 57 : Example 58 } fo) . ’ . o . “A N i) T\ >

R N_ N nL N J \ ’

HOH oN “NOR Ja 0 “N q § om © N” NGONHCH;

CONHCH3 nn, } Example 59 Example 60 - \ / \/ o I o) / NH

LOD Rae ;

How H H 0” oe 0% NN” conHCH; -“CONHCH; NI

Example 61 Example 62 iE

Blo | eS Te 0 H H | 0 H H

N | SO;NHPh | SOpNHPh

Example 63 | Example 6 | ) patsy Than : QO H N H HN ~ SO,NHPh | J.

Exampic 05 Example £6 s <} SO,NHPh

Example 67 oo Example 68 Co 0 0 2~

JN ci “ NPN

O. iY LT . H H H H DE ' OEt : oo. AS —OEt 7 AW 72 . NH co

Example 69 Example 70

To. Lise “i 8

N_ \ :

NTN NTN N NN .

H Hy NOR a co

Lom g : AN, ACOH

Ny

Example 71 Example 72 . 0 FF o] y

NALD SN LO)

NG N” NX, Ng N7 ON

N H H N ; “N H H A

OEt 74

AN, 0 AW - ]

Example 73 Example 74

X ro x

Tel ~v “WT i N “A ry oO : “A. A, ( Nan Ao (

NN Ob g H H : Yep Y~p

Example 75 Example 76 x 0 x

IS Oo IN : | HH J Z g H H 77

Y~p Yep

Example 77 Example 78

X o SN X . I \ 7] UC jo] XN oud, | # NC

H H g Shy NTN SP g <} ) a . YD Y—p ° : - wherein X or Y is O, S, NR6, -NR6SO2-, NR6CO-, alkylene, O-(CH2)n-, NR6-(CH2)n-, wherein one of the methylene units may be substituted with an oxo group, or X or Y is a direct bond; D is taken from the groups ideritified in Chart I:

Chant 1 : ’ ) Re 0 Ry ’ . Ry Rs Ra Ss fu 0 N o ‘0 iN ’

I) N s N le) N N \ Va Ng R

The TH TH Jo 1% To : Bs Co nfie BN wt a wy AY

D-1 : D2 p-3t4 p-4f4 D-5 D-6 : fw Ref nf °o ANS RAYA : . To- © Re 3A A, Ri, p-& SANA

To) . 4 4 ’ H —~ Ne / N Hoo Ra “ih A 4 ~ D-10 D-11 . . Rs (VRY [6] . ]

D7 D-8 D-9 - 0 [o] [o] : 0

EN Re IAN NPN Pn h ORs

N ; N N AA AS A ORs x 0 0

AN ORs Tg A OR; Re ore ke Rs iN 4 Yo) .

D-12 oo D-14 Das D-16 D-17 [o] Tanne OH SH . . Re . } . : ol : 3 “N Fl 0 fy [of rs 0 COoH hoy” Nu Nw .

Je pd ho—— [2] oH 0 H L LJ

RY HC CHa Hie Che A # A # : : . ORs 5 f +, CA oS ’ D-22 D-23

D-18 p-19 D-20 D-21 | : 0 a) H HoH ZR x 0 rn IO de oe °C “SC -. 0 N~ N - HN NT TZ NA n o 0 | ] .

Orn Or NES ww w” Sw Nw x

Va a AF SF he he i A +, ) p24 : D-25 D-26 D-27 D-2% Dae

SOwRs - COZRy ! 0. 0 . ( COR, o NH Rg i XJ 4 Va ~~ SON(Ra): Na N Rs ore ° Re NS yd AN ORg -

D-31 D-32 D-33 D-34 D-36 i

D-30 D-35 ’ Specific examples of the present invention are illustrated by their structural formulae below:

Example 79 Example 80 : } 0 } 0 oO ~~" : 0 NST ‘ “A NL > PALLY CS . SN N” °N g N H H .

H H i . . J. . : NT S 0

J =o Pa 0 N

Example 81 Example 82

Co 0 NP EN 0 0 SN Co

Cr DLO ~S. S,

N N— lo] ] Q '

Example 83 Example 84 0 © SSN : 0 SN .

RV cenciie Nicaasl

N 7 \

NN ) Noy oy A

NI Ls oN o N

Example 85 ) Example 86 } : o . . i \ J NT) N “ 1 h

NG” SN SN Na SN / : SN N . . . H H g i H H . - Shs : i | FHa .

Ce g : nN

ES We l= 0%) ™N o% : o : 0 H [o] H 2 87 ’ Example 88 : ol 0. N °

DATO pS LOO

N N N XN

FH CHs oo : y—N : : nN

H=o | =o

Oo? ~N oF ~N

O H o H . ’ Example 89 . Example 90 [o] © XN

RN Toaas pSSTs nas - N I BS

N FF . . ~N N Hy @ Nan Wo

FHa ch . _N 3 h No Sy oF =o o H oN . ) fo) . .

Example 91 oo Example 92 o

LATO DOO

Ia wr NA,

NNT ONS . Ny H : . “HH g S :

J 00 : 0 - ’ : 2 oo 4

NTN NH :

HC % : ©

Example 93 ] Example 94 ' 1) 0 lo] AS lo] pN -

LLC LLY MAGI

“Hi, TO DU oN

NOW H g HH 0 Lo oo : ¥ 2s . N=" \ N \ :

NH NH

Ho ooh

HG HC

Example 95 ’ Example 96 ; . 0} = ° =

DAOC hua e 58! - I, Pp

HoH 9 NOR H 00 : 1 BY a a | NH , C HaC

Example a ' Example 98 0

CATO D0

NTN ) H H ) ‘ fo] (e] jo} ’ 0 EN ya \/ hp: cH ~~ ’ WENDEL : oS 3

ET Ho CH,

GL 99 Example 100 . . fo) o 9 EN 0)

DLOCTO DLO

N N A

NY N N 9 . P Nan N ZN oc O 0 ’ \Y4 : o 9 PO 8 CH \W 4

Ne ~N7 3 ANAK, Hs " Cs H CHa

Example 101 Example 102 :

NOCD ISAS

© oN I \

WON ON 9 Nan No ZF

Q TWN

’ o O 0 \V 4 S o 0 0 : S H \ # . iE WN “n° 3 J os .

RC Ho dh,

’ Example 103 Example 104 ’ ] EE “ I ir Ta

Ml N

DALY WP N \ A WA - ~N ) N H H .

H H . | . [o] ’ [0] ) . - N OH : OH

OH .

N OH N } . eo) 0 1 105 Example 106 fo 0 N ° fo} : . N, .

N7 TN N N_ : HE g ae oN o | 0] \ OH" : N OH <0

A OH A OH

0 'e}

Example 107 Example 108 0 o_ XN o

J \ 1 4g OU o XN

NQ A IN g } N N N J) Noy on pr [eo] . 4 : N 4 OH a. ~ 0% / } OH

Yo AN {

Example 109 Example 110 . 0 Oy ~ “r 0 Na ~~ . 1] N ol $ AP RAN ) NA WP . N 9 NH oH .

HH

GH; © . CH; O oJ ] N . in” N= HN -

Ha oH Hac oh 2C . 3C . 2 ti Example 112 lo} 0 NN 0 0.

SUNOS . ig) DE

N

SER C IER ee =

Ce oe 1} o HN—p/ -

H3C- CHa HC ° CH, . 1C aC . : Example 113 Example 114 . 0 0 NN psSToens AOD

N 7 I \ :

J ERRG J, >) ~ PN ~~ - : 012 : CH; 0

N ] :

HN HN N . . o .

HsC CH3 HaC 0 CHa aC ol :

Example ns Example 116 ) le} 0 AA “n SO e ot C) A . Ao WL

NH oH ) H H

Clo ge % 3 0

Example 117 - Example 118 [e] 0 x : o 0} ud, JOAe “A LOO

NOH OH 9 Z SNOONTN N

Co N N ~ \ 3 0 : 0

Example 119 Example 120

[0] 0 XN ' psSleens TC

N ~ I \

SONY 0) iv. i _

N . % L_s° to

Example 121 ~ Example 122 0 : 0 OT i he'd es! SOS: HO Lb . Sn NTN 0) Noy oH : oo fH. H : . Oo - (oe) : \V . a. WV 1% 0? Ny h@) " AS

H :

XT 123 , Example 124 . 0 0 x 0 © } sS isan oli STs ans

Qo 0 : .

WV : V 0 0 Co 0 Co

H H

Example 125 Example 126 0 0 NN : Pe

HAT hao o

N ]

NON 9 gl i on A oe

Oo [e] h

V V oO nN” AD fe) NT NY . .

Ho

Example 127 Example 128 ° o oO “ 1 SY

JN JL _P° ND Ny oN Ly “SN N N N H H 3% 0 g 0 Nn" NconkcH, 0 IQ CONHCH3 _— ~ TCONHCHy

Example 129 Example 130 ’ . 0 0 : 0] : RN lo}

N N N :

YY Y&R - 0 N"" NGONHCH, 0 N"NCONHCH,

N_— _— : Example 131 Example 132 : 0 (o} RN . 0 x \ 0) MRS 0 N

Bul P Is uS [

HH H H

ZZ \

Cm bu : CONHCH3 N_— :

Example 133 Example 134 . o } o SNe Wa “ 1 NST)

J \ A 9 oo r UN N” °N : A . . “Nn N N N H H 3 S 4 } " SONHPh SOZNHPh

Example 135 : Example 136 . : lo) 0 o ! EN fo ~~ pee! SOAs hd ON ~N ONTN =N Nay? NTN oN

H H 9 H H .

SO NHPh SO;NHPh

Example 137 Example 138° (6) > '

[0] N Oo - aN

DATO Thy ut | _ BES @

HOH ) NNT :

SOoNHPh SC,NHPh

: Example 139 Example 140 o)

LOCO OO ot C) ( 4p wn A

NLR ) H H -&_~OEt 2A OEt a Ny Ny 1 141 Example 142 0 0 x o o ySicas elie: Vicagy

N

: yy : wy _-OEt OEt

A —

CW Nu

Example 143 Example 144 0 0 NN : o x

HDALOCT hao e

N_ I \ . SDS IIRL e's - _~OEt | OEt

Nr a S

NH

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 10/746,545, filed December 24, 2003, and

Anti-Cancer Medicaments, S/N 10/746,607 filed December 24, 2003. 164

Amended sheet: 3 October 2006

Claims (48)

We Claim:

1. A compound having the formula (R~(X)-)m-A-NH-CO-NH-D-(E))-(Y)-Q @ : wherein: R) is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NRg-, -NRgSO,-, -NRgCO-, alkynyls, alkenyls, alkylenes, -O(CHy)p-, and -NRg(CH;)y-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CH,)y-, and -NR¢(CH,)s-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH,),- 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, and —(E)-(Y)-Q is joined to D at an ortho position relative to the NH group attached to D; jisOorl; misOorl; nisOorl; qisOorl; tisOor 1; 166 Amended sheet: 3 October 2006 a ¥

Q is selected from the group consisting of R R, o Re i Re Fu Re s N, No oo Ol 0, N y S Th TH TH T= J JT N © N © N AN ug SN gn ys EI SL HN we ® Q-1 ” Q2 QR QR Q-4 06 A Re R, P R, P o QQ ° 0 A ya NN FA, FA Re, AM Re SAK ~ © Ne N Ne z AE J : me wh ~ : Ry 00 0 Q-7 Q-8 Q9 Q-10 Q-11 0 0 Q 0 fo) 0 R, “OL Reg Reng SN “A 9% N N Rs OR, aS ORs Rs aa AYN , 4 'o) » . , , , © ’ wan Q-i2 os Q14 Q-15 Q-16 Q17 fo} www OH H “, FE . J Rs S y He CO, CH, Ho CH, L J L (A oR, H,C } ¢ i 1 va , “w oe H-19 os 0a Q-22 Q-23 [o] o] H H He ZR, Jaen Aan Of DES A LOT Ig ) No { Xw i Xu AN AN | ve ra Poor Wwe Q-21 ’ PY : “ is aon 0-28 Nn_10 Q-25 Q-26 Q-27 ~ Q-20 SOR, COZR, o 0. J ( 0 ) . Re | XJ Nn NN SONR), Fo [Non ~N" R, i$ oA “<r, Rg n oS » Nr oS NN A y Nd AA wa NF he Lm o£ 030 Q2 os Q-3 Q-35 167 Amended sheet: 3 October 2006

: each W is independently and individually taken from the group consisting of CH or N; each Ry group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, 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 R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each Rs is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each Rg is individually selected from the group consisting of -H, alkyls, allyls, and B-trimethylsilylethyl; each Ry is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each Ry group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two Rg groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and each Z is individually selected from the group consisting of -O- and - NR4)-; each ring of formula (I) optionally includes one or more of Ry, where R; is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; except that: 168 : Amended sheet: 3 October 2006 y T when Q is Q-7, q is 0, and Rs and D are phenyl, then A is not phenyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl, or imidazolyl; when Q is Q-8, then Y is not -CH,0-; when Q is Q-10, t is 0, and E is phenyl, then any R; on E is not an o- alkoxy; when Q is Q-11, t is 0, and E is phenyl, then any R; on E is not an o- alkoxy; when Q is Q-24, Q-25, Q-26, or Q-31, then the compound of formula (I) is selected from the group consisting of R R 7 R Da 0 7s 2 ww 0 Wy yy ecm NE a A HARM , : and ] NN wherein each W is individually selected from the group consisting of -CH- and -N-; each G, is individually selected from the group consisting of -O-, -S-, and - N(R4)-; and * denotes the point of attachment to Q-24, Q-25, Q-26, or Q-31 as follows: 9 00 0 00 Yr i WP Vor 1 AZRe Oz Ay He wy ea al GE Ra Rs CQ OF 0 PD - - Q-24 Q-25 Q-26 or Q-31 ‘wherein each Z is individually selected from the group consisting of -O- and —N(R4)-; 169 Amended sheet: 3 October 2006 v ip when Q is Q-35 as shown 0 0 ZRqg ZR ”y (© A 10 Q-35 (para) ) Q-35 (meta) wherein G is selected from the group consisting of -O-, -S-, -NR4-, and -CH;-, kisOor1l,anduis 1, 2, 3, or 4, then (R}-(X)-)-A-NH-CO-NH-D-(E) )-(Y)-* is selected from the group consisting of R R 7 Ry Tv Oo VB bY w Sw 0) SF CA-(X)-Rym Ay Arm NS N iT KA orm ! , , and . H

2. The compound of claim 1, wherein 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. 170 Amended sheet: 3 October 2006 v r

3. The compound of claim 2, where R; is selected from the group consisting of N Gt fr OL Q > > = QO , O [0] 4 Pg ’ NTR Re hy ’ N Rs wn wn hN an A ¢ { oO ECS On 0" >N""0 VS TR SA cl (RL N H © H Ra R ) ce We Re ANN Ne -N SN YN CS ~ + XL \ NTN HO HO HUT i HO H > H , > , and \ } Ry Re each R; is individually selected from the group consisting of -H, alkyls, aminos, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, halogens, alkoxys, and hydroxys; each Rj is individually selected from the group consisting of -H, alkyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, alkoxys, hydroxys, cyanos, halogens, perfluoroalkyls, alkylsulfinyls, alkylsulfonyls, R{NHSO,-, and - NHSO;R,.

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, purinyl, and 171 Amended sheet: 3 October 2006

Kl T ! wn Se, Ww, oh J wy wy ‘ where each W, is individually selected from the group consisting of -CH- and

-N-.

5. A molecule having the formula (R1-(X))-)m-A-NH-CO-NH-D-(E))-(Y)-Q an wherein: R; is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NRg-, -NR¢SOz-, -NRgCO-, alkynyls, alkenyls, alkylenes, -O(CHy),-, and -NRg(CH;)y-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CHy)h-, and -NRg(CHz)n-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH,),- 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; 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; 172 Amended sheet: 3 October 2006

» jisOorl; misQorl; nisOor 1; qisOor 1; tisOorl; Q is selected from the group consisting of Re R. Re S J 0, J . oul A he hg he he hE a 7 Ho O [o} N p= N =o Ne =o AN wt , ag" A , Hy = 4 s , wf ND vn R, % er Q2 Q3™ Ra 0 25, Ry R ny R. 2 [o} Q 0 0 Vi J 4 . \ / £ \ 4 Jo A, AA, Re, Pe NNN 2) 4 H ~_ PON N an Ro Gt Ga ¢ Q-7 Q-8 Q-9 Q-10 Q-11 0 o 0 0 ” 9)

[0] 4 x, R, Ris SN NPN “N Rs No Up SUVS NIV ONIN De OR, EN OR, R¢ OR, x 4 Rs © , Wf % , -1 » , , s : wan ar on Q-14 Qs Q-16 Q17 R, pd _ - 5 fo) a “"v Jol i i h Rs & P i ad co, [vo wl Sw g Sw ug / cl on, HC Oe CH, L, i. L, (A oR, : He , id cow mq ots 19 om: oa Qn Q-23 Top TN Lo Nr © NRT AN " Pa Cf A I 7% H | H SO,H 00 x A, A x J J 0 Wad LZ LS a Q-24 Q-25 Me le Q-27 Q-28 Q-29 SO;R, COZR, o 0. J I o ) COZR, Re || pe Nom nN SONR), Ro Sor, ~N R, $ Ng r, p » HN» i wd , vA , od wd . od ,and J H 030 Q-31 032 os Q-34 Q-35 173 Amended sheet: 3 October 2006 each W is independently and individually taken from the group consisting of CH or N; each Ry group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, 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 Ry groups are bonded with the same atom, the two R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each Rs is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each Rg is individually selected from the group consisting of -H, alkyls, allyls, and B-trimethylsilylethyl; each Rg is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each Ry group is individually selected from the group consisting of -H, -F, and alkyls, wherein when two Rg groups are geminal alkyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and each Z is individually selected from the group consisting of -O- and - N(R4)-;

each ring of formula (I) optionally includes one or more of R;, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos,

cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys,

alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls,

alkylsulfonyls, aminosulfonyls, and perfluoroalkyls;

for use in a method of modulating the activation state of p38 a-kinase,

174 Amended sheet: 3 October 2006

; q wherein the method comprises the step of contacting said kinase with the molecule and thereby causing modulation of said activation state.

6. The molecule of claim 5, said contacting step occurring at the region of a switch control pocket of said kinase.

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

9. The molecule of claim 8, said region being selected from the group consisting of the a-C helix, the a-D helix, the catalytic loop, the switch control ligand sequence, and the C-lobe residues and combinations thereof.

i0. The moiecuie of claim 9, said a-C helix including SEQ ID NO. 2.

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

12. The molecule 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 molecule of claim 9, said C-lobe residues including SEQ ID NO.

6. 175 Amended sheet: 3 October 2006 v 1

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

15. The molecule of claim 5, said activation state being selected from the group consisting of the upregulated and downregulated states.

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

17. The molecule of claim 5, said molecule being an agonist of the off switch control pocket for said kinase.

18. The molecule of claim 5, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory discase, bone resorptive diseases, graft-versus-host reaction, Chron’s disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.

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

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

21. An adduct comprising a molecule of claim 1 bound with a kinase. 176 Amended sheet: 3 October 2006 :

22. The adduct of claim 21, said molecule binding at the region of a switch control pocket of said kinase.

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 (I) molecule.

24. The adduct of claim 22, said switch control pocket selected from the group 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 a-C helix, the o-D helix, the catalytic loop, the switch control ligand sequence, and the C-lobe residues and combinations thereof.

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

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

28. The adduct of claim 25, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 5, SEQ ID NO. 6, and combinations thereof.

29, The adduct of claim 25, said C-lobe residues including W197, M198, H199, Y200.

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

31. Use of a molecule having the formula 177 Amended sheet: 3 October 2006

Coby

(R1-(X))-)m-A-NH-CO-NH-D-(E))-(Y)-Q ay wherein:

R; is selected from the group consisting of aryls and heteroaryls; each X and Y is individually selected from the group consisting of -O-, -S-, -NRs-, -NR¢SO;-, -NRcCO-, alkynyls, alkenyls, alkylenes, -O(CHz)h-, and -NRg(CHjy)n-, where each h is individually selected from the group consisting of 1, 2, 3, or 4, and where for each of alkylenes, -O(CHy)u-, and -NRg(CHaz),-, one of the methylene groups present therein may be optionally double-bonded to a side-chain oxo group except that where -O(CH,)p- 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; 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;

jisOorl;

misOorl;

nisOorl;

qgisOorl;

tisOorl;

Q is selected from the group consisting of

178 Amended sheet: 3 October 2006 su 0 Fo . Re o J s Al N \ y o od a N 4 Th TH Jo J JL gs gs of i Ug N I \ 4 No. Qi Q2 Qf Q4™ or Q-6 " o Ja R, P R, P 0 A Ya 0 A A J TN A NN AA Se MN N , R, CR Q-7 Q-8 Q-9 Q-10 Q-11 o) Q Q 0 0 0 R, “OL Ry Rey SVN A J ] LAS ~ x ’ OR, Ng | on, Ri oR, f 0 AY W \ i -12 s i wn or Q-14 Q15 Q-16 Q-17 0 nan OH SH

R. 0 JOSIE ~ coo OS OY 3 HC >] cen, Oo ( ™ ORs ro ore fC , ne or a > ’ wd Z ’ iC ’ iC a 23 Q-18 Q-19 Q-20 Q-21 Q- fo) H H ZR,

RY . Jaen ne 5 © Re _Ry © NR Q N v Hi N ‘ SOH NS B AN °° Rq A Nu Sr NA TY Q-24 Q-25 Q-26 © Q27 Q-28 Q-29 COZR, o 0. pe ( ; , | be; oe 0 N COR SONR), Re on fo} N . i$ o Be, XN » N | ~ | N | Ny ,and ; Ton Th rT ) Ll 0-30 Q-32 0 Q-34 Q-35 179 Amended sheet: 3 October 2006 ei each W is independently and individually taken from the group consisting of CH or N; each R4 group is individually selected from the group consisting of -H, alkyls, aminoalkyls, alkoxyalkyls, aryls, aralkyls, heterocyclyls, and heterocyclylalkyls except when the R, 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 R4 groups optionally form an alicyclic or heterocyclic 4-7 membered ring; each Rs is individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arylthios, cyanos, halogens, perfluoroalkyls, alkylcarbonyls, and nitros; each Rg is individually selected from the group consisting of -H, alkyls, allyls, and B-trimethylsilylethyl; each Ry is individually selected from the group consisting of alkyls, aralkyls, heterocyclyls, and heterocyclylalkyls; each Rg group is individually selected from the group consisting of -H, -F, and alkyis, wherein when two Rg groups are geminai aikyl groups, said geminal alkyl groups may be cyclized to form a 3-6 membered ring; and each Z is individually selected from the group consisting of -O- and -NR4)-; each ring of formula (I) optionally includes one or more of R;, where R7 is a noninterfering substituent individually selected from the group consisting of -H, alkyls, aryls, heterocyclyls, alkylaminos, arylaminos, cycloalkylaminos, heterocyclylaminos, hydroxys, alkoxys, aryloxys, alkylthios, arthylthios, cyanos, halogens, nitrilos, nitros, alkylsulfinyls, alkylsulfonyls, aminosulfonyls, and perfluoroalkyls; in the manufacture of a medicament for use in a method of modulating

180 Amended sheet: 3 October 2006 the activation state of p38 a-kinase, wherein the method comprises the step of contacting said kinase with said molecule; and thereby causing modulation of said activation state.

32. The use of claim 31, said contacting step occurring at the region of a switch control pocket of said kinase.

33. The use of claim 32, said switch control pocket of said kinase comprising an amino acid residue sequence operable for binding to said Formula (II) molecule.

34. The use of claim 32, said switch control pocket selected from the group consisting of simple, composite and combined switch control pockets.

35. The use of claim 34, said region being selected from the group consisting of the a-C helix, the a-D helix, the catalytic loop, the switch control ligand sequence, and the C-lobe residues and combinations thereof.

36. The use of claim 35, said a-C helix including SEQ ID NO. 2.

37. The use of claim 35, said catalytic loop including SEQ ID NO. 3.

38. The use of claim 35, said switch control ligand sequence being selected from the group consisting of SEQ ID NO. 4, SEQ ID NO. 5, and combinations thereof.

39. The use of claim 35, said C-lobe residues including SEQ ID NO. 6.

40. The use of claim 31, said kinase selected from the group consisting of the consensus wild type sequence and disease polymorphs thereof. 181 Amended sheet: 3 October 2006 or. ~ ® Ia) vy .

41. The use of claim 31, said activation state being selected from the group consisting of the upregulated and downregulated states.

42. The use of claim 31, said molecule being an antagonist of the on switch control pocket for said kinase.

43. The use of claim 31, said molecule being an agonist of the off switch control pocket for said kinase.

44. The use of claim 31, said method including the step of administering said molecule to an individual undergoing treatment for a condition selected from the group consisting of human inflammation, rheumatoid arthritis, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic pulmonary inflammatory disease, bone resorptive diseases, graft- versus-host reaction, Chron’s disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof.

45. The use of claim 44, said molecule being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.

46. The use of claim 31, said molecule having the structure of the compound of claim 1.

47. A compound of claim 1, as specifically described herein.

48. An adduct of claim 21, substantially as herein described with reference to any one of the illustrative examples. 182 Amended sheet: 3 October 2006