AU2003204708B2 - Inhibition of Raf Kinase using Substituted Heterocyclic Ureas - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Bayer Corporation CULLEN CO.

Level 26 239 George Street Brisbane Q1d 4000 Invention Title: Inhibition of Raf Kinase Substituted Heterocyclic Ureas Using The following statement is a full description of this invention, including the best method of performing it, known to us: INHIBITION OF RAF KINASE USING SUBSTITUTED HETEROCYCLIC UREAS Field of the Invention This invention relates to the us eof a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Background of the Invention The p21" oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann.

Rep. Med. Chew. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins.

In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by coexpression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J.

Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991. 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).

Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21 r the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are'useful in the treatment of human or animal, murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating solid cancers, such as, for example, carcinomas of the lungs, pancreas, thyroid, bladder or colon, myeloid disorders myeloid leukemia) or adenomas villous colon adenoma).

The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds and methods for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula I: 0 A-NH-C-NH-B I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below.

The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.

Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of which is a 5-6 member aromatic ring. One or more of these rings may have 1-4 carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms.

Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, isoquinoline, phthalimidinyl and combinations thereof, such as, diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenylamine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pyridinylnaphthyl thioether, and phthalimidylmethylphenyl.

Examples of suitable heteroaryl groups include, but are not limited to, 5-12 carbonatom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.

For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 2- or 3pyrrolyl, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 4- or 5-oxazolyl, 4or 5-isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothiazolyl, 3- or 4-pyridyl, 4-, or 6-pyrimidinyl, 1,2,3-triazol-l-, or -5-yl, 1,2,4-triazol-l-, or -5-yl, 1- or tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2or -5-yI, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 5- or 6-2H-thiopyranyl, 3- or 4-4Hthiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 6- or 7-benzofuryl, 4-, 6- or 7-benzothienyl, 6- or 7-indolyl, 4- or benzimidazolyl, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 5- 6- or 7-benzisoxazolyl, 6- or 7-benzothiazolyl, 6- or 7-benzisothiazolyl, 6- or 7-benz-1,3-oxadiazolyl, 7- or 8quinolinyl, 8- isoquinolinyl, 4- or 9-carbazolyl, 2-, 8- or 9-acridinyl, or 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl. 5-methyl-2thienyl, 4-methyl-2-thienyl, I-methyl-3-pyrryl, I-methyl-3-pyrazolyl. 5-methyl-2thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl portions of groups, alkoxy, etc., throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

Suitable aryl groups include, for example, phenyl and 1- and 2-naphthyi.

Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, etc. The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C 4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups.

Suitable halogens include F, Cl, Br, and/or I, from one to persubstitution all H atoms on the group are replaced by halogen atom), being possible, mixed substitution of halogen atom types also being possible on a given moiety.

As indicated above, these ring systems can be unsubstituted or substituted by substituents such as halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CN, -COR 5

-C(O)R

5

-NO

2

-NR'R',

-NR'C(O)OR -NR 5

C(O)R

5

C

1 alkyl, alkenyl, C,-C,o alkoxy, C,-C, 1 cycloalkyl, C 6 aryl, C 7

-C

2 4 alkaryl, C,-C 3 heteroaryl, C 4

-C,

3 alkheteroaryl, substituted alkyl, substituted C,-Co, alkenyl, substituted C,-C,o alkoxy, substituted C,-Co, cycloalkyl, substituted C 4 alkheteroaryl and -Y-Ar.

Where a substituent, X or is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of-CN,

-COR

5

-C(O)R

5 -C(O)NRR -OR 5

-NR'R

s 1

-NRC(O)R',

-NRsC(O)OR' and halogen up to per-halo substitution.

I

The moieties R' and R" are preferably independently selected from H. C,-Clo alkyl,

C,-C,

0 alkenyl, C 3

-C,

0 cycloalkyl, C,-C, 4 aryl, C 3

-C,

3 heteroaryl, C,-C, 4 alkaryl, C 4

-C,

alkheteroaryl, up to per-halosubstituted

C,-C

0 alkyl, up to per-halosubstituted C,-Co alkenyl, up to per-halosubstituted

C

2 -Clo cycloalkyl, up to per-halosubstituted Cr-C, 4 aryl and up to per-halosubstituted C 3 heteroaryl.

The bridging group Y is preferably

-CH(OH)-,

-(CH

2 -CHX, and where m 1-3, and X' is halogen.

The moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by wherein ni is 0 to 3.

Each Z substituent is preferably independently selected from the group consisting of -CN, -CO,RS, -C(O)NR'R 5 NR', -NO 2 SRS, NR'R', -NR'C(0)ORs,

-NR

5 C(O)R, -SO 2 RS, -SONR'Rs, C,-Co alkyl, C,-C 0 o alkoxy, C,-C 10 cycloalkyl, C 6 aryl, C 3 heteroaryl, C,-C 24 alkaryl, C 4 alkheteroaryl, substituted alkyl, substituted cycloalkyl, substituted C,-C, 4 alkaryl and substituted 23 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of-CN, -COR', -ORS, -SR 5

-NO

2 -NRRS', -NR'C(O)RS', -NRsC()OR 5

CI-C,

0 alkyl, alkoxy, cycloalkyl, heteroaryl, C,-

C,

4 aryl, C 7

-C,

4 alkaryl.

The aryl and heteroaryl moieties of B of Formula I are preferably selected from the group consisting of

I

0

R

5

N

0

R

and and which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n 0-3.

Xn -Q-4YQi- z, The aryl and heteroaryl moieties of B are more preferably of the formula: wherein Y is selected from the group consisting of-O-, -CHS-, -CHO- and -OCH,- and X' is halogen.

Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4 members of the group consisting of N, O and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution.

X, Z, n and nl are as defined above and s 0 or 1.

In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, or Y-Q' is phthalimidinyl substituted or unsubstituted by halogen up to per-halo substitution. Z and X are preferably independently selected from the group consisting of -Rb. -OR 6

-SR

6 and -NHR', wherein R' is hydrogen, C,-C,,-alkyl or C 3 cycloalkyl and R 7 is preferably selected from the group consisting of hydrogen, C, C -alkyl, C 3 -C,-cycloalkyl and C 6 -Co-aryl, wherein R' and R' can be substituted by halogen or up to per-halosubstitution.

The heteroaryl moiety A of formula I is preferably selected from the group consisting of: RC Ra N R RC 4 R' R R R1 R% N O N N N N N N RIR R R R I .A IRand

S

R R The substituent R' is preferably selected from the group consisting of halogen,C3-Co alkyl, cycloalkyl, Ci-C 1 heteroaryl, aryl, C,-C,4 alkaryl,_up to perhalosubstituted alkyl and up to per-halosubstituted C 3 cycloalkyl, up to perhalosubstituted C,-C,3 heteroaryl, up to per-halosubstituted C6-C,, aryl and up to perhalosubstituted alkaryl.

The substituent R 2 is preferably selected from the group consisting of H, -CO,R -C(O)NR 3 alkyl, cycloalkyl, alkaryl, C4-C23 alkheteroaryl, substituted C,-C alkyl, substituted cycloalkyl, substituted C,- C, alkaryl and substituted alkheteroaryl. Where R' is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, COR, -C(O)-NR 3 R' -OR 4 and halogen up to per-halosubstitution.

R' and R' are preferably independently selected from the group consisting of H, -OR',

-NR

4

R

4 -COR, -C(O)NRR 4 CI-Clo alkyl, C 3 -Co cycloalkyl, C 6

-C

14 aryl, heteroaryl, alkaryl, C 4 alkheteroaryl, up to per-halosubstituted alkyl, up to per-halosubstituted cycloalkyl, up to per-halosubstituted C,-

C,

4 aryl and up to per-halosubstituted C 3 heteroaryl.

R' and R 4 are preferably independently selected from the group consisting of H, C,- Clo alkyl, C 3 -Co cycloalkyl, C,-C, 4 aryl, heteroaryl; C-C 2 4 alkaryl, alkheteroaryl, up to per-halosubstituted alkyl, up to per-halosubstituted cycloalkyl, up to per-halosubstituted C 6 aryl and up to per-halosubstituted heteroaryl.

R' is preferably alkyl, cycloalkyl, up to per-halosubstituted alkyl and up to per-halosubstituted C3-C, cycloalkyl, Rb is preferably hydrogen or halogen.

R' is hydrogen, halogen, alkyl, up to per-halosubstituted C,-C,o alkyl or combines with R' and the ring carbon atoms to which R' and RC are bound to form a or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from O, N and S; The invention also relates to compounds of general formula I described above and includes pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula R1

N

N NH-C-NH- R2

NH-C-NH-B

wherein R2 R' and B are as defined above; 9 and both 5.3- and 3,5- isoxazolyl ureas of the formulae

R'

NH-C-NH-B

R'

N^

I

NH-C-NH-B

wherein R' and B are also as defined above.

Component B for these compounds is a 1-3 ring aromatic ring structure selected from the group consisting of:

RO

O

RS

or which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here R' and R 5 are as defined above, n 0-2 and each X' substituent is independently selected from the group of X or from the group consisting of-CN, -CO,R 5

-C(O)R

5

-C(O)NR

5

R

5

-OR

5 NO,, -NR'R 5 C,-C,o alkyl, C, ,,-alkenyl, C,.,,-alkoxy, cycloalkyl, aryl and alkaryl.

The substituent X is selected from the group consisting of -NR 5 C(0)OR',

NR

5 C(O)R, C 3

-C

3 heteroaryl, C 4

-C

2 3 alkheteroaryl, substituted alkyl, substituted C 2 ,,,-alkenyl, substituted C 1 1 ,-alkoxy, substituted C 3 cycloalkyl, substituted C 6

-C,

4 aryl, substituted alkaryl, substituted C 3 heteroaryl, substituted C,-C2, alkheteroaryl, and -Y-Ar, where Y and Ar are as defined above. If X is a substituted group, as indicated previously above, it is substituted by one or more substituents independently selected from the group consisting of-CN, -C(O)NRSR', -SR 5 -NRsR 5 N02, -NRC(O)R', -NR 5 C(O)ORS' and halogen up to per-halosubstitution, where R 5 and R' are as defined above.

The components of B are subject to the following provisos, where R' is t-butyl and R' is methyl for the pyrazolyl ureas, B is not

C()OC

4

H,

Where R' is t-butyl for the 5,3-isoxazolyl ureas, B is not Re wherein R' is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-propyl, -C(O)NH-

-OCH,CH(CH)

2 or -O-CH 2 -phenyl. Where R' is t-butyl for the isaxazole ureas, B is not 0 a O-CH 2 _0 and where R' is -CH2 -t-butyl for the 3,5 -isoxazolyl ureas, B is not 0

CH

3 Preferred pyrazolyl ureas, 3,5-isoxazolyl ureas and 5,3-isoxazolyl ureas are those wherein B is of the formula xn l wherein Q, X, Z, Y, n, s and n I are as defined above.

Preferred pyrazole ureas more particularly include those wherein Q is phenyl or pyridiny], Q' is pyridinyl, phenyl or benzothiazolyl, Y is

-SCH,-,

-OCI-L or and Z is H, -SCH,o -NH-C(O)-CPH~p- 1 wherein p is 1-4, n s=lI andnlI 0-I1. Specific examplesof preferred pyrazolyl ureasre:

N-(

3 -ter:-Butyl-5-pyrazolyl)-N'-(4-phenyloxyphenyl)urea; 3 -(3-methylaminocarbonylphenyl)oxyphenyl)urea; t(3 -(4-pyridinyl)thiophenyl)urea; '-(4-(4-pyridinyl)thiophenyl)urea;

N-(

3 -tert-Buyl-5-pyrazoylyAT t( 4 -(4-pyridinyl)oxyphenyl)urea; 4 4 -pyridinyl)methylphenyl)urea; -Methyl-3 -tert-butyl-5 -pyrazolyl)-N'-(4-phenyloxyphenyl)urea I -Methyl-3 -rer:-butyl-5-pyrazolyl)-N 3 4 -pyridinyl)thiophenyl)urea; 1 -Methyl-3-rert-butyl-5-pyrazolyl)-N'-(( 4 -(4-pyridinyl)thiomethyl)phenyl)urea; 1 -Methyl-3-:ert-butyl-5-pyrazolyl)-N 4 -(4-pyridinyl)thiophenyi)urea; 1 -Methyl-3-tert-butyl-5-pyrazo Iyl)-N 4 -(4-pyridinyl)oxyphenyl)urea; 1-Methyl -3-tert-butyl-5-pyrazolyl)-N'-(( 4 4 -pyridinyl)niethyloxy)phenyl).

urea; I -Methyl-3-rert-butyl-5-pyr-azolyl)-N t( 3 -(2-benzothiazolyl)oxypheny)urea; N-(3-terz-butyl-5-pyrazoly1)-N '-(3-(4-pyridyl)thiophenyl) urea; '-(4-(4-pyridyl)thiophenyl) urea;

N-(

3 -terz-butyl-5-pyrazoly)N'-(3-(4-pyidyl)oxyphelyl) urea;

N-(

3 -Iert-butyl-5-pyrzolyl)-N.(4-(4-pyiidyl)oxyphenyl) urea; I-mcrhyl-3-terr-butyl-5 -pyrazolyl)-N 3 -(4-pyridylfthiophenyl) urea; 1-methyl-3-rer:-butyl-5-pyrazolyl)w '-(4-(4-pyridyl)thiophenyl) urea; 1 -methyl-3-terz-butyl-5-pyrazolyl)-N -(3-(4-pyridyl)oxyphenyl) urea; and 1-methyl-3-rerr-butyl-5 -pyrazolyl)-N '-(4-(4-pyridyl)oxyphenyl) urea.

Preferred 3,5-isoxazolyl ureas more particularly include those wherein Q is phenyl or pyridiny], Q' is phenyl, benzolhiazolyl or pyridinyl, Y is or -CH 2 Z is -CH 3 Cl. -OCH, or -C(O)-CH 3 ni 0, S 1, and ni 0-1. Specific examples of preferred ureas are N-(3 -Isopropyl-5-i soxazolyl)-N'-(4-(4-pyridiny])thiophenyl)urea;

N-(

3 -zer:-Butyl-5-isoxazolyl)w '-(4-(4-methoxyphenyl)oxyphenvl )urea;

N-(

3 -terz-ButyM..-iscxazolyl '-(S-(2-(4-acetylphenyl)oxyjpvridinyl)urea; '-(3-(4-pyridinylftbiophenyl )urea;

N-(

3 -tert- Butyi-5 -i sox azolyl) -N '-(4-(4-pyrid inyl)methylphenyl )urea; N-(3 -rert-Butyl-5-isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; -(4-(4-pyridinyl)oxyphenyl)urea; 4 4 -methyl- 3 -pyridinyl)oxyphenyl)urea; N-(3 -rer:-Butyl-5-isoxazoly)N '-(3-(2-benzothiazolyl)oxyphenyl)urea; 1,1-Dimethylpropyl)-5-isoxazolyl)w '-(4-(4-methylphenyl )oxyphenyl)urea; 1,1-Dimethylpropyl)-5 -isoxazolyl)..Nt(3-(4-pyridinyl)thiophenyI)urea; N-(3 -Dimethylpropyl)-5-isoxazolyl)N-(4-4pyridiny)oxypheny)urea; 1,1 -Dimethylpropyl)-5-ioaoy)N(4(-yiiy~tipey~ra 1,1 -Dim ethylpropyl 5-isoxazo lyl)-N '45 -(2-(4-methoxyphenyl)oxy) pyridinyl)urea; 1-Methyl-i -ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N '(3-(4-pyridinyl)thiophenyl)urea; N-(3-isopropy1-5-isoxazolyly.Ar'-(3-(4-(2-methylcarhamoyl)pyridyl)oxyphenyl) urea;

N-(

3 -isopropyl-5-isoxazolyl)-N '-(4-(4-(2-methylcarbamnoyl)pyridyl).

oxyphenyl) urea; N-3tr-uy--sxzll-'(-4(-ehlabmy) pyridyl)oxyphenyl) urea; N-(3-Iert-butyl-5-iscxazolyl)-Nq'-(4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; -(3-(4-(2-methylcarbamoyl)pyridyl)thiophenyl) urea; 1,1-diniethylprop- I-yl)-5 -isoxazolyl)-N 43 -(4-(2-methylcarbamoyl)yridyl)oxyphenyl) urea; 1,1-dimethyiprop- 1 -yl) -5 -isoxazolyl)-N -m ethyl carbamoyl)pyridyl)oxyphenyl) urea.; and 13 3 -chloro-4-(4-(2-methylcarbamoyl)pyridyl)thiophenyl) urea.

Preferred 5,3-isoxazolyl ureas mare particularly include those wherein Q is is phenyl or pyridinyl, Q' is phenyl, benzothiazolyl or pyridinyl, Y is or X is CH, and Z is CH 2 p- wherein p 1-4, -C(0)CH 3

-CH

3 -OH, -OCJ%, -CN, phenyl, or -OCH 3 n 0 or 1, s 0 or 1, and n I= 0 or 1. Specific examples of preferred 5,3-isoxazolyl ureas are: N-(5-tert-Butyl-3 -isoxazolyl-N '-(4-(4-hydroxyphenyl )oxyphenyl)urea; -:er:-Butyl-3-isoxazoly])-N 4 3 -hydroxyphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3 -i soxazolyl)-N '-(4-(4-acetylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylpheny)urea; N-(5-tert-Butyl-3-isoxazolyl)-N -(4-phenyloxypheny])urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methylaminocarbonylphenyl)y thiophenyl)urea; N-(5-tert-Butyl-3-i soxazolyl)-N 1,2-methylenedioxy)phenyl)oxyphenyl)urea; N-(5-:ert-Butyl-3-isoxazolyl)-N '-(4-(3-pyridinyl)axyphenyl)urea; N-(5-zert-Butyl-3-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; N-(5-tern-ButyI-3-isoxazolyi)-N '-(4-(4-pyridyl)thiophenyl)urea; N-(5-zert-Butyl-3-isoxazolyl)-N -(4-(4-pyridinyl)methylphenyl)urea; -reri-ButyI-3-isoxazolyl)-N -(3-(4-pyridinyl)oxyphenyl)urea; N-(5-rn-Butyl-3-isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; -rerz-Butyl-3 -isoxazolyl)-N '-(3-(3-methyl-4-pyridinyl)oxyphenyl)urea; N-(5-tent-Butyl-3 -isoxazolyl)-N -methyl-4-pyridinyl)thiophenyl)urea; N-(5-rert-Butyl-3-isoxazolyl)-N -metbyl-4-pyridinyl)thiophenyl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N '-(3-(4-methyl-3-pyr-idinyl)axyphenyt)urea; N-(5-eerz-Butyl-3-isoxazolyl)-N '-(4-(3-methyl-4-pyridinyl)oxyphenyl)urea; N-(5-rert-Butyl-3-isoxazolyl)-N -(3-(2-benzothiaiolyl)oxyphenyl)urea; N-(5-eerz-butyl-3 -isoxazolyl)-N -(3-chloro-4-(4-(2-methylcarbanioyl)pyridyl)oxyphenyl) urea; N-(5-rerz-butyl-3 -isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-rer:-butyl-3 -isoxazo lyI)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)thiophenyl) urea; N-(5-rert-butyl-3 -isoxazolyl)-N '-(2-methyl-4-(4-(2-methyl carbanioyl)pyridyl)oxyphenyl) urea; 14 5-zert-butyl-3-isoxazolyl)-N -(4-(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; N-(5-zert-butyl-3-isoxazolyr)-N'-(3 -(4-(2-carhamoyl)pyridyl )oxyphenyl) urea; N-(5-terI-butyl-3-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; -tert-butyl-3-isoxazolyl)-N -(4-(4-(2-methylcarbamoyl)pyridyl)thiophenyl) urea; N-(5-ter:-butyl-3-isoxazolyl)-N 3 -chloro- 4 -(4-(2-methylcarbamoyl)pyidy1> oxyphenyl) urea; and N-(5-tert-butyl-3 -isoxazolyl)-N -methylcarbamoyl)phenyl)oxyphenyl) urea.

Additionally included are thienyl ureas of the formulae

R'

sO N b N0 Rb NH-C-NH-B

R

NH-C-NH-B

or 0 11

NH-C-NH-B

wherein R' Rb and B are as defined above. Preferred B components for the thienyl ureas of this invention have aromatic ring structures selected from the group consisting of: 0N N N7

N

and N These aromatic ring structures can be substituted or unsubstituted by halogen, up to per-halosubstitution. The X' substituents are independently selected from the group consisting of X or from the group consisting of, -CN, alkyl.

The X substituents are independently selected from the group consisting of -CO,R 5 -C(O)NRsR 5 -NR'C(0)OR',

C,-C

0 cycloalkyl,

C,-C,

4 aryl, C,-C, 4 alkaryl, C 3

-C,

3 heteroaryl, C0-C, 3 alkheteroaryl, and substituted C,alkyl, substituted C2-,,-alkenyl, substituted C,,,-alkoxy, substituted C,-C 0 cycloalkyl, substituted C.-C, 4 aryl, substituted alkaryl, substituted C 3 heteroaryl, substituted C 4 alkheteroaryl, and -Y-Ar. Where X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO,R 5 -C(O)NRSR', -NR'R, -NO,, -NRSC(O)R', -NR'C(0)OR' and halogen up to per-halo substitution. The moieties

R

5

R

5 Y and Ar are as defined above and n 0-2.

The components for B are subject to the proviso that where R' is t-butyl and Rb is H for the 3-thienyl ureas, B is not of the formula S C CH(CH 3 2 Preferred thienyl ureas include those wherein B is of the formula Xn -Q-(Y-Q1)S-Zni1 and Q, Y, X, Z, n, s and ni are as defined above. The preferred thienyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or Z is -Cl, -CH 3 -OH or -OCH,, n 0, s 0 or 1, and n] 0-2. Specific examples of preferred thienyl ureas are: N-(3-lsopropyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(3-ter-Butyl-5-isoxazolyl)-N'-(4-(4-methoxyphenyl)oxyphenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea; N-(3-;err-Butyl-5-isoxazolyl)-N'-(3-(4-pyridinyl)thiophenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)methylphenyl)urea; 16 N '-(4-(4-pyridinyl)thiophenyl)urea; '-(4-(4-pyridi nyl)oxyphenyl)urea:, 4 -(4-methyl-3-pyridinyl)oxyphenyl)urea; 3 2 -benzothiazolyl)oxyphenyl)urea; 1,1 -Dimerhylpropyl)-5-isaxazolyl)-N '-(4-(4-methylphenyl)oxyphenyl )urea:, 1,1 -Dimethylpropyl)-5-isoxazolyl)-N '-(3-(4-pyridinyl)thiopheny1)urea 1,1 -Dimethyipropy l)-5-isoxazolyl)-N t{4-(4-pyridiny1)oxypheny1)urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N 4 4 -pyridinyl)thiophenyl)urea -Dimethylpropyl-5 -isoxazolyl)-N'-( 5 2 -(4-methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl-I -ethylpropyl)-5-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; and 1-M ethyl- I -ethylpropyl)-5-isoxazolyl)-N -(3-(4-pyridinyl)thiophenyl)urea.

Preferred thiophenes include: N-(5-:ert-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl)oxyphenyl) urea; N-(5-tert-buty1-3-thieny)-Nt$(4(4-hydroxyphenyl)oxyphenyj) urea; N-(5-tert-butyl-3-thienyl)-N -(4-(3-methylpbenyl)oxyphenyl) urea; and N-(5-terz-butyl-3-thienyl)-N'-<4-(4-pyridyl)thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: Ra RI N I84lBRbNHCHwherein Rb, R' and B are as defined above. The thiadiazolyl and furyl ureas have preferred aromatic ring structures for B identical to those for the pyrazolyl, thienyl and isoxazolyt ureas shown above, Such ring structures can be unsubstituted or substituted by halogen, up to per-halosubstitution, and each XV substituent is independently selected ftrm the group consisting of X or from the group-consi sting of -CN. -NO, ,-0R 5 and C 1

-C

10 alkyl. The X substituents are selected from the group consisting of -CO2R', -C(O)R 5

-C(Q)NR

5

R

5

-NR

5

R

5 -NR'C(0)ORt, -NR'C(O)R. substituted C, 1 ,,-alkenyl, substituted C,.,,-alkoxy. 0 cycloalkyl,

-C

6

-C,

4 aryl, -C 7 alkaryl. C 3 heteroaryl, C,-C, 3 alkheteroaryl, and substituted alkyl, substituted cycloalkyl, substituted aryl, substituted alkaryl, substituted heteroaryl, substituted C 4 alkheteroaryl and -Y-Ar. Each of R 5 and Ar are as defined above, n 0-2, and the substituents on X where X is a substituted group are as defined for the pyrazolyl isoxazolyl and thienyl ureas.

This invention also includes pharmaceutical compositions that include compounds described above and a physiologically acceptable carrier.

Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula and Q, X, Y, Z, n, s, and nl are as defined above. The preferred thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or n 0, s I and nl 0. Specific examples of preferred thiadiazolyl ureas are: N-(5-zert-Butyl-2-(l -thia-3 ,4-diazolyl))-N -(3-(4-pyridinyl)thiophenyl)urea; N-(5-:erz-Butyl-2-( 1 -rhia-3,4-diazolyi))-N'-(4-(4-pyridinyl)oxyphenyl)urea; N-(5-tert-butyl-2-( 1 -thia-3,4-diazolyl))-N '-(3-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-teri-butyl-2-( I -thia-3.4-diazolyl))-N '-(4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-terr-butyl-2-( 1 -thia-3,4-diazolyl))-N '-(3-chloro-4-(4-(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-zer:-butyl-2-( I -thia-3,4-diazolyl))-N '-(2-chloro-4-(4-(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-terl-butyl-2-( I -thia-3,4-diazolyl))-N '-(3-(4-pyridyl)thiophenyl) urea; -zerl-butyl-2-( I -thia-3,4-diazolyl))-N '-(2-methyl-4-(4-(2methylcarbarnoyl)pyridyl)oxyphenyl) urea; and -dimethylprop- I -thia-3,4-diazolyl))-N'-(4-(3carbamoylphenyl)oxypheny]) urea.

The preferred furyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or-S-, Z is -CI or -OCH, s 0 or 1, n 0 and nI 0-2.

09/05 '06 12:50 FAX 61 7 3229 3384 CULLEN CO. [1008

O

The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the an O and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic c acid, acetic acid, trifluoioacetic acid, malic acid, tartaric acid, citric acid, lactic acid, M oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, o phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations Li- Na' or alkaline earth cations Mg Ca'" or Ba-2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3,0]non-5-ene (DBN) and 1,8diazabicyclo[5.4.0]undec-7-ene (DBU).

A number of the compounds of Fonnula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.

The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess Raf kinase inhibitory activity.

A definition of the specific embodiment of the invention claimed herein follows.

In a broad format, the invention provides a method for the treatment of cancerous cell growth mediated by rafkinase comprising administering a compound of formula 1 0

II

A-NH-C-NH-B I wherein B is phenyl, pyridinyl, pyrirnidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, ID 09/05 '06 12:50 FAX 61 7 3229 3384 CULLEFN CO. Q009o V a18- 0 isCoxazoly, hiazolyl, ist iazolyl balkfyl, beuzlothienyl, Cido lyl buoyrazolyl, 00 beozcoalyl, bhenylisoxazolyl, beuzothazolyl or beaziothizolyl sutitte bye haor O moesubstituen indelyl penety serldfomsbstthed roup conistnfhle, up to per lhosbtttodXwherein nWs and eac Xaie independently selected from the-IDaklC-I group consisin ofi -S-0NRi, )NR,

SR

5 o NR'C(O)R" NR 5 NC(O), Co)lky, -C 2 ly, CH2 -Cle), alko 2)"y,C-C O~A cyolks phnyl, pyridinyl, nphthidiyl, isoqinoinyl, qurinoinyl uaphtto per ble-y sbtitutedly] C 1

-C

10 alyl, p totrhiazlosubstitC iaoalkyl, ptol persthalosbstituten 1

C

0 oy up to per-hlsbttto halobtitutedysuCs-C uteyclalky, ahend Y-Ar; 0t whinR and eac are independently selected from th rupcn istn Cf-C 1 0 l, C 2 -Cw alkenyl, 10 R cyc2oalcy, p to pe-alosbyitte 1 -Co alkyl, up tlo y-oll Perphalo-substituted C-Co alkyl and up to perhalo-substituted CC cycloalkyl, iN 0 1-0 anandshaoen Ari phnl pyrdiyl py3miil Pyrnl pyiainlahtyqinlnl wherein R' is selected from the group consisting of halogen, C3-Cio alkyl, C3rCIO 09/05 '06 12:51 FAX 61 7 3229 3384 qULbBNi$A CO. I0i 1 Sb cycloalkyl, C 1

C

1 heteroaryl, Q 6 -1 4 aryl, C7-24 aLilaryl, up to per-halosubstituted C 1

-C,

00 alkyl, up to per-halosubstititted

C

3 -CID cycloalkyl, up to per-halosubstituted

C

1

-C

13 O hieter-oaryl, up to per-halosubstituted C 6 14 arYl, and up to per-halosubstituted C 7 -4 alkaryl; o 1(R2 is selected from the group consisting of HK -C(O)RW, -CO 2 Rt, -C(O)NR 3

R

3 M Ci-C 10 alkyl, C 3

-C

10 cyoloalkyl, C7-CM4 alkarYl, C4-Cn. alkheteroaryl, substituted C,-C 10 Oalkyl, substituted CI-Cl0 cycloalkyl, substituted C 7 -C24 alkaiyl and substituted C 4 -C23 alkheteroaryl, where W( is a substituted group, it is substituted by one or more substitoents independently selected from the group consisting of -CN, CO 2

.R

4

-C(O)-NKRR

3

-NO

2 -OWe, -SR 4 and halogen up to per-halosubstitution, wherein W( and are independently selected from the group consisting of H, QOW, -SRW, -NRR, -C(O)RW, -C0 2

R

4

-C(O)NXR

4 4, Cr-Cio alkyl, C 3

-C

10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl or quinolinyl up to per-halosubstituted. C,-C, 0 alkyl, up to per-hialosubstituted CI-Clo cycloalkyl, and up to per-halosubstituted, phenyl, pyridinyl, naphthyl, isoquinolinyl or quinolinyl; and wherein 1(4 and Re are independently selected from the group consisting of H, C 1 CIO aikyl, C 3

-C,

0 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted C 1

-C

10 alikyl, up to per-halosubstituted C 3

-C

10 cyclonikyl, and up to per-lialosubstituted, phenyl, pyridinyl, naphithyl, isoquinolinyl or quinolinyl W(f is alkyl, Cs-C, 0 cycloalkyl, up to per-halosubstituted C,-C10 alkyl and up to per-halosubstituted C 3

-C,

0 cycloalkyl; and Ris hydrogen or halogen, R' is hydrogen, halogen, C 1

-C

10 alkyl, up to per-halosubstituted C,-C 10 alkyl or comnbines with Ri' and the dung cabon atoms to which R(1 and rY are bound to formi a 5- or 6-menibered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from 0, N and S; subject to the proviso that Where A is t0B

N

B is not 09/05 '06 12:51 FAX 61 7 3229 3384 CULLEN CO, 0 0 ci 18c a>, 0 00

O-(CH

2

)-CH

3 0 wherein n 2-4, oor 0 -0 O/ O-CH 2

CH(CH

3 2 General Preparative Methods The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some of which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, with more detailed examples being presented in the experimental section describing the working examples.

Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permnagon Press: Oxford, UK (1984).

March. Advanced Organic Chemistry, Ed.; John Wiley: New York (1985)). For Qoil example. 3-substituted-5-aminoisoxazoles are available by the reaction of hydroxylamine with an cc-cyanoketone as shown in Scheme 1. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an cyanoketone with hydrazine or a monosubstituted hydrazine affords the 3substituted- or 1,3-disubstituted-5-aminopyrazole Pyrazoles unsubstituted at N-1 (R2=H) may be acylated at N-1, for example using di-tert-butyl dicarbonate, to give pyrazole 7. Similarly, reaction of nitrile 8 with an -thioacetate ester gives the substituted-3-amino-2-thiophenecarboxylate Ishizaki et al. JP 6025221).

Decarboxylation of ester 9 may be achieved by protection of the amine, for example as the tert-butoxy (BOC) carbamate followed by saponification and treatment with acid. When BOC protection is used, decarboxylation may be accompanied by deprotection giving the substituted 3-thiopheneammonium salt 11. Alternatively, ammonium salt 11 may be directly generated through saponification of ester 9 followed by treatment with acid.

CH

3

CN

R'

1) base I N 0 I 2)

H

2 NOH*HCI 0' NH R X 3 1 base

R

1 0 R 2

NHNH

2 4 /I R C N N RIKC N NH 2

O

2 RO

X

R' N NH 2

R

t HS CO 2 R

OR

-C -S 7 CN

NH

2 8 C0 2

R

9 1) OH- O O

R

1

R

1 1) OH" NH3 2) H

NHBOC

CO

2

R

11 Scheme I. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3" Ed.; John Wiley: New York (1985); Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H, or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAIH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3" Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

H

2 catalyst (eg. Ni, Pd, Pt) ArNO 2 l- ArNH 2 M(0) (eg. Fe, Sn, Ca) Scheme II Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO 3 or an alternative NO,' source. Nitroaryls may be further elaborated prior to reduction.

Thus, nitroaryls substituted with HN03 Ar-H le ArNO 2 potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme

III).

2N ArSH R base 12 O2N SS-Ar OSH Br-Ar s 13 R CuO base 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 21 with an azide source, followed by rearrangement affords the isocyanate.

The corresponding carboxylic acid (22) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic amine.

Het-NH 2 16

H

2 N-Ar 19 COC2 COC12 H2N-Ar O Het-NH 2 Het-NCO HetN ,NAr OCN-Ar 17 H H N3/ DPPA N3 DPPA 0 0 0 0 He X Het OH X Ar HO LAr 21 22 23 24 S Scheme IV Selected Methods of Urea Formation (Het heterocycle) 1-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed by treatment with phosgene or a phosgene equivalent. Reaction of anhydride 25 with an aryl amine can generate acid 26 which may spontaneously decarboxylate, or may be isolated. If isolated, decarboxylation of acid 26 may be induced upon heating.

S

RO 2 C-

NH

2 1) OH_ 2)00012

S

-NH

H

2 N-Ar 0 S 1N J

N'A

HO

2 C H H 26 0 A b "N IkN' I H HI 27L Scheme V Urea Formation via Isatoic-like Anbydridles Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes phannaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray or sublingually, rectally or vaginally in dosage unit formulations. The termn 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdennal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in 24 order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing 26 the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. W094/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.

Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cg-C,, fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic 27 acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated Cg-C,, fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components.

Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.

For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.

28 It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics.

It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.

It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.

The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Attorney Docket BAYER 8 Vl, filed on December 22, 1997, as Serial No.

08/996,343, converted on December 22, 1998.

The compounds are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, according to procedures disclosed below. The following examples are for illustrative purposes only and are not intended, nor should they be construde to limit the invention in any way.

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stat&d, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg.

All temperatures are reported uncorrected in degrees Celsius Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. Thinlayer chromatography (TLC) was performed on Whatman® pre-coated glass-backed silica gel 60A F-254 250 mrn plates. Visualization of plates was effected by one or more of the following techniques: ultraviolet illumination, exposure to iodine vapor, immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, immersion of the plate in a cerium sulfate solution followed by heating, and/or immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science' silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either MeSi (8 0.00) or residual protonated solvent (CHC13, 7.26; MeOH 8 3.30; DMSO 2.49) as standard. Carbon NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 5 77.0; MeOD-d 3 49.0; DMSO-d 6 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (El) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 gA. Liquidcesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (1x10" torr to 2.5xl0 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.

HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett- Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy eV).

Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. All ureas displayed NMR spectra, LRMS and either elemental analysis or HRMS consistant with assigned structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl cone concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(I H)-pyrimidinone DMF N. N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate EtOH ethanol (100%) EtO diethyl ether Et 3 N triethylamine m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoles 0 cN Step 1. 3-Oxo-4-methylpentanenitrile: A slurry of sodium hydride (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 °C for 15 min,, then a solution of acetonitrile (13.5 mL, 258 mmol) in benzene (52 mL) was added dropwise via addition funnel followed by a solution of ethyl isobutyrate (15 g, 129 mmol) in benzene (52 mL). The reaction mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water mL) via addition funnel. The organic layer was separated and set aside. EtOAc (100 mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (conc. HC1) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgSO,), and concentrated in vacuo to give the acyanoketone as a yellow oil which was used in the next step without further purification.

0 NH 2 Step 2. 5-Amino-3-isopropylisoxazole: Hydroxylamine hydrochloride (10.3 g, 148 mmol) was slowly added to an ice cold solution of NaOH (25.9 g, 645 mmol) in water (73 mL) and the resulting solution was poured into a solution of crude 3-oxo-4methylpentanenitrile while stirring. The resulting yellow solution was heated at 50 °C for 2.5 hours to produce a less dense yellow oil. The warm reaction mixture was immediately extracted with CHC1, (3 x 100 mL) without cooling. The combined organic layers were dried (MgSO,), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% CH,CI) to afford the desired isoxazole as a yellow solid (11.3 g, mp 63-65 TLC R CHC1,) 0.19; 'H-NMR (DMSO-d 6 d 1.12 J-7.0 Hz, 6H), 2.72 (sept, Hz, 1H), 4.80 2H), 6.44 IH); FAB-MS m/z (rel abundance) 127 67%).

A3. General Method for the Preparation of 5-Amino-l-alkyl-3-alkylpyrazoles

N,

N

NHZ

NC

5-Amino-3-tert-butyl-1-(2-cyanoethyl)pyrazole: A solution of 4,4-dimethyl-3oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (EtO/hexane) to afford the desired product (2.5 g, TLC hexane) Rf0.31; 'H-NMR (DMSO-d5) 8 1.13 9H), 2.82 J=6.9 Hz, 2H), 4.04 J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 1H).

A 4. Synthesis of Synthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids

S

NH

Step 1. 7-tert-Butyl-2H-thieno[3,2-d]oxazine-2,4(lH)-dione: A mixture of methyl (7.5 g, 35.2 mmol) and KOH (5.92 g) in MeOH (24 mL) and water (24 mL) was stirred at 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 mL). Phosgene (20% in toluene, 70 mL) was added dropwise over a 2 h period. The resulting mixture was stirred at room temperature overnight and the resulting precipitate was triturated (acetone) to afford the desired anhydride (5.78 g, 'H- NMR (CDC1,) 8 1.38 9H), 2.48 1H), 6.75 1H); FAB-MS m/z (rel abundance) 226 100%).

S N N N HOOC H H Step 2. N-(5-tert-Butyl-2-carboxy-3-thienyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea: A solution of 7-tert-butyl-2H-thieno[3,2-d]oxazine-2,4(1H)-dione (0.176 g, 0.78 mmol) and 4-(4-pyridinylmethyl)aniline (0.144 g, 0.78 mmol) in THF (5 mL) was heated at the reflux temp. for 25 h. After cooling to room temp., the resulting solid was triturated with EtO to afford the desired urea (0.25 g, mp 187-189 OC; TLC (50% EtOAc/50% pet. ether) R/ 0.04; 'H-NMR (DMSO-d 6 5 1.34 9H), 3.90 2H), 7.15 J=7Hz, 2H), 7.20 J=3 Hz, 2H), 7.40 J=7 Hz, 2H), 7.80 (s 1H), 8.45 J=3 Hz, 2H) 9.55 1H), 9.85 1H), 12.50 (br s, 1H); FAB-MS m/z (rel abundance) 410 IN

NN

H H Step 3. N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea: A vial containing N-(5-tert-butyi-2-carboxy-3-thienyl)-N'-(4-(4-pyridinylmethyl)pbenyl)urea (0.068 g, 0.15 mmol) was heated to 199 °C in an oil bath. After gas evolution ceased, the material was cooled and purified by preparative HPLC (C-18 column; gradient from 20% CHCN/79.9% H0O/0.1% TFA to 99.9% HO/0.1% TFA) to give the desired product (0.024 g, TLC (50% EtOAc/50% pet. ether) Rf 0.18; 'H- NMR (DMSO-d) 8 1.33 9H), 4.12 2H), 6.77 6.95 1H), 7.17 J=9 Hz, 2H), 7.48 J=9 Hz, 2H), 7.69 J=7 Hz, 1H), 8.58 1H), 8.68 Hz, 2H), 8.75 1H); EI-MS m/z 365 A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-alkyl-2-thiophenecarboxylate esters

S

NH3 Cl" 5-tert-Butyl-3-thiopheneammonium Chloride: To a solution of methyl tert-butyl-2-thiophene-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp. for 2.25 h. A cone. HC1 solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 mL) and a saturated NaHCO, solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCI solution (150 mL), dried (NaSO 4 and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification.

Synthesis 3-Amino-5-alkylthiophenes from N-BOC 3-Amino-5-alkyl-2thiophenecarboxylate esters S 0 MeO 2 C H Step 1. Methyl 3-(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylate: To a solution of methyl 3-amino-5-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 OC was added di-tert-butyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and N.N-dimethylaminopyridine (86 g, 0.70 mol, 1.00 equiv) and the resulting mixture was stirred at room temp for 7 d. The resulting dark solution was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately The resulting red solids were dissolved in CHC1 2 (3 L) and sequentially washed with a 1 M H 3

PO

4 solution (2 x 750 mL), a saturated NaHCO 3 solution (800 mL) and a saturated NaCI solution (2 x 800 mL), dried (NaSO,) and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 then treated with water (500 mL) to afford the desired product as an off-white solid (163 g, 'H-NMR (CDCI 3 5 1.38 9H), 1.51 (s, 9H), 3.84 3H), 7.68 1H), 9.35 (br s, 1H); FAB-MS m/z (rel abundance) 314 S N0

HO

2 C H Step 2. 3-(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic Acid: To a solution of methyl 3-(tert-butoxycarbonylamino)-5-rert-butyl-2thiophenecarboxylate (90.0 g, 0.287 mol) in THF (630 mL) and MeOH (630 mL) was added a solution of NaOH (42.5 g, 1.06 mL) in water (630 mL). The resulting mixture was heated at 60 OC for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0 OC. The pH was adjusted to approximately 7 with a 36 N HCI solution (approximately I L) while maintaining the internal temperature at approximately 0 The resulting mixture was treated with EtOAc (4 The pH was adjusted to approximately 2 with a 1.0 N HCI solution (500 mL). The organic phase was washed with a saturated NaCI solution (4 x 1.5 dried and concentrated to approximately 200 mL under reduced pressure. The residue was treated with hexane (1 L) to form a light pink (41.6 Resubmission of the mother liquor to the concentration-precipitation protocol afforded additional product (38.4 g, 93% total yield): 'H-NMR (CDC1,) 8 1.94 9H), 1.54 9H), 7.73 1H), 9.19 (br s, 1H); FAB-MS m/z (rel abundance) 300

S

NH

3 Cr Step 3. 5-tert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(tertbutoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HCI solution (4.0 M in dioxane, 12.5 mL, 0.050 mol, 5.0 equiv), and the resulting mixture was heated at 80 °C for 2 h. The resulting cloudy solution was allowed to cool to room temp forming some precipitate. The slurry was diluted with EtOAc (50 mL) and cooled to -20 OC. The resulting solids were collected and dried overnight under reduced pressure to give the desired salt as an off-white solid (1.72 g, 'H-NMR (DMSO-d,) 8 1.31 9H), 6.84 J=1.48 Hz, IH), 7.31 J=1.47 Hz, IH), 10.27 (brs, 3H).

General Method for the Synthesis of BOC-Protected Pyrazoles

N,

N

N

H

2

O

5-Amino-3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole: To a solution of 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CH,Cl, (140 mL) was added di-tert-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp. for 13 h, then diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired carbamate (6.26 g, mp 63-64 TLC acetone/95% CHC1,); 'H-NMR (DMSO-d 6 5 1.15 9H), 1.54 9H), 5.22 1H), 6.11 2H); FAB-MS m/z A6. General Method for the Synthesis of 2-Aminothiadiazoles N S N

NH

2 2-Amino-5-(1-(l-ethyl)propyl)thiadiazine: To concentrated sulfuric acid (9.1 mL) was slowly added 2-ethylbutyric acid (10.0 g, 86 mmol, 1.2 equiv). To this mixture was slowly added thiosemicarbazide (6.56 g, 72 mmol, 1 equiv). The reaction mixture was heated at 85 °C for 7 h, then cooled to room temperature, and treated with a concentrated NH,OHsolution until basic. The resulting solids were filtered to afford 2-amino-5-(-(1-ethyl)propyl)thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, mp 155-158 TLC MeOH/ CHCi 3 R/0.14; 'H-NMR (DMSO-d 6 50.80 J=7.35 Hz, 6H), 1.42-1.60 2H), i 38 1.59-1.71 2H), 2.65-2.74 1H), 7.00 (br s, 2H); HPLC ES-MS m/z 172 A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles

O

NNH2 Step 1. Isobutyric Hydrazide: A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60 °C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, which was used inb the next step withour further purification.

N

NH

2 Step 2. 2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 KHCO, (0.102 and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 The resulting mixture was heated at the refulx temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH,CI, mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO,) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 A8. General Method for the Synthesis of 2-Aminooxazoles 0

OH

Step 1. 3,3-Dimethyl-l-hydroxy-2-butanone: A neat sample of 1-bromo-3,3dimethyl-2-butanone (33.3 g) at 0 °C was treated with a IN NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (NaSO 4 and concentrated under reduced pressure to 39 give 3.

3 -dimethyl-l-hydroxy-2-butanone (19 g, 100%), which was used inb the next step withour further purification.

N

O"

NH

2 Step 2. 2 -Amino-4-isopropyl-1,3-oxazole: To a solution of 3,3-dimethyl-lhydroxy-2-butanone (4.0 g) and cyanimide (50% w/w, 2.86 g) in THF (10 mL) was added a IN NaOAc solution (8 mL), followed by tetra-n-butylammonium hydroxide (0.4 M, 3.6 mL), then a IN NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with Et,O (3 x mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CH,CI, (3 x 25 mL). The combined organic layers were dried (Na,SO4) and concentrated under reduced pressure to afford 2-Amino-4isopropyl-1,3-oxazole (1.94 g, HPLC ES-MS m/z 141 A9. Method for the Synthesis of

N-N

N

NH

2 To a solution of 5-aminotetrazole (5 NaOH (2.04 g) and water (25 mL) in EtOH (115 mL) at the reflux temperature was added 2-bromopropane The resulting mixture was heated at the reflux temperature for 6 d, then cooled to room temperature, and concentrated under reduced pressure. The resulting aqueous mixture was washed with CH,CI, (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1- and 2-isopropyl-5-aminotetrazole which was used without further purification: HPLC ES-MS m/z 128 B. General Methods for Synthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene

H

2

N

4-(4-Pyridinylmethyl)aniline: To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g, 32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry was shaken under a H, atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 'H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite*. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 'H-NMR (DMSO-d,) 6 3.74 2H), 4.91 (br s, 2H), 6.48 J=8.46 Hz, 2H), 6.86 J=8.09 Hz, 2H), 7.16 J=5.88 Hz, 2H), 8.40 J=5.88 Hz, 2H); El- MS m/z 184 This material was used in urea formation reactions without further purification.

General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H20 (0.5 mL) in AcOH 5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H20 (50 mL), basified to pH 10 by adding solid K,CO, in portions (Caution: foaming). The organic layer was washed with a saturated NaCI solution, dried (MgSO,), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as-a thick oil (0.135 g, TLC (30% EtOAc/70% hexanes) R, 0.20.

la. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N r la OMe Step 1. 1-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was added dropwise a sl6ution of 4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, then a solution of l-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then cooled to room temp., quenched with HO, and concentrated in vacuo.

The residue was partitioned between EtOAc (200 mL) and H,O (200 mL) The organic layer was sequentially washed with HO (2 x 200 mL), a saturated NaHCO, solution (200 mL), and a saturated NaCl solution (200 mL), dried and concentrated in vacuo. The residue was triturated (EtO/hexane) to afford 1methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDCI 3 6 3.83 (s, 3H), 6.93-7.04 6H), 8.18 J=9.2 Hz, 2H); El-MS m/z 245

H

2 N O OMe Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of l-methoxy-4-(4nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C g) and the resulting slurry was shaken under a H, atmosphere (50 psi) for 18 h.

The reaction mixture was filtered through a pad of Celite® with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR (CDC13) 8 3.54 (br s, 2H), 3.78 3H), 6.65 J=8.8 Hz, 2H), 6.79-6.92 6H); EI- MS m/z 215 3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

CF

3

S"T

OpA 42 Step 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with EtO (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et,O (2 x 100 mL). The organic layers were washed with a saturated NaC1 solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The solid residue was triturated with Et,O to afford the desired product as a tan solid (3.8 g, TLC (30% EtOAc/70% hexane) R 0.06; 'H-NMR (DMSO-d) 8 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 J=8.7 Hz, 1H), 8.46 (dd, J=2.4, 8.7Hz, 1H), 8.54-8.56 3H).

CF

3

H

2 N N Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder g, 71.6 mmol), acetic acid (100 mL), and water (I mL) were stirred at room temp. for 4 h. The mixture was diluted with EtO (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSOJ), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 5 0% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 TLC (50% EtOAc/50% hexane) R 0.10; 'H-NMR (DMSO-d 6 56.21 2H), 6.84-6.87 3H), 7.10 J=2.4 Hz, 1H), 7.39 J=8.4 Hz, 1H), 8.29 J=6.3 Hz, 2H).

13c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 43 OTN S S 0 2 N

N

Step 1. 4-( 2 -(4-Phenyl)thiazolyl)thio-l-nitrobenzene: A solution of 2-mercapto-4phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4nitrobenzene (2.3 mL, 21.7 mmoles) followed by KCO, (3.18 g, 23 mmol), and the mixture was heated at approximately 65 OC overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated with a Et 2 O/hexane solution to afford the desired product (6.1 TLC (25% EtOAc/75% hexane) R/0.49; 'H-NMR (CDCI,) S 7.35-7.47 3H), 7.58-7.63 3H), 7.90 J=6.9 Hz, 2H), 8.19 J=9.0 Hz, 2H).

H2N S

S

Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio- l-nitrobenzene was reduced in a manner analagous to that used in the preparation of 3- (trifluoromethyl)-4-(4-pyridinylthio)aniline: TLC (25% EtOAc/75% hexane) Rf 0.18; 'H-NMR (CDCI,) 5 3.89 (br s, 2H), 6.72-6.77 2H), 7.26-7.53 6H), 7.85-7.89 2H).

d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction S0 2

N

Step 1. 4-(6-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 2-methylpyridine (5.0 g, 45.8 mmol) and 1-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K 2

CO

3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried and concentrated in vacuo to afford the desired product (8.7 g, The this material was carried to the next step without further purification.

0

N

H

2 N Oa Step 2. 4-(6-Methyl-3-pyridinyloxy)aniline: A solution of 4-(6-methyl-3pyridinyloxy)-l-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H.

atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, EI-MS m/z 200 le. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 OyOMe 0 2 N OMe Step 1. 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 tL, 6.4 mmol) in anh DMF (20 mL) was added KCO 3 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (NaSO,), and concentrated in vacuo to afford the desired product (0.8 g, The crude product was carried to the next step without further purification.

0 OMe

H

2 N OMe Step 2. 4-(3,4-Dimethoxyphenoxy)aniline: A solution of 4-(3,4-dimethoxyphenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to Pd/C (0.100 g) and the resulting mixture was placed under a H. atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite' and concentrated in vacuo to afford the desired product as a white solid (0.6 g, El-MS m/z 245 13f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N

O

Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added KCO, (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na,SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product g, 32 This material was used in the next step without further purification.

H

2 N

ON

3 Step 2. 3-(3-Pyridinyloxy)aniline: A solution of 3-(-3-pyridinyloxy)-lnitrobenzene (2.0 g, 9.2 mmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (1.6 g, S EI-MS m/z 186 t3g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 46 ON N Step 1. 3 -(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxy- (5.0 g, 45.8 mmol), 1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper(I) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K,CO 3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NaSO,), and concentrated in vacuo The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%).

H

2 N N.,.O Step 2. 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3pyridinyloxy)-l-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to Pd/C (0.100 g) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (0.9 g, CI-MS m/z 201 13h. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N Z,-N Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv) and KCO, (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred overnight at room temp. The resulting mixture was treated with water (600 mL) to generate a precipitate. This mixture was stirred for 1 h, and the solids were separated and sequentially washed with a 1 N NaOH solution (25 mL), water (25 mL) 47 and pet ether (25 mL) to give the desired product (7.05 g, mp 80-82 TLC EtOAc/70% pet ether) R 0.79; 'H-NMR (DMSO-d,) 5 2.31 3H), 7.08 (d, 8.46 Hz, 2H), 7.19 J=9.20 Hz, 1H), 7.24 J-8.09 Hz, 2H), 8.58 (dd, J=2.94, 8.82 Hz, 1H), 8.99 J=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 100%).

CI" H 3 N H cr Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dibydrochloride: A solution nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 The reaction mixture was then placed under a H, atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celite®. A solution of HCI in Et20 was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, mp 208-210 OC (dec); TLC (50% EtOAc/50% pet ether) R 0.42; 'H-NMR (DMSO-d,) 8 2.25 3H), 6.98 J=8.45 Hz, 2H), 7.04 J=8.82 Hz, 1H), 7.19 J=8.09 Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H), 8.63 J=2.57 Hz, 1H); EI-MS m/z (rel abundance) 100%).

3i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(3-Thienylthio)-l-nitrobenzene: To a solution of 4-nitrothiophenol 1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper(II) oxide (0.5 g, 3.7 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and the resulting mixture was heated at 130 OC with stirring for 42 h and then allowed to cool to room temp. The reaction mixture was then poured into a mixture of ice and a 6N HCI solution (200 mL) and the resulting aqueous mixture was 48 extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a I M NaOH solution (2 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (MgSO,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, GC-MS m/z 237

H

2 N' S

S

Step 2. 4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B 1.

B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction HN N

H

2 N O N 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC-MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp. and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCI solution (2 x 50 mL), dried (MgSO,), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).

3k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Br OMe Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc hexane) R,0.57.

Ho OMe Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 OC was added an nbutyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture ofa 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a 1N HCI solution then extracted with EtO (2 x 100 mL). The combined organic layers were dried (NaSO 4 and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 0 2 N N OMe Step 3. 4 -(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene: To a stirred slurry of NaH 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp. for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mnixture was heated to 95 °C overnight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSO,) and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g,

H

2 N N OMe Step 4. 4 -(5-(2-Methoxy)pyridyl)oxyaniline: 4-(5-(2-Methoxy)pyridyl)oxy-lnitrobenzene was reduced to the aniline in a,manner analogous to that described in Method B3d, Step2.

1. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine aN N

H

2 N S

N

3-(4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K,CO, (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100mL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et,O/hexane solution to afford the desired product (4.6 g, TLC (100 ethyl acetate) R 0.29; 'H-NMR (DMSO-d,) 8 5.41 2H), 6.64-6.74 3H), 7.01 J=4.8, 2H), 7.14 J=7.8 Hz, 1H), 8.32 J=4.8, 2H).

b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine

H

2 N O 4 2 -Methyl-4-pyridinyloxy)aniline: To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100 OC with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO4), and concentrated in vacuo.

The resulting oil was purified by flash chromatography (50 EtOAc/50% hexane) to afford the desired product as a yellow oil CI-MS m/z 201 B4c. General Method for Substituted Aniline Synthesis via Nucleophilie Aromatic Substitution using a Halopyridine Me

N=N

Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4nitroaniline (2.0 g, 13.2 mmol) and K,CO, (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmoI). The reaction mixture was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried (Na SO,) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4nitrophenyl)-4-pyridylamine (0.42 g) H2 Me

H

2 N N Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4pyridylamine was reduced in a manner analogous to that described in Method B1.

General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene 0 2 N 0 Step 1. 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitrophenylthio)phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 OC was added NaH (60% in mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 OC until gas evolution stopped (15 min), then a solution of iodobutane (1.12 g, .690 ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 The reaction was stirred at room temp. for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with Et,O (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL), dried (MgSO4), and concentrated under reduced pressure to give a clear yellow oil, which was purified by silica gel chromatography (gradient from 20% EtOAc/80% hexane to 50% EtOAc/50% hexane) to give the product as a yellow solid (1.24 g, TLC (20% EtOAc/80% hexane) R,0.75; 'H- NMR (DMSO-d,) 5 0.92 J= 7.5 Hz, 3H), 1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 J= 6.6 Hz, 2H), 7.08 J=8.7 Hz, 2H), 7.17 J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 8.09 J= 9 Hz, 2H).

Step 2. 4-(4-Butoxyphenyl)tbioaniline: 4-(4-Butoxyphenyl)thio-l-nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3- (trifluoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step TLC (33% EtOAc/77% hexane) R 0.38.

B6. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes H2N N O

H

4 4 -tert-Butoxycarbamoylbenzyl)aniline: To a solution of 4,4'-methylenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of ditert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp. for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-tert-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp. for 16 h. The resulting mixture was diluted with Et,O (200 mL), sequentially washed with a 53 saturated NaHCO, solution (100 ml), water (100 mL) and a saturated NaCI solution mL), dried (MgSO4), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a white solid 2.09 g, TLC (50% EtOAc/50% hexane) R, 0.45; 'H-NMR (DMSO-d,) 8 1.43 9H), 3.63 2H), 4.85 (br s, 2H), 6.44 J=8.4 Hz, 2H), 6.80 J=8.1 Hz, 2H), 7.00 J=8.4 Hz, 2H), 7.28 J=8.1 Hz. 2H), 9.18 (br s, 1H); FAB-MS m/z 298 General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction 0N^ Step 1. 3-(4-Nitrobenzyl)pyridine: A solution of 3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 The resulting mixture was allowed to cool to room temp. then poured into ice water (350 mL). The aqueous mixture then made basic with a lN NaOH solution, then extracted with Et,O (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g. GC- MS m/z 214

H

2

N"

Step 2. 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method B 1.

General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction 54 0 2 N N Step 1. 4 -(I-Imidazolylmethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g, 7.3 mmol) and 4 -nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added KCO, (1.0 g, 7.3 mmol). The resulting mixture was stirred at rooom temp. for 18 h and then poured into water (200 mL) and the resulting aqueous-solution wasextracted with EtOAc (3 x 50 cmL). The combined organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x mL), dried (MgSO,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, EI-MS m/z 203

H

2 N N Step 2. 4-(1-Imidazolylmethyl)aniline: 4-(1-Imidazolylmethyl)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.

Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction

OH

ON C

N

Step 1. 4 -(l-Hydroxy-l-(4-pyridyl)methyl-l-nitrobenzene: To a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH,C1, (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 OC, and the mixture was stirred at room temp. overnight.

The reaction mixture was successively washed with a 10% NaHSO 3 solution (50 mL), a saturated KCO, solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO 4 and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous NH, solution (30 mL).

The mixture was stirred at room temp. for 1 h, then was concentrated under reduced pressure. The residue was poured into a mixture of water (50 mL) and CH,C1, mL). The organic layer was dried (MgSO4), concentrated under reduced pressure. and purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired product as a white solid. (0.53 g, mp 110-118 TLC (80% hexane) R/0.12; FAB-MS m/z 367 100%).

OH

H

2 N Step 2. 4-(l-Hydroxy-l-(4-pyridyl)methylaniline: 4-(l-Hydroxy-l-(4-pyridyl)methyl-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.

Formation of 2 -(N-methylcarbamoyl)pyridines via the Menisci reaction 0 CI NH 2 Step 1. 2 -(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added cone. H.SO, (3.55 mL) (exotherm). To this was added H 2 0 2 (17 mL, 30% wt in H20) followed by FeSO,7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for lh then was heated slowly over 4 h at 45 When bubbling subsided,the reaction was heated at 60 oC for 16 h. The opaque brown solution was diluted with H20 (700 mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCI solution (3 x 150 mIL. The combined organics were dried (MgSO.) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc 50% hexane to 80% EtOAc hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(Nmethylcarbamoyl)-4-chloropyridine in yield (0.61 g, TLC (50% hexane) R/0.50; MS; 'H NMR (CDCI 3 d 8.44 1 H, J 5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd. 1H. J 2.4, 5.4 Hz, CICHCN), 3.04 (d.

3H, J= 5.1 Hz. methyl); CI-MS m/z 171 B11. Generalmethod for the Synthesis of w-Sulfonylphenyl Anilines 0 0 0 2 N O ,Me 0-0 Step 1. 4 4 -Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4methylthiophenoxy)-1-ntirobenzene (2 g, 7.66 mmol) in CHC1, (75 mL) at 0 OC was slowly added mCPBA (57-86%, 4 and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-lnitrobenzene as a solid (2.1 g).

Step 2. 4-(4-Methylsulfonylphenoxy)-l-an iline: 4-(4-Methylsulfonylphenoxy)-1nitrobenzene was reduced to the aniline in a manner anaologous to that described in Method B3d, step 2.

B12. General Method for Synthesis of o-Alkoxy-o-carboxyphenyl Anilines 0 O MOMe 0 2 N OMe Step 1. 4 3 -Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of 3 -carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added K,CO, (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat the reflux tempoerature overnight, then cooled to room temperature and filtered through a pad of Celite®. The resulting solution was concentrrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography EtOAc 50% hexane) to give 4 -(3-methoxycarbonyl-4-methoxyphenoxy)-lnitrobenzene as a yellow powder (3 mp 115 118 °C.

0

OH

Step 2. 4 3 -Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene (1.2 KOH (0.33 g),and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated at the reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN HCI solution.

The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4 and concentrated under reduced pressure to give 4-(3-carboxy-4methoxyphenoxy)-1 -nitrobenzene (1.04 g).

C. General Methods of Urea Formation Cla. Reaction of a Heterocyclic Amine with an Isocyanate N N H H N-(5-tert-Butyl-3-thienyl)-N'-(4-phenoxyphenyl)urea: To a solution of butyl-3-thiophene-ammonium chloride (prepared as described in Method A4b; 7.28 g, 46.9 mmol, 1.0 equiv) in anh DMF (80 mL) was added 4-phenoxyphenyl isocyanate (8.92 g, 42.21 mmol, 0.9 equiv) in one portion. The resulting solution was stirred at 50-60 °C overnight, then diluted with EtOAc (300 mL). The resulting solution was sequentially washed with H,O (200 mL), a 1 N HCI solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na,SO4), and concentrated under reduced pressure.

The resulting off-white solid was recrystallized (EtOAc/hexane) to give a white solid (13.7 g, which was contaminated with approximately 5% of bis(4phenoxyphenyl)urea. A portion of this material (4.67 g) was purified by flash chromatography EtOAc/27% CHCl,/64% cyclohexane) to afforded the desired product as a white solid (3.17 g).

Clb. Reaction of a Heterocyclic Amine with an Isocyanate L0 N N H H N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-phenoxyphenyl)urea: To a solution of amino-3-tert-butylisoxazole (8.93 g, 63.7 mmol, 1 eq.) in CHCI, (60 mL) was-added 4-phenyloxyphenyl isocyanate (15.47 g, 73.3 mmol, 1.15 eq.) dropwise. The mixture was heated at the reflux temp. for 2 days, eventually adding additional CHC1I mL). The resulting mixture was poured into water (500 mL) and extracted with EtO (3 x 200 mL). The organic layer was dried (MgSO,) then concentrated under reduced pressure. The residue was recrystallized (EtOAc) to give the desired product (15.7 g, mp 182-184 OC; TLC acetone/95% acetone) R,0,27; 'H-NMR (DMSO-d) 8 1.23 9H), 6.02 1H), 6.97 (dd, J=0.2, 8.8 Hz, 2H), 6.93 J=8.8 Hz, 2H), 7.08 J=7.4 Hz, 1H), 7.34 2H), 7.45 (dd, J=2.2, 6.6 Hz, 2H), 8.80 1H), 10.04 (s, 1H); FAB-MS m/z (rel abundance) 352 Clc. Reaction of a Heterocyclic Amine with an Isocyanate N N N H H H

N-(

3 -tert-Butyl-5-pyrazolyl)-N'-(4-(4-methylphenyl)oxyphenyl)urea: A solution of 5-amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4-(4methylphenoxy)phenyl isocyanate (0.225 g, 1.0 mmol 1.0 equiv) in toluene (10 mL) was heated at the reflux temp. overnight. The resulting mixture was cooled to room temp and quenched with MeOH (a few mL). After stirring for 30 min, the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, mp 204 OC; TLC acetone/95% CH,Cl 2

R

1 0.92; 'H-NMR (DMSO-d,) 8 1.22 9H), 2.24 3H), 5.92 1H), 6.83 J=8.4 Hz, 2H), 6.90 J=8.8 Hz, 2H), 7.13 J=8.4 Hz, 2H), 7.40 J=8.8 Hz, 2H), 8.85 1H), 9.20 (br s, 1H), 11.94 (br s, IH); EI-MS m/z 364 Cld. Reaction of a Heterocyclic Amine with an Isocyanate N N CI H H C1 N-(5-tert-Butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-terr-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL, 2.02 mmol) in CH,C1, (10 mL) to clarify the mixture and the resulting solution was stirred at room temp. overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHCO, solution (15 mL), a IN HC1 solution (15 mL) and a saturated NaCI solution (15 mL), dried (NaSO4), and concentrated under reduced pressure. A portion of the residue was by preparative HPLC (C-18 column; 60% acetonitrile/40% water/0.05% TFA) to give the desired urea (0.180 g, mp 169-170 TLC (20% EtOAc/80% hexane) R/ 0.57; 'H- NMR (DMSO-d,) 8 1.31 9H), 6.79 1H), 7.03 1H), 7.24-7.33 2H), 8.16 (dd, J=1.84, 7.72 Hz, 1H), 8.35 1H), 9.60 1H); "C-NMR (DMSO-d,) 6 31.9 34.0, 103.4, 116.1, 119.3, 120.0, 123.4, 128.1, 131.6, 135.6, 138.1, 151.7, 155.2; FAB-MS m/z (rel abundance) 343 345 347 12%).

Cle. Reaction of a Heterocyclic Amine with an Isocyanate 0 N

CI

N N N N C H H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(3,4-dichlorophenyl)urea: A solution of 3-terr-butyl-N'-(ert-butoxycarbonyl)pyrazole (Method A5; 0.150 g, 0.63 mmol) and 3,4-dichlorophenyl isocyanate (0.118 g, 0.63 mmol) were in toluene (3.1 mL) was stirred at 55 *C for 2 d. The toluene was removed in vacuo and the solid was redissolved in a mixture of CH,C1, (3 mL) and TFA (1.5 mL). After 30 min. the solvent was removed in vacuo and the residue-was taken up in EtOAc (10 mL). The resulting mixture was sequentially washed with a saturated NaHCO, solution (10 mL) and a NaCI solution (5 mL), dried (NaSO4), and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 40% EtOAc/ 60% hexane to 5% hexane) to give the desired product (0.102 g, mp 182-184 °C; TLC (40% EtOAc/60% hexane) R,0.05, FAB-MS m/z 327 i. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline

N

0 N=C=0 Step 1. 3-tert-Butyl-5-isoxazolyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CHC1 2 (20 mL) at 0 OC was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-tert-butylisoxazole (0.305 g, 2.18 mmol). The resulting solution was allowed to warm to room temp. over 1 h, and then was concentrated under reduced pressure. The solid residue dried in vacuo for 0.5 h.

N N

S

N0 N'N H H Step 2. N-(3-rert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinylthio)phenyl)urea: The crude 3-tert-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4-(4-pyridinylthio)aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 °C for 2 h then cooled to room temp. and diluted with an EtOAc/CH,CI, solution 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgSO,), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CHC1, to 4% MeOH/6%

CHCI

2 to afford a foam, which was triturated (EtO/hexane) in combination with sonication to give the product as a white powder (0.18 g, TLC CHCl,) Rf0.21; 'H-NMR (DMSO-d,) 5 1.23 9H), 6.06 1H), 6.95 J=5 Hz, 2H), 7.51 J=8 Hz, 2H), 7.62 J=8 Hz. 2H), 8.32 J=5 Hz. 2H), 9.13 1H), 10 .19 1H); FAB-MS m/z 369 Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline N N=C=O Step 1. 5-tert-Butyl-3-isoxazolyl Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CHCl (1 L) was added butylisoxazole (10.0 g, 71 mmol) followed by pyridine (46 mL, 569 mmol). The mixture was allowed to warm to room temp and stirred overnight (ca. 16 then mixture was concentrated in vacuo. The residue was dissolved in anh. THF (350 mL) and stirred for 10 min. The orange precipitate (pyridinium hydrochloride) was removed and the isocyanate-containing filtrate (approximately 0.2 M in THF) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) m/z 166 S S N N N H H Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinylthio)phenyl)urea: To a solution of 5-tert-butyl-3-isoxazolyl isocyanate (247 mL, 0.2 M in THF, 49.4 mmol) was added 4-(4-pyridinylthio)aniline (5 g, 24.72 mmol), followed by THF (50 mL) then pyridine (4.0 mL, 49 mmol) to neutralize any residual acid. The mixture was stirred overnight (ca. 18 h) at room temp. Then diluted with EtOAc (300 mL). The organic layer was washed successively with a saturated NaCI solution (100 mL), a saturated NaHC03 solution (100 mL), and a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated in vacuo. The resulting material was purified by MPLC (2 x 300 g silica gel, 30 EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 mp 178-179 OC; 'H-NMR (DMSO-d 6 5 1.28 9H), 6.51 62 1H), 6.96 J=6.25 Hz, 2H), 7.52 J=8.82 Hz. 2H), 7.62 J=8.83 Hz. 2H), 8.33 J=6.25 Hz, 2H), 9.10 1H), 9.61 1H); EI-MS n/z 368 Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline

N

N N N H H H

N-(

3 -tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH,C1 (13 mL) at 0 OC was slowly added pyridine (0.105 mL) was added slowly over a 5 min, then 4-(4pyridinyloxy)aniline (0.250 g, 1.3 mmol) was added in one aliquot causing a transient yellow color to appear. The solution was stirred at 0 OC for 1 h, then was allowed to warm to room temp. over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-tert-butyl- N'-(tert-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 OC for 12 h forming a white precipitate. The solids were dissolved in a 1N HCI solution and allowed to stir at room temp. for 1 h to form a new precipitate. The white solid was washed (50% Et,0/50% pet. ether) to afford the desired urea (0.139 g, mp >228 °C dec; TLC (10% MeOH/ CHC1,) R, 0.239; 'H-NMR (DMSO-d,) 8 1.24 9H), 5.97 1H), 6.88 J=6.25 Hz, 2H), 7.10 J=8.82 Hz, 2H), 7.53 J=9.2 Hz, 2H), 8.43 J=6.25 Hz, 2H), 8.92 (br s, 1H), 9.25 (br s, 1H), 12.00 (br s, 1H); EI-MS m/z rel abundance 351 (M 24%).

i. Reaction of a Heterocyclic Amine with N,N'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline 00 N N N

N

I H H N-(3-tert-Butyl-1-methyl-5-pyrazolyl)-N'-4(4-pyridinyloxy)phenyl)urea: To a solution of 5-amino-3-tert-butyl-I-methylpyrazole (189 g, 1.24 mol) in anh. CH,C1, (2.3 L) was added NN'-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The mixture was allowed to stir at ambient temperature for 5 h before adding 4-(4pyridinyloxy)aniline. The reaction mixture was heated to 36 °C for 16 h. The resulting mixture was cooled to room temp, diluted with EtOAc (2 L) and washed with H 2 0 (8 L) and a saturated NaCI solution (4 The organic layer was dried (Na,SO 4 and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et,0/l 1.2% hexane, 2.5 L) to afford the desired urea as a white solid (230 g, mp 149-152 OC; 'H-NMR (DMSO-d,) 8 1.18 9H), 3.57 (s, 3H), 6.02 1H), 6.85 J=6.0 Hz, 2H), 7.08 J=9.0 Hz, 2H), 7.52 J=9.0 Hz, 2H), 8.40 J=6.0 Hz, 2H), 8.46 1H), 8.97 1H); FAB-LSIMS m/z 366 Reaction of a Heterocyclic Amine with N,N'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline NN

S

H H H

N-(

3 -ert-Butyl-5-pyrazolyl)-N'-(3-(4-pyridinylthio)p henyl)urea: To a solution of 3 -tert-butyl-N'-(tert-butoxycarbonyl)pyrazole (0.282 g, 1.18 mmol) in

CH

2 C1, (1.2 mL) was added N,N'-carbonyldiimidazole (0.200 g, 1.24 mmol) and the mixture was allowed to stir at room temp. for 1 day. 3-(4-Pyridinylthio)aniline (0.239 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp. for I day. Then resulting solution was treated with a 10% citric acid solution (2 mL) and was allowed to stir for 4 h. The organic layer was extracted with EtOAc (3 x 15 mL), dried (MgSO,), and concentrated in vacuo. The residue was diluted with CH,Cl, (5 mL) and trifluoroacetic acid (2 mL) and the resulting solution was allowed to stir for 4 h. The trifluoroacetic reaction mixture was made basic with a saturated NaHCO solution, then extracted with CH,CI, (3 x 15 mL). The combined organic layers were dried (MgSO,, and concentrated in vacuo. The residue was purified by flash chromatography MeOH/95% CHCL 2 The resulting brown solid was triturated with sonication (50% Et,0/50% pet. ether) to give the desired urea (0.122 g, 28%): mp >224 OC dec; TLC MeOH/ 95% CHCIl) Rf 0.067; 'H-NMR (DMSO-d 6 6 1.23 9H), 5.98 1H), 7.04 (dm, J=13.24 Hz, 2H), 7.15-7.19 1H), 7.40-7.47 2H), 7.80-7.82 1H), 8.36 (dm, J=15.44 Hz, 2H), 8.96 (br s, 1H), 9.32 (br s, 1H), 11.97 (br s, 1H); FAB-MS m/z (rel abundance) 368 100%).

a. Reaction of Substituted Aniline with N,N'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine N N N N N N I H H N-(3-tert-Butyl-l-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea: To a solution of 4-(4-pyridinylmethyl)aniline (0.200 g, 1.08 mmol) in CH,CI, (10 mL) was added ,N'-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for 1 h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-amino-3-tert-butyl-1methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 °C overnight. The reaction mixture was cooled to room temp and purified by column chromatography (gradient from 20% acetone/80% CHC1, to 60% acetone/40% CHC1) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, TLC (4% MeOH/96% CHCI 2 R, 0.15; 'H-NMR (DMSO-d,) 6 1.19 9H), 3.57 3H), 3.89 2H), 6.02 IH), 7.14 J=8.4 Hz, 2H), 7.21 J=6 Hz, 2H), 7.37 J=8.4 Hz, 2H), 8.45-8.42 3H), 8.81 1H); FAB-MS m/z 364 Reaction of Substituted Aniline with N,N'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine N O N H H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(2-benzothiazolyloxy)phenyl)urea: A solution of 3 -(2-benzothiazolyloxy)aniline (0.24 g, 1.0 mmol, 1.0 equiv) and N.N'carbonyldiimidazole (0.162 g, 1.0 mmol, 1.0 equiv) in toluene (10 mL) was stirred at room temp for I h. 5-Amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol) was added and the resulting mixture was heated at the reflux temp. overnight. The resulting mixture was poured into water and extracted with CHCI, (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CHzC1 2 Petroleum ether was added and resulting white precipitate was resubmitted to the crystallization protocol to afford the desired product (0.015 g, mp 110-111 OC; TLC acetone/95% CH 2 Cl2) R0.05; 'H-NMR (DMSO-d,) 8 1.24 9H), 5.97 1H), 7.00-7.04 1H), 7.21-7.44 4H), 7.68 J=5.5 Hz, 1H), 7.92 J=7.7 Hz, IH), 7.70 1H), 8.95 1H), 9.34 (br s, 1H), 11.98 (br s, IH); EI- MS m/z 408 .Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline 0 S N N

N

H H N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH,C1 2 (5 mL) was added a solution of 4-(4-pyridinyloxy)aniline (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH,CI, (5 mL). The resulting mixture was allowed to warm to room temp. and was stirred for 1 h, then was concentrated under reduced pressure. The residue was dissolved in CH,C1, (5 mL), then treated with butylthiopheneammonium chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h. then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHCO, solution (50 mL) and a saturated NaCl solution (50 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% hexane to 100% EtOAc) to give the desired product (0.38 g TLC hexane) R 0.13; 'H-NMR (CDC1,) 6 1.26 9H), 6.65 J=1.48 Hz, 1H), 6.76 (dd, J=1.47, 4.24 Hz, 2H), 6.86 J=1.47 Hz, 1H), 6.91 J=8.82 Hz, 2H), 7.31 J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 J=1.47 Hz, 2H); 'C-NMR (CDCI,) 8 32.1 34.4, 106.2, 112.0 116.6, 121.3 121.5 134.9, 136.1, 149.0, 151.0 154.0, 156.9, 165.2; FAB-MS m/z (rel abundance) 368 100%).

General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine

N/*NI

'0 N N H H N-(3-tert-Butyl-4-methyl-5-isoxazolyl)-N'-(2-fluorenyl)urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (1.OmL) was added a solution of 5-amino-4-methyl-3-tert-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL).

The reaction mixture was stirred at 70 °C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was-stirred at 40 °C for 3 h and then at RT for 17-h to produce a precipitate. The solids were washed with EtzO and hexanes to give the desired urea as a beige solid (25 mg, mp 179-181 OC; 'H-NMR (DMSO-d 6 8 1.28 9H), 2.47 67 3H), 3.86 2H), 7.22 J=7.3 Hz, 1H), 7.34 2H), 7.51 J=7.3 Hz, 1H), 7.76 3H), 8.89 1H), 9.03 1H); HPLC ES-MS m/z 362 C6. General Method for Urea Formation by Curtius Rearrangement and Carbamate Trapping 0

N

3 Step 1. 5-Methyl-2-(azidocarbonyl)thiophene: To a solution of 5-Methyl-2thiophenecarboxylic acid (1.06 g, 7.5 mmol) and Et 3 N (1.25 mL, 9.0 mmol) in acetone mL) at -10 °C was slowly added ethyl chloroformate (1.07 mL, 11.2 mmol) to keep the internal temperature below 5 OC. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the reaction mixture was stirred for 2 h at 0 °C.

The resulting mixture was diluted with CHC1 2 (10 mL) and washed with a saturated NaCl solution (10 mL). The aqueous layer was back-extracted with CHCI, (10 mL), and the combined organic layers were dried (MgSO,) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc/ 90% hexanes) to give the azidoester (0.94 g, Azidoester (100 mg, 0.6 mmol) in anhydrous toluene mL) was heated to reflux for 1 h then cooled to rt. This solution was used as a stock solution for subsequent reactions.

OCN

Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp. for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions.

H H Step 3. N-(5-tert-Butyl-3-isoxazolyl)-N'-(5-methyl-2-thienyl)urea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp.

68 was added 3 -amino-5-tert-butylisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a I N HCI solution (2 x 25 mL) and a saturated NaCI solution. (25 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, mp 200-201 oC; TLC (20% EtOAc/80% hexane) R,0.20; EI-MS mz 368 C7. General Methods for Urea Formation by Curtius Rearrangement and Isocyanate Trapping Cl

CHO

Step 1. 3-Chloro-4,4-dimethylpent-2-enal: POC1, (67.2 mL, 0.72 mol) was added to cooled (0 OC) DMF (60.6 mL, 0.78 mol) at rate to keep the internal temperature below 20 OC. The viscous slurry was heated until solids melted (approximately OC), then pinacolone (37.5 mL, 0.30 mol) was added in one portion. The reaction mixture was then to 55 °C for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCI solution (200 mL), dried (NaSO) and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH 2 Cl) to give the desired aldehyde as an orange oil (15.5 g, TLC hexane) R 1 0.54; 'H NMR (CDCl 3 d 1.26 9H), 6.15 J=7.0 Hz, IH), 10.05 J=6.6 Hz, 1H).

COzMe Step 2. Methyl 5-tert-butyl-2-thiophenecarboxylate: To a solution of 3-chloro- 4,4-dimethylpent-2-enal (1.93 g, 13.2 mmol) in anh. DMF (60 mL) was added a solution of NaS (1.23 g, 15.8 mmol) in water (10 mL). The resulting mixture was stirred at room temp. for 15 min to generate a white precipitate, then the slurry was 69 treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids.

The reaction mixture was stirred at room temp. for 1.5 h, then treated with a 1 N HC1 solution (200 mL) and stirred for 1 h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HCI solution (200 mL), water (2 x 200 mL) and a saturated NaCI solution (200 mL), dried (Na,SO 4 and concentrated under reduced pressure. The residue was purified using column chromatography EtOAc/95% hexane) to afford the desired product (0.95 g, TLC (20% EtOAc/80% hexane) Rf 0.79; 'H NMR (CDCI 3 8 1.39 9H), 3.85 3H), 6.84 J=3.7 Hz, 1H), 7.62 J=4.1 Hz, 1H); GC-MS m/z (rel abundance) 198

CO

2

H

Step 3. 5 -tert-Butyl-2-thiophenecarboxylic acid: Methyl 5-tert-butyl-2thiophenecarboxylate (0.10 g, 0.51 mmol) was added to a KOH solution (0.33 M in MeOH/10% water, 2.4 mL, 0.80 mmol) and the resulting mixture was heated at the reflux temperature for 3 h. EtOAc (5 mL) was added to the reaction mixture, then the pH was adjusted to approximately 3 using a 1 N HCI solution. The resulting organic phase was washed with water (5 mL), dried (NaSO,), and concentrated under reduced pressure (0.4 mmHg) to give the desired carboxylic acid as a yellow solid (0.067 g, TLC (20% EtOAc/79.5% hexane/0.5% AcOH) Rf 0.29; 'H NMR (CDCI,) 6 1.41 9H), 6.89 J=3.7 Hz, 1H), 7.73 J=3.7 Hz, 1H), 12.30 (br s, 1H); "C NMR (CDCI 3 8 32.1 35.2, 122.9, 129.2, 135.1, 167.5, 168.2.

N N

IC

H H c Step 4. N-(5-tert-Butyl-2-thienyl)-N'-(2,3-dichlorophenyl)urea: A mixture of tert-butyl-2-thiophenecarboxylic acid (0.066 g, 0.036 mmol), DPPA (0.109 g, 0.39 mmol) and Et,N (0.040 g, 0.39 mmol) in toluene (4 mL) was heated to 80 °C for 2 h, 2,3-dichloroaniline (0.116 g, 0.72 mmol) was added, and the reaction mixture was heated to 80°C for an additional 2 h. The resulting mixture was allowed to cool to room temp. and treated with EtOAc (50 mL). The organic layer was washed with a I N HC1 solution (3 x 50 mL), a saturated NaHCO, solution (50 mL), and a saturated NaCI solution (50 mL), dried (Na,SO4), and concentrated under reduced pressure.

The residue was purified by column chromatography EtOAc/95% hexane) to afford the desired urea as a purple solid (0.030 g, TLC (10% hexane) Rf0.28; 'H NMR (CDC13) 8 1.34 9H), 6.59 (br s, 2H), 7.10-7.13 2H), 7.66 (br s, 1H), 8.13 (dd, J=2.9, 7.8 Hz, 1H); "C NMR (CDCI 3 6 32.2 34.6, 117.4, 119.0 7 119.1I, 119.2, 121.5, 124.4, 127.6, 132.6, 135.2, 136.6, 153.4; HPLC ES-MS m/z (rel abundance) 343 100%), 345 347 14%).

C8. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a triphosgene solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).

The vial was capped and heat at 80 oC for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h. cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase

HPLC.

D. Misc. Methods of Urea Synthesis DI. Electrophylic Halogenation N N Br H H

N-(

2 -Bromo-5-tert-butyl-3-thienyl)-N'.(4-methylphenyl)urea: To a slurry of tert-butyl-3-thienyl)-N'-( 4 -methylphenyl)urea (0.50 g, 1.7 mmol) in CHCI 3 (20 mL) at room temp was slowly added a solution of Br, (0.09 mL. 1.7 mmol) in CHCI 3 (10 mL) via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure, and the residue triturated (2 x Et,O/hexane) to give the brominated product as a tan powder (0.43 g, mp 161- 163 TLC (20% EtOAc/ 80% hexane) R,0.71; 'H NMR (DMSO-d,) 8 1.29 9H), 2.22 3H), 7.07 J=8.46 Hz, 2H), 7.31 J=8.46 Hz, 2H), 7.38 1H), 8.19 (s, 1H), 9.02 IH); "C NMR (DMSO-d,) 5 20.3, 31.6 34.7, 89.6, 117.5, 118.1 129.2 130.8, 136.0, 136.9, 151.8, 155.2; FAB-MS m/z (rel abundance) 367 369 100%).

D2. Synthesis of wc-Alkoxy Ureas NON

OH

H H Step 1. N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-hydroxyphenyl)oxyphenyl)urea:

A

solution ofN-(5-tert-butyl-3-thienyl)-N'-( 4 -(4-methoxyphenyl)oxyphenyl)urea (1.2 g, 3 mmol) in CH,C1 2 (50 mL) was cooled to -78 °C and treated with BBr, (1.0 M in CHCl 2 4.5 mL, 4.5 mmol, 1.5 equiv) dropwise via syringe. The resulting bright yellow mixture was warmed slowly to room temp and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), then washed with a saturated NaHCO, solution (50 mL) and a saturated NaCI solution (50 mL), dried (NaSO4), and concentrated under reduced pressure. The residue was purified via flash chromatography (gradient from hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan foam (1.1 g, TLC (20% EtOAc/80% hexane) R, 0.23; 'H NMR (DMSO-d) 6 1.30 9H), 6.72-6.84 7H), 6.97 J=1.47 Hz, 1H), 7.37 (dm, J=9.19 Hz, 2H), 8.49 1H), 8.69 1H), 9.25 1H); FAB-MS m/z (rel abundance) 383 33%).

S N N O O H H Step 2. N-(5-tert-Butyl-3-thienyl)-N'-(4(4--ethoxyphenyl)oxyphenyl)urea: To a mixture of N-(5-tert-butyl-3-thienyl)-N'-( 4 4 -hydroxyphenyl)oxyphenyl)urea (0.20 g, mmol) and CsCO, (0.18 g, 0.55 mmol, 1.1 equiv) in reagent grade acetone mL) was added ethyl iodide (0.08 mL, 1.0 mmol, 2 equiv) via syringe, and the resulting slurry was heated at the reflux temp. for 17 h. The reaction was cooled, filtered, and the solids were washed with EtOAc. The combined organics were concentrated under reduced pressure, and the residue was purified via preparative HPLC (60% CH,CN/40% H,0/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, mp 155-156 TLC (20% EtOAC/ 80% hexane) R,0.40; 'H- NMR (DMSO-d 6 8 1.30 9H), 1.30 J=6.99 Hz, 3H), 3,97 J=6.99 Hz, 2H), 6.80 J=1.47 Hz, 1H), 6.86 (dm, J=8.82 Hz, 2H), 6.90 4H), 6.98 J=1.47, 1H), 7.40 (dm, J=8.83.Hz, 2H), 8.54 1H), 8.73 1H); "C-NMR (DMSO-d 6 8 14.7, 32.0 33.9, 63.3, 102.5, 115.5 116.3, 118.4 119.7 119.8 (2C), 135.0, 136.3, 150.4, 152.1, 152.4, 154.4, 154.7; FAB-MS m/z (rel abundance) 411 D3. Synthesis of co-Carbamoyl Ureas 0 0 0 N N S H H

H

N-(3-tert-Butyl-1-methyl-5-pyrazolyl)-N'-(4-(4acetaminophenyl)methylphenyl)urea: To a solution of pyrazolyl)-N'-(4-(4-aminophenyl)methylphenyl)urea (0.300 g, 0.795 mmol) in CH,C1, mL) at 0 °C was added acetyl chloride (0.057 mL, 0.795 mmol), followed by anhydrous EtN (0.111 mL, 0.795 mmol). The solution was allowed to warm to room temp over 4 h, then was diluted with EtOAc (200 mL). The organic layer was sequentially washed with a 1M HCI solution (125 mL) then water (100 mL), dried (MgSO), and concentrated under reduced pressure. The resulting residue was 73 purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid (0.160 g, TLC (EtOAc) R 0.33; 'H-NMR (DMSO-d 6 8 1.17 (s, 9H), 1.98 3H), 3.55 3H). 3.78 2H), 6.00 1H), 7.07 J=8.5 Hz, 2H), 7.09 J=8.5 Hz, 2H), 7.32 J=8.5 Hz, 2H), 7.44 J=8.5 Hz, 2H), 8.38 1H), 8.75 IH), 9.82 1H); FAB-MS m/z 420 General Method for the Conversion of Ester-Containing Ureas into Alcohol- Containing Ureas N, 0 it I fN N N N CI H O H H Cl N-(N'-(2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'-(23-dichlorophenyl)urea:

A

solution of 2 ,3-dichlorophenylamino)carbonyloxyethyl)-3-tert-butyl-5 pyrazolyl)-N'-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH 0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at -65 °C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (3 mL). The resulting organic phase was washed with a saturated NaCI solution mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was crystallized (Et,O) to afford the desired product as a white solid (0.17 g, 64 TLC EtOAc/40% hexane) R/0.16; 'H-NMR (DMSO-d,) 6 1.23 9H), 3.70 J=5.7 Hz, 2H), 4.10 J=5.7 Hz, 2H), 6.23 1H), 7.29-7.32 2H), 8.06-8.09 1H), 9.00 (br s, 1H), 9.70 (br s, 1H); FAB-MS m/z (rel abundance) 371 100%).

DSa. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas 74 Step 1. N-(N'-(Carboxymethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3dichlorophenyl)urea: A solution of pyrazolyl)-N'-(2.3-dichlorophenyl)urea (prepared as described in Method A3, 0.46 g, 1.11 mmoles) and NaOH (1.2 mL, 5N in water. 6.0 mmoles) in EtOH (7 mL) was stirred at room temp. for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (4 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was crystallized (Et,O/hexane) to afford the desired product as a white solid (0.38 g, TLC (10% MeOH/90% CH2C12) R/0.04; 'H-NMR (DMSO-d 6 8 1.21 9H), 4.81 2H), 6.19 1H), 7.28-7.35 2H), 8.09-8.12 IH), 8.76 (br s, IH), 9.52 (br s, 1H); FAB-MS m/z (rel abundance) 385 100%).

N N N CI MeHN H H I 0 Step 2. N-(N'-((Methylcarbamoyl)methyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3dichlorophenyl)urea: A solution of pyrazolyl)-N'-(2,3-dichlorophenyl)urea (100 mg, 0.26 mmole) and N,N'carbonyldiimidazole (45 mg, 0.28 mmole) in CH,CI, (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CH,CI 2 R 0.81). Dry methylamine hydrochloride (28 mg, 0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The reaction mixture was stirred at room temp. overnight, then diluted with CHC1l, washed with water (30 mL), a saturated NaCI solution (30 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% acetone/90% CHC1, to CHCI,) and the residue was crystallized (EtO/hexane) to afford the desired product (47 mg, TLC (60% acetone/40% CH,CI,) R/ 0.59; 'H-NMR (DMSO-d,) 5 1.20 9H), 2.63 J=4.5 Hz, 3H), 4.59 2H), 6.15 1H), 7.28- 7.34 2H), 8.02-8.12 2H), 8.79 (br s, 1H), 9.20 (br s, 1H); FAB-MS m/z (rel abundance) 398 General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas 0 ~0 N N N

COH

H H Step 1. N-(5-tert-Butyl- 3 -isoxazolyl)-N'(4-(4-carboxyphenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-( 4 4 -ethoxyoxycarbonyIphenyl)oxyphenyl)urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added a 1M NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HCI solution (20 mL) to form a white precipitate. The solids were washed with water (50 mL) and hexane (50 mL) and then dried (approximately 0.4 mmHg) to afford the desired product (0.368 g, 75 This material was carried to the next step without further purification.

N NN A NNHMe

O

H H oD Step 2. N-(5-tert-ButyI-3-isoxazolyl)-N'-(4-(4-(N-methylcarbamoyl)phenyl)oxyphenyl)urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4carboxyphenyl)oxyphenyl)urea (0.100 g, 0.25 mmol), methylamine (2.0 M in THF; 0.140 mL, 0.278 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.39 mmol), and N-methylmorpholine (0.030 mL, 0.27 mmol) in a mixture of THF (3 mL) and DMF (3mL) was allowed to stir overnight at room temp. then was poured into a IM citric acid solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined extracts were sequentially washed with water (3 x mL) and a saturated NaCL solution (2 x 10 mL), dried (NaSO,), filtered, and concentrated in vacuo The resulting crude oil was purified by flash chromatography 76 EtOAc/40% hexane) to afford the desired product as a white solid (42 mg, EI-MS m/z 409 General Method for the Conversion of o-Amine-Containing Ureas into Amide- Containing Ureas 0 N N N NH 2 H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-aminophenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-tert-butoxycarbonylaminophenyl)oxyphenyl)-urea (prepared in a manner analogous to Methods B6 then C2b; 0.050 g, 0.11 mmol) in anh 1,4-dioxane (3 mL) was added a cone HCI solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp The mixture was then poured into water (10 mL) and EtOAc(10 mL) and made basic using a 1M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO4), and concentrated in vacuo to afford the desired product as a white solid (26 mg, EI-MS m/z 367 D7. General Method for the Oxidation of Pyridine-Containing Ureas N N N 'O H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(N-oxo-4-pyridinyl)methylphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHC1, (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated K 2 CO, solution (10 mL). After 5 min, the solution was diluted with CHCI, (50 mL). The organic layer was washed successively with a saturated aqueous NaHSO, solution (25 mL), a saturated NaHCO 3 solution mL) and a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated in 77 vacuo. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the N-oxide (0.082 g, 79%).

3. General Method for the Acylation of a Hydroxy-Containing Urea 0 0 0 N N NO H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetoxyphenyloxy)phenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyloxy)phenyl)urea (0.100 g, 0.272 mmol), N,N-dimethylaminopyridine (0.003 g, 0.027 mmol) and Et,N (0.075 mL, 0.544 mmol) in anh THF (5 mL) was added acetic anhydride (0.028 mL, 0.299 mmol), and the resulting mixture was stirred at room temp. for 5 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The resulting solution was sequentially washed with a citric acid solution (10 mL), a saturated NaHCO, solution (10 mL) and a saturated NaCI solution (10 mL), dried and concentrated under reduced pressure to give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmHg): TLC (40% EtOAc/60% hexane) R, 0.55; FAB-MS m/z 410 D9. Synthesis of o-Alkoxypyridines N N N N O H H H Step 1. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(2(1H)-pyridinon-5-yl)oxyphenyl)urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(5-(2-methoxy)pyridyl)oxyaniline (prepared in a manner analogous to that described in Methods B3k and C3b; 1.2 g, 3.14 mmol) and trimethylsilyl iodide (0.89 mL, 6.28 mmol) in CH 2

CI,

mL) was allowed to stir overnight at room temp., then was to 40 OC for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (gradient from 80% EtOAc/20% hexans to 78 EtOAc) to give the desired product (0.87 g, mp 175-180 TLC EtOAc/20% hexane) Rf0.05; FAB-MS m/z 369 100%).

^NUN N, N N N N OEt H H Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(5-(2-Ethoxy)pyridyl)oxyphenyl)urea: A slurry of N-(5-ter-butyl-3-isoxazolyl)-N'-(4-(2(l (0.1 g, 0.27 mmol) and Ag,CO 3 (0.05 g, 0.18 mmol) in benzene (3 mL) was stirred at room temp. for 10 min. lodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite" then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, mp 146 oC; TLC (40% hexane) RI 0.49; FAB-MS m/z 397 100%).

DI0. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide- Containing Urea

N

H H

OH

N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(1-hydroxyethyl)phenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(1acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods BI and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH 4 (0.008 g, 0.21 mmol) in one portion. The mixture was allowed to stir for 2 h at room temp., then was concentrated in vacuo. Water (20 mL) and a 3M HCI solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (MgSO4), and concentrated in vacuo The resulting white solid was purified by trituration (Et,O/hexane) to afford the desired product (0.021 g, 32 mp 80-85 OC; 'H NMR (DMSO-d,) 5 1.26 9H), 2.50 3H). 4.67 1H), 5.10 (br s, 1H), 6.45 1H), 6.90 4H), 7.29 J=9.0 Hz, 2H), 7.42 J=9.0 Hz.

2H), 8.76 1H), 9.44 1H); HPLC ES-MS 396 Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy- Substituted Ureas 001 N OPh N N N Ph H H 3 -isoxazolyl)-N'-(4-(3-(benzyloxycarbonylamino)phenyl)oxyphenyl)urea: To a solution of the N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(3carboxyphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods B3a, Step 2 and C2b; 1.0 g, 2.5 mmol) in anh toluene (20 mL) was added Et3N (0.395 mL, 2.8 mmol) and DPPA (0.610 mL, 2.8 mmol). The mixture was heated at 80 °C with stirring for 1.5 h then allowed to cool to room temp. Benzyl alcohol (0.370 mL, 3.5 mmol) was added and the mixture was heated at 80 °C with stirring for 3 h then allowed to cool to room temp. The resulting mixture was poured into a 10% HCI solution (50 mL) and teh resulting solution extracted with EtOAc (3 x mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCI (2 x 50 mL), dried (NaSO,), and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 mp 73-75 'H NMR (DMSO-d 6 1.26 9H), 5.10 2H), 6.46 IH), 6.55 J=7.0 Hz, 1H), 6.94 J=7.0 Hz, 2H), 7.70 7H), 8.78 1H), 9.46 1H), 9.81 1H); HPLC ES-MS m/z 501 The following compounds have been synthesized according to the General Methods Listed above: Table 1.

5-Substituted-3-asoxazolvl Ureas R1.R 0 N N Nf H H Mass np TLC Solvent Spec. Synth.

Entry R' 0 C) *R x [ySource] Method I t-Bu 148- 352 CIC 149

[FAB]

2 -B-u 176- 0.16 5% 386 C2b 177 MeOHI

[FAR]

CH2CI2 3 t-Bu C1 0.50 30% 400 C2b EtQAc/

[HPLC

hexane ES-MS] 4 i-Bu 156- 0.50 30% 366 C2b 157 EtOAc/ (MrH)-

[HPLC

hexane ES-MS] i-Bu Me 0.80 40% 492 C2b Me EtOAc/ Me Et 60% [-PLC Me Et hexane ES-MS] 6 -Bu 190- 0.15 30% 350 C2b C N 191 EtOAc/ [El] hexane 7 -Bu 0.55 20% 352 C2b EtOAci

[FAB]

hexane 8 f-Bu 0.25 20% 367 C2b EtOAc/ [EI] hexane 9 t-Bu P 0 0.15 20% 363 C2b Ph EtOAc/ [EI] hexane i-Bu Me 0.30 20% 381 C2b EtOAcf [EI] hexane 1 I-Bu N 0.25 30% 425 B3b C2b Sk EtOAcf

[HPLC

hexane ES-MSI 12 i-Bu 175- 0.25 30% 409 83a. Step 177 EtOAc/ 1, B3b [HPLC Step 2.

S_ hexane ES-MS) _C2b 13 i-Bu 0 0.35 30% 402 B3b, C2b Et0Ac/

[HPLC

hexane ES-MS1 14 t-Bu 0 0.20 30% 403 B3b, C2b N /EtOAc/

[HPLC

hexane ES-MS] t-Bu 0.25 30% 419 f3b. EtOAc/

[HPLC

hexane ES-MS 16 i-Bu 0.20 30% 419 l3h, C2b EtOAcl (M+H)

[HPLC

hexane ES-MS 17 i-Bu 0.40 30% 352 C2b EtOAcf (M+H) 0-0 70% IHPLC hexane ES-MS1 i1 t-Bu /+40 30% 365 C2b EtOAcf LEI] o hexane 19 i-Bu 0.15 30% 367 B3a, C2b.

E\OAc/ [El] D2 Step I hexane i-Bu s 5 Me 200- 0.20 20% 280 C6 201 EtOAc!

[FAB]

hexane 21 i-Bu 178- 368 B4a, C2b 179 [El) 22 I-Bu 2 N 164- 0.25 30% 351 Bi, C2b c 165 EtOAc!

[FAB]

hexane 23 e-Bu H2 N 170- 0.15 30% 351 B7, RI, C 172 EtOAc/ C2b

[FAB]

hexane 24 i-Bu 0 179- 010 30% 387 C2b 182 EtOAc/ 70%

[FAR]

hexane 82 i-Ru 0 0.55 40% 410 B3b. C2b.

EtOAc/ D2 Step 1, Me 60% [FAR] DE hexan 26 I-Bu Me 176- 0.55 25% 366 B3a. C2b 182 EIOAc/

[FAB]

bexane 27 I-Bu Me 0.40 25% 366 R3a. C2b EtOAci

[FA]

hexane 28 -Bu Me 150- 0.45 25% 380 R3a, C2b 158 EtOAc/

[FAB]

hexane 29 I-Bu HO 0.30 25% 368 C2b EtOAc/ (M+H)t

[FAB]

hexane t-Bu Ci 118- 0.50 25% 420 R3a Step 122 EtOAc/ 1, B3b [FAR] Step 2, hexane C2b 31 I-Bu j7 195- 0.30 25% 397 C2b 197 EIOAc/ [FAB] hexane 32 t-Bu Me 0.80 25% 366 R3a, C2b EtOAc/

[FAB]

hexane 33 I-Bu 137- 0.55 30% 382 B3a, C2b 141 156 EtOAc/ 70% [FAB] hexane 34 i-Ru 0 P 137- 0.60 25% 410 R3a, C2b, 141 EfOAc/ D2

[FAB]

hexane t-Bu o-O1 4 0.60 25% 410 B3a, C~b, 166 ElOAc/ D2

[FAB)

hexane 36 i-Ru OH 78-80 0.15 25% 368 C2b 0 EtOAc/

[FAB]

hexane 37 i-Ru 167- 374 B3i, Bl, 169 C2b [FABi 38 i-Ru 0 CO, 200 0.30 5% 396 B3a Step dec MeOHI 2, C2b

[FAB]

AcOHl 94.5% CH2C12 39 1 i-Bu CO 2

K

0 5% MeOH.

0.5% AcOH/ 94.5% rllu*rlll 396 (M+H)-r

[FAB]

83a Step 2. C2b I-Bu H, 203- 0.35 10% 340 B8. B2b.

JC-N- 206 MeOH C2b

[FAB]

AcOHi 89.5% EtOAc 41 i-Ru 0 177- 419 B8. B2b, -H180 C2b

[FAB]

42 I-Bu 158- 0.25 30% 369 R4a. C2b 159 EtOAcf St N 70% [FAB] hexane 43 -Ru CF 3 180- 0.15 30% 437 f4a, C2b 181 ELOAcI

[FAB]

hexane 44 I-Bu E 140- 0.25 20% 396 B3a, C2b, 142 EtOAc/ D2

[FAB]

hexane i-Ru N 68-71 0.30 50% 370 B4a, C2b k EtOAc/ N 50% [FAB] hexane 46 i-Bu N 183- 0.30 30% 403 C2b S-a C1 186 ELOAcI

[CI]

hexane 47 I-Bu 98- 0.25 10% 454 C2b 101 EIOAci

F

3 C 90% [FAR] hexane 48 r-Bu 1 163- 0.25 20% 394 BI, C2b 0O 166 EtOAc/ Mc 80%

[FAB]

hexane 49 i-Bu S 144- 0.25 20% 399 C2b 147 EtOAc/

[FAR]

hexane i-Bu OMC 155- 0.25 40% 383 C2b 0 O 157 EtOAc/

[FAD]

hexane 51 r-Ru 162- 0.35 25% 386 C2b 164 EtOAcf

[FAB]

hexane f 52 r-Bu 149- 0.15 15% 382 C2b 520 rB 3 EtOAc/

[FAB]

hexane ii 77-80 0.30 30% 408 4i+) B3e. C2b 53 'Ru .30 EtOAc/ [El] hexane 54 t-Bu a oCN i162- 0.17 40% 354 13j, C2b 4 u16- EtOAc/ (M9H)+

[FAB]

73-76 00 hexane N 73-76 0.20 30% 368 B2. C2b EtOAc/ [EI] hexane 56 i-Bu MeO 73-75 0.15 25% 428 B2, C2b EtOAc/

[FAB]

OMe hexane 57 t-Bu s ome 143- 0.25 30% 398 83e, C2b 145 EtOAc/

[FAB]

hexane 58 I-Bu 148- 0.25 30% 428 83e C2b 151 EtOAc! OMe 70% (FAB] hexane 59 i-Bu 0.30 100% 353 B4b, C3b EtOAc

[FAB

i-Bu 126- 0.25 30% 412 B3eC2b 0 OMe 129 EtOAc/ (M4H)i OMe 70% [FAB] hexane 61 t-Bu 1 201- 0.25 10% 396 B3a C2b, 204 EtOAc/ D2 QEt 90% [FAR] hexane 62 t-Bu I S- N 163- 0.30 40% 369 94a, Cab 163 EIOAc/ (M+-H)C

[FAR]

hexane 63 t-Bu 162- 0.20 25% 363 C2b 163 EtOAc/ [El] 64 I-Ru N 127- 0.22 40% 353 3e Step 129 EiOAc/ 1, B2, [FAR] C2b hexane i-Bu 85-87 0.20 50% 402 83e Step EtOAc/ [EI] 1, B2, C2b bexane 66 t-Bu NIeO 108- 0.25 10% 381 3e. C2b 110 EtOAc: [El] hexane 67 t-Bu 186- 0.25 30% 367 B6, C2b, 189 EtOAc! D6

[FAB]

hexane 68 i-Ru 0 221- 0.25 60% 409 13e, C2b, Ni-k 224 EtOAc (MH)

[FAB]

hexane 69 t-Ru 0 114- 0.25 60% 409 3e, C2b, 3-NHMe 117 EtQAc/ o 40% [FAR] hexane i-Ru 0 201- 0.25 60% 423 R3e, C2b, >NM2 203 EtOAc/

[FAR]

hexane 71 t-Ru -J F 148- 0.25 20% 370 R3e, C2b 151 EtOAc/

[FAB]

hexane 72 i-Bu OMe 188- 0.25 20% 382 B3e, C2b 201 EtOAc!

[FAB]

hexane 73 s-Bu N 134- 0.25 20% 367 B3e. C2b JO txj Me 136 EtOAc/

[FAB]

hexane 74 t-Bu 176- 0.25 50% 403 B3e, C2b 178 EtOAc/

[FAB]

hexane t-Bu -N 132- 0.52 40% 383 B3k, C3b 0 OMe 134 EtOAc/

[FAB]

hexane 76 s-Ru H160- 0.79 75% 381 C3a a o 162 EtOAc/ (M4-1)+

[FAB]

hexane 77 i-Bu 140- 0.25 50% 352 B4b, C3b 143 EtOAc] [El] CH2CI2 78 I-Bu 147- 0.25 50% 352 13f, C3b 150 EIOAc' [El] N CH2CI2 79 s-Bu -F7\ 166- 0.44 50% 396 C3b ,O 0 170 EtOAc/ (M+H- 0 50% [FAB] hexane I I Me 190- 0.25 50% EtOAc! 50% CI-2C12 367

(M+H)

[FAB]

I B3g. C3b 81 I-Bu M 136- 0.25 50% 367 B4b. C3b M 140 EtOAc/

(M±H)

0 50% [FAB] -CH2C12 82 i-Bu Me 65-67 0.25 50/ 367 14b. C3b EtOAc/

[FAD)

CH2CI2 83 i-Bu Me 68-72 0.25 50% 383 R4a. C3b EtOAc/

[FAB]

CH2CI2 84 i-Bu N 146 0.49 40% 397 B3k C3b EtOAc/ (M+H)i D9

[FAB]

hexane t-Bu Me 164- 0.25 50% 382 B4a. C3b 165 EtOAc/ [EI] 16 CH2CI2 86 t-Bu ,r-NH 175- 0.25 20% 485 D3e, C3b, ph 0 177 EtOAc/

[FAB]

hexane 87 i-Bu H 137- 0.30 50% 366 C3a, D2 Zr N-jr0 H 141 EtOAc/ [El] step 1 hexane 88 I-Bu Ph-NH 120- 0.25 2(r/ 471 3e. C3b, 122 EtOAc!

[HPLC

hexane ES-MS] 89 t-Bu Et-NH 168- 0.25 50% 423 B3e, Ob, 0 170 EtOAc/

[HPLC

hexane ES-MS i-Bu i HJ OH 80-85 0.25 50% 396 DI, C2b, EtOAcf Me 50% [HPLC hexane ES-MS1 91 r-Bu 0 73-75 0.25 30% 501 B3e, Cb 04 EtOAc!

DII

Ph-/ NH 70%

[HPLC

hexane ES-MS] 92 i-Bu Me 0.50 5% 366 Bla acetone/

[FAB]

C12C12 93 i-Bu CF 3 199- 0.59 5% 419 Bla 200 acetone' [FAB] CH2C12 ID..C I CF.1 5% acetone, 419 (M)1 Bla [FAB] I i-Bu Me 78-82 025 10% 379 Weh, C3b EtOAc [El] Me CH2CI2 96 -u 214- 0.75 60% 463 C2b, D3 v t N 0 217 EfOAc/

F

3 C 40% [FAB] hexane 97 I-Bu 0 235 0.35 25% 402 83b, C2b EtQAc/ (M±H)+v hexane 98 I-Bu i153- 0.25 30% 424 We, C~b Oft 155 EtOAc/

[FAB]

aexane 99 -u -N 100 0.62 40%/o 411 R3a. RI, OPr-i EtOAc/ C3b

[FAR]

1 hexane 100 i-BuO 110- -0.15 1000/ 367 115 EtOAc

[FAB]

Table 1. S-Substituted-3-isoxazolv Ureas continued R'.R0 N N N- H H Mass mp TLC Solvent Spec. Synth.

Entry R' R2 R System Sourcel Method 101 i-BU 0 NH,, 0.50 100% 410 810, B4b, EtOAc C2b 0 e\N

[FAR]

102 -u O 153- 395 Cb 0 155 Me[Al I [FAB] 103 t-Ru 0 0.52 100% 396 BR1O, 84b,

NH

2 EtOAc C2b

[HPLC

ES-MS

104 -Bu 0 N0.75 100% 396 RIO, 24b, 2 EzOAc C2b O\N [HPLC ES-MSJ I 105 i-Bu 0 107- 0.85 100%' 410 B10. B4b.

NHMe 110 EtOAc C2b S ON

[FAB]

106 i-Bu 0132- B3d step

NH

2 135 2, C3a 107 t-Bu 0 0.58 100% C3a. NHPr-n EtOAc 108 t-Bu 0 0.58 100% C3a, EtOAc 109 I-Bu 0 137- 0.62 100% 439 83a step 140 EcOAc 1, B12, ifltO OM e (HPLC D~b step FS-MS) 2, C3a 110 I-Bu 0 163- 0.73 100% 425 B3a step NHMe 166 ELOAc 1, 812, 0& OH [HPLC D5b step %frMS 2, C3a 111 i-Bu 0-O -j So M 180- 83b step 181 1, B11, 83d step 2, C2a 112 i-Bu 0 135- B3b, C2a Me 139 113 i-Bu g- 9 0 212- B3 d step 215 2a, C2a 114 (-Bu MeHN -0 98- B3d step S: 100 2, C2a 115 i-Bu 135- 810, B4b, 0 NHMe 138 C2a 116 I-Bu 0 219- 0.78 80% 437 C3a, H 0 ()Me 221 EtOAcf step 2 hexane [HFLC ES-MS1 117 t-Bu 160- B3a step o 164 1 B3d step 2, C3a 118 t-Bu 0 NHe 124 0.39 5% Clc, N N EtOAc/ Ci hexane 119 :-Bu 73-75 0.41 10)0% 479 BWa, C4a, EtOAc NH [HPLC o ES-MS] 120 i-Bu 0 NHc0.32 100%/ 436 Cib. OH~ EtOAc step I [HPLC step 2 ES-MS1 121 t-Ru CN0.23 10% 506 83a, C4a,- '-HMeOW

LHPLC

/CH2CI2 ES-MSI 122 i-flu 06110.18 10% 1506 B3a, C4a, N IMcOH/ D~b Et' -N 90% [HPLC o2 -u 0 6 CH2 I2

ES-MS]

123 i-flu q 229- 0.37 40% 435 D5b step i231 EtOAc/ 1, B3d N. Me 60% [HPLC step 2, bexane_ ES-MS1 C3a 124 :-flu 0 N\ 0.21 5% 508 B3a, C4a, 0~ N- McOH/ D~b

[HPLC

/-06 CH2C2 ES-MSj 125 i-flu 0 167- 0.34 5% 424 COb, NHEt 170 MeOW/ N45% [HPLC EtOAc/ ES-MS] 126 I-flu 0 124 0.26 5% COb, cl NH-Me MeOHI EtOAc/ 127 1-lu Me0 NHe125- 0.28 5% COb, D~b Me H~e128 MeOH/ EtOAc/ 128 i-Bu 0 0.37 50% 426 COb -e NHMe EtOAc/ (Mi-1)+ Me S /50% pet [HPLC ___ether ES-MS] 129 i-flu 0 0.10 50% 424 COb NMe 2 EtOAc/ (M-iH)+ ,ES-MS1 130 t-Ru NH 0.18 70% 472 D5b step2 &-lNH0EtOAc: 030% [HPLC liexane ES-MS] 131 t-Bu 0e 0.32 582 COb Me

[HPLC

ES-MS]

0 0 132 r-Ru F 0.57 558 COb 0 N

ES-MS]

0 133 f-Ru r 0 0.21 598 COb 0 N~ [H-PLC ON

ES.MS]

0 0 134 r-Bu F -H0.86 489 COb o [HPLC

ES-MS]

135 r-Ru 0.64 514 COb FIN-vN [HPLC

ES-MS]

0-67) 136 e-Ru Me0-, 0.29 453 C3b -\NH

(HPLC

ES-MSj 137 f-Ru N 030 502 COb 0 [IPLC o ES-MS] 138 I-Ru oN~IiNH0.50 556 COb 0 N NH(M+H)+

[HPLC

0 ES-MS] 139 -Bu 0.27 541 C3b N

[HPLC

0 ES-MS 0-0 140 t-Ru 0 211- 0.27 50% 426 Cb NHMe 212 EtOAc! S -eN50% pet [HPLC ___ether ES-MSI 141 t-Bu 0 H r\ 195- B8.,C2a 198 142 f-Bu CF 3 170- C3a 171 143 i-Bu Me 141- 0.63 5% 382 B3b step 144 acetone/ 1,2, Cld

[FAB]

CH2CI2 144 i-Bu F 0.57 5% 386 B3b step acetone! 1,2. CId

[FAB]

CH2CI2 145 i-Bu F 145- 0.44 5% 370 B3b step 148 acetone! 1,2. Cid

[FAB]

CH2CI2 146 i-Bu F 197- 0.50 5% 404 B3b step 0 j\ 202 acetone! 1,2, Cid

[FAB]

cCH2CI2 147 r-Bu F 0.60 5% 404 83b step acetone! 1,2, Cld

[FAB]

F CH2C12 148 -Bu -%Me 126- 0.17 30% 366 B4c, C4a 129 MeOH/

[FAB]

EtOAc 149 r-Ru H 383 C3b

(HPLC

S-MS] 150 i-Bu H 156- 0.48 40% 395 C3a. D2 159 EtOAc! stept, step hexane [HPLC 2

ES-MS]

151 i-Bu -JnH 157- 0.51 409 C3a, D9 159 (M+1)t step 1, [HPLC scep2

ES-MSI

152 -Ru 130- 0.60 437 C3a, D9 132 step I, [HPLC step2

ES-MSI

153 r-Bu /\VH 146- 0.54 40% 9 r-N NIOPTd 150 EtOAci step1, step hexane (HPLC 2

ES-MS]

154 f-flu 145- 0.57 40% 423 C3a, D2 OBu-s 148 EtOAc! (Mi-H)-r stepI, step bexane [HPLC 2

ES-MS

155 f-Bu _Q H 1 175- 0.51 40% 457 C3a, D2 N- 0 178 EtOAc! stepi, step hexane [HPLC 2

SES-MS]

156 r-Bu 149- 0.48 4 0% 407 C3a. DI jN 152 EtOAc/ step I hexane [HPLC step 2

ES-MS]

157 f-BuE t 146- 0.36 40% 409 C3a -N-a OMe 147 EtOAc!

(M+H)

hexane [HPLC

ES-MS]

158 t-Bu 4x/Me-f 156- 0.43 40% 395 C3a 158 EtOAc/ hexane [FAR] 159 r-u s 164- 0.52 5% 396 B3b step 168 acetone/ (M+H)i 1,2, CId Me Me 95% [HPLC CH2Cl2 ES-MS] 160 t-Bu\N 0.36 5% 380 R3b step acetone (M+Hfr 1,2, Cld Me Me 95% (FAB] CH2C12 161 t-Bu 169- 368 C3b M 171 162 f-Bu 168 0.11 50% FFAB 1 b SN/1 pet 163 r-Bu Ys.Q.S 146 etheT b 164 f-Ru /0.45 100% 369 C2b EtOAc

[FAB]

165 t-Ru /\0.20 100% 367 B9, C2b EtOAc (M4-1-)i HO~ N(FAR] 166 r-Bu C 187- 0.46 30% 421 C3b 188 EtOAc! ci hexane [FAB] 167 *-Bu 133 0.36 409 C~a, D9 step2 1, N [F;AB] step2 168 t-Bu OPr-i 0.39 40% 411 C3a. D9 0 EtOA/ step I 60% [FAR] step2 hexane 169 t-Bu OEt 0.32 5% 397 B3k, CS 0- acetone/ 95% (HPLC CH2CI2 ES-MS 170 t-Bu OMe 0.21 5% 383 B3k. CS N acetone! 95% [HPLC CH2C2 ES-MS1 171 I-Ru /0.60 100% 365 C2b EtOAc (MA-H)+

NFAB]

172 t-Bu 0.16 30% 369 C8 EtOAcI

[HPLC

hexane ES-MS1 173 t-Ru 125- 0.09 5% C3b N129 MeOH/ C 1 IIMNI %EtOAc/ hexane 174 I-Bu Oj SMe 147- B3b, C2a 149 175 t-Bu H 0I 0.30 100% 380 C3a, D~b 1 -uN00 EtOAc step2

[HPLC

ES-MS

176 i-Ru /0.50 25% 353 MS EtOAc/ B

F

3 C 75% [CI] 4b, C8 hexane Table 2.3-Substituted-5-isoxazolyl Ureas

N'

fi R2 O N N' H H Mass Spec.

up TLC Solvent (Source] Synth.

Entry R' R_ (OC) R, System ethod 177 Me f- 169- 0.25 5% 324 Clb 170 acetone

[FAB]

CH2CI2 178 i-Pr 153- 0.54 50% 338 Clb 153 EtOAc! pet [FAB] ether 179 180 94 MeP 1 66- 0.54 i-Pr t;2- 0.29 50%-I EtOAci pet ether 5% 352 f M+H y-

[FAB]

355I 181 i-Pr [82 i-Pr 183 i-Pr 0 -NHMe 0 Me 169- 170 184 i-Pr 185 i-Pr 186 i-Pr Me -Q NHMe O\ N

N

0,20 0.10 0.09 0.23 0.29 0.03 MeOH/ C[-2C12 50% EtOAci hexane 50% EIOAc/ pet ether s0o EtQAc/ hexane 50 ox EtOAc/ hexanc 30% EtOAcf hexane 50%1 EIQAc/ 50% pet ether 50 EtOAc/ hexane

(FAB]

395-

[HPLC

ES-MSj 396

[HPLC

ES-

353

(HPLC

ES-MSj 389

[HPLC

-ESMS1 352 (M+Hye-

[HPLC

E-S]

396

[HPLC

40! (M+fl)±

[FAB]

(M-tH)±

[HPLC

ES-MSI

364 CElb A2.

R4a, C3a Cs- COb C8 194- 195 C8 C8 COb C8 C8 Cib 187 188 189 1 X Me 117 #js4frMe 175- 0.3T 50% EtOAc/ 190 Ru 191 z-Bu S~ S-KQN 0.21 0.52 [92 t 184 i-Ru 182 pet ether 5% MeOH/ CH2C12 50% EtOAc/ hexane

[FAB]

369 (M+Hys-

[FAB]

426'- (M+i-p±

[FAR]

352

[FABJ

C2a B5. C4a 193 1 t-Bu

OJ&M

T 60% EtOAc 366

[FAB]

194 195 196 '97 1 -RuN 210 0.05 5% 353 C3a dec acetone/

[FAB]

CHC2 i-Bu OQ OMe 174- 0.25 5% 382 C3a 175 acetone'

[FAR)

CH2C]2 t- Nu 90-92 0.16 5% 409 C2a acetone/ ih II95%

[FAR]

s_ CH2Cl2 o-c: 5% acetone/ I-Lilflll 409

[FA]

198 N 196- 0.17 5% 368 A2, 0 e 192 MeQHJ (M E~h, [FAR] C3a CH2CI2 199 t-Ru G- 204- 0.27 50% 383 A2, 206 EtOAct (M4H)+ B3a, pet [FAB] C3a ether 200 -Bu H 179- 351 A2, C3a CL \N 180

[FAB

201 i-Bu 0.33 50% 414 A2, EtOAc/ [EI] B4a, pet C3a ether 202 z-Bu Me 188- 0.49 50% 399 A2, 189 EtOAc;' 4a, pet [HPLC C3a 203 i-u 0 ether ES-MS) \u a 179- 0.14 5% 395 A2, N Mej 180 MeOH/ B4a, [FAR] C3a CH2CI2 204 i-Ru ~197- 0.02 10% 353 A2, 199 acetone! (MrH)+ B3h, [FAR] C3a CH2CI2 205 1-Bu Cl 136- 0.33 50% 421 A2, 0 139 EtOAc/ B3h.

C 50% pet [FAB] C3a

N

ether 206 I-Ru 213 0.05 5% 369 C3a dec acetone! (M4H)+ S 95% [FAB] CH2C12 207 i-Eu Q Ml 0.60 5% 274 C2a MeOH/

[FAB]

CH2C12 tBuS y& 118- 0.19 5% 387 A2, -E \~121 MeOHI B4a, (FAB] C3a 209 t-Eu 0 i2117- 0.13 5% A2, COb NHMc 219 MeOHI 0 CHC13 210 r-Eu 0A48 50% 394 C8 0~9 ~EtOAc/ me 50% [HPLC ____hexane ES-MS] 211 i-Eu 0T 0.17 30% 364 C8 EtOAc/ (MI-H)s

[HPLC

______hexane ES-M1 212 t-Eu 00.79 70% 421 B3a 0EtOAc/ step 1I NH 30% [HPLC BMd o hexane ES-MS] step 2, C3a 213 i-Eu -0.50 50% 407 B3a 7 f EtOAc/ step 1I NE 50% [HPLC E3d o hexane ES-MS] step 2, CMa 214 i-Eu 0 182- 0.25 5% 424 COh.

O NHEt 185 MOHI Db N45% [HPLC '--'EIOAcJ ES-MS] hexane 215 i-flu 0 198- 0.20 5% 444 COb, NHN~e 200 MeOH/ (MA-H)4 fib -N 45% [HLC EtOAc/ ES-MSJ 216 i-Eu 0 0.24 50% 426 COb NHMe EtOAcl S N50% pet [HPLC ether

ES-MS$I

217 sflu 0 215- 426 COb Se He217 N [HPLC 218 i-fl 0 188- 0.22 50% 410 COb MiMe 200 EtOAc! 50% pet [HPLC ether ES-ME] 219 i-Bu Y~jj. 214- 035 5% A2. C2b 215 acetonl CH2CI2 220 I-Bu 0 180me IS C3b 221 i-Bu I 160- 0.58 50% 336 (Mt) C3b 162 EtQAcl (CI pet ether 222 i-Bu 0.18 50% C3b EtOAcf pet ether 223 I-Bu CF, 163- 0.21 5% 453 C3b 165 MeOH/

[HPLC

CH2CI2

ES-MS]

224 i-Bu 71 208- 0.17 5% 353 C3b aN 211 MeOH/

[FAB]

CH2C12 225 I-Bu _0 109- 0.17 5% 369 C3b 112 MeOH/

[FA]

CH2CI2 226 i-u S155- 0.57 10% 453 C3b 26% 3 156 MeOH/ C12C12 [FAR] 227 i-Bu N-0 231- 0.54 10% 534 C3b NH 234 MeOH/ (MH)- \1 o-K7 >wi CI2C12 [FAB] 228 i-fU /179- 0.24 5% AZ. C3b N 180 MeOW o- a Me CHCI3 229 i-fu 0.30 5% 370 A2, C3b -t ~/FMeOHl

[FAB]

CHC13 230 -Bu 178- 0.20 5% A2. C3b 180 MeOH/ CHC13 231 i-Bu 186- 0.20 5% A2. C3b yN 187 MeOH/ Me CHC13 232 i-flu 149- 0.28 5% A2. C3b -N 152 MeOH/ s S CHC13 233 r-Ru 0 CF 3 210- 0.06 10% 421 C3b 213 MeOH/ N CH2C12 [FAR_ 234 r-Bu 9M e 132- 0.43 5% A2. COh 133 MeOHI ____CHC13 235 i-Bu 71-73 0.27 5% A2. COb MeOM! O\N CHC13 236 :-Bu Cl 176- 0.44 10% 437 COb 177 MeQH/ (M4-H)+ C, CH2C12 [FAB]) 237, u 0.09 50 351 C8 237 i-a ~C-E EtOAv-/ N 50% [IIPLC hexane ES-MSJ 238 i-Ba -fV 0.1A6 50% 403 C8 UEIOAc/ (M+H)s

[HPLC

ES-MS]

23 -u .5 50 381 C8 23 tBu 1 N EtOAc/ Me 50% [HPLC hexane ES-MSI 240 t-Ba 215- 0.'19 100% 370 Clb 216 EWOAc

[HPLC

241 i-Bu m 0.42 N=NSM MeOH/ ____CH2CI2 242 z-Bu 0.74 100% 366 B4b, C8 tfO~~9/EtOAc Me [HPLC

ES-MSI

243 t-Ba o 0.12 30% 421 CS Th..qF tOAc/ (M-iH)i-

F

3 C70%

[HPLC

hexane ES-MS1 tB00.8 100% 368 B4b, C8 245 i-u .6 EtOAc HO [H PLC J 246 i-Ru 142- 0.13 5%l A2, COb 144 MeOI{/ EIOAct _______hexane 247 I-Bu 0 205- 0.31 50% 410 COb NHMe 207 EtOAc/ N 50% pet [1-PLC o ether ES-MS1 248 Me f 154- 0.50 50% 365 Cib Me -rQ- j 155 EtOAc/ [El] Et 50% pet ther 249 Mc 160- 0.37 5% 380 Cib v~z' 162 acetone Et 95%

[FAB]

CH2CI2 250 Me C 1 Ci 196- 0.58 5% 342 Cib F Me 199 acetonei

[FAB]

CH2CI2 251 Me 137- 0.25 5% 396 A2.

Et O M 138 acetone/ B3a' [FAB] -C3a CH2CI2 252 Me 1 H 0.18 5% 364 A2,C3a N ~NMeOHW [El] Et CHC13 253 Me 215- 383 A2, Mer -221 (M +H)i B4a, S-JN dec fFAB] C3a 254 Me 187- 0.42 10% 383 AZ Me s S- CN 188 McOH/ B4a, tCHC13 [FA] C3a 255 Me 90-92 0.19 30% 366 A2, C3a EtOAc/ [Ell Et 70% pet I ether 257 Me N< 199- 0.33 70% 423 A2, 0-K 200 EtOAc/ B3e, Et S30% pet [FAR] C3a ether 258 Me 0 117- 0.14 5% A2, C3b -k-Me NHMe 119 MeOH/ Et 0 CHC13 259 Me 0 0.37 75% 409 C8 t Me EtOAc/

[HPLC

bexane ES-MS] 260 Me 0 194- 0.25 50% 424 C3b NHe 195 EtOAc/ Et -9 50% pet [HPLC 0 Nether ES-MS1 J 261 Me 0 216- 0.20 50% 424 C3b e iMe 217 EtOAc/ Et N 50% pet [1PLC ether ES-MS 262 Me 62-65 0.18 5% A2, C3b -b-er MeOH/ Et N 5CH1 s 95% 263 Me Me 86-89 0.16 5% A2, C3b Me MeOH/ Ft 8 t CHC13 264 Me 145- 0.32 5% A2. C3b -Me 0146 MeOHI Et CHC13 265 Me 0.23 5% 381 A2.C3b Ft N MeOI (M+H)-r

IFAB]

CHC13 266 Me OMe 0.20 5% 396 A2. C3b tMe acetone/ Et 95% (FAD] CH2CI2 267 Me 0.38 50 366 C8 -\Me EtOAc! Ft o i 50% [HPLC hexane Es-MS 268 Me 0.14 50 367 CS Me o EtOAc'

[HPLC

hexane ES-MS1 269 Me 0.21 50 383 C8 t -Me EtOAc)

[HPLC

hexane FS-MS 270 Me 12 0.10 50 365 C8 I-MC EtOAc/ Ft N 50% fHPLC hexane ES-MS 271 Me 0.14 50 365 C8 Me C EtOAcd Ft N 50% [HPLC hexane FS-MS] 272 Me 0.35 50% 382 C8 -e aEtOAc! Ft HO 50% [HPLC hexane ES-MSI 273 Me 0.48 50% 382 C8 Me EtOAcf Ft OH 50% [HPLC hexane FS-MS] 274 Me 0.20 100% 367 B4b, CS Me EKOAc Et O N

[HPLC

275 Me IN 0.56 100% 435 B4b. C8 Mt EtOAc

F

3 C

[HPLC

ES-MSI

276 Me \1 0.57 75% 383 CS /Me 0 EtOAc/ N 25%

[HPLC

hexane ES-MS] 277 Me 0.40 100% B, CS tN EtOAc 00 278 Me OMe 63-65 410 A2.C3a O

(M+H-

Et [FAB] 279 Me 84 0.16 5% 381 A2,C3a -kEt Et 4 01 MeOl-I

[FAB]

CHC13 280 Me 189- 0.16 5% 397 A2, E N 192 MeOH/ B4a, [HPLC C3a CHC13 ES-MSI 281 Me 189- 0.17 5% 397 A2, LCEt 191 MeOH/ (MtH)-I B4a, Et S- N 95% [FAB] C3a CHC13 282 Me Et 0 'cl 123- 414 A2.C3a 125 Et

[FABI

283 Me 175- 0.16 5% 379 A2, C3a Et C C\ 177 MeOH/

[FABJ

CHC13 284 Me 135- 0.33 5% A2, C3b El 137 MeOH/ Et CHC13 285 Me Mc 67 0.4] 5% A2, C3b -k-Er MeOH/ Et CHC13 286 155- 0.38 500/ 377 Cib 156 EtOAc/ [El] pet ether 287 0.18 5% 379 A2,C3b MeOH/ (MH)+

[FAB]

CHC13 Table 3. N'-Substituted-3-eert-butyl-5-pyrazolyl Ureas N N N' 3 1H H Mass Spec.

mp TLC Solvent [Source] Synth.

Ex. R1 R2 0 C) R, System M ethod 289 H 0.07 50% 393 C8 EtOAc/ (MH)-

[HPLC

hexane ES-MS] 290 H OM 181- 381 C2b 183

[FAB

Me 0 0.30 50 EtOAC 50% hexane 365

[HPLC

ES-MS]

C8 292 H N 366 C8 -a o-,;Me I I [FAB 293 H y \r S 0.53 50% 398 CS 293 H /3 oMe 0 EtOAc/

(HPLC

hexane ES-MSJ 294 H 369 CS

[IPLC

ES-MS1 295 H 0,27 50% 351 CIc EtOAc!

[FAB]

hexane 296 H CI C1 0.59 50% 327 GIc EtOAc/

(FAB]

hexane 297 H 9

H

2 p 0.30 60% 350 C4a acetone/ (M+H)1

[FAB]

CH2Cl2 298 H \0.07 5% 368 B4a, 1 MeOH/ C4a S 95%

[FAB]

GHCI3 H 0.18 5% 367 B4a, 2994 \S-MeOHI [El] C4a CHC13 300 H 0 160- 408 A5, B6, Ak 0 161 C3b HO CF 3 NHMe [FAB] isolated at TFA salt 301 H S 228- 0.24 10% 351 C3a 232 MeOH/ (EI] dcc CHC13 302 HI 204 0.06 5% 364 C3b acetone/ [El] CH2C12 303 H 110- 0.05 5% 408 C3b N 111 acetone] 0-1 _CH2CI2 304 MH 0.10 20% 380 C4a O.CL acetone!

[FAB]

I CH2CI2 305 Me 0 99- 0.19 1003 452 B3a tNHMC 101 EtOAc step 1, OMe [HPLC B12, ES-MS] step 2, C3a 306 Me H H 2 0.48 30% 378 BI, C3a tjtC C H~,N acetone (M+H)I

[FAB]

CH2C2 307 Me i Me 135- 0.03 30% 408 C3a N O~O Me 137 EtOAc/

[HPLC

bexane ES-MS1 308 Me 0.35 70% 382 84a, N acetone/ C4a

[FAB]

CI2C2 309 Me 0.46 70% 382 B4a, acetone/ C4a Si ~30% [FAB] 310 Me CF 3 0.32 70% 450 B3b, acetone! C4a

[FAB]

CH2C12 311 Me 0.09 50% 381 C4a EtOAc!

[FAB]

hexane 312 Me 0.61 100% 397 B3c, EtOAc C4a

[FAB]

313 Me 0.25 50% 453 B5, C4a EtOAcf (MH)±

[FAB]

hexane 314 Me 7

H

2 NH 0.65 100% 462 B6, C4a C N H-N EtOAC (M+H i o

[FAB]

i-Ru 315 Me -H 0.67 100% 478 B6, C4a JCl- NH EtOAc =o

[FAB]

t-BuO 316 Me Ha 0.50 100% 378 C4a C NH~2 EtOAC

[FABI

317 Me H2 0.33 100% 420 C4a, D3 jC NH EtOAc O [FAB] Me 318 Me H, 0.60 10% 478 C4a, D3 C N H water/ 0 90% [FAB] H0 2 C CH3CN 319 Me H 0.55 100% 434 C4a. D3 EtOAc =o

[FAR]

320 Me 0.52 100% 380 C4a EtOAc I_ [FAB] 321 Me C 0.25 60% 366 C4a acetone! (M±H)

[FAB]

CH2CI2 322 Me a O 7 NH 0.52 100% 452 C4a. D3 j-H 02 EtOAc EtO(FAB] 323 Me H 2 0.34 60% 396 C4a acetone!

[FAB]

CI2C12 324 Me H20.36 60% 396 C4a acetone!

[FAB]

CH2CI2 325 Me 147- 365 CIc 149 rABI 326 Mc/e HL 161- 0.15 4% 364 C2b 162 MeOH 96% [FAB] CH2CI2 327 Me I 228 379 C2b Me dec

[FAB

328 Me 0.30 5% 422 C2b N MeOH/ (MtH)+ 0 1 95% [FAB] s CH2CI2 329 Me 0.46 100% 464 R3c.

N -EtOAc C4a

[FAB]

330 Me~ N 0.52 100% 506 B3c, S-KQ M s EtOAc C4a CF. [FAB] 331 Me 0.75 100% 421 R3c, EtOAc C4a

[FAB]

332 'Me 0.50 100% 465 33c,

SCF

3 EIOAc C4a

IFAB

333 Me /0.50 100% 349 C4a EtOAc

[FABI

334 Me Q 0.60 100% 471 B2.C4a EtOAc (M-d-lh

[FAB]

335 Me JNH 0.52 100% 466 C4a. D3 1 NH EtOAc (MI+H)4 i-Bu

[FAB]

336 Me O-r- 0.42 100% 439 B5. C4a EtOAc (M-H)r

[FAB]

337 -CHrCF, /\oy 433 C3a IrAR1 338 -(CH,)IN 0.37 50% 404 A3, Clb EtOAc/ (MiH)+

[HPLC

hexane ES-M L 339 0 Me-NH 159- 508 A5, B6, 161 C2b 0 0-6 [FAB] Table 4. 5-Substituted-2-thiadiazolvlI Urnas N 4IN AN' H H Mass Spec.

mp TLC Solvent (Source] Synth.

Entr R' 0 CQ R, System Method 340 i-flu M0.37 5% 399 fi~a, C3a MeOl-I

[FAB]

CH2CI2 341 i-flu 5 N 0.26 5% 370 COa 'LAIMeOH/

[FAB]

342 I-flu/\ 386 B4a, COa KN [FAB] 343 i-Ba M 0.30 5% 383 Clb -0 Mcacetone/

[FAB]

___CH2CI2 344 t-Bu 00.60 10% 412 COb 0 MeOH/ (M+H)i Ne CK2CI2 [FABI 345 i-flu 0 245- 0.23 100% 456 B3a step NHe250 EtOAc (M-4H)t 1, B 12, 0 ONMe WHLC D5b step 2, C3a 346 r-Bu O 0.10 50% COb NHMe EtOAc! 0 ~50% pei ether 347 i-flu 0 0.13 50% 441 COb N~e 2 EtOAc/ e250% pet [I-PLC ether ES-MS1 348 i-flu 0 0.14 5% 441 COb, NH~t MeOH/ 0 (N45%

[HPLC

0 NEtOAc/ ES-MS] hexane 349 i-flu 0 0.23 5% 461 Ob, C I NHMe MeOW-l D~h 45%\ ~Ac [HPLC Et~/ES-MS] hexane 350 i-flu 0 0.09 5% 461 C3b, C1 NHMe MeOH/ (M+ll)4 Dib N45% [HPLC EtOAc! ES-MSJ hexane Me NHMe 0 5% MeCH! 45% EtOAc/ 500/a hexane 441

EHPLC

ES-MS]

352 t-Eu 0 159- 0.10 50% 427 COb O NHMe 160 EtOAcI N 50% pei [HPLC _____ether ES-MS] 353 r-Eu Cl 0.47 10% 438 C3b \l MeOH! (M+1-Iy o ClCI-2C12 [FAD] 354 r-Ru 0.31 10% 371 COb MeOI-/ N CH2CI2 [FAB] 355 t-Eu CI 0.51 100/ 400 COb MeOH/ oC Cl CH2CI2 [FAB] 356 i-Bu y 1 0.43 10% 385 Cm 0 Me MeOH/ (M+H)-r CH2CI2 [FAR]B 357 I-Bu y Sm 0.70 10% 416 COb Me OW N CH2C12_ [EABl 358 i-Ru 0.11 50 O/ 438 Cs N tOAc/ r 3 cN 50% [HPLC _____hexane ES-MS] 359 t-Ru 0.06 5% 432 COb \JS~SMCMeOHI

[FAD]

____CH2CI2 -6 -B 0.20 50% 385 C8 36 iRu/\ -K7 EtOAc/ HO 50% [HPLC hexane ES-MS] 361 i-Ru me -107- 0.05 30% 412 C3a OMe 110 EIOAc/

[HPLC

hexane ES-MS] 362 t-Bu 0.16 100% 370 C8 EtOAc (M+H)4 o-CN

____ES-MSI

363 Me 0 0.12 100% C4a, Me NH(EtOAc Et 0_

N~

364 Me 0 183- R3d step M e N, 185 2, C3a Ft 0MeOH/ Et 94% [FAR] _____CHC13 366 Me 248- 0.34 6% A6. Cih AMeN 249 MeOH/ 94% CHC13 367 Me 0.20 400 A6. C3b E4tM SEN [FAB] 368 Et 0- 1 182- 0.33 5% A6. C3b \t c 183 MeOH/ CHC13 369 Et S- 180- 0.19 5% A6,C3b Ft '181 MeOH/ CHC13 370 Et 168- 0.24 50 A6, C3b t O 169 MeOH/ CHC13 371 Et 0 C\N 168- 0.17 6% A6. C3b 0t \171 McOHI 94% CHC13 372 Et 156- 0.19 6% A6, C3b -t 158 MeOH/ 94% CHC13 Table 5. 5-Substituted-3-thienvl Ureas 0 S N N 'R H H mp TLC Solvent Mass Synth.

Entry R R2 R, System Spec. Method 373 i-Bu 144- 0.68 5% A4b.

145 acetone/ Cia CH2CI2 374 I-Bu Me 0.52 30% 381 Et2O/ (MIH)pet [HPLC ether ES-MS] 375 i-Ru 0 OMe 0.26 30% 397 need Et2O/ recipie pet [HPLC ether ES-MS] 376 t-Bu N 0.28 50% 368 need Et2O/ recipie pet [HPLC ether ES-MSj 377 i-Bu 6k 0 57 381 A4a

FABJ

378 t-Bu/ H, 0.15 50% 365 A4a C C\ N EtOAc/ [El] pet ether 379 I-Bu O 0.44 50% 383 A4a EtOAc/ (M+H) pet [FAR] ether 380 t-Bu 0\ S C\N 384 A4a fFABI 381 t-Bu 1 176- 0.45 20% 425 D2 177 EtOAcf (MiH)+

[FAR]

hexane Table S. Additional Ureas Mass Spec.

rp TLC Solvent [Source] Synth.

0 C) R, System Method 382 161- 0.71 20% 367 Dl Mc 163 EtOAcf 0 80% 369 NA NN bMehexane Br H H I [FAB H H BIOLOGICAL EXAMPLES In Vitro raf Kinase Assay: In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCI, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaC1. This protein solution L) is mixed with water (5 pL) or with compounds diluted with distilled water from mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 pL [y-"P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HC1, pH 120 mM NaC1, 1.6 mM DTT, 16 mM MgCI,. The reaction mixtures are incubated at 32 usually for 22 min. Incorporation of "P into protein is assayed by harvesting the reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 gM ATP and 0.4 gM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by 112 electrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging Analyzer System.

All compounds exemplified displayed IC, 0 s of between 1 nM and 10 p.M.

Cellular Assay: For in vitro growth assay, human tumor cell lines, including but not limited to HCT116 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage independent growth in soft agar. Human tumor cell lines were obtained from ATCC (Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% CO, incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring 'H-thymidine incorporation into DNA following an 8 h culture with 1 fpCu 'H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 3 H-thymidine incorporation by liquid scintillant counting.

For anchorage independent cell growth, cells are plated at 1 x 10 J to 3 x 10' in 0.4% Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing only 0.64% agar in RPMI complete media in 24-well tissue culture plates. Complete media plus dilution series of compounds are added to wells and incubated at 37 "C in a 5% CO, incubator for 10-14 days with repeated feedings of fresh media containing compound at 3-4 day intervals. Colony formation is monitored and total cell mass, average colony size and number of colonies are quantitated using image capture technology and image analysis software (Image Pro Plus, media Cybernetics).

113

O

O

CThese assays establish that the compounds of Formula I are active to inhibit raf kinase )activity and to inhibit oncogenic cell growth.

l In Vivo Assay: An in vivo assay of the inhibitory effect of the compounds on tumors solid 00 O cancers) mediated by raf kinase can be performed as follows:

O

06 N CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1 x 106 en3 O cells with human colon adenocarcinoma cell line. The mice are dosed i.v. or p.o.

O

at 10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is between 50-100 mg. Animals are dosed for 14 consecutive days once a day; tumor size was monitored with calipers twice a week.

The inhibitory effect of the compounds on raf kinase and therefore on tumors solid cancers) mediated by raf kinase can further be demonstrated in vivo according to the technique of Monia et al. (Nat. Med. 1996, 2, 668-75).

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.

Claims (25)

1. A method for the treatment of cancerous cell growth mediated by raf o 5 kinase comprising administering a compound of formula I 00 A-NH-C-Nil-B wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, fblryl, thienyl, pyrrolyl, iniclazolyl, pyrazolyl, oxazolyl, isoxazo~yl, thiazolyl, isotbiazolyl, benzofuiryl, bentotbienyl, indoly], benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or bentisotbiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and wherein n is 0-3 and each X is independently selected from the group consisting of -C21, -CO 2 R 5 q(O)NR 5 -C(O)RW, -NO 2 -OR 5 SRW, -NR 5 R 5 -NR 5 C(O)0R 5 -NRWC(O)R 5 C 1 C 10 alkyl, C2z-Cio alkenyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, phenyl, pyridinyl, naphthyt, isoquinolinyl, quinolinlyl up to per halo-substituted C 1 -C 10 ailkyl, up to per halo-substituted C2-Clo alkenyl, up to per halo-sabstituted CI-Clo alkoxy, tip to per halo-substituted C3-Cjo cycloalkcyl, and -Y-Ar; wherein W 5 and R 5 are independently selected frm IfI, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 cycloalkyl. up to per-halosubstituted C 1 -C 10 alkyl, up to per- halosubstituted C,-C 1 alkenyl and up to per-halosubstitirted C 3 -Ci wherein Y is -N(R 5 -(CH 2 -(CH 2 -NR 5 C(O)NR 5 -(CH 2 4(CH 2 ),nN(R 5 -O(CH 2 -CIxW, -S{(CH 2 )nr and 44(R)(CH 2 m 1-3, and X'is halogen; and Ar is phentyl, pyridiny], pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phithalimidinyl, furyl, thienyl, -pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isotbiazolyl, benzofiiryt, benzothienyl, 09/05 '06 12:51 FAX 61 7 3229 3384 CULLEN CO. 1013 Oa- 0 115 indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyi or 00 benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and o optionally substituted by Z 01 wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO 2 R, -C(O)NR 5 R 5 NR, cl 5 NO 2 -OR, SR 5 -NRR 5 -NRC(0)OR, -NRC(O)R 5 -SOR2, oC SO2N C-Co0 alkyl, C1-Co alkoxy, C3-CIo cycloalkyl, up to per halo- Cl substituted Ci-Clo alkyl, and up to per halo-substituted C3-CIO cycloalkyl, and A is a heteroaryl moiety selected from the group consisting of RRi Ri N Re N Rc N O N o a and N R2/ wherein R' is selected from the group consisting of halogen, C-Clo alkyl, C,-Clo cycloalkyl, Cj-C3 heteroaryl, C6-14 aryl, 07-24 alkaryl, up to per-halosubstituted Ci- Clo alkyl, up to per-halosubstituted C3-CIo cycloalcyl, up to per-halosubstituted Ci-Cn heteroaryl, up to per-halosubstituted C6-14 aryl, and up to per-halosubstituted C-24 alkaryl; R2 is selected from the group consisting of H, -CO2R', -C(O)NRR 3 C-Clo alkyl, Ca-Cto cycloalkyl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted Ci- Clo alkyl, substituted C2-C 0 o cycloalkyl, substituted C7-C24 alkaryl and substituted C 4 C 23 alkheteroaryl, where R2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, CO 2 R, -C(O)-NR R 3 -NO 2 -OR4, -S 4 and halogen up to per-halosubstitution, wherein R 3 and R' are independently selected from the group consisting of H, -OR4, -SR4, -NRe'R 4 -COR -C(O)NRR, C,-Clo ailcyl, C3-CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl or quinolinyl uLip to per-halosubstituted Cr- Clo alkyl, up to per-halosubstituted C3-Cio cycloalkyl, and up to per-halosubstituted, phenyl, pyridinyl, naphhyl, isoquinolinyl or quinolinyl; and 09/05 '06 12:52 FAX 61 7 3229 3384 CULLEN CO. 1014 IO 116 wherein R and R 4 are independently selected from the group consisting of H, CI-Clo akyl, C 3 -Co 10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl 00 up to per-halosubstituted C-Clo alkyl, up to per-halosubstitutled C 3 -C 1 O cycloalkyl, and up to per-halosubstituted, phenyl, pyridinyl, naphthyl, isoquinolinyl or quinolinyl R is CI-Clo alkyl, C,-Cio cycloalkyl, up to per-halosubstituted C]-Clo alkyl N and up to per-halosubstituted C 3 -Cio cycloalkyl; and o Rb is hydrogen or halogen, Re is hydrogen, halogen, CI-Cjo alkyl, up to per-halosubstituted CI-C 1 o alkyl or combines with R' and the ring carbon atoms to which R' and Re are bound to form a 5- or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from O, N and S; subject to the proviso that where A is t-Bu O N B is not 0 O-(CH,)n-CH 3 wherein n 2-4, or 0 O- CH 2 CH(CH) 2

2. A method as in claim 1, wherein B is X Xn 09/05 '08 12:52 FAX 61 7 3229 3384 CUJLLEN CO, Q01oi 117 0 o wherein n =1-3 and each X is idependently selected from the group consisting of CI_ 4 alkyl, up to per- o halosubstituted CI- 4 alky) and -Y-Ar;- 0 ~wherein Y is -N(R 5 -(CH 2 1 -(C1{ 2 -NR 5 C(O)NR -NR 5 -C(O)NR 5 -(CH 2 )znS-, 4C4t)mN(R -O(CH4 2 -Cl-DC, -Cr 2 -S-(CH2)nr, and N(R)(CH 2 )M_3 m =1 and X'is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, f'uryl, thienyl, pyrrolyl, intidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, beuzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzotliiazolyl or benzisothiazolyl, optionally substituited. by halogen up to per-halosubstitution and optionally substituted by wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -C0 2 R 5 -C(O)NRR, -NO 2 -OR 5 SR', NR, -NR 5 C(O)0R 5 -C(O)W 5 -NR 5 C()R 5 -S0 2 R 5 -SOR c 1 -c 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl up to per halo-substituted C 1 -C 10 alkyl, arId up to per hal o-substituted C 3 -C 1 0 cycloalcyl wherein R 5 and R 5 'are independently selected from H, C 1 -Clo alkyl, C 2 -Cio alkenyl, C3-Cia cycloalkyl, up to per-halosubstituted C 1 -C 10 ailkyl, up'to per-halosubstituted C 2 -C 10 alkenyl and up to per-halosubstituted C 3 -C 10 cycloalkyl.

3. A method of claim 1, wherein Bis xn wherein Y is selected from the group consisting of -CH 2 -SCH 2 -CJA 2 S-, -CX2, -CXtI-, -CH 2 O- and 09/05 '06 12:52 FAX 61 7 3229 3384 CULLEN CO. I 016 0 0 118 Xa is halogen, 00 Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution; QI is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, N 5 quinolinyl, isoquinolinyl, phthalimidinyl, fulryl, thienyl, pyrrolyl, imidazolyl, C pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, C indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution, X, Z, n and nl are as defined in claim 1, and s= 0 or 1.

4. A method as in claim 3, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- balosubstitution, Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, and each X is independently selected from the group consisting of -R6, -OR and NHR 7 wherein R6 is hydrogen, C 1 -C 1 o-alkyl or C 3 -Clo-cycloalkyl and R' is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -Cs-cycoalkyl wherein R6 and R'7 can be substituted by halogen or up to per-halosubstitution. A method as in claim 4, wherein B is of the formula Xn Qt Zn wherein Q is phenyl or pyridinyl, optionally substituted by halogen up to per- halosubstitution, Q 1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -CH 2 -SCH2-, -CH20-, -OCH 2 or -C 2 X is CI-C 4 alkyl or up to per-balosubstituted C 1 -C 4 alkyl and Z is as defined in claim 1 n 0 or 1, s 1 and n1 0-1. 09/05 '06 12:52 FAX 61 7 3229 3384 ___CULLEN CO. Q~017 ct 119

6. A methlod as in claim 5, wherein B is of the formula 0 enn l),-n wherein Q is phenyl or pyridinyl, Q' is pyridinyl, phenyl or benzothiazo]yI, Y is -CH 2 -Sd-I 2 -CH 2 -0CH 2 or -Gil 2 and Z is -SCI- 3 or -NH-C(O)- GCfI 2 P1 1 wherein p is 1-4, n 0, s 1 and nl 0- 1

7. A inethod as in claim 1 comprising administering a compound selected from the group consisting of N-(3-tert-Buty-5-prazoy)-N-(4-pheloxyphelY)uYea; N-(3-ieri-Butyl-5-pyrazolyl)-N'-(3-(3- methylsmainocarbonylphenyl)oxyphenyl)urea; N-(3O-tert-Buty1-5-pyrazoly)-N'-(3-(4-pyidily)thiophelArea; N-3tr-uy--yvoy).N-4(-yiiy~hohnltra N-(3-t -uy--yaoy)N-4-4prdnloyhniue- AM-3..rert-Buty-5-pyaoy)-N'(4(4-pyridnyl)mthy1phenflY)urea; N-(l1 Methy1-3-IerI-butyl-5-pyzoly)-N'-(4-PheYoxyphieYl)urea; N-lMty--etbtl5pr/oy)-'(-4prdnltipey~ra N-(1 -Methyl-3-tert-butyl-5-pyrazoly)-N 4 4 4 pyridinyl)tbiomethyl)phenyl)urea; N-(l -Methyl-3-rert-butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urew; N-(l -Melhyl-3-tert-butyl-5-pyrazolyl)-N-(4-(4-pyridiYl)OXYPheflYl)uma; UV-(1 -Methyl-3-tert-butyl-5-pyrazolyl)-N'-(( 4 4 pyridinyl)methyloxy)phenyl)urea; N-(1 .Methyl-3-tern-butyl-5-pyrazolyl)-N'-(3-(2- benzothiazolyl)oxyphenyl)urea; 1V-(3-.e-butyl-5-pyrazolyl)-N '-(3-(4-pyridyl)thiophenyl) urea; N-(3-:erttbutyl-5-pyrazoy)-N'-(4-(pyridY1)tiiOPh1Yl) urea; N-(3-zert-butyl-5-pyrazolyl)-N -(3-(4-pyridyl)oxyphenyl) urea; N-(3-terr-buty1-5-pyrazoly1)-N'-(4-(4-pyridy)oxyphelYl) urea; N-(1 -mnethy-3-tert-buty-5-pyrazolyl)-N -(3-(4-pyridyl)tiophelYl) urea; N-(1 -methyl-3 -tert-butyl-5-pyrazolyl)-N '-(4-(4-pyridyl}Ehiophcnyl) urea; 09/05 '06 12:53 FAX 61 7 3229 3384 CULLEN CO. 018 120 N-(l -methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl) urea; 00 N-(l -metyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyrdl)oyphenyn l) urea; 0 and pharariceutically acceptable salts thereof. 8 A method as in claim 5, wherein R 1 is t-butyl. 0

9. A method as in claim 1 comprising administering a compound of the formula R 0 0 I I I N NH-C-NH-B wherein R' and B are as defined in claim 1. A method as in claim 9, wherein B is of the formula xn wherein Q is phenyl or pyridinyl, optionally substituted by halogen up to per- halosubstitution, Q is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is or X is C 1 -C 4 alky] or up to per-halosubstituted C 1 -C alkyl and Z is as defined in claim 1 CIH3, n 0 or 1, s 0 or I and nl 0 or 1.

11. A method as in claim 1 comprising administering a compound selected from the group consisting of: N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyl)oxypheny)ura; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-hydroxyphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl)oxyphenyl)urea; 09/05 '06 12:53 F-AX 61 7 3229 3384 CULLEN CO. Iii ct 121 0c' N-(5-iert-Butyl-3-isoxazolyl)-N '-(4-phenyloxypheny1)urea; o N-(5-:ert-Butyl-3-isoxazolyl)-N '-(4-(3-methylanhinocarbonylphenYl)- thiophenyl)urea; NV-(5-terr-Butyl-3o-isoxazolyl)-N'-(4-( 4 ,2-xnethyLenedioxy)phenyl)- 0 oxyphenyl)urea; o 5ir-uy-3ioaoy)Y(4(-yiiy~cxpey~ra N-(5-eert-Butyl-3-isoxazoly)-N-(4-(4-pyridy)thiopheflYl)Jea; N-(5-tert-Butyl-3-isoxazoy)-N-(4-(4-pyridiny)U thyphefl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N'-(3-(4-pyridinyl)oxyphelyl)urea; N-(5-tert-B3Ltyl-3-isoxaoly)-N'-(3-(4-pyridil)thophenfly)uICW N-(5-terl-Butyl-3-isoxazoly)-N'-(3-(3-methyl-4-pyridinyl)oxypheflyl)Utiea; N-(5-tert-Butyl-3-isoxazolyl)-N-(3-(3-methyl-4-pyidiyl)thiopheYl)urC2; N-(5-teri-Buty1-3-isoxazoly1)-N'-(4-(3-metl-4-pyridinyl)thopheny)urft; N-(5-tert-Buty1-3-isoxazoly1)-NV'-(3-(4-meffiy1-3-pyridinyl)oxypheny)urea; N-(5-te-KButyl-3-isoxazolyl)-N'-(4-(3-.methyl-4-pyridinyloxypheniyl)urea; N-(5-tert-Butyl-3-isxazolyl)-W-(3-(2-benzothiazolyl)oxypheyl)urea; N-(5-teri-butyl-3-isoxazolyl)-N '-(3-chloro-4-(4-(2-r-nethylcarbamnoyl)pyridyl)- oxyphenyl) urea; N-(5-tent-butyl.3-isoxazolyl)-N'-(4-(4-(2-methylcarbwnoyl)pyridyl)- oxyphenyl) urea; N-(5-ienr-butyl-3-isoxzazolyl)-N-(3-(4-(2-methylcarbamoyl)pyridyl)- tbiopheriyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(2-methyl-4-(4-(2-methylarbanoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N-(4-(4-(2-carbaxoyl)pyridyl)oxypheuy) urea; N-(5-tert-butyl-3-isoxazlyl)-N -(4-(2-cab atoyl)pyridyl)oxyphenyl) urea; N-(5-tert.-butyl-3-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-AT'-(4-(4-(2-methylcarbarnoyl)pyridyl)- thiophenyl) urea; N-(5-ter(-butyl-3 -isoxazolyll)-N' -chiloro-4-(4-(2-methylcarbaznoyl)pyridyl)- oxyphenyl) urea; NV-(5-ieri-butyl-3-isoxazolyl)-NV'-(4-(3 -rethiylcarbamnoyl)phenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof. 09/05 '06 12:53 FAX 61 7 3229 3384 ___CULLEN &k CO. 122 001-2. A method as in claim 10, wherin R' is t-butyl.

13. A method as in claim 1 comprising administering a compound of the Cl 5 fonnula. Nl 0 wherein R' and R are as defined in claim 1I

14. A method as in claim 13, wherein B is of the formula I Q is phenyl or pyridinyl optionally substituted by halogen uip to per-halosubstitution, Q 1 is phenyl, benzothiazolyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, Y is or -CH 2 X is C 1 -C 4 alkyl or up to per-halosubstituted C-C 4 aky, Zis as defined inclaim n0 or, s= 1, andfl= o~rl1. A method as in claim 1 comprising administering a compound selected fr-om, the group consisting of N-(3 -lsopropyl-5-isoxazolyl)-N'-(4-(4-pyidinyl)thiophelyl)urea; N-3tr-Ltl5iOa~y)N-4(-ehxpey~xpey~ra N-(3 -terr-Butyl-5-isoxazolyl)-N '-(5-(2-(4-acetylphenyl)oxy)pyridinylurea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(3-(4-pydilyl)thiophly)UYea; N-3tr-uy--sxzll-'(-4prdnlmtypey~ra N-3lr-uy--sxzll-,(-4prdnltiohly~ra N-(3-rert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphnylurea NV-(3-teri-Buty-5-isoxazoly)-N'-(4-(4-methy-3-pyridiyl)oKyphe1yl)urea; ?'-(3-terl-Batl5ioaoy)N-3(-b ohaoy~xpey~ra 09/05 '06 12:53 FAX 61 7 3229 3384 CULLEN CO. Z~021 123 4 -Dimethlylpropyl)-5-iS0X8zO1Yl)N'-{ 4 4 0c' methylphenyl)oxyphenyl)-uea; o 1 Diniethylpropy)-5-isOxazoY1)-N '-(3-(4-pydidinyl)thiophelyl)urea; mtypoy)--sxzll-'-4(-yiiil~xppnlw 0 5 ,1 -Diinethylpropyl)-5-i soxazoly1)-N'-K4-(4-pyidil)thioPhel)rea; 1-Dinmethyipropyl-5-isoxazoly)-N'( 5 2 -4 o methoxyphenyl)oxy)pyridilyl)urea; -Methyl-i -ethylpropyl)-5-isoxazolyl)-N pyridinyl)oxyphenyl)urtea; N-(3-(l1-Methyl- 1-etbylpropyl)-5-isoxazolyl)-N'-(3 pyridinyl)thiophenyl)urea;, N-(3 -isopropyl-5-isoxazolyl)-N'-(3-(4-(2-metl~ylarbIfoyl)PYridYlY- oxyphenyl) urea; N-(3''-isopropyl-5-isoxazolyl)-N'-(4-(4-(2-ethylcarbaflloyl)pyridyl)- oxypheriyl) urea; N-(3 -rert-butyl-5-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(3-ieri-butyl-5-isoxazolyl)-N-(4-(4-(2-methylcarballoyl)pyridy)- oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N -(3-(4-(2-methykcarbainoy1)pyridyl)- thiophenyl) urea; I-dimetbyiprop- 1-yl)-5-isoxazolyl)-N'-(3-(4-(2- methylcarbamoyl)pyridyl)-oxyphlenyl) urea; N-(3-(1Il -dimethyiprop- 1-yJ)-5-isoxazolyl)-N' methylcarbamoyrl)pyridyl)-oxyphenyl) urea NV-(3-rerr--butyl-5-isoxazolyl)-N'-(3-chloro-4-(4-(2-rnethylcabamoyl)pyridy)- thiophenyl) urea and pharmaceutically acceptable salts thereof.

16. A method as in claim 13, wherein R' is t-butyl.

17. The method of claim 1 comprising administering a compound of the fonnula: R N' I 1 0 r NH-C-NH-B 09/05 '06 12:54 FAX 61 7 3229 3384 CULLEN CO. I022 \O 124 0O 00 0 wherein R2 is selected from the group consisting of H, -C(O)R4, -COzR, oC -C(O)NR 3 R 3 C 1 -Clo alkyl, C 3 -C 1 o cycloalkyl, substituted Ci-Clo alkyl, substituted 0 C3-C1O cycloalkyl, where if R3 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R 4 -C(O)-NR 3 R -NO 2 -OR4, -SR4, and halogen up to per-halosubstitution, wherein R3 and R' are independently selected from the group consisting of H, CI-Clo alkyl, Cr-Clo cycloalkyl, up to per-halosubstituted C 1 -Clo alkyl, and up to per- halosubstituted C 3 -Clo cycloalkyl, and wherein R4 and R4' are independently selected from the group consisting of H, CI-Co 10 alkyl, C 3 -Co 10 cycloallkyl, up to per-halosubstituted C 1 -Clo alkyl and up to per- halosubstituted C3-CIo cycloalkyl, wherein R1 is selected from the group consisting of C 3 -Cs alkyl, C 3 -C 6 cycloalkyl, up to per-halosubstituted C 3 -C 6 alkyl and up to per-halosubstituted C 3 -C 6 cycloalkyl, B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl; substituted by pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X'n and wherein n 0-2; each X' is independently selected from the group of -CN, -CO2R 5 C(O)R, -C(O)NRR 5 -OR, -NR 5 RS, C 1 -C 1 o alkyl, C2.lo-alkenyl, Cj-lo-alkoxy, C 3 -Clo cycloalkyl, -SR, -NRSC(O)OR 5 NR 5 C(O)R 5 substituted C 1 -Co alkyl, substituted C2. 1 o-alkenyl, substituted C.i-o-alkoxy, substituted C 3 -Clo cycloalkyl, wherein if X' is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R 5 -C(O)NRR", -ORg, -SR, -NR 5 Rs NO,, -NRSC(O)Rs -NR'C(0)OR and halogen up to per-halosubstitution; 09/05 '06 12:54 FAX 61 7 3229 3384 CULLEN CCL, 0~023 cxl 125 wherein WY and R5' are independently selected from H, C 1 -C 10 alkyl, C 2 -io- alkenyl, C 3 -Cio Cyclo0alkyl, Cg-C 14 aryl, C2 3 -C 1 3 heteroaryl, C,-C 24 1 alkaryl, Cs-C23 0 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl; up to per-halosubstituted C,..io- alkenyl ankd up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CHa)m0 1 O NRC(O)NR 5 R 3 -NR 5 -<CH 2 -(0H 2 )mN(R 5 Y, _O(CH 2 1 -CF-DC, -CXv2, -S-(CHZ)nr and -N(Rb(CH 2 mn=1-3, and X'is halogen; and Ar is phienyl, pyridinyl, pyrimnidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phathaliinidinyl, furyl, thienyl, pyrroly], iniidazolyl, pyrazoly], oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, beuzofiryl, benzotbienyl, indolyl, beazopyrazolyl, benzoxazolyl, benzisoxazolyl, beazothiazolyl or beuzisothiazolyl, subject to the proviso that where Y is -(CH 2 or Ar is not phenyl wherein Ar is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Z 1 wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)R 5 =0, -C(0)NRR, -C(O)R 5 -NO 2 SW 5 NRR, NIVC(O)0R 5 -NR 5 S0 2 W, -SO 2 Rf' YCICio alkyl, C 1 -CIa alkoxy, C 3 -C 10 cycloalkyl, substituted C 1 CIO alkyl, and substituted C 3 -C 10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituerits independently selected from the group consisting of -CN, -C0 2 RW, -C(O)NR 5 R 5 -OR 5 -SR 5 -NRR% NRC(O)R 5 -NR 5 C(O)OR' C 1 -C 10 alkyl, C 1 -C 10 alkoxyl, and Ca-Cia cycloalkyl.

18. The mnethod of claim 17, wherein 13 is xn -Q -Y Q n wherein Y is selected from the group consisting of -CH 2 -CfI 2 S-, -CC,2, -GrEH-, -CHO-, and -OCH2-, XC is halogen, 09/05 '08 12:54 FAX 61 7 3229 3384 CULLEN Co. I024 Oa- 0 Ct 126 Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; 00 Q' is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, C benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, subject to the proviso that where Y is -CH2- or Q 1 is not phenyl, X' is C,-C4 alkyl or N halosubstituted CI-C 4 alkyl up to per halo, Z, n and nI are as defined in claim 17.

19. The method of claim 18, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, and X' is as defined in claim 18, and Z is selected from the group consisting of -OR 6 and -NHR 7 wherein R6 is hydrogen, C 1 -Cio-alkyl or C 3 -Clo-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Clo-alkyl, and C 3 -C 6 -cycloalkyl wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution. The method of claim 18, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-balosubstitution, Q 1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -CH 2 -SCH 2 -CH7O-, -OCI-I 2 or -CH2-, X1 is as defined in claim 18, and Z is -SCH 3 or -NH-C(0)-CH 2 p- 1 wherein p is 1-4, n 0 or 1 and nI 0-1 09/05 '06 12:54 FAX 61 7 3229 3384 CULLEN CO. 0~025 127 t-Bu 00 N 0 N NH-C-NH-B Cl21. The method of claim 1, comprising administering a compound of the o formula wherein 1(2 is as defined in claimn 31 and B is phenyl, pyridinyl, pyximidmnyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquiniolinyl, phthalimnidinyl, furyl, thieriyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazol-yl, thiazolyl, isothiazolyl, benzofwiyl, benzothienyl, indolyl, beuzopyrazolyl, benzoxazolyl, benzisoxazolyL, benzothfazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per- halosubstitution, and wherein iu is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)NR 5 R 5 -C(O)RW, -NO 2 -OR 5 SW, -NRR, NR 5 C(O)0R 5 -NR 5 C(O)R 5 C 1 -C 1 0 alkyl, C2-C 10 alkenyl, C 1 -Clo alkoxy, CYCO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo- substituted C 1 -C 13 alkyl, up to per halo-substituted C 2 -Cio alkenyl, up to per halo- substituted C 1 -C 10 alkoxy, up to per hl~o-substituted C 3 -C 10 cycloalicyl, and -Y-Ar; wherein W( and 1(5'are independently selected from H, C 1 -C 10 alkyl, C 2 -CIO alkenyl, C 2 ;-C 10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted Cr-Cio alkenyl, up to per- halosabstituted C 3 -C 1 0 cycloalkyl, and up to per-hatosubstituted phenyl, pyridinyl, naphthyl, isoquinoli-nyl and quinolinyl wherein Y is -(CTrt2)-m, -CH(Ofl)-, -<GH 2 -NR 5 C(O)NR 5 NR%' -NR 5 -C(O)NWt, <(Cjz)rS-, -(dH- 2 )rnN(R 5 -O(CH- 2 _c~xa, -CXar, -S-(CH 2 and -N(R 5 )(CH2n, m=I1-3, andxVis halogen; and Ar is phenyl, pyridinyl, pyrinfidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolintyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazo.yl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, beuzofiffyl, benzothienyl, 09/05 '06 12:55 FAX 61 7 3229 3384 CUJLLEN CO.. Z~026 128 indolyl, beuopyrazolyl, beazoxazolyl, benzisoxatolyl, benzothiazojyt or 00 bcnzisotbiazolyl, optionally Substituted by halogen up to per-halosubstitution and o optionally substituted by Z, 01 wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO 2 NR!, NO 2 SR', -NRR", -NR 5 C(O)0R 5 -NR 5 -SO 2 R', oSO 2 NR', C 1 -Cio alkyl, C 1 -Cio altoxyl, (2 3 -C 10 cycloallkyl, up to per halo- 0 substituted C 1 -C 10 alkyl, and up to per halo -substituted (2 3 -C 10 cycloalkyl, subject to the proviso that where R 8 is methyl B is not C(O)0C 4 H

22. Thc method of claim 17, wherein the compound administered is selected from the group consisting of: N-(3-tert-B-LtyI-5-pyrazoly1)-N-(4-phflyloxyphelyl)area; -pyrazolyl)-N methylaminocarbonylphenyl)oxyphenyl)urea; -(4-pyri dinyl)tbiophenyl)uxea; N-(3 -tert-Buty]-5-pyrazoly1)-N'-(4-(4-pyridiny)oxypelyl)urea; N-(1 -Methyl-3-teri-butyl-5-pyrazoly)-N'-X4-( 4 pyridinyl~tiomethyl)phenyl)urea-; -Methyl-3-tert-butyl1-5-pyrazolyl)-N'-((4-( 4 -prdnltiheyuea pyridinyl)metbyloxy)phenyl)urea; N-(1-Metbyl-3-iefli-butyl-5-pyrazoIYl)-N benzothliazolyl)oxyphienyl)urea; N-(3-tert-batyl-5-pyrazolyl)-N'-(3-(4-pyidyl)thiOphelyl) urea; N(3 -rert-butyl-5-pyrszolyl)-N'-(4-(4-pyridyl)thiophelyl) urea; 09/05 '06 12:55 FAX 61 7 3229 3384 CULLEN CO. [a 027 ct 129 N-(3 -teri-butyl-5-pyrazoly)-N-(3-(4-pyridyl)OXYPhenfl) urea; N-3tr-uy--yaoy)-,(-4prdloyhnt urea; 00 1 hl3tetbtl5pyaoy)N-(-4prdl~hohnl urea; oN-(1 -mty--etbtl5przll-'(-4prdltipinl urea; NV-(1 -mty-Jtr-uy--yaoyl-'(-4prdloyhn urea; oN-(1 ehl3tr-btl5przly)N-4(-yrdloyhnl urea; o and pharmaceutically acceptable salts thereof.

23. The method of claim 1, comprising administering a compound of the formula 0N N I NH-C-NH-B wherein R1' is selected from the group consisting Of (2 3 -C 6 alkyl, C3-r cycloalkcyl, up to per-halosubstituted C3-C6 alkyl and up to per-halosubstituted C 3 -C 10 cycloalkyl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl which is substituted by X, optionally substituted by halogen, up to per- balosubstitution, and optionally substituted by X1'~ wherein ni 0-2; each X1 is independently selected from the group of X or from the group consisting of -CN, -CO2R, -C(O)RW, -C(O)NR 5 NO 2 -NR 5 R 5 0,-C 10 ailkyl, C 2 1 -alkenyl, C 1 ,-alkoxy, Cr-Clo cycloallcyl, and C 6 -C 14 and X is selected from the group consisting of -NR 5 C(O)0R 5 NR 5 C(O)R 5 C 3 -C1 3 heteroaryl, substituted CI-C10 alkyl, Substituted C 2 10 -alkenyl, substituted C 1 jo)-alkoxy, substituted C 3 -C1 0 cycloalkyl, substituted C 6 -C 1 4 aryl, substituted C 3 -C13 heteroaryl, and -Y-Ar, and wherein if X is a substituted group, it is substituited by one or more sub stituents independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)Rt -C(O)NRR, -ORW, -NR 5 R 5 NO. 2 -NR 5 C(O)R 5 -NR 5 C(O)0R 5 and halogen up to per-halosubstitution; nQ/CIK 'AR 19&RK PAY 91 7 1990 IqAA rTrT T VV L rn a (128 130 0 wherein WY and R5' are independently selected from H, Ci-C 10 ailkyl, C 2 00 alkenyl, 0 3 -C 1 0 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 o alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C2.ja- alkenyl, and up to per-halosubstituted C 3 -C 10 cycloalicyl, wherein Y is 1 {(CH 2 -NR 5 C(O)NR -NR 5 o C(O)NR 5 -(CH 2 -(CH 2 1,,N(R 5 0O(CH 2 0 -CHXW, -Ct 2 -S-(CH 2 )nr and -N(R 5 )(CH2)r, m. and XV is halogen; and Ar is wherein B is phenyl, pyridinyl, pyrim-idinyl, pyraziniyl, pyridazinyl, naplithyl, quinohinyl, isoquinolinyl, phthallinidinyl, fury], thienyl, pyrrolyt, inidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, berizofuryl, benzothienyl, indolyl, benzopymrzolyl, beuzoxazoly], benzisoxazolyl, beuzothiazoly] or berizisothiazolyl, subject to the proviso that where Y is -(CH)-Tm or Ar is not phenyl, wherein Ar is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Z. 1 wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -GN, -COWR, -C(O)Rt 0Q, -C(O)NR 5 RU' -C(O)RW, NO 2 -OR 5 SR5, NR 5 R, -NRC(O)0R 5 -NR 5 C(0)R 5 -SO2R', -502 R' 5 R 5 C 1 C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloallcyl, substituted C 1 -Clo alkyl, and substituted C 3 -CIr, cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of CN, -C0 2 R 5 C(O)NR'R', -OR 5 -SR 5 -NR 5 R 5 -NR 5 C(O)R 5 -NR 5 C(O)0R 5 C 1 -Clo ailkyl, CI-C 10 alkoxyl, and C 3 -C 10 cycloallcyl, subject to the proviso that where R' is t- butyl, B is not 0-0-0 wherein RY is -NHC(0)-O-t-butyl, -0-n-pentyl, -O-ni-butyl, -O-n-propyl, -C(O)NH-(CH 3 2 -OCH 2 CH(CH- 3 or AQJAM 'AR t9 Ma VAT al 7 q990 qqRA rVT T WM JL rn R 029 00C 0 13 -0--H4 Y- /z, o 24. Thenl methodif l 23, wherinl Byain isiaiy, ahhl benziswheiaz nisuslected fr the groiup consitingof-O- u Sp t e-CIa 2 -,SCH 2 -tuio,- CHbje-t -CoL)- -C(po )-,thtwhrYi oCrH. nd -OC nt-I 2 1ISCI xaky s halogsie IC lclu t e ao n Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halo sustittitun [a 030 09/05 '06 12:56 FAX 81 7 3229 3384 CUILLEN CO.~13 132 oQ1 is selected from the group consisting of phenyl, pyridinyl, naphthy], pyrirrndinyl, quinoline, isoquinoilne. imidazole and beuzothiazolyl, optionally o0 substituted by halogen, up to per-halo, X' is as defined in claim 24 and Z is selected from the group consisting of -R 6 -OR 6 and -NHR], wherein R' is hydrogen, C,-C 10 -alkcyl or C 3 -C 10 -cycloalkyl and R 7 is selected from the group consisting of hydrogeni, C 3 -C 10 -alkyl, and C 3 -C 6 -cycloalkyl wherein R6 and R7 can be o substituted by halogen or up to per-halosubstitution.

26. The method of claim 24, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Q1 is pyridinyl, phenyl or benzotbiazolyl optionally substituted by halogen up to per-balosubstiturion, Y is or -CH 2 XI is as defined in claim 24, Z is--NI--C()-CHI-I 2 1 wherein, p is 1-4, -CH 3 -0OH, -0C14 3 -0C 2 H 5 -CN or -C(0)CH 3 n 0 or 1, and n I 0 or I

27. The method of claimn 23, wherein thte compound administered is selected from the group consisting of: N-(5-ieri-Butyl-3 -isoxaz7oly)-N'-(4-(4-hydroxyphenyl)oxypbenyl)urea; N-(5-rert-Butyl-3 -isoxazolyl)-N'-(4-(3-hydroxyphenyl)oxyphenyl)urea; N-(5-zeri-Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl)oxyphenyl)urea; N-(5-tere-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyl)urea; A-(5-et-Butyl--isoxazolyl)-A'-(4-phenyloxyphienyl)u~rea; N-(5-rert-Butyl-3-isoxazolyl)-N'-(4-(3-methiylaniinocarbonylphienyl)- thiophenyl)urea; N-(5-LerL-Butyl-3 -isoxazolyl)-N'-(4-(4-(l ,2-methylenedioxy)phenlyl)- oxyphenyl)urea; NV-(5-tert-Duttyl-3-isoxazolyl)-NV'-(4-(3-pyridinuyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridyl)thiophenyl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N'-(4-(4-pyridinoyl)methylphenyl)urea; N-(5-ieri-Butyl-3 -isoxazolyl)-N'-(3-(4-pyridinyl)oxyphienyl)urea; N-(5-ierI-Butyl-3--isoxazolyl)-N'-(3-(4-pyridiinyl)thiophenyl)urea; N-(5-rerr-Butyl-3 -isoxazoly1)-N'-(3-(3 -methyl-4-pyridinyl)oxyphenyl)urea; 09/05 '06 12:56 FAX 61. 7 3229 3384 Va 0 0 ci CULLEN CO. 133 Z031 Q-) 0 N-(5-tert-Butyl-3 -ioaoy)N-3(-ehl4-yiiy~bolay~ra N-(5-rerz-Butyl-3-isoxazclyl)-N'-(4-(3-mcthyl-4-pyridinyl)thiopheny)urca; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-rnethyl-3-pyiiduayl)oxyphenyl)urea; N-(5-terrt-Butyl-3-isoxazolyl)-N '-(4-(3-methyl-4-pyridiniyl)oxyphenyl)urca; N-(5-rn-Butyl-3-isoxazolyl)-N'-(3-(2-benzothiazolyl)oxyphenyl)Lurea; N-(5-tert-b-utyl-3-isoxezolyl)-N'-(3 -chloro-4-(4-(2-rnethylcarbamoyl)pyridyl)- oxypheuyl)urea; N-(5-rert-butyl-3-isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-rert-butyl-3'-isoxazolyl)-N'-(3-(4-(2-methykca.bamoyl)pyridyl)- tliiophenyl) urea; N-(5-tern-butyl-3-isoxazolyl)-N-(2-mcthyl-4-(4-(2-methylcarbai-noyl)pyridyl)- oxyphcnyl)urea; N-(5-rert-butyl-3-isoxazolyl)-N'-(4-(4-(2--carbamoyl)pyridy)oxyphenyl) urea; N-(5-cert-butyl-3-isoxazolyl)-N'-(3-(4-(2-carbamioyl)pyridyl)oxypheny) urea; N-(5-ten--butyl-3 -isoxazolyl)-N'-(3-(4-(2-miethiylcarbamoyl)pyridyl)- oxyphenyl) urea; A-(5-tert-butyl--isoxazolyl)-N'-(4-(4-(2-mcthylcarbamoy)pyridy)- thiophe~nyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N '-(3-chloro-4-(4-(-inethylcarbamoyl)pyridyl)- oxyphenyl)urea; N-(5-tert-butyi-3-isoxazolyl)-N -methylcarbamoyl)pheniyl)oxyphcnyl) urea;, and pharmaceutically acceptable salts thereof

28. The method of claim 1, comprising administering a compound of the formula t-Bu N IH NH-C-NH-B nQ/nR Ing 19&MA VAT al 7 1990 qqAA rTTT T VINT k rn rA 032 ct 134 o wherein B is 5-rnethyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naplithyl, quinolinyl, isoquinolinyl, 00 o phthalimidinyl, furyl, thieny], pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl thiazolyl, isothiazolyl, benzoirnyl, benzothienyl, indolyl, benzopyrazolyi, beuzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisotl'iazolyl, substituted by one o or more subst'ituents independently selected from the group consisting of halogen, up o to per-halosubstitution, and X~, wherein n is 0-3 and each X is independently selected from the grouip consisting of -CNt -C0 2 RW, -C(O)NR 5 Rt -C(O)RW, -NO 2 -OR1 5 SWY, -NRR NR 5 C(O)OR" t -NR 5 C(O)R 5 C 1 -C 10 alkyl, C 2 -C 10 ailcenyl, C 1 -Clo alkoxy, C 2 -C 10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl, up to per halo- substituted C 1 -C 10 alkyl, up to per halo-substituted C 2 -C 10 alkenyl, up to per halo- substituted C 1 -C 10 alkoxy and, up to per halo-substituted Ca-C 10 cycloalkyl, wherein RW and W'"are independently selected from H, C 1 -C 10 alkyl, C2-C 10 alkenyl, C 3 -C 10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl uip to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 2 -C 10 alkenyl, and up to per-hialosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 -NR 5 C(0)NR 5 NR 5 -NR 5 -C(Q)NR 5 -(C11 2 -CH 2 )mN(R 5 0(CIHi)n, -cHxa, -CXY2, -S(CF1 2 and -N(R)(CH 2 mn 1-3, and XV is halogen; and Ar is phenyl, pyridinyl., pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalinidinyl, furyl, thienyl, pyrrolyl, inidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuxyl, benzothienyl, indolyl, benzopyrazolyl., benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Z,, wherein n1i is 0 to 3 and each Z is independently selected from the group consisting of -GCN, -C0 2 R 5 -C(O)NR 5 R 5 NR', -NO 2 SWY, NR'% -NRYC(O)OR", -C(O)R 5 -NR 5 C(O)R 5 -so 2 S0 2 NRR. CI-Coakl C 1 -C 10 alkoxyl, C 3 -C 10 cycloalkyl, up to per halo-substituted C 1 -C 10 alkyl and up to per halo-substituted C 3 -C 10 cycloalkyl; subject to the proviso that 09/05 '06 12:57 FAX 61 7 3229 3384 CULLEN CO O 0 135 oB is not 00 0 Re wherein R 6 is -N4C(Q)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, o -C(O)NH-(CH 3 2 -OCI- 2 CH(CH1 3 2 or -O-CH 2

29. The method of claim I comprising administering a compound of the R1 N u: 11 NH-C-NH-B formula wherein R' is selected from the group consisting of C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl, up to per-halosubstituted C 3 -C 6 alcyl, and up to per-halosubstituted C3-C 6 cycloalkyl, and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl, which is substituted by X, optionally substituted by halogen, up to per-halosubstitution, and optionally substituted by X'1, wherein n= 0-2; each X' is independently selected from the group of X or from the group consisting of -CN, -CO 2 Rs, -C(O)Rs, -C(O)NRsRs', -OR, NO2, -NR"R 5 C 1 -C 1 o alkyl, Cz2o1-alenyl, Clo-alkoxy, C3-Clo cycloalkyl, C 6 -C 1 4 aryl and C--C 24 alkaryl, and X is selected fromrn the group consisting of -NR'C(0)OR, NR 5 C(O)Rs, C 3 -Ci 3 heteroaryl, substituted C 1 -Clo alkyl, substituted C 2 ,o-alkenyl, substituted CI-lo- [a033 Ph 034 09/fl5 'AR 12:57 FAT Ri 7 329 3384 r'Trr vx Co ;iA 136 o alkoxy, substituted C3-Clo cycloalkyl, substituted C 6 -C 14 aryl, substituted C 3 -C13 heteroaryl, and -Y-Ar, and wherein if X is a substituted group, it is substituted by one o0 or more substituents independently selected from the group consisting of -CN, -C0 2 -C(O)R 5 -C(O)NR 5 R 5 -OR 5 -NR 5 R 5 NO 2 -NR 5 C(O)R 5 -NRC(O)0R 5 and halogen up to per-halosubstitution; wherein RW and R 5 are independently selected from H, C 1 -C 10 alkyl, C,- 10 O aikenyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 12 heteroaryl, C-C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -C 10 alkyl, up to per-halusubstituted C 2 10 alkenyl, and up to per-halosubstituted Q.-C, 0 cycloalkyl, wherein Y is N(R 5 4(CH 2 )m0, -NRC(O)NR 5 -NR 5 C(O)NR 5 -(CII 2 -(CHJ 2 0O(CH 2 -CHsc, -CXv2, and -N(R 5 )(CH 2 m 1-3, and X t is halogen; and Ar is phenyl, pyridinyl, pyximidinyl, pyrazinyl, pyridazinyl, naplithyl, quinoliriy], isoquinolinyl, phtbalimidinyl, fliryl, rhienyl, pyrrolyl, itnidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isotbiazoly], beuzofliryl, benzothienyl, indolyl, benzopyrazolyl, beuzoxazolyl, beuzisoxazolyl, beazothiazolyl or benzisothiazolyl, subject to the proviso that where Y is <(CH 2 or Ar is not phenyl, wherein Ar which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by 4i, wherein Wi is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 W, -C(O)R5, O0, -C(O)NR 5 R, -C(Q)RW, NO,, SR', NRR 5 -NRC(O)0R 5 -NR 5 CO)R 5 -502 R 5 R 5 C 1 C 1 0 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, substituted C 1 -C 10 alkyl and substituted C 3 -C 10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituerits independently selected from the group consisting of -GCN, -C0 2 R 5 C(O)NR 5 R 5 -ORW, -SW 5 -NRR, -NR 5 C(O)R 5 and -NR 5 C(0)0R 5 Gi- C 10 alkyl, C 1 -C 10 alkoxyl, and C3-C1g cycloalkyl, and where R' is -CH t-butyl, 09/05 '06 12:57 FAX 61 7 3229 3384 CULLEN CO. [it 035 0 00H BQQ is not 01 -C (II- C -0 an OCH 3 aogn The mehodil of laim 29n, herein B hen isrlliiazll Ysbseecte fro the grvs ta hrou cnistnof-,-- -CH 2 or -C(I 2 Q1CHS-,heyl Q, is pnyl ra pyrid ilai ubsitutdX1i ICaly or unisubstituted b aoeu opr bezisotialyl, nusiue rusbsie yhlgnup to per- ahoubliuto.

31. TFhe method of claim 30, wherein 0n/05 nit 12 M.7 FA al4 10n qqOA CULLEN a CO 1; 1030 O 00 138 0 Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstittition, 00 SQ' is selected from the group consisting of phenyl, pyridinyl, nIaphthyl, pyrimnidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X' is as defined in claim 30 and o Z is selected from the group consisting of -OR 6 and -NHR', wherein R 6 O is hydrogen, Ci-Clo-alkyl or C 3 -Clo-ycloalkyl and R7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and Cs-Cs-cycloalkyl, wherein R 6 and R7 can be substituted by halogen or up to per-halosubstitution.

32. The method of claim 1, comprising administering a compound of the formula t-Bu N0 O NH-C-N H-B wherein B is as defined in claim 1.

33. A method of claim 30, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Q' is phenyl, benzothiazolyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Y is or -CI-i 2 X' is as defined in claim 30, n 0 or 1, Z is -CH 3 OC 2 H1 or -OCH 3 and n1 0 or 1.

34. The method of claim 29, wherein the compound administered is selected from the group consisting of: N-(3-Isopropyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(3-zert-Butyl-5-isoxazolyl)-N'-(4-(4-methoxyphenyl)oxyphenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)uea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(3 -(4-pyridinyl)thiophenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)methylphenyl)urea; 09/A5 'AR 12:58 FAX 61 7 3229! 38 CULT.EN CAO~ A! 139 N-(3 -tert-Buty1-5-isoxazoly1)-N'-(4-(4-pyridiny1)tbiophieny)urea; 0 N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyrzidinyl)oxyplbeyl)urea; N-(3-rert-Butyl -5-isoxazolyl)-N'-(4-(4-methyl-3-pyridinyl)oxyphienyl)urea; o0 N-(3-tert-Butyl-5-isoxazolyl)-N-(3-(2-benzotltazolyi)oxyphenyl)urea; o 1 -Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4- ,nethylphenyl)oxyphenyl)urea; ON-(3 -Dimethiylpropy1)-5-isoxazoly1)-N'-(3-(4-pyridinyI)thi ophienyl) urea; 0 N-(3 -Dimethylpropyl)-5-isoxazolyl)-IV'-(4-(4-pyridinyl)oxyphenyl)urea; N-(3 -Dimnethylpropyl)-5-isoxazolyl)-N (4-pyridinyl)thiophienyl) urea;, 1,1 -Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-(4- inethoxyphenyl)oxy)pyridinyl)urea; N-(3-(l-Methyl-l -ethyLpropyl)-5-isoxazolyl)-N'-(4-(4- pyridinyl)oxyphenyl)urea; NA-(3 -Methyl-lI-ethylpropyl)-5-isoxazolyl)-N'-(3 pyridinyl)thiophenyl)-urea; soxazolyl)-N'-(3-(4-(2-inethylcarbm-noyl)pyridyl)- oxyphenyl) utrea; N-(3-isopropyl-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamnoyl)pyridyl)- oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N-(3-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(3 -iert-butyl-5-isoxazcly1)-N'-(4-(4-(2--metbylcarcbamoyl)pyridyl)- oxyphienyl) urea; N-(3-ierz-butyl-5-isoxazolyl)-N -(3-(4-(2-methylcabamoyl)pyridyl)- thiophenyl) urea; 1-dhnethylprop- 1-yl)-5-isoxuzolyl)-N'-(3-(4-(2-methylcarbamoyl)- pyridyl)oxyphenyl) urea; N-(3 -dimethylprop-1 -yl)-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)- py-ridyl)oxyphenyl) urea; N-(3-iert-butyl-5-isoxazolyl)-N'-(3-ohloro-4-(4-(2-methylcarbamnoyl)pyridyl)- thiophenyl) urea; and pharmaceutically acceptable salts thereof. [a 037 09/05 '00 12'55 PAX 01 7 1333 31Rd CULLE N CO r; 1038 09/05 '06 12:58 FAX 81 7 329Q 3384A CTTTTPT' k CA Va 0 0 140 0 R1 00 0 S 0 Rb NH-C-NH-B 0 A method as in claim 1, wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imniidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or bezisothiazolyl substituted by -Y-Ar and optionally substituted by halogen up to per-halosubstitution, C 1 -C 4 alkyl and up to per-halosubstituted C 1 -C 4 alkyl, wherein Y and Ar are as defined in claim 1.

36. A method as in claim 1, wherein B is a) phenyl, pyridinyl, naphthyl, quinolinyl or isoquinolinyl, substituted by -Y- Ar and optionally substituted by halogen up to per-halosubstitution, C 1 -C 4 alkyl and up to per-halosubstituted C 1 -C 4 alkyl, wherein Y and Ar are as defined in claim 1; b) thienyl substituted by methyl; or c) indolyl substituted by phenyl or pyridyl. DATED this ninth day of May 2006 BAYER CORPORATION By their Patent Attorneys CULLEN CO.