Background of the Invention The p21 as 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. Ante.

Rep. Med. Chez. 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 directe 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 co- expression 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. Chez. 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).

Summarv of the Invention The present invention provides compound which are inhibitors of the enzyme raf <BR> <BR> <BR> <BR> <BR> kinase. Since the enzyme is a downstream effector of p21raS, the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e. g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compound are useful in the treatment of human or animal, e. g., 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, i. e., by inhibiting raf kinase. Accordingly, the compound of the invention are useful in treating solid cancers, such as, for example, carcinomas (e. g., of the lungs, pancreas, thyroid, bladder or colon, myeloid disorders (e. g., myeloid leukemia) or adenomas (e. g., villous colon adenoma).

The present invention therefore provides compound 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 directe to compound and methods for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula 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 moities can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moities, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.

Suitable aryl and heteroaryl moities for B of formula I inclue, 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 replace 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 inclue, but are not limited to, 5-12 carbon- atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e. g., 1-4 carbon atoms in one or more of the rings can be replace 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, 1-, 2-or 3- pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 1,2, 3-triazol-1-, -4- or -5-yl, 1,2, 4-triazol-1-, -3- or -5-yl, 1- or 5- tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or-5-yl, 1,3,4-thiadiazol-2- or-5-yl, 1,2,4-oxadiazol-3- or-5-yl, 1,3,4-thiadiazol-2- or-5-yl, 1,3,4-thiadiazol-3- or-5-yl, 1,2,3-thiadiazol-4-or-5-yl, 2-, 3-, 4-, 5-or 6-2H-thiopyranyl, 2-, 3-or 4-4H- thiopyranyl, 3-or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4-or 5- benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-6-or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 2-, 4-, 5-, 6-or 7-ben-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8- quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 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-2- thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyls 5-methyl-2- thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

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

Suitable aryl groups inclue, for example, phenyl and 1-and 2-naphthyl.

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

Suitable halogens include F, Cl, Br, and/or I, from one to persubstitution (i. e., all H atoms on the group are replace 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 moities of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, -CO2R5,-C(O)NR5R5',-C(O)R5,-NO2,-OR5,-SR5,-NR5R5',-CN, -NR5C(O)OR5',alkyl,C2-C10alkenyl,C1-C10alkoxy4C3-C10C1-C10 <BR> <BR> <BR> cycloalkyl, C6-C, 4 aryl, Cl-C2, alkaryl, C3-C13 heteroaryl, Cl-CI-3 alkheteroaryl, substituted substitutedC2-C10alkenyl,ksubstitutedC1-C10alkoxy4alkyl, substituted C3-Cll cycloalkyl, substituted Cl-C23 alkheteroaryl and-Y-Ar.

Where a substituent, X or X', is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of-CN, -C(O)NR5R5',-OR5,-SR5,-NG5R5',-NO2,-NR5C(O)R5',-CO2R5,-C(O)R 5, -NR5C(O)OR5' and halogen up to per-halo substitution.

The moities R5 and R5' are preferably independently selected from H. C,-C, o alkyl, C3-C10cycloalky,C6-C14aryl,C3-C13heteroaryl,C7-C24alkaryl,C4 -C23C2-C10alkenyl, alkheteroaryl, up to per-halo substituted Cl-Clo alkyl, up to per-halosubstituted C2-C10 alkenyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C6-C14 aryl and up to per-halosubstituted C3-C13 heteroaryl.

The bridging group Y is preferably-O-,-S-,-N (R5)-,-(CH2)-m,-C (O)-,-CH (OH)-, -(CH2)mN)R5)-,-O*CH2)m-,-CHXa,-CXa2-,-S-(CH2)m-and-(CH2)mO-, -(CH2)mS-, -N (R') (CHZ)",-, where in = 1-3, and Xi vis 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 Znl, Wherein nl is 0 to 3.

Each Z substituent is preferably independently selected from the group consisting of -C(O)NR5R5',-C(O)-NR5,-NO2,-OR5,-SR5,-NR5R5',-NR5C(O)OR5',-C N,-CO2R5, <BR> <BR> <BR> <BR> =O, -NR5C(O)R5', -SO2R5, -SO2NR5R5', C1-C10 alkyl, Cl-Cl, alkoxy, C3-C,,,<BR> <BR> <BR> <BR> <BR> <BR> <BR> cycloalkyl, Cl-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C,-3 alkheteroaryl, substituted C,-C, 0 alkyl, substituted C3-C13 cycloalkyl, substituted C7-C24 alkaryl and substituted C4-C23 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of-CN, -CO2R5, -SR5,-NO2,-NR5R5',=O,-NR5C(O)R5',-OR5, alkyl,C1-C10alkoxy,C3-C10cycloalkyl,C3-C13heteroaryl,C6--NR5 C(O)OR5',C1-C10 C14 aryl, alkaryl.

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

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

The aryl and heteroaryl moities of B are more preferably of the formula: wherein Y is selected from the group consisting of-O-,-S-,-CH2-,-SCH2-,-CH2S-, -CH (OH)-,-C (O)-, -CSa2, -CXaH-, -CH2O- and -OCH2- and Xa 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 n I 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 -R6, -OR6, -SR6, and -NHR7, wherein R6 is hydrogen, C1-C10-alkyl or C,-C,,,- cycloalkyl and R7 is preferably selected from the group consisting of hydrogen, C3- andC6-C10-aryl,whereinR6andR7canbesubstitutedbyC10-alkyl,C3- C6-cycloalkyl halogen or up to per-halosubstitution.

The heteroaryl moiety A of formula I is preferably selected from the group consisting of : The substituent R'is preferably selected from the group consisting of halogen, C3-C10 alkyl, C, -C,,, cycloalkyl, Cl-C13 heteroaryl, Cl-C13 aryl, C1-C24 alkaryl, _up to per- halosubstituted C,-C,,, alkyl and up to per-halosubstituted C3-C10 cycloalkyl, up to per- halosubstituted C1-C13 heteroaryl, up to per-halosubstituted Cl-C13 aryl and up to per- halosubstituted alkaryl.

The substituent R2 is preferably selected from the group consisting of H,-C (O)R4, C1-C10alkyl,C3-c10cycloalkyl,C7-C24alkyl,C4-C23-CO2R4,-C(O)N R3R3', alkheteroaryl, substituted C1-C10 alkyl, substitutedC3-C, ll cycloalkyl, substituted C,-<BR> C24 alkaryl and substituted c4-c23 alkheteroaryl. Where R2 is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, - CO2R4, -C(O)-NR3R3', -NO2, -OR4, SR4, and halogen up to per-halosubstitution.

R3 and R3 are preferably independently selected from the group consisting of H,-OR', -SR4, -NR4R4, -C(O)R4, -CO2R4, -C (O) N R4R4, C-Clo alkyl, C3-C10 cycloalkyl, Cl-C14 aryl, C3-C1 3 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted <BR> <BR> <BR> C1-C10 alkyl, up to per-halosubstituted C3-C, o cycloalkyl, up to per-halosubstituted C6- anduptoper-halosubstitutedC3-C13heteroaryl.C14aryl R4 and R4' are preferably independently selected from the group consisting of H, C,- C3-C10cycloalkyl,C6-C14aryl,C3-C13heteroaryl;C7-C24alkaryl,C 4-C23C10alkyl, alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C6-C1 4 aryl and up to per-halosubstituted C3-C13 heteroaryl.

Ra is preferably C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C,-C, o alkyl and up to per-halosubstituted C3-C10 cycloalkyl.

Rb is preferably hydrogen or halogen. hydrogen,halogen,C1-C10alkyl,uptoper-halosubstitutedC1-C10al kylorRcis <BR> <BR> <BR> combines with R'and the ring carbon atoms to which R'and Rc are bound to form a 5-or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from O, N and S; The invention also relates to compound of general formula I described above and inclues pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula wherein R2, R'and B are as defined above; and both 5,3-and 3,5- isoxazolyl ureas of the formulae

wherein R'and B are also as defined above.

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

which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here Rs and R5' 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, R5,-C (O) R, -C(O)NR5R5',-NR5R5',C1-C1-alkyl,C2-10-alkenyl,C1-10-alkoxy,- N2,

C6-C14arylandC7-C24alkaryl.C3-C10cycloalkyl, The substituent X is selected from the group consisting of -SR5, -NR5C (O) OR5, heteroaryl,C4-C23alkheteroaryl,substitutedC1C10alkyl,NR5C(O) R5,C3-C13 substituted C, _, o-alkenyl, substituted C1-10-alkoxy, substituted C3-Cl, ) cycloalkyl, substituted C6-C14 aryl, substituted C7-C2, alkaryl, substituted C3-C13 heteroaryl, substituted C4-C23 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,-CORS,- C (O) R5,-C (O) NR5R5', -OR5, -SR5, -NR5R5', NO2, -NR5C (O) R 5"-NR5C (O) OR 5'and halogen up to per-halosubstitution, where R5 and R5' are as defined above.

The components of B are subject to the following provisos, where R'is t-butyl and R2 is methyl for the pyrazolyl ureas, B is not

Where R1 is t-butyl for the 5,3-isoxazolyl ureas, B is not wherein R6 is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-propyl, -C (O) NH- (CH3) 2, -OCH2CH(CH3)2, or -O-CH2, -phenyl. Where R'is t-butyl for the 3,5- isoxazole ureas, B is not and where R'is-CHZ-t-butyl for the 3,5-isoxazolyl ureas, B is not Preferred pyrazolyl ureas, 3,5-isoxazolyl ureas and 5,3-isoxazolyl ureas are those wherein B is of the formula

wherein Q, Q', X, Z, Y, n, s and nl are as defined above.

Preferred pyrazole ureas more particularly include those wherein Q is phenyl or pyridinyl, Q'is pyridinyl, phenyl or benzothiazolyl, Y is-0-,-S-,-CH. S-,-SCH.-, -CH, O-,-OCH.-or-CH2-, and Z is H, -SCH3, or-NH-C (O)-CPH, PY,, wherein p is 1-4, n = 0, s = I and nl = 0-1. Specific examples of preferred pyrazolyl ureas are: N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-phenyloxyphenyl)(3-tert-B utyl-5-pyrazolyl)-N'-(4-phenyloxyphenyl) urea; n-(3-tert-Butyl-5-pyrazolyl)-N'-(3-METHYLAMINOCARBONYLPHENYL )- oxyphenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(4-pyridinyl)(3-tert-Buty l-5-pyrazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)(3-tert-Buty l-5-pyrazolyl)-N'-(4-(4-pyridinyl) thiophenyl) urea; N-(3-tert-B utyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)(3-tert-B utyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) methylphenyl) urea; N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-phenyloxyphenyl) (l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-phenyloxyphenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N- (l-Methyl-3-tert-butyl-5-pyrazolyl)-N'- ( (4- (4-pyridinyl)thiomethyl)- phenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) thiophenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)met hyloxy)phenyl)- urea; N- (l-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (3- (2-benzothiazolyl) oxyphenyl)- urea; N-(3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)(3-tert-butyl- 5-pyrazolyl)-N'-(3-(4-pyridyl) thiophenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)(3-tert-butyl- 5-pyrazolyl)-N'-(4-(4-pyridyl) thiophenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)(3-tert-butyl- 5-pyrazolyl)-N'-(3-(4-pyridyl) oxyphenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)(3-tert-butyl- 5-pyrazolyl)-N'-(4-(4-pyridyl) oxyphenyl) urea; N-(1-methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridiyl) thiophenyl) urea; N- (I-methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridyl) thlophenyl) urea; N- (I-methyl-3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridyl) oxyphenyl) urea; and N-(1-methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)(1-me thyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl) oxyphenyl) urea.

Preferred 3,5-isoxazolyl ureas more particularly include those wherein Q is phenyl or pyridinyl, Q'is phenyl, benzothiazolyl or pyridinyl, Y is-O-,-S-or-CH2-, Z is-CH3,

Cl,-OCH3 or-C (O)-CH3, n = 0, s = 1, and n I = 0-1. Specific examples of preferred 3,5-isoxazolyl ureas are: N- (3-Isopropyl-S-isoxazolyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-methoxyphenyl) oxyphenyl)(3-tert-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-tert-Butyl-5-isoxazolyl)-N'- (3- (4-pyn'dinyl) thlophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl) methylphenyl)(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl) methylphenyl) urea; N- (3-tert-Butyl-5-isoxazolyi)-N'- (4- (4-pyridinyI) thiophenyl) urea; N- (3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyn'dinyl) oxyphenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-methyl-3-pyridinyl)(3 -tert-Butyl-5-isoxazolyl)-N'-(4-(4-methyl-3-pyridinyl) oxyphenyl) urea; N- (3-tert-Butyl-5-isoxazolyl)-N'- (3- (2-benzothiazolyl) oxyphenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-4(methylphenyl _oxyphenyl)- urea; N- (3- (1, 1-Dimethylpropyl)-5-isoxazolyl)-N'- (3- (4-pyn*dinyl) thiophenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl) thiophenyl) urea; N-(3-(l, l-Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-(4-methoxyphenyl)(3- (l, l-Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-(4-methoxyphenyl) oxy)- pyridinyl) urea; N-(3-(1-Methyl-l-ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridin yl)(3-(1-Methyl-l-ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridi nyl) oxyphenyl)- urea; N-(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridin yl)(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridi nyl) thiophenyl)- urea; N-(3-isopropyl-5-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)(3- isopropyl-5-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; N-(3-isopropyl-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)(3- isopropyl-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; N- (3-tert-butyl-5-isoxazolyl)-N'- (3- (4- (2-methylcarbamoyl)- pyridyl) oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)(3 -tert-butyl-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; N-(3-tert-butyl-5-isoxaxolyl)-N'-(3-(4-(2-methylcarbamoyl)py ridyl)- thiophenyl) urea; _ N (3- (1, 1-dimethylprop-1-yl)-S-isoxazolyl)-N'- (3- (4- (2-methylcarbamoyl)- yridyl) oxyphenyl) urea; N-(3-(1,1-dimethylprop-1-yl)-5-isoxazolyl)-N'-(4-(4-(2-methy lcarbamoyl)- pyridyl) oxyphenyl) urea; and

N- (3-tert-butvl-5-isoxazolyl)-N'- (3-chloro-4- (4- (2-methylcarbamoyl) pyridyl)- thiophenyl) urea.

Preferred 5,3-isoxazolyl ureas more particularly include those wherein Q is is phenyl or pyridinyl, Q'is phenyl, benzothiazolyl or pyridinyl, Y is-O-,-S-or-CH2-, X is CH3 and Z is-C (O) NH-, CpH2p+"wherein p = 1-4,-C (O) CH3,-CH3,-OH,-OC2Hs, -CN, phenyl, or-OCH3, n = 0 or 1, s = 0 or l, and nl = 0 or 1. Specific examples of preferred 5,3-isoxazolyl ureas are: N- (5-tert-Butvl-3-isoxazolyl)-N'- (4- (4-hydroxyphenyl) oxyphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (4- (3-hydroxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl)(5-tert- Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyl)(5-tert-Bu tyl-3-isoxazolyl)-N'-(3-benzoylphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl)(5-tert- Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methylaminocarbonylph enyl)- thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(1,(5-tert-Butyl-3-is oxazolyl)-N'-(4-(4-(1, 2-methylenedioxy) phenyl)- oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-pyridinyl)(5-tert-But yl-3-isoxazolyl)-N'-(4-(3-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)(5-tert-But yl-3-isoxazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridyl)(5-tert-Butyl -3-isoxazolyl)-N'-(4-(4-pyridyl) thiophenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) methylphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyn*dinyl) oxyphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyridinyl) thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(3-methyl-4-pyridinyl)(5 -tert-Butyl-3-isoxazolyl)-N'-(3-(3-methyl-4-pyridinyl) oxyphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (3- (3-methyl-4-pyridinyl) thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methyl-4-pyridinyl) thiophenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-methyl-3-pyn'dinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methyl-4-pyridinyl) oxyphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (3- (2-benzothiazolyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3-chloro-4-(4-(2-methylcar bamoyl)(5-tert-butyl-3-isoxazolyl)-N'-(3-chloro-4-(4-(2-meth ylcarbamoyl) pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)(5 -tert-butyl-3-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)py ridyl)- thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(2-methyl-4-(4-(2-methylcar bamoyl)(5-tert-butyl-3-isoxazolyl)-N'-(2-methyl-4-(4-(2-meth ylcarbamoyl) pyridyl)- oxyphenyl) urea;

N- (5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-carbamoyl) pyridyl) oxyphenyl) urea; N- (5-tert-butyl-3-isoxazolyl)-N'- (3- (4- (2-carbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)py ridyl)- oxyphenyl) urea; N- (5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-methylcarbamoyl)pyridyl)- thiophenyl) urea; N- (5-tert-butyl-3-isoxazolyl)-N'- (3-chloro-4- (4- (2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; and N- (5-tert-butyl-3-isoxazolyl)-N'- (4- (3-methylcarbamoyl) phenyl) oxyphenyl) urea.

Additionally included are thienyl ureas of the formulae

wherein R', Ru rand 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:

These aromatic ring structures can be substituted or unsubstituted by halogen, up to per-halosubstitution. The X'substituents are independently selected from té group consisting of X or from the group consisting of -CN, -OR5, -NR5R5', C1-C10 alkyl.

The X substituents are independently selected from the group consisting of-CO2R5, -C (O) NR5R5,-C (O) Rs,-NO"-SRS,-NR5C (O) OR5',-NR5C (O) R5', C3-C10 cycloalkyl, C6-C14 aryl, C7-C24 alkaryl, C3-C13 heteroaryl, C4-C,-3 alkheteroaryl, and substituted C,- C10C10alkyl, substituted C1-10-alkoxy,substitutedC3-C10substituted cycloalkyl, substituted C6-C, 4 aryl, substituted CI-C,-4 alkaryl, substituted C3-C, 3 heteroaryl, substituted C4-C23 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,-CORS,-C (O) R',-C (O) NR5R5', -OR5, -SR5, -NR5R5', -NO2, -NR5C(O)R5', -NR5C (O) OR 5'and halogen up to per-halo substitution. The moities R5, R5, 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 Preferred thienyl ureas include those wherein B is of the formula and Q, Q', Y, X, Z, n, s and nl are as defined above. The preferred thienyl ureas more particularly include those wherein Q is phenyl, Q'is phenyl or pytidinyl, Y is -O- or -S-, Z is-Cl,-CH3,-OH or-OCH,, n = 0, s = 0 or 1, and nl = 0-2. Specific examples of preferred thienyl ureas are: N- (3-Isopropyl-5-isoxazolyl)-N'- (4- (4-pyridinyl) thlophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-methoxyphenyl)(3-tert -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-tert-Butyl-5-isoxazolyl)-N'-(3-(4-pyridinyl)(3-tert-But yl-5-isoxazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)(3-tert-But yl-5-isoxazolyl)-N'-(4-(4-pyridinyl) methylphenyl) urea;

N- (3-ent-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxpyhenyl)u rea; N- (3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-methyl-3-pyridinyl) oxyphenyl) urea; N- (3-tert-Butyl-5-isoxazolyl)-N'- (3- (2-benzothiazolyl) oxyphenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-methylpheny l)- oxyphenyl) ure ; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl)t hiophenyl)urea; N-(3-(1,1-Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-(4-methoxyph enyl)- oxy) pyridinyl) urea; N-(3-(1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridin yl)- oxyphenyl) urea; and N- (3- ( 1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'- (3- (4-pyridinyl) thio- phenyl) urea.

Preferred thiophenes include: N-(5-tert-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl) oxyphenyl)(5-tert-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl) oxyphenyl) urea; N- (5-tert-butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl) oxyphenyl) urea; N- (5-tert-butyl-3-thienyl)-N'- (4- (3-methylphenyl) oxyphenyl) urea; and N- (5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl) thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: wherein Ra, 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 isoxazolyl ureas shown above. Such ring structures can be unsubstituted or substituted by halogen, up to per-halosubstitution, and each X'substituent is independently selected from the group consisting of X or from the group consisting of -CN,-NO,-ORS and C,-C, o alkyl. The X substituents are selected from the group consisting of-SR',-CO, R',-C (O) R5,-C (O) NR5R5', -NR5R5', -NR5C (O) OR5,

C2-10-alkenyl,substitutedC1-10-alkoxy,-C3-C10cycloalkyl,-NR5 C(O)R5',substituted -C7-C24,alkaryl,C3-C13heteroaryl,C4-C23alkheteroaryl,andsubs tituted-C6-C14aryl, <BR> <BR> <BR> C,-C, 0 alkyl, substituted C3-Clll cycloalkyl, substituted aryl, substituted alkaryl, substituted heteroaryl, substituted C4-C23 alkheteroaryl and-Y-Ar. Each of R5, 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 inclues pharmaceutical compositions that include compound described above and a physiologically acceptable carrier.

Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula and Q, 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 -0-or-S-, n = 0, s = 1 and nl = 0. Specific examples of preferred thiadiazolyl ureas are: N-(5-tert-Butyl-2-(1-thia-3,4-diazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; n-(5-tert-Butyl-2-(1-thia-34-diazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(3-(4-(2-methylc arbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(4-(4-(2-methylc arbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-2-(l-thia-3, 4-diazolyl))-N'-(3-chloro-4-(4-(2- methylcarbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(2-chloro-4-(4-( 2- methylcarbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(3-(4-pyridyl) thiophenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(2-methyl-4-(4-( 2- methylcarbamoyl) pyridyl) oxyphenyl) urea; and N (5- (1, 1-dimethylprop-1-yl)-2- (1-thia-3, 4-diazolyl))-N'- (4- (3- carbamoylphenyl) oxyphenyl) urea.

The preferred furyl ureas more particularly include those wherein Q is phenyl, Q'is phenyl or pyridinyl, Y is-O-or-S-, Z is-Cl or-OCH3, s=0 or 1, n = 0 and n1 = 0-2.

The present invention is also directe to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li- Nat or K-), alkaline earth cations (e. g., Mg+2, Ca~~ or Ba~'), 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, N, N-dimethylaminopyndine (DMAP), 1,4-diazabiclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU).

A number of the compound of Formula 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 compound described in Formula I which possess Raf kinase inhibitory activity.

General Preparative Methods The compound of Formula I may be prepared by use of known chemical rections 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 <BR> <BR> <BR> <BR> al. Comprehensive Heterocyclic Chemistry ; Permagon Press: Oxford, LTK (1984).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985)). For

example, 3-substituted-5-aminoisoxazoles (3) are available by the rection of hydroxylamine with an a-cyanoketone (2). as shown in Scheme I. Cyanoketone 2, in turn, is available from the rection of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Rection of an- cyanoketone with hydrazine (R-=H) or a monosubstituted hydrazine affords the 3- substituted-or 1,3-disubstituted-5-aminopyrazole (5). 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, rection of nitrile 8 with an-thioacetate ester gives the 5- substituted-3-amino-2-thiophenecarboxylate (9, 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 (10), 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. CH3CN Rl R' 1)base O NU ) RX HzNOHHCI NH2 3 1 base Ri 0 NHNH2 4 N'-I CON , NH2 O 2 Rz II 6 Ri ruz N R2 = H N I R HSCOZR I low CN S-NH2 8 C02R 9 1) OH- 2) H+ II II /_OOO'\ IF 1) OH' S + + S i NH3 2) H NHBOC C02R 11 10

Scheme 1. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3rd 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 H2 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 LiAIH4 (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, 3rd Ed. ; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). H2/catalyst / (eg. Ni, Pd, Pt) \ ArN02H ArNH2 M (0) (eg. Fe, Sn, Ca) Scheme 11 Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HN03, or an alternative NO, + source. Nitroaryls may be further elaborated prior to reduction.

Thus, nitroaryls substituted with potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution rections on treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or phenoxide. Nitroaryls may also undergo Ullman-type coupling rections (Scheme III). 02N \ F basa 12 02N * I -S-A r 02N gr-Ar 13 R jSH R CuO/base 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve rection of a heteroaryl isocyanate (17) with an aryl amine (16). 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, rection 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 ragent. A urea may also be generated from the rection of an aryl isocyanate (20) with a heterocyclic amine.

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. Rection 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.

Scheme V Urea Formation via Isatoic-like Anhydrides Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

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

The compound may be administered orally, topically, parenterally, by inhalation or spray or sublingually, rectally or vaginally in dosage unit formulations. The term 'administration by injection'includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compound 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

order to provide palatale preparations. Tablets contain the active ingredient in mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tables. These excipients may be, for exemple 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 compound 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 mixture 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 alcools, 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 mixture 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 compound may also be in the form of non-aqueous liquid formulations, e. g., 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 alcool. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatale 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 mulsions. 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-occuning 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 mulsions 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 compound may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing

the dru (2 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.

Compound 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. Wu94/04157 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 combine 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 alcools such as ethanol or isopropyl alcool, 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 alcools, 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 inclue, for example, monohydroxy or polyhydroxy alcools such as ethanol, propylene glycol or benzyl alcool, saturated or unsaturated C8-C, 8 fatty alcools such as lauryl alcohol or cetyl alcool, saturated or unsaturated C8 C, g 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

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 alcools, saturated or unsaturated C8-C, 8 fatty alcools, saturated or unsaturated C8-C, 8 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 compound 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.

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, ive., 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 V 1, filed on December 22,1997, as Serial No.

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

The compound are producible from known compound (or from starting materials which, in turn, are producible from known compounds), e. g., through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, e. g., 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 rections 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 canula, and introduced into rection vessels through rubber septa. Unless otherwise stated, the term concentration under reduced pressure'refers to use of a Buchi rotary evaporator at approximately 15 mmHg.

All temperatures are reporte uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. Thin- layer chromatography (TLC) was performed on Whatman pre-coated glass-backed silica gel 60A F-254 250Lm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) 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 Sciencet silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparats or a Mettler FP66 automate melting point apparats and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either <BR> <BR> <BR> <BR> Me, Si (6 0.00) or residual protonated solvent (CHCI3 6 26;7. MEOH 8 30;3. DMSO 8 2.49) as standard. Carbon ('3C) NMR spectra were measured with a General Electric <BR> <BR> <BR> <BR> GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl3 6 0;77. MeOD-d3; 6<BR> <BR> <BR> <BR> <BR> <BR> 49.0; DMSO-d6 # 5)39. as standard. Low solution mass spectra (MS) and high solution mass spectra (HRMS) were either obtained as electron impact (EI) 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°C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 1A. Liquid- cesium 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 (lx10-4 torr to 2. Sx 10-4 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 su-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; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 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 assigne structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl conc concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H)-pyrimidinone

DMF NN-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate EtOH ethanol (100%) Et, O diethyl ether Et3N 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 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 rection mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water (50 <BR> <BR> <BR> 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 acidifie to approximately pH 1 (conc. HCI) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combine with the original organic layer, dried (MgSO4), and concentrated in vacuo to give the a- cyanoketone as a yellow oil which was used in the next step without further purification.

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-4- methylpentanenitrile while stirring. The resulting yellow solution was heated at 50°C for 2.5 hours to produce a less dense yellow oil. The warm rection mixture was immediately extracted with CHOC13 (3 x 100 mL) without cooling. The combine organic layers were dried (MgSO4), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% CH, Cl,) to afford the desired isoxazole as a yellow solid (11.3 g, 70%): mp 63-65°C ; TLC Rf (5% acetone/95% CH2Cl2) 0.19;'H-NMR (DMSO-d6) d 1.12 (d, J=7.0 Hz, 6H), 2.72 (sept, J=7.0 Hz, 1H), 4.80 (s, 2H), 6.44 (s, 1H); FAB-MS m/z (rel abundance) 127 ( (M+H) *; 67%).

A3. General Method for the Preparation of 5-Amino-1-alkyl-3-alkylpyrazoles 5-Amino-3-tert-butyl-1- (2-cyanoethyl) pyrazole: A solution of 4,4-dimethyl-3- oxopentanenitrile (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 rection. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from 40% EtOAc/60% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (Et2O/hexane) to afford the desired product (2.5 g, 30%) : TLC (30% EtOAc/70% hexane) Rf 0.31;'H-NMR (DMSO-db) 8 131. (s, 9H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 (s, 1 H).

A 4. Synthesis of 3-Amino-5-alkylthiophenes A4a. Synthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxvlation of Thiophenecarboxylic Acids Step 1. 7-tert-Butyl-2H-thienol3, 2-dloxazine-2,4 (1H)-dione : A mixture of methyl 3-amino-5-tert-butylthiophenecarboxylate (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 rection mixture was concentrated under reduced pressure and the residue was dissolve 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, 73%):'H- <BR> <BR> <BR> NMR (CDC13) 6 381. (s, 9H), 2.48 (s, 1H), 6.75 (s, 1H); FAB-MS m/z (rel abundance) 226 (M+H)+,100%). 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-doxazine-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 Et2O to afford the desired urea (0.25 g, 78%): mp 187-189 <BR> <BR> °C ; TLC (50% EtOAc/50% pet. ether) Rf 0.04;'H-NMR (DMSO-d6) 6 341. (s, 9H), 3.90 (s, 2H), 7.15 (d, J=7Hz, 2H), 7.20 (d, J=3 Hz, 2H), 7.40 (d, J=7 Hz, 2H), 7.80 (s 1H), 8.45 (d, J=3 Hz, 2H) 9.55 (s, 1H), 9.85 (s, 1H), 12.50 (br s, 1H); FAB-MS m/z (rel abundance) 410 ( (M+H) +; 20%).

Step 3. N (5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinylmethyl) phenyl) urea: A vial containing N- (5-tert-butyl-2-carboxy-3-thienyl)-N'-(4-(4-pyridinylmethyl) phenyl)- 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 purifie by preparative HPLC (C-18 column; gradient from 20% CH3CN/79.9% H, 0/0. I % TFA to 99.9% H, O/0. 1 % TFA) to give the desired product (0.024 g, 43%): TLC (50% EtOAc/50% pet. ether) Rf 0.18;'H- <BR> <BR> <BR> NMR (DMSO-db) 8 331. (s, 9H), 4.12 (s, 2H), 6.77 (s, 1H), 6.95 (s, 1H), 7.17 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.69 (d, J=7 Hz, 1H), 8.58 (s, 1 H), 8.68 (d, J=7 Hz, 2H), 8.75 (s, 1H); EI-MS m/z 365 (M+).

A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-alkyl-2-thiophene- carboxylate esters 5-tert-Butyl-3-thiopheneammonium Chloride: To a solution of methyl 3-amino-5- 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 conc. HCI solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observe. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspende in EtOAc (150 mL) and a saturated NaHCO3 solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCl solution (150 mL), dried (Na, S04), and concentrated under reduced pressure to <BR> <BR> <BR> give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification. A4c. Synthesis 3-Amino-5-alkylthiophenes from N-BOC 3-Amino-5-alkyl-2- thiophenecarboxylate esters

Step 1. Methyl 3- (tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxy- late: To a solution of methyl 3-amino-S-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5°C 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 20°C. The resulting red solids were dissolve in CH2Cl2 (3 L) and sequentially washed with a 1 M H3PO4 solution (2 x 750 mL), a saturated NaHC03 solution (800 mL) and a saturated NaCl solution (2 x 800 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting orange solids were dissolve in abs. EtOH (2 L) by warming to 49°C, then treated with water (500 mL) to afford the desired <BR> <BR> <BR> product as an off-white solid (163 g, 74%):'H-NMR (CDCl3) 6 381. (s, 9H), 1.51 (s, 9H), 3.84 (s, 3H), 7.68 (s, 1H), 9.35 (br s, 1H); FAB-MS m/z (rel abundance) 314 (M+H),45%),

Step 2.3- (tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxyli c Acid: To a solution of methyl 3- (tert-butoxycarbonylamino)-S-tert-butyl-2- thiophenecarboxylate (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°C for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0°C. The pH was adjusted to approximately 7 with a

1.0 N HCI solution (approximately 1 L) while maintaining the internal temperature at approximately 0 °C. The resulting mixture was treated with EtOAc (4 L). The pH was adjusted to approximately 2 with a 1.0 N HCl solution (500 mL). The organic phase was washed with a saturated NaCl solution (4 x 1.5 L), dried (Na2SO4), and concentrated to approximately 200 mL under reduced pressure. The residue was treated with hexane (1 L) to form a light pink (41.6 g). Resubmission of the mother liquor to the concentration-precipitation protocol afforded additional product (38.4 g, <BR> <BR> <BR> 93% total yield):'H-NMR (CDCl3) 6 941. (s, 9H), 1.54 (s, 9H), 7.73 (s, 1H), 9.19 (br s, 1H); FAB-MS m/z (rel abundance) 300 ((M+H)+, 50%).

Step 3.5-tert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(tert- butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HCl 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 °C. The resulting solids were collecte and dried overnight under reduced pressure to give the desired salt as <BR> <BR> <BR> an off-white solid (1.72 g, 90%):'H-NMR (DMSO-db) 8 311. (s, 9H), 6.84 (d, J=1.48 Hz, 1H), 7.31 (d, J=1.47 Hz, 1H), 10.27 (br s, 3H).

A5. General Method for the Synthesis of BOC-Protected Pyrazoles

5-Amino-3-tert-butyl-N'-(tert-butoxycarbonyl)(tert-butoxycar bonyl) pyrazole: To a solution of 5-amino- 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CH2Cl2 (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 (MgSO4) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired carbamate (6.26 g, 92%): mp 63-64°C ; TLC Rf (5% acetone/95% CH2Cl2) ;'H-NMR (DMSO-db) 8 151. (s, 9H), 1.54 (s, 9H), 5.22 (s, 1H), 6.11 (s, 2H); FAB-MS m/z ((M+H)+).

A6. General Method for the Synthesis of 2-Aminothiadiazoles 2-Amino-5- (l- (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 rection mixture was heated at 85°C for 7 h, then cooled to room temperature, and treated with a concentrated NH40Hsolution until basic. The resulting solids were filtered to afford 2-amino-5- (1-(1-ethyl) propyl) thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, 51%): mp 155-158°C ; TLC (5% MeOH/95% CHC13) Rf 0.14;'H-NMR (DMSO-d6) 8 800. (t, J=7.35 Hz, 6H), 1.42-1.60 (m, 2H),

1.59-1.71 (m, 2H), 2.65-2.74 (m, 1H), 7.00 (br s, 2H); HPLC ES-MS nl/-172<BR> ((M+H)-) A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles 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, 10%), which was used inb the next step withour further purification. Step 2.2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 g), KHC03 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 g). The resulting mixture was heated at the refulx temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH2Cl2 (5 mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO4) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+), A8. General Method for the Synthesis of 2-Aminooxazoles Step 1.3,3-Dimethyl-1-hydroxy-2-butanone: A neat sample of 1-bromo-3,3- dimethyl-2-butanone (33.3 g) at 0 °C was treated with a 1N NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combine organics were dried (Na, S04) and concentrated under reduced pressure to give 3, 3-dimethyl-1-hydroxy-2-butanone (19 g, 100%), which was used inb the next step withour further purification.

Step 2.2-Amino-4-isopropyl-1,3-oxazole: To a solution of 3, 3-dimethyl-1- hydroxy-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 1N NaOH solution (1.45 mL). The resulting mixture 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 Et2O (3 x 25 mL). The combine organic layers were treated with a 1N NaOH solution tuntil basic, then extracted with CH, CL, (3 x 25 mL). The combine organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 2-Amino-4- isopropyl-1,3-oxazole (1.94 g, 41%): HPLC ES-MS m/z 141 ( (M+H) T).

A9. Method for the Synthesis of Substituted-5-aminotetrazoles : To a solution of 5-aminotetrazole (5 g), NaOH (2.04 g) and water (25 mL) in EtOH (115 mL) at the reflux temperature was added 2-bromopropane (5.9g). 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 CH2Cl2 (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1-and 2-isopropyl-S-aminotetrazole (50%), which was used without further purification: HPLC ES-MS m/z 128 ( (M+H)').

B. General Methods for Svnthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene 4- (4-Pyridinvimethyl) 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 rection. The mixture was filtered through a short pad of Celte@. The filtrate was concentrated in vacuo to afford a white solid (5.4 <BR> <BR> <BR> <BR> g, 90%):'H-NMR (DMSO-d6) 6 743. (s, 2H), 4.91 (br s, 2H), 6.48 (d, J=8.46 Hz, 2H), 6.86 (d, J=8.09 Hz, 2H), 7.16 (d, J=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); El- MS m/z 184 (M-). This material was used in urea formation rections without further purification. B2. General Method for Substituted Aniline Formation via dissolving Metal Reduction of a Nitroarene

4-(2-Pyridinylthio) aniline: To a solution of 4- (2-pyridinylthio)-1-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 rection mixture was diluted with EtOAc (75 mL) and H20 (50 mL), basified to pH 10 by adding solid K, C03 in portions :(Caution foaming). The organic layer was washed with a saturated NaCl solution, dried (MgS04), concentrated in vacuo. The residual solid was purifie by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) Rf 0.20.

B3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1.1-Methoxy-4- (4-nitrophenoxy) benzene: To a suspension of NaH (95%, 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was added dropwise a solution of 4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The rection was stirred 1 h, then a solution of 1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The rection was heated at 95 °C overnight, then cooled to room temp., quenched with H2O, and concentrated in vacuo.

The residue was partitioned between EtOAc (200 mL) and H, O (200 mL). The organic layer was sequentially washed with H, O (2 x 200 mL), a saturated NaHCO3 solution (200 mL), and a saturated NaCI solution (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was triturated (Et, O/hexane) to afford 1- <BR> <BR> <BR> methoxy-4- (4-nitrophenoxy) benzene (12.2 g, 100%):'H-NMR (CDCl3) 6 833. (s, 3H), 6.93-7.04 (ion, 6H), 8.18 (d, J=9.2 Hz, 2H); EI-MS m/z 245 (M').

Step 2.4- (4-Methoxyphenoxy) aniline: To a solution of l-methoxy-4-(4- nitrophenoxy) benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g) and the resulting slurry was shaken under a H2 atmosphere (50 psi) for 18 h.

The rection mixture was filtered through a pad of Celitet with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidifie (10.6 g, 100%):'H-NMR <BR> <BR> <BR> (CDCl3) 6 543. (br s, 2H), 3.78 (s, 3H), 6.65 (d, J=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI- MS m/z 215 (M'). B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1.3- (Trifluoromethyl)-4- (4-pyridinylthio) nitrobenzene: A solution of 4- mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-mitrobenzotrifluoride (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 rection. The mixture was diluted with Et2O (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 NaCI solution (100 mL), dried (MgS04), 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, 54%): TLC (30% EtOAc/70% hexane) Rf 0.06; 'H-NMR (DMSO-db) 8 7.33 (dd, J=1.2,4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd, J=2.4,8.7Hz, 1H), 8.54-8.56 (m, 3H).

Step 2.3- (Trifluoromethyl)-4- (4-pyridinylthio) aniline: A slurry of 3- trifluoromethyl-4-(4-pyridinylthio) nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for 4 h. The mixture was diluted with Et2O (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combine organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50% hexane) Rf 0.10;'H-NMR (DMSO-d6) <BR> <BR> 6 216. (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2. 4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6. 3 Hz, 2H). B3c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(2-(4-Phenyl) thiazolyl) thio-1-nitrobenzene : A solution of 2-mercapto-4- phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4- nitrobenzene (2.3 mL, 21.7 mmoles) followed by K, CO, (3.18 g, 23 mmol), and the mixture was heated at approximately 65 °C overnight. The rection mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the <BR> <BR> desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49;'H-NMR (CDC13) 6<BR> <BR> <BR> 7.35-7.47 (ion, 3H), 7.58-7.63 (ion, 3H), 7.90 (d, J=6. 9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H). Step 2.4- (2- (4-Phenyl) thiazolyl) thioaniline: 4- (2- (4-Phenyl) thiazolyl) thio-1-nitro- benzene 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; <BR> <BR> 'H-NMR (CDCI3) 6 893. (br s, 2H), 6.72-6.77 (ion, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H).

B3d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(6-Methyl-3-pyridinyloxy)-1-nitrobenzene : To a solution of 5-hydroxy- 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 KZC03 (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 combine organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na. SO4), and concentrated in vacuo to afford the desired product (8.7 g, 83%). The this material was carried to the next step without further purification.

Step 2.4- (6-Methyl-3-pyridinyloxy) aniline: A solution of 4-(6-methyl-3- pyridinyloxy)-1-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to 10% Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H, atmosphere (ballon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celitet and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, 92%): EI-MS m/z 200 (Mt).

B3e. General Method for Substituted Aniline Formation via Nitroarene Formation

Through Nucleophilic Aromatic Substitution, Followed by Reduction ,OOMe<BR> <BR> <BR> <BR> i<BR> <BR> <BR> 02N OMe Step 1.4- (3, 4-Dimethoxyphenoxy)-l-nitrobenzene : To a solution of 3,4- dimethoxyphenol (1.0 g, 6.4 mmol) and 1-fluoro-4-nitrobenzene (700 µL, 6.4 mmol) in anh DMF (20 mL) was added K2CO3 (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 combine organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (Na, S04), and concentrated in vacuo to afford the desired product (0.8 g, 54%). The crude product was carried to the next step without further purification.

Step 2. 4-(3,4-Dimethoxyphenoxy) aniline: A solution of 4- (3,4-dimethoxy- phenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10%

Pd/C (0.100 g) and the resulting mixture was placed under a H2 atmosphere (ballon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celitet and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z 245 (M). B3f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1.3- (3-Pyridinyloxy)-1-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), 1-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 K. C03 (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 combine 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 purifie by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (2.0 g, 32 %). This material was used in the next step without further purification.

Step 2. 3-(3-Pyridinyloxy) aniline: A solution of 3- (3-pyridinyloxy)-1- nitrobenzene (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 H2 atmosphere (ballon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celites and concentrated in vacuo to afford the desired product as a red oil (1.6 g, 94%): EI-MS m/z 186 (M). B3g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 3-(5-Methyl-3-pyridinyloxy)-1-nitrobenzene : To a solution of 3-hydroxy- 5-methylpyridine (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, C03 (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 combine organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purifie by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%).

Step 2.3- (5-Methyl-3-pyridinyloxy)-1-nitrobenzene: A solution of 3- (5-methyl-3- pyridinyloxy)-1-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture was placed under a H, atmosphere (ballon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celiteh and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H) +).

2B3h. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1.5-Nitro-2- (4-methylphenoxy) pyridine: To a solution of 2-chloro-5- nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv) and K2CO3 (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)

and pet ether (25 mL) to give the desired product (7.05 g, 76%): mp 80-82 °C ; TLC <BR> <BR> 930% EtOAc/70% pet ether) Rf 0.79;'H-NMR (DMSO-db) 8 312. (s, 3H), 7.08 (d, J=8.46 Hz, 2H), 7.19 (d, J=9.20 Hz, 1H), 7.24 (d, J=8.09 Hz, 2H), 8.58 (dd, J=2.94, 8.82 Hz, 1H), 8.99 (d, J=2.95 Hz, 1H) ; FAB-MS m/z (rel abundance) 231 ((M+H)-), 100%).

Step 2.5-Amino-2- (4-methylphenoxy) pyridine Dihydrochloride: A solution 5- nitro-2-(4-methylphenoxy) pyridine (6.94 g, 30 mmol, l eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The rection mixture was then placed under a H2 atmosphere and was vigorously stirred for 2.5 h. The rection mixture was filtered through a pad of Celite#. A solution of HCl in EtO 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, 92%): mp <BR> <BR> <BR> 208-210 °C (dec); TLC (50% EtOAc/50% pet ether) Rf 0.42;'H-NMR (DMSO-db) 8 2.25 (s, 3H), 6.98 (d, J=8.45 Hz, 2H), 7.04 (d, J=8. 82 Hz, 1H), 7.19 (d, J=8.09 Hz, 2H), 8.46 (dd, J=2. 57,8.46 Hz, 1H), 8.63 (d, J=2. 57 Hz, 1H); EI-MS m/z (rel abundance) (M', 100%).

B3i. General Method for Substituted Aniline Formation via Nitroarene Formation

Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(3-Thienylethio)-1-nitrobenzene : To a solution of 4-nitrothiophenol (80% pure; 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 °C with stirring for 42 h and then allowed to cool to room temp. The rection mixture was then poured into a mixture of ice and a 6N HCl solution (200 mL) and the resulting aqueous mixture was

extracted with EtOAc (3 x 100 mL). The combine organic layers were sequentially washed with a lM NaOH solution (2 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (MgS04), and concentrated in vacuo. The residual oil was purifie by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS ntlz 237 (M).

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 4- (5-Pyrimininyloxy) aniline: 4-Aminophenol (1.0 g, 9.2 mmol) was dissolve in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1-9 9,13.7 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 rection 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 (MgSO4), and concentrated in vacuo. The residular solids were purifie by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).

B3k. General Method for Substituted Aniline Formation via Nitroarene Formation

Through Nucleophilic Aromatic Substitution, Followed by Reduction 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 rection vessel for 42 h, then allowed to cool to room temp. The rection

mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combine organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95% yield): TLC (10% EtOAc/ 90% hexane) Rf0.57.

Step 2.5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2- methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at-78 °C was added an n- butyllithium 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 rection mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30%; approx. 50 mL). The resulting yellow and slightly turbid rection mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The rection mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a 1N HCI solution then extracted with Et, O (2 x 100 mL). The combine organic layers were dried (Na., S04) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%).

Step 3.4- (5- (2-Methoxy) pyridyl) oxy-1-nitrobenzene: To a stirred slurry of NaH (97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2- methoxypyridine (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 rection mixture 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 (MgS04) and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).

Step 4.4- (5-(2-Methoxv) pyridyl) oxvaniline: 4- (5- (2-Methoxy) pyridyl) oxy-l- nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.

B4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine

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 K2CO3 (16.7 g, 121 mmoles). The rection mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (I OOML). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combine organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), 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 <BR> <BR> <BR> g, 66%): TLC (100 % ethyl acetate) Rf 0.29;'H-NMR (DMSO-d6) 6 415. (s, 2H), 6.64-6.74 (ion, 3H), 7.01 (d, J=4.8,2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8,2H).

2B4b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine

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 rection mixture was heated at 100 °C 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 combine extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2SO4), and concentrated in vacuo.

The resulting oil was purifie by flash chromatography (50 % EtOAc/50% hexane) to afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ( (M+H)-).

B4c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine Step 1. Methyl (4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4- nitroaniline (2.0 g, 13.2 mmol) and K, CO3 (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The rection 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 (Na2SO4) and concentrated under reduced pressure. The residue was purifie by column chromatography (silica gel, gradient from 80% EtOAc/20% hexanes to 100% EtOAc) to afford methyl (4- nitrophenyl)-4-pyridylamine (0.42 g) Step 2. Methyl (4-aminophenyl)-4-pyridylamine: Methyl (4-nitrophenyl)-4- pyridylamine was reduced in a manner analogous to that described in Method B 1.

B5. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene Step 1.4- (4-Butoxyphenyl) thio-1-nitrobenzene: To a solution of 4- (4-nitrophenyl- thio) phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C 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 °C. The rection 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 rection was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with Et2O (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL), dried (MgS04), and concentrated under reduced pressure to give a clear yellow oil, which was purifie 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, 67%): TLC (20% EtOAc/80% hexane) Rf 0.75;'H- <BR> <BR> <BR> NMR (DMSO-d6) 6 920. (t, J= 7.5 Hz, 3H), 1.42 (app hex, J=7.5 Hzz 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 8.09 (d, J= 9 Hz, 2H).

Step 2.4- (4-Butoxyphenyl) thioaniline: 4-(4-Butoxyphenyl)thio-1-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 2): TLC (33% EtOAc/77% hexane) R#O. 38.

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

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 di- tert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The rection 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 nicol, 0.02 equiv) was added and the rection stirred at the reflux temp. for 16 h. The resulting mixture was diluted with Et, O (200 mL), sequentially washed with a

saturated NAHCO,, solution (100 ml), water (100 mL) and a saturated NaCI solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting white solid was purifie 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, 46%): TLC (50% EtOAc/50% hexane) Rf 0.45;'H-NMR <BR> <BR> (DMSO-db) 8 431. (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, J=8. 4 Hz, 2H), 6.80 (d, J=8. 1 Hz, 2H), 7.00 (d, J=8. 4 Hz, 2H), 7.28 (d, J=8. 1 Hz, 2H), 9.18 (br s, 1H); FAB-MS (M+).298 1B7. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction

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 °C. 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 1N NaOH solution, then extracted with Et, O (4 x 100 mL). The combine extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2SO4), and concentrated in vacuo. The residual oil was purifie by MPLC (silica gel; 50 % EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC- MS mlz 214 (M'). 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.

B8. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed bv Reduction

Step 1. 4-(1-Imidazolylmetyl)-1-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 K2CO3 (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 mL). The combine organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (MgSO4), and concentrated in vacuo. The residual oil was purifie by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, 91%) : EI-MS m/z 203 (M').

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

1B9. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compound Followed by Reduction

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

The rection mixture was successively washed with a 10% NaHSO3 solution (50 mL), a saturated K2CO3 solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolve in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolve in MeOH (25 mL) and treated with a 20% aqueous NH3 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-'C'2 (50

mL). The organic layer was dried (MgS04), concentrated under reduced pressure. and<BR> <BR> purifie by column chromatography (80% EtOAc/20% hexane) to afford the desired<BR> <BR> product as a white solid. (0.53 g, :8%) mp 110-118 °C ; TLC (80% EtOAc/20%<BR> <BR> hexane) Rf 0.12; FAB-MS nt/z 367 ((M+H)+, 100%).

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

B10. Formation of 2- (N-methylcarbamoyl) pyridines via the Menisci rection

Step 1.2- (N-methylearbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive rection.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. H. S04 (3.55 mL) (exotherm). To this was added H, O, (17 mL, 30% wt in H20) followed by FeSO4 7H2O (0.55 g) to produce an exotherm. The rection was stirred in the dark at ambient temp for 1 h then was heated slowly over 4 h at 45 °C. When bubbling subside, the rection was heated at 60 °C 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 mlL. The combine organics were dried (MgSO4) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purifie by silica gel chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/ 20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2- (N- methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS;'H NMR (CDCI3): d 8.44 (d, 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, ClCHCN), 3.04 (d.<BR> <P>3H, J = 5.1 Hz. methyl); CI-MS ntlz 171 ( (M+H) +).<BR> <BR> fortheSynthesisof#-SulfonylphenylAnilinesB11.Generalmethod

Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene : To a solution of 4- (4- methylthiophenoxy)-1-ntirobenzene (2 g, 7.66 mmol) in CH, CI2 (75 mL) at 0 °C was slowly added mCPBA (57-86%, 4 g), and the rection mixture was stirred at room temperature for 5 h. The rection mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgSO4), and concentrated under reduced pressure to give 4- (4-methylsulfonylphenoxy)-1- nitrobenzene as a solid (2.1 g).

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

B12. General Method for Synthesis of #-Alkoxy-#-carboxyphenyl Anilines Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-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, C03 (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, absorbe onto silica gel, and purifie by column chromatography (50% EtOAc/50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy)-1- nitrobenzene as a yellow powder (3 g): mp 115 118 °C.

Step 2.4- (3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene: A mixture of 4- (3- methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), 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 dissolve 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 (MgSO4) and concentrated under reduced pressure to give 4- (3-carboxy-4- methoxyphenoxy)-1-nitrobenzene (1.04 g).

C. General Methods of Urea Formation Cla. Rection of a Heterocyclic Amine with an Isocyanate N-(5-tert-Butyl-3-thienyl)-N'-(4-phenoxyphenyl)(5-tert-Butyl -3-thienyl)-N'-(4-phenoxyphenyl) urea: To a solution of 5-tert- 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, S04), and concentrated under reduced pressure.

The resulting off-white solid was recrystallized (EtOAc/hexane) to give a white solid (13.7 g, 88%), which was contaminated with approximately 5% of bis (4- phenoxyphenyl) urea. A portion of this material (4.67 g) was purifie by flash chromatography (9% EtOAc/27% CH2CI,/64% cyclohexane) to afforded the desired product as a white solid (3.17 g).

Clb. Rection of a Heterocyclic Amine with an Isocvanate

N-(3-tert-Butyl-5-isoxazolyl)-N'-(40phenoxyphenyl)urea : To a solution of 5- amino-4-tert-butylisoxazole (8.93 g, 63.7 mmol, 1 eq.) in CH2Cl2 (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 CH, CL, (80 mL). The resulting mixture was poured into water (500 mL) and extracted with Et, O (3 x 200 mL). The organic layer was dried (MgSO4) then concentrated under reduced pressure. The residue was recrystallized (EtOAc) to give the desired product (15.7 g, 70%): mp 182-184 °C ; TLC (5% acetone/95% acetone) R#O. 27;'H-NMR (DMSO-db) 8 231. (s, 9H), 6.02 (s, 1H), 6.97 (dd, J=0. 2,8.8 Hz, 2H), 6.93 (d, J=8. 8 Hz, 2H), 7.08 (t, J=7. 4 Hz, 1H), 7.34 (ion, 2H), 7.45 (dd, J=2. 2,6.6 Hz, 2H), 8.80 (s, 1H), 10.04 (s, 1H); FAB-MS m/z (rel abundance) 352 ((M+H)+, 70%).

Clé. Rection of a Heterocyclic Amine with an Isocyanate N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-methylphenyl)(3-tert-B utyl-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- (4- methylphenoxy) 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 purifie by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, 33%): mp 204 <BR> <BR> <BR> °C; TLC (5% acetone/95% CHCIz) R 0.92;'H-NMR (DMSO-db) 8 1. 2@2 (s, 9H), 2.24 (s, 3H), 5.92 (s, 1H), 6.83 (d, J=8. 4 Hz, 2H), 6.90 (d, J=8. 8 Hz, 2H), 7.13 (d, J=8. 4 Hz, 2H), 7.40 (d, J=8. 8 Hz, 2H), 8.85 (s, 1H), 9.20 (br s, 1H), 11.94 (br s, 1H) ; EI-MS (M+).m/z364 Cld. Rection of a Heterocyclic Amine with an Isocyanate

N-(5-tert-Butyl-3-thienyl)-N'-(2,(5-tert-Butyl-3-thienyl)-N' -(2, 3-dichlorophenyl) urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-tert-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL, 2.02 mmol) in CH, CI, (10 mL) to clarify the mixture and the resulting solution was stirred at room temp. overnight. The rection 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 NaHCO3 solution (15 mL), a 1N HCI solution (15 mL) and a saturated NaCl solution (15 mL), dried (Na, S04), 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, 34%): mp 169-170 °C ; TLC (20% EtOAc/80% hexane) Rf 0.57;'H- <BR> <BR> <BR> NMR (DMSO-d6) 6 311. (s, 9H), 6.79 (s, 1H), 7.03 (s, 1H), 7.24-7.33 (ion, 2H), 8.16 (dd, J=1.84,7.72 Hz, 1H), 8.35 (s, 1H), 9.60 (s, 1H);"C-NMR (DMSO-db) 8 931.

(3C), 34.0,103.4,116.1,119.3,120.0,123.4,128.1,131.6,135.6,138.1,1 51.7,155.2; FAB-MS abundance)343((M+H)+,83%),345((M+H+2)+,56%),347(rel ((M+H+4)+,12%).

Cle. Rection of a Heterocyclic Amine with an Isocyanate N-(3-tert-Butyl-5-pyrazolyl)-N'-(3,(3-tert-Butyl-5-pyrazolyl )-N'-(3, 4-dichlorophenyl) urea: A solution of 5-amino- 3-tert-butyl-N'-(tert-butoxycarbonyl)(tert-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, CL, (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 NaHC03 solution (10 mL) and a NaCI solution (5 mL), dried (Na., SO), and concentrated in vacuo. The residue was purifie by flash chromatography (gradient from 40% EtOAc/60% hexane to 55% EtOAc/ 5% hexane) to give the desired product (0.102 g, 48%): mp 182-184 °C ; TLC (40% EtOAc/60% hexane) Rf 0.05, FAB-MS m/z 327 ((M+H)+).

C2a. Rection of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then

Rection with Substituted Aniline

Step 1.3-tert-Butyl-5-isoxazolyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CH.-C'2 (20 mL) at 0 °C 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.

Step 2. N- (3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinylthio) phenyl) urea: The crude 3-tert-butyl-5-isoxazolyl isocyanate was suspende 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, Cl, solution (4: 1,125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting yellow oil was purifie by column chromatography (silica gel, gradient from 2% MeOH/98% CH, CL, to 4% MeOH/6% CH2Cl2) to afford a foam, which was triturated (Et, O/hexane) in combination with sonication to give the product as a white powder (0.18 g, 49%): TLC (5% MeOH/95% CHANCI,) Rf 0.21;'H-NMR (DMSO-d6) 8 231. (s, 9H), 6.06 (s, 1H), 6.95 (d, J=5 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 8.32 (d, J=5 Hz 2H), 9.13 (s, 1H), 10.19 (s, 1H) ; FAB-MS m/z 369 ( (M+H) +).

C2b. Rection of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed

bv Rection with Substituted Aniline

Step 1.5-tert-Butyl-3-isoxazolyl Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CH2C12 (1 L) was added 3-amino-5-tert- 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 h), then mixture was concentrated in vacuo. The residue was dissolve 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 (Mt).

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 NaCI solution (100 mL), dried (MgS04), and concentrated in vacuo. The resulting material was purifie by MPLC (2 x 300 g silica gel, 30 % EtOAc/70% hexane) to afford the desired product as a <BR> <BR> <BR> white solid (8.24 g, 90 %): mp 178-179 °C ;'H-NMR (DMSO-db) 8 281. (s, 9H), 6.51 (s, 1H). 6.96 (d, J=6.25 Hz, 2H), 7.52 (d, J=8.82 Hz, 2H), 7.62 (d, J=8. 83 Hz. 2H), 8.33 (d, J=6.25 Hz, 2H), 9.10 (s, 1H), 9.61 (s, 1H) ; EI-MS nilz 368 (M-).

C2c. Rection of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed

by Rection with Substituted Aniline

N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy)(3-tert-B utyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy) phenyl) urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH, C'2 (13 mL) at 0 °C was slowly added pyridine (0.105 mL) was added slowly over a 5 min, then 4-(4- pyridinyloxy) 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 °C for l h, then was allowed to warm to room temp. over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspende 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 rection mixture was heated at 70 °C for 12 h forcing a white precipitate. The solids were dissolve in a 1NHCl solution and allowed to stir at room temp. for 1 h to form a new precipitate. The white solid was washed (50% Et2O/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 °C dec; TLC (10% MeOH/90% <BR> <BR> CHCl3) Rf 0.239;'H-NMR (DMSO-db) 8 241. (s, 9H), 5.97 (s, 1H), 6.88 (d, J=6. 25 Hz, 2H), 7.10 (d, J=8.82 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 8.43 (d, 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%). C3a. Rection of a Heterocyclic Amine with N,N'-Carbonyldiimidazole Followed by Rection with a Substituted Aniline

C3b.

N (3-tert-Butyt-1-methyl-5-pyrazolyl)-N'- (4- (4-pyridinyloxy) phenyl) urea: To a solution of 5-amino-3-tert-butyl-1-metylpyrazole (189 g, 1.24 mol) in anh. CH, CI, (2.3 L) was added N,N'-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The mixture was allowed to stir at ambient temperature for 5 h before adding 4- (4- pyridinyloxy) aniline. The rection 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, O (8 L) and a saturated NaCI solution (4 L). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purifie by crystallization (44.4% EtOAc/44.4% Et2O/00. 2% hexane, 2.5 L) to afford the desired urea as a white <BR> <BR> <BR> solid (230 g, 51%): mp 149-152 °C ;'H-NMR (DMSO-d6) 6 181. (s, 9H), 3.57 (s, 3H), 6.02 (s, 1H), 6.85 (d, J=6. 0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 8.40 (d, J=6. 0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H); FAB-LSIMS m/z 366 ((M+H)+).

Rection of a Heterocyclic Amine with N,N'-Carbonyldiimidazole Followed by Rection with a Substituted Aniline N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(4-pyridinylthio)(3-tert- Butyl-5-pyrazolyl)-N'-(3-(4-pyridinylthio) phenyl) urea: To a solution of 5-amino-3-tert-butyl-N1-(tert-butoxycarbonyl) pyrazole (0.282 g, 1.18 mmol) in CH, C12 (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 rection solution in one aliquot and the resulting mixture was allowed to stir at room temp. for 1 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 (MgS04), 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 rection mixture was made basic with a saturated NaHCO3 solution, then extracted with CH, CL, (3 x 15 mL). The combine organic layers were dried <BR> <BR> <BR> (Mgso,) and concentrated in vacuo. The residue was purifie by flash chromatography (5% MeOH/95% CH2Cl2). The resulting brown solid was triturated with sonication (50% Et2O/50% pet. ether) to give the desired urea (0.122 g, 28%): <BR> <BR> <BR> mp >224 °C dec; TLC (5% MeOH/95% CHCI3) Rf 0.067;'H-NMR (DMSO-db) 8 1.23 (s, 9H), 5.98 (s, 1H), 7.04 (dm, J=13. 24 Hz, 2H), 7.15-7.19 (m, 1H), 7.40-7.47 (m, 2H), 7.80-7.82 (m, 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 (M', 100%).

C4a. Rection of Substituted Aniline with N,N"-Carbonyldiimidazole Followed by

Rection with a Heterocyclic Amine

N (3-tert-Butyl-1-methyl-5-pyrazolyl)-N'- (4- (4-pyridinylmethyl) phenyl) urea: To a solution of 4- (4-pyridinylmethyl) aniline (0.200 g, 1.08 mmol) in CH2CI2 (10 mL) was added N, 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 rection mixture was then treated with 5-amino-3-tert-butyl-1- methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 °C overnight. The rection mixture was cooled to room temp and purifie by column chromatography (gradient from 20% acetone/80% CH2CI2 to 60% acetone/40% CHZCl2) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, 58%): TLC (4% <BR> <BR> <BR> MeOH/96% CH, C'2) Rf 0.15;'H-NMR (DMSO-db) 8 191. (s, 9H), 3.57 (s, 3H), 3.89 (s, 2H), 6.02 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 8.45-8.42 (ion, 3H), 8.81 (s, 1H); FAB-MS m/z 364 (M+H)+).

C4c.

C4b. Rection of Substituted Aniline with N, N'-Carbonyldiimidazole Followed b Rection with a Heterocvclic Amine 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 1 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 CH, CL, (3 x 50 mL). The combine organic layers were concentrated under reduced pressure and dissolve in a minimal amount of CH, Cl,. Petroleum ether was added and resulting white precipitate was resubmitted to the crystallization protocol to afford the desired product (0.015 g, 4%): mp 110-111 °C ; TLC (5% acetone/95% CH, Cl,) Rf 0.05;'H-NMR (DMSO-d6) 8 241.

(s, 9H), 5.97 (s, 1H), 7.00-7.04 (m, 1H), 7.21-7.44 (m, 4H), 7.68 (d, J=5.5 Hz, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.70 (s, 1H), 8.95 (s, 1H), 9.34 (br s, 1H), 11.98 (br s, 1H) ; EI- MS m/z 408 (M').

Rection of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Rection with Substituted Aniline N (5-tert-Butyl-3-thienyt)-N'- (4- (4-pyridinyloxy) phenyl) urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH2Cl2 (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, CL, (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

C5.

residue was dissolved in CH, CL. (5 mL), then treated with 5-tert- <BR> <BR> <BR> <BR> 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 NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% EtOAc/70% hexane to 100% EtOAc) to give the desired product (0.38 g, 97%): TLC (50% <BR> <BR> <BR> <BR> EtOAc/50% hexane) Rf 0.13;'H-NMR (CDCl3) 6 1.26 (s, 9H), 6.65 (d, J=1.48 Hz, 1 H), 6.76 (dd, J=1. 47,4.24 Hz, 2H), 6.86 (d, J=1.47 Hz, 1 H), 6.91 (d, J=8.82 Hz, 2H), 7.31 (d, J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, J=1.47 Hz, 2H) ; 13C-NMR <BR> <BR> <BR> <BR> (CDCl3) 6 32.1 (3C), 34.4,106.2,112.0 (2C), 116.6,121.3 (2C), 121.5 (2C), 134.9, 136.1,149.0,151.0 (2C), 154.0,156.9,165.2; FAB-MS m/z (rel abundance) 368 ((M+H)+,100%).

(s, 3H), 3.86 (s, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.34 (m, 2H), 7.51 (d, J=7.3 Hz, lH), 7.76 (m, 3H), 8.89 (s, lH), 9.03 (s, lH); HPLC ES-MS m/z 362 ( (M+H)-).

C6. General Method for Urea Formation by Curtius Rearrangement and Carbamate Trapping Step 1.5-Methyl-2- (azidocarbonyl) thiophene: To a solution of 5-Methyl-2- thiophenecarboxylic acid (1.06 g, 7.5 mmol) and Et3N (1.25 mL, 9.0 mmol) in acetone (50 mL) at-10 °C was slowly added ethyl chloroformate (1.07 mL, 11.2 mmol) to keep the interna temperature below 5 °C. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the rection mixture was stirred for 2 h at 0 °C.

The resulting mixture was diluted with CH, C'2 (10 mL) and washed with a saturated NaCl solution (10 mL). The aqueous layer was back-extracted with CH, C'2 (10 mL), and the combine organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purifie by column chromatography (10% EtOAc/90% hexanes) to give the azidoester (0.94 g, 75%). Azidoester (100 mg, 0.6 mmol) in anhydrous toluene (10 mL) was heated to reflux for 1 h then cooled to rt. This solution was used as a stock solution for subsequent rections.

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 rections. Step3. N-(5-tert-Butyl-3-isoxazolyl)-N'-(5-methyl-2-thienyl)(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.

was added 3-amino-5-tert-butylisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The rection mixture was diluted with EtOAc (50 mL) and sequentially washed with a 1 N HCI solution (2 x 25 mL) and a saturated NaCI solution (25 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purifie by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, 93%): mp 200-201 °C ; TLC (20% EtOAc/80% hexane) Rf 0.20; EI-MS m/z 368 (M+).

C7. General Methods for Urea Formation by Curtius Rearrangement and Isocyanate Trapping

Step 1.3-Chloro-4,4-dimethylpent-2-enal: PORC13 (67.2 mL, 0.72 mol) was added to cooled (0 °C) DMF (60.6 mL, 0.78 mol) at rate to keep the internal temperature below 20 °C. The viscous slurry was heated until solids melted (approximately 40 °C), then pinacolone (37.5 mL, 0.30 mol) was added in one portion. The rection 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 (Na2SO4) and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH, C12) to give the desired aldehyde as an orange oil (15.5 g, 35%): TLC (5% EtOAc/95% hexane) Rf0. 54;'H NMR (CDC13) d 1.26 (s, 9H), 6.15 (d, J=7.0 Hz, 1H), 10.05 (d, J=6.6 Hz, 1H).

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 Na2S (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

treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids.

The rection mixture was stirred at room temp. for 1.5 h, then treated with a I N HCI 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 l N HCI solution (200 mL), water (2 x 200 mL) and a saturated NaCI solution (200 mL), dried (Na, S04) and concentrated under reduced pressure. The residue was purifie using column chromatography (5% EtOAc/95% hexane) to afford the desired product (0.95 <BR> <BR> <BR> g, 36%): TLC (20% EtOAc/80% hexane) Rf 0.79;'H NMR (CDCI3) 8 1. 39 (s, 9H), 3.85 (s, 3H), 6.84 (d, J=3.7 Hz, 1H), 7.62 (d, J=4.1 Hz, 1 H); GC-MS m/z (rel abundance) 198 (M-, 25%).

Step 3.5-tert-Butyl-2-thiophenecarboxylic acid: Methyl 5-tert-butyl-2- thiophenecarboxylate (0.10 g, 0.51 mmol) was added to a KOH solution (0.33 M in 90% 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 rection 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 (Na2SO4), and concentrated under reduced pressure (0.4 mmHg) to give the desired carboxylic acid as a yellow solid (0.067 g, 73%): TLC (20% EtOAc/79.5% hexane/0.5% AcOH) Rt 0.29;'H NMR (CDC13) 6 411. (s, 9H), 6.89 (d, J=3.7 Hz, 1H), 7.73 (d, J=3.7 Hz, 1H), 12.30 (br s,<BR> <BR> 1H); 13C NMR (CDCl3) 6 132. (3C), 35.2,122.9,129.2,135.1,167.5,168.2.

Step4. N-(5-tert-Butyl-2-thienyl)-N'-(2,(5-tert-Butyl-2-thienyl)-N' -(2, 3-dichlorophenyl) urea: A mixture of 5- tert-butyl-2-thiophenecarboxylic acid (0.066 g, 0.036 mmol), DPPA (0.109 g, 0.39 mmol) and Et3N (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 rection 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 HCI solution (3 x 50 mL), a saturated NaHC03 solution (50 mL), and a saturated NaCI solution (50 mL), dried (Na, SO4), and concentrated under reduced pressure. The residue was purifie by column chromatography (5% EtOAc/95% hexane) to afford the desired urea as a purple solid (0.030 g, 24%): TLC (10% EtOAc/90% hexane) Rf0. 28;'H NMR (CDC13) 6 341. (s, 9H), 6.59 (br s, 2H), 7.10-7.13 (ion, 2H),<BR> 7.66 (br s, 1H), 8.13 (dd, J=2.9,7.8 Hz, 1H) ;'3C NMR (CDC13) 6 232. (3C), 34.6, 117.4,119.0', 119.15,119.2,121.5,124.4,127.6,132.6,135.2,136.6,153.4; HPLC ES-MS m/z (rel abundance) 343 ((M+H)+, 100%), 345 ((M+H+2)+, 67%), 347 ( (M+H+4)', 14%).

C8. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolve in dichloroethane (0.10 M). 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 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 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 purifie by reverse phase HPLC.

D. Misc. Methods of Urea Synthesis D1. Electrophylic Halogenation N-(2-Bromo-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl)(2-Bro mo-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl) urea: To a slurry of N- (5- tert-butyl-3-thienyl)-N'- (4-methylphenyl) urea (0.50 g, 1.7 mmol) in CHCl3 (20 mL) at

room temp was slowly added a solution of Br, (0.09 mL, 1.7 mmol) in CHOC'3 (10 mL) via addition funnel causing the rection mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete rection. The rection was concentrated under reduced pressure, and the residue triturated (2 x Et2O/hexane) to give the brominated product as a tan powder (0.43 g, 76%): mp 161- 163 °C ; TLC (20% EtOAc/80% hexane) Rf 0. 71;'H NMR (DMSO-db) 8 291. (s, 9H), 2.22 (s, 3H), 7.07 (d, J=8.46 Hz, 2H), 7.31 (d, J=8.46 Hz, 2H), 7.38 (s, 1H), 8.19 (s, 1H), 9.02 (s, 1H) ;'3C NMR (DMSO-db) 8 3,31.620. (3C), 34.7,89.6,117.5,118.1 (2C), 129.2 (2C), 130.8,136.0,136.9,151.8,155.2; FAB-MS m/z (rel abundance) 367 ( (M+H)-, 98%), 369 (M+2+H) +, 100%).

D2. #-AlkoxyUreasof Step 1. N- (5-tert-Butyl-3-thienyl)-N'-(4-(4-hydroxyphenyl) oxyphenyl) urea: A solution of N (5-tert-butyl-3-thienyl)-N'- (4- (4-methoxyphenyl) oxyphenyl) urea (1.2 g, 3 mmol) in CH, C'2 (50 mL) was cooled to-78 °C and treated with BBr3 (1.0 M in CH, C12) 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 dissolve in EtOAc (50 mL), then washed with a saturated NaHCO3 solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purifie via flash chromatography (gradient from 10% EtOAc/90% hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan <BR> <BR> <BR> foam (1. 1 g, 92%): TLC (20% EtOAc/80% hexane) Rf 0.23;'H NMR (DMSO-d6) 6<BR> <BR> <BR> 1. 30 (s, 9H), 6.72-6.84 (ion, 7H), 6.97 (d, J=1.47 Hz, 1H), 7.37 (dm, J=9.19 Hz, 2H), 8.49 (s, 1H), 8.69 (s, 1H), 9.25 (s, 1H); FAB-MS m/z (rel abundance) 383 ((M+H)+, 33%).

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, 0.5 mmol) and Cs2CO3 (0.18 g, 0.55 mmol, 1.1 equiv) in reagent grade acetone (10 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 rection was cooled, filtered, and the solids were washed with EtOAc. The combine organics were concentrated under reduced pressure, and the residue was purifie via preparative HPLC (60% CH3CN/40% H, O/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, 73%): mp 155-165 °C ; TLC (20% EtOAC/80% hexane) Rf0. 40;'H- NMR (DMSO-d6) 6 301. (s, 9H), 1.30 (t, J=6.99 Hz, 3H), 3.97 (q, J=6.99 Hz, 2H), 6.80 (d, J=1.47 Hz, 1H), 6.86 (dm, J=8.82 Hz, 2H), 6.90 (s, 4H), 6.98 (d, J=1.47, 1H), 7.40 (dm, J=8.83 Hz, 2H), 8.54 (s, 1H), 8.73 (s, 1H); 13C-NMR (DMSO-d6) # 7,14. 32.0 (3C), 33.9,63.3,102.5,115.5 (2C), 116.3,118.4 (2C), 119.7 (2C), 119.8 (2C), 135.0,136.3,150.4,152.1,152.4,154.4,154.7; FAB-MS m/z (rel abundance) 411 ( (M+H)-, 15%).<BR> <BR> <P> D3. Synthesis of w-Carbamoyl Ureas N (3-tert-Butyl-1-methyl-5-pyrazolyl)-N'- (4- (4- acetaminophenyl) methylphenyl) urea: To a solution of N-(3-tert-butyl-1-methyl-5- pyrazolyl)-N'- (4- (4-aminophenyl) methylphenyl) urea (0.300 g, 0.795 mmol) in CH, CL, (15 mL) at 0 °C was added acetyl chloride (0.057 mL, 0.795 mmol), followed by anhydrous Et3N (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 HCl solution (125 mL) then water (100 mL), dried (MgS04), and concentrated under reduced pressure. The resulting residue was

purifie by filtration through a pad of silica (EtOAc) to give the desired product as a <BR> <BR> white solid (0.160 g, 48%): TLC (EtOAc) Rf0. 33;'H-NMR (DMSO-d6) 6 171. (s, 9H), 1.98 (s, 3H), 3.55 (s, 3H), 3.78 (s, 2H), 6.00 (s, 1H), 7.07 (d, J=8.5 Hz, 2H), 7.09 (d, J=8. 5 Hz, 2H), 7.32 (d, J=8. 5 Hz, 2H), 7.44 (d, J=8. 5 Hz, 2H), 8.38 (s, 1H), 8.75 (s, 1H), 9.82 (s, 1H) ; FAB-MS m/z 420 ((M+H)+).

D4. General Method for the Conversion of Ester-Containing Ureas into Alcool- ContainingUreas N-(N'-(2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,(N'-( 2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2, 3-dichlorophenyl) urea: A solution of N (N'- (2- (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, SN in water, 4.0 mmoles) in EtOH (7 mL) was heated at65 °C for 3 h at which time TLC indicated complete rection. The rection mixture was diluted with EtOAc (25 mL) and acidifie with a 2N HCI solution (3 mL). The resulting organic phase was washed with a saturated NaCI solution (25 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized (EtO) to afford the desired product as a white solid (0.17 g, 64 %): TLC (60% EtOAc/40% hexane) Rf 0.16;'H-NMR (DMSO-d6) 6 231. (s, 9H), 3.70 (t, J=5. 7 Hz, 2H), 4.10 (t, J=5. 7 Hz, 2H), 6.23 (s, 1H), 7.29-7.32 (ion, 2H), 8.06-8.09 (m, 1H), 9.00 (br s, 1H), 9.70 (br s, 1H) ; FAB-MS m/z (rel abundance) 3 71 ( (M+H)', 100%).

Dosa. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas

Step 1. N-(N1-(Carboxymethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,3- dichlorophenl) urea: A solution of N-(N'-(ethoxycarbonylmethyl)-3-tert-butyl-5- pyrazolyl)-N'- (2,3-dichlorophenyl) urea (prepared as described in Method A3,0.46 g, 1. 11 mmoles) and NaOH (1.2 mL, SN in water, 6.0 mmoles) in EtOH (7 mL) was stirred at room temp. for 2 h at which time TLC indicated complete rection. The rection mixture was diluted with EtOAc (25 mL) and acidifie with a 2N HCI solution (4 mL). The resulting organic phase was washed with a saturated NaCI solution (25 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized (Et2O/hexane) to afford the desired product as a white solid <BR> <BR> <BR> <BR> (0.38 g, 89%): TLC (10% MeOH/90% CH2CI2) Rf 0.04;'H-NMR (DMSO-d6) 6 211.

(s, 9H), 4.81 (s, 2H), 6.19 (s, 1H), 7.28-7.35 (m, 2H), 8.09-8.12 (m, 1H), 8.76 (br s, 1H), 9.52 (br s, IH); FAB-MS m/z (rel abundance) 385 ( (M+H)-, 100%).

Step 2. N- (N'-((Methylcarbamoyl) methyl)-3-tert-buty1-5-pyrazolyl)-N'-(2, 3- dichlorophenyl) urea: A solution of N-(N1-(carboxymethyl)-3-tert-butyl-5- <BR> <BR> <BR> pyrazolyl)-N'- (2,3-dichlorophenyl) urea (100 mg, 0.26 mmole) and Non'- carbonyldiimidazole (45 mg, 0.28 mmole) in CH. CI2 (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CH2Cl2) Rf0. 81). Dry methylamine hydrochloride (28 mg, 0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The rection mixture was stirred at room temp. overnight, then diluted with CH2Cl2, washed with water (30 mL), a saturated NaCl solution (30 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purifie by column chromatography (gradient from 10% acetone/90% CH, CL, to 40% acetone/60% CH, C12) and the residue was crystallized (Et2O/hexane) to afford the desired product (47 mg, 46%): TLC (60% acetone/40% CH2Cl2) Rf 0.59;'H-NMR <BR> <BR> (DMSO-db) 8 201. (s, 9H), 2.63 (d, J=4.5 Hz, 3H), 4.59 (s, 2H), 6.15 (s, 1H), 7.28-

7.34 (m, 2H), 8.02-8.12 (m, 2H), 8.79 (br s, IH), 9.20 (br s, 1 H); FAB-MS m/z (rel abundance) 398 ( (M+H) +, 30%).

D5b. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas Step 1. N- (5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-carboxyphenyl) oxyphenyl) urea: To a solution ofN- (5-tert-butyl-3-isoxazolyl)-N'- (4- (4-ethoxyoxycarbonylphenyl)- oxyphenyl) urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added a IM 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.

Step 2. N (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4- (N methylcarbamoyl)- phenyl) oxyphenyl) urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4- carboxyphenyl) 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 1 M citric acid solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combine extracts were sequentially washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (Na, SO ;), filtered, and concentrated in vacuo. The resulting crude oil was purifie by flash chromatography

(60 % EtOAc/40% hexane) to afford the desired product as a white solid (42 ma.

40%): 409((+H)+).m/z D6. General Method for the Conversion of o-Amine-Containing Ureas into Amide- Containing Ureas N (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-aminopheoyl) oxyphenyl) urea: To a solution of N- (5-tert-butyl-3-isoxazolyl)-N'-(4-(4-tert-butoxyCarbonylamin ophenyl) oxy- phenyl)-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 conc 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 combine organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product as a white solid (26 mg, 66%). EI-MS m/z 367 ( (M+ H)').

D7. General Method for the Oxidation of Pyridine-Containing Ureas N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(N-oxo-4-pyridinyl)(5-te rt-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 CHOC'3 (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mrnol) and the resulting solution was stirred at room temp for 16 h. The rection mixture was then treated with a saturated K, CO, solution (10 mL). After 5 min, the solution was diluted with CHOC'3 (50 mL). The organic layer was washed successively with a saturated aqueous NaHS03 solution (25 mL), a saturated NaHC03 solution (25 mL) and a saturated NaCI solution (25 mL), dried (MgSO4), and concentrated in

vacuo. The residual solid was purifie by MPLC (15% MeOH/85% EtOAc) to give the N-oxide (0.082 g, 79%).

D8. General Method for the Acylation of a Hydroxy-Containing Urea N (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-acetoxyphenyloxy) phenyl) urea: To a solution of N-(5-tert-butyl-3-isoxazoly)-N'-(4-(4-hydroxyphenyloxy) phenyl) urea (0.100 g, 0.272 mmol), N,N-dimethylaminopyridine (0.003 g, 0.027 mmol) and Et3N (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 dissolve in EtOAc (10 mL). The resulting solution was sequentially washed with a 5% citric acid solution (10 mL), a saturated NaHCO3 solution (10 mL) and a saturated NaCI solution (10 mL), dried (Na, S04), and concentrated under reduced pressure to give an oil which slowly solidifie to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmHg): TLC (40% EtOAc/60% hexane) Rf 0.55; FAB-MS ((M+H)+).410 D9. Synthesis of w-Alkoxypyridines 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, CL, (30 mL) was allowed to stir overnight at room temp., then was to 40 °C for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purifie by column chromatography (gradient from 80% EtOAc/20% hexans to 15% MeOH/85% EtOAc) to give the desired product (0.87 g, 75%): mp 175-180 °C ; TLC (80% EtOAc/20% hexane) Rf0. 05; FAB-MS m/z 369 ( (M+H)-, 100%).

Step 2. N- (5-tert-Butyl-3-isoxazolyl)-N'-(4-(5-(2-Ethoxy) pyridyl) oxyphenyl) urea: A slurry of N- (5-terr-butyl-3-isoxazolyl)-N'- (4- (2 ( 11-pyridinon-5-yl) oxyphenyl) urea (0.1 g, 0.27 mmol) and A92COI (0.05 g, 0.18 mmol) in benzene (3 mL) was stirred at room temp. for 10 min. Iodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The rection mixture was allowed to cool to room temp., and was filtered through a plug of Celitet then concentrated under reduced pressure. The residue was purifie by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, 38%): mp 146 °C ; TLC (40% EtOAc/60% hexane) Rf 0.49; FAB-MS m/z 397 ((M+H)+, 100%).

D10. Reduction of an Aldehyde-or Ketone-Containing Urea to a Hydroxide- Containing Urea 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- (l- acetylphenyl) oxyphenyl) urea (prepared in a manner analogous to that described in Methods B1 and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH4 (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 combine organic layers were washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (MgS04), and concentrated in vacuo. The resulting white solid was purifie by trituration (Et20/hexane) to afford the desired product (0.021 g,

32 %): mp 80-85 °C ;'H NMR (DMSO-d6) 6 261. (s, 9H), 2.50 (s, 3H), 4.67 (m. I H), 5.10 (br s. 1H), 6.45 (s, 1H), 6.90 (m, 4H), 7.29 (d, J=9.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 8.76 (s, lH), 9.44 (s, lH); HPLC ES-MS m/z 396 ((M+H)+).

911. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy- Substituted Ureas N (5-tert-Butyl-3-isoxazolyl)-N'- (4- (3- (benzyloxycarbonylamino) phenyl)- oxyphenyl) urea: To a solution of the N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(3- carboxyphenyl) 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 50 mL). The combine organic layers were washed with water (3 x 50 mL) and a saturated NaCI (2 x 50 mL), dried (Na2SO4), and concentrated in vacuo. The crude oil was purifie by column chromatography (30% EtOAc/70% hexane) to afford the <BR> <BR> <BR> desired product as a white solid (0.7 g, 60 %): mp 73-75 °C ;'H NMR (DMSO-d6) 6 1.26 (s, 9H), 5.10 (s, 2H), 6.46 (s, 1H), 6.55 (d, J=7.0 Hz, 1H), 6.94 (d, J=7.0 Hz, <BR> <BR> <BR> 2H), 7.70 (ion, 7H), 8.78 (s, 1H), 9.46 (s, 1H), 9.81 (s, 1H); HPLC ES-MS nilz 501 ((M+H)+).

The following compounds have been synthesized according to the General Methods listed above: Table 1. 5-Substituted-3-isoxazolyl Ureas Mass mp TLC Solvent Spec. Synth. En R'R- (°C) R S stem Source Method t-Bu AOA 148-352 Clc /\/149 (M+H) + FAB 2 t-Bu 176-0.16 5% 386 C2b \=/< 177 MeOH/ (M+H) + 95% [FAB] CH2C12 3 t-Bu 0.50 30% 400 C2b EtOAc/ (M+H) + /\ O \/Me 70°/a [HPLC hexane ES-MU 4 t-Bu 156-0.50 30% 366 C2b 157 EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 5 t-Bu Me 0.80 40% 492 C2b /\ O \/Me EtOAc/ (M+H) + Me Et 60% [HPLC Me Et hexane ES-MS] 6 t-Bu HZ 190-0.15 30% 350 (M+) C2b CN 191 EtOAc/ [EI] 70% hexane 7 t-Bu 0.55 20% 352 C2b w 0 EtOAci (M+H) + 80% [FAB] hexane 8 t-Bu AS\ 0.25 20% 367 (M+) C2b /EtOAc/ [EI] 80% hexane 9 t-Bu 0 0.15 20% 363 (M+) C2b Ph EtOAc/ [EIJ 80% hexane 10 t-Bu Me 0.30 20% 381 (M+) C2b EtOAc/ [EI] 80% hexane I 1 t-Bu N w 0. 2s 30% 425 B3b, C2b S-- I EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 12 t-Bu 175-0.25 30% 409 B3a, Step 177 EtOAc/ (M+H) + 1, B3b 0--, I-70% [HPLC Step 2, S. hexane ES-MS1 C2b 13 t-Bu h o _ 035 30% 402 B3b, C2b EtOAc/ (M+H) + 70% [HPLC hexane _ ES-MSl 14 t-Bu 0.20 30% 403 B3b, C2b \ EtOAc/ (M+H) + 70% [HPLC hexane ES-MS 15 t-Bu hS n 0.25 30% 419 B3b, C2b EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 16 t-Bu s 0.20 30% 419 B3b, C2b EtOAc/ (M+H) + 70% [HPLC hexane ES-MS 17 t-Bu < 0.40 30% 352 C2b EtOAc/ (M+H) + On 70% [HPLC hexane ES-MS 18 t-Bu 0.40 30% 365 (M+) C2b EtOAc/ [EI] OS 70% hexane 19 t-Bu AOH 0. 15 30% 367 (M+) E3a, C2b EtOAc/ [EI] D2 Step 1 70% hexane 20 t-Bu S Me 200-0.20 20% 280 C6 201 EtOAc/ (M+H) + 80% [FAB] hexane 21 t-Bu (M+) B4a, C2b 179 [EI] 22 t-Bu H N 164-0.25 30% 351 B1, C2b /165 EtOAc/ (M+H) + 70% [FAB] hexane 23 t-Bu I-IZ N 170-0.15 30% 351 B7, Bl, wCt 172 EtOAc/ (M+H) + C2b 70% [FAB] hexane 24 t-Bu 179-0.20 30% 387 C2b 182 EtOAc/ (M+H) + 70% [FAB] hexane 2 t-Bu 0 055 40% 410 B3b. C2b, 0 EtOAc ; (M+H)-D2 Step 1, Me 60% [FAB] D8 hexane 26 t-Bu Me 176-0.55 25% 366 B3a, C2b EtOAc/ (M+H) + 75% [FAB] hexane 27 t-Bu Me 0.40 25% 366 B3a, C2b EtOAc/ (M+H) + /\ O \/75% [FAB] hexane 28 t-Bu Me 150-0.45 25% 380 B3a. C2b 158 EtOAc/ (M+H) + ---O-O Me 75% [FAB] hexane 29 t-Bu HO 0.30 25% 368 C2b EtOAc/ (M+H) + 75% [FAB] hexane 30 t-Bu ci 118-0.50 25% 420 B3a Step 122 EtOAc/ (M+H) + 1, B3b _. OCI 75% [FAB] Step 2, hexane C2b 31 t-Bu \ 195-0.30 25% 397 (M+) C2b 197 EtOAc/ [FAB] 75% hexane 32 t-Bu Me 0.80 25% 366 B3a, C2b EtOAc/ (M+H) + wOt 75% [FAB] hexane 33 t-Bu 0 OMe 1S5-0.55 30% 382 B3a, C2b 156 EtOAc/ (M+H) + 70% [FAB] hexane 34 t-Bu FR/=\ 137-0=62 25% 410 B3a, C2b, 141 EtOAc/ (M+H) + D2 75% [FAB] hexane 35 t-Bu OPr-i 164-0. 60 25% 410 B3a, C2b, 166 EtOAc/ (M+H) + D2 75% [FAB] hexane 36 t-Bu OH 78-80 0.15 25% 368 C2b EtOAc/ (M+H) + /\ O \/75% [FAB] hexane 37 t-Bu S 167-374 B3i, B I, S 169 (M+H) + C2b FAB 38 t-Bu 200 0.30 5% 396 B3a Step -dec MeOH/ (M+H) + 2, C2b 0. 5% (FAB] AcOH/ 94. 5% CH2CI2 39 t-Bu CO, H 234 0.30 5% 396 B3a Step dec MeOH. (M+H) 2. C2b 0. 5% [FAB] AcOH ! 94.5% CH2C12 40 t-Bu H 203-0.35 10% 340 B8. B2b. C-N N 206 MeOH (M+H) + C2b 0. 5% [FAB] AcOH/ 89. 5°/a EtOAc 41 t-Bu O 177-419 B8. B2b, /\ H'-\ 180 (M+H) + C2b Ji [FAB] O 42 t-Bu 158-0.25 30% 369 B4a, C2b 159 EtOAc/ (M+H) + 70% FAB hexane 43 t-Bu CF3 180-0.15 30% 437 B4a, C2b 181 EtOAc,' (M+H) + 70% [FAB] hexane 44 t-Bu 140-0.25 20% 396 B3a, C2b, 142 EtOAc/ (M+H) + D2 80% [FAB] hexane 45 t-Bu N 68-71 0.30 50% 370 B4a, C2b /\ S.\ EtOAc/ (M+H) + 50% [FAB] hexane 46 t-Bu N 183-0.30 30% 403 C2b eS <CI 186 EtOAc/ (M+H) + 70% [CI] hexane 47 t-Bu 25 10% 454 C2b 101 EtOAc,, (M+H) + F3C 90% [FAB] texane 48 t-Bu O 163-0. 25 20% 394 B1, C2b /166 EtOAc/ (M+H) + Me gpo [FAB] hexane 49 t-Bu 144-0.25 20% 399 C2b O SMe 147 EtOAc/ (M+H) + 80% [FAB] hexane 50 t-Bu 155-0.25 40% 383 C2b 157 EtOAc/' (M+H) + N 60% [FAB] hexane 51 t-Bu 162-0.35 25% 386 C2b 164 EtOAc/ (M+H) + 75% [FAB] hexane 52 t-Bu 149-0. 1 382 C2b S Me I50 EtOAc ! (M-H) 85% [FAB] hexane 53 t-Bu N 77-80 0.30 30% 408 (M+) B3e, C2b EtOAc/ [EI] 70% hexane 54 t-Bu 162-0.17 40% 354 B3j, C2b 164 EtOAc/ (MH) + 60% [FAB] hexane 55 t-Bu N 73-76 0.20 30% 368 (M+) B2, C2b \/EtOAc/ [EI] 70% hexane 56 t-Bu MeO 73-75 0.15 25% 428 B2, C2b EtOAc/ (M+H) + \/75°/a [FAB] OMe hexane 57 t-Bu 143-0.25 30% 398 B3e, C2b 145 EtOAc/ (M+H) + 70% [FAB] hexane 58 t-Bu 25 30% 428 B3e, C2b vSw OMe 151 EtOAc/ (M+H) + OMe 70% [FAB) hexane 59 t-Bu 0.30 100% 353 B4b, C3b EtOAc (M+H) + FAB 60 t-Bu 126-0.25 30% 412 B3e, C2b 129 EtOAc/ (M+H) + OMe 70% [FAB] hexane 61 t-Bu/\ 201-0.25 10% 396 B3a, C2b, 204 EtOAc/ (M+H) + D2 OEt 90% [FAB] hexane 62 t-Bu N 163-030 40% 369 B4a, C2b S \/164 EtOAc/ (M+H) + 60% [FAB) hexane 63 t-Bu 162-0.20 25% 363 (M+) C2b 163 EtOAc/ [EI] 75% O hexane 64 t-Bu N 127-0.22 40% 353 B3e Step wOt 129 EtOAc/ (M+H) + 1, B2, 60% [FAB] C2b hexane 65 t-Bu/ 85-87 0.20 50% 402 (M+) B3e Step EtOAc/ [Ell 1, B2, 50% C2b hexane I 66 t-Bu MeO 108-0. 25 10% 381 (M*) B3e « C2b 110 EtOAc : [EIJ \/90% hexane 67 t-Bu 186-0.25 30% 367 B6, C2b, 189 EtOAc ! (M+H) + D6 70% [FAB] hexane 68 t-Bu-0 221-0.25 60% 409 B3e, C2b, -NHMe 224 EtOAci (M+H) + DSb 40% [FAB] hexane 69 t-Bu O 114-0.25 60% 409 B3e, C2b, SNHMe 117 EtOAc/ (M+H) + D5b /\ O \/40% [FAB] hexane 70 t-Bu O 201-0.25 60% 423 B3e, C2b, ,-NMe2 203 EtOAc/ (M+H) + D5b /\ O \/40% [FABJ texane 71 t-Bu 148-025 20% 370 B3e, C2b 151 EtOAc/ (M+H) + 80% [FAB] hexane 72 t-Bu OMe 188-0.25 20% 382 B3e, C2b 201 EtOAc/ (M+H) + \/80% (FAB] hexane 73 t-Bu N 134-0.25 20% 367 B3e, C2b O Me 136 EtOAc/ (M+H) + 80% [FAB] hexane 74 t-Bu 176-0.25 50% 403 B3e, C2b 0 178 EtOAc/ (M+H) + N-50% [FAB] hexane 75 t-Bu N I32-0.52 40% 383 B3k, C3b 134 EtOAc/ (M+H) + 60% [FAB] hexane 76 t-Bu H 160-0.79 75% 381 C3a w N wOMe 162 EtOAc/ (M+H) + 25% [FAB] hexane 77 t-Bu 140-0.25 50% 352 (M+) B4b, C3b 143 EtOAc ! [EI] 0-\CN 50% . u CH2C12 78 t-Bu < 147-0.25 50% 352 (M+) B3f, C3b 150 EtOAc,,' [EI] p, 50% N CH2C12 79 t-Bu 166-0.44 50% 396 C3b 170 EtOAc/ (M+H) + O 50% [FAB] hexane 80 t-Bu/ 190-O. ZS 50% 367 B3g, C3b -N 193 EtOAci (M+H) + O Me 50% [FAB] CH2CI2 81 t-Bu 136-o 28 50% 367 B4b, C3b -Q 140 EtOAcil (M+H) + p ; SO% [FAB] CH2CI2 82 t-Bu Me 65-67 0.25 50% 367 B4b. C3b EtOAc/ (M+H) + < otXN 50% [FAB] CH2C12 83 t-Bu Me 68-72 0.25 50% 383 B4a, C3b EtOAc/ (M+H) + 50% [FAB) CH2C12 84 t-Bu N 146 0.49 40% 397 B3k C3b, 397 B3k C3b, totOEt EtOAc/ (M+H) + D9 60% [FAB] hexane 85 t-Bu Me 164-0.25 50% 382 (M+) B4a, C3b 165 EtOAc/ [EI] --SN 50% CH2C12 86 t-BuNH 175-0.25 20% 485 B3e, C3b, Ph) =O 177 EtOAc/ (M+H) + D5b 80% [FAB] texane 87 t-Bu H 137-0.30 50% 366 (M+) C3a, D2 vN<OH 141 EtOAc/ [EI) step 1 50% hexane 88 t-Bu PU-NE 120-0.25 20% 471 B3e, C3b, j= o 122 EtOAc/ (M+H) + D5b 80% [HPLC hexane ES-MS 89 t-Bu Et-NH 168-0.25 50% 423 B3e, C3b, 170 EtOAc/ (M+H) + D5b 50% [HPLC hexane ES-MS 90 t-Bu H OH 80-85 0.25 50% 396 B1, C2b, EtOAc/ (M+H) + DIO Me 50% [HPLC hexane ES-MS1 91 t-Bu O 73-75 0.25 30% 501 B3e, C3b, EtOAc/ (M+H) + D 11 Ph NH 70% [HPLC hexane ES-MS] 92 t-Bu Me 0.50 5% 366 Bla acetone/ (M+H) + \/95% [FAB] CH2C12 93 t-Bu CF3 199-0.59 5% 419 (M+) Bla 200 acetone/ [FAB] 95% CH2CI2

94 t-Bu Caf, 0.59 5% 419 (! M+) Bla acetone [FAB] \/95% CH2Cl2 95 t-Bu Me 78-82 0.25 10% 379 (M+) B3e, C3b EtOAc [EI] \/90°/a Me CH2Cl2 96 t-Bu NH 7560%463214-0. C2b, D3 =0 217 EtOAc/ (M+H) + F3C 40% [FAB] hexane 97 t-Bu-235 0.35 25% 402 B3b, C2b EtOAc (M+H) +v 75% hexane 98 t-Bu O 153-0.25 30% 424 B3e, C2b OEt 155 EtOAc/ (M+H) + nOm 70% [FAB] hexane 99 t-Bu N 100 0.62 40% 411 B3a. Bl, wO<OPr-i EtOAc/ (M+H) + C3b 60% [FAB] hexane 100 t-Bu OH 110-0.15 100% 367 N 115 EtOAc (M+H) + FAB Table 1. 5-Substituted-3-isoxazolyl Ureas-continued Mass mp TLC Solvent Spec. Synth. En R'R'°C R S stem Source Method 101 t-Bu O 0.50 100% 410 B10, B4b, NHME EtOAc (M+H) + C2b [FAB] 102 t-Bu 0 153-395 C3b / O \/Me 155 (M+H) + FAB 103 t-Bu O 0.52 100% 396 B 10, B4b, eNH2 EtOAc (M+H) + C2b O N [HPLC ES-MU 104 t-Bu n ° 0.75 100% 396 B 10, B4b, NHZ EtOAc (M+H) + C2b N [HPLC ES-MS 105 t-Bu fi5 O 107-0.85 1000, Ó 410 XB10. B4b. NHME 110 EtOAc (M+H) O N [FAB] 106 t-Bu 0 132-B3d step eNH2 135 2, C3a o _ 107 t-Bu 58 100% C3a, DSb EtOAc 108 t-Bu O 0.58 100% C3a, D5b EtOAc O \/ 109 t-Bu O 137-0.62 100% 439 B3a step 140 EtOAc (M+H) + 1, B12, OMe [HPLC D5b step ES-MS 2, C3a 110 t-Bu O 163-0.73 100% 425 B3a step 166 EtOAc (M+H) + 1, B12, O OH [HPLC DSb step ES-MU 2, C3a 111 t-Bu/\ p SO., Me 1g0-B3b step 181 l, B11, B3d step 2, C2a 112 t-Bu O 135-B3b, C2a Me 139 113 t-Bu _ 212-B3d step _' $NHMe 215 2a, C2a 114 t-Bu MeHN p 98-B3d step s : 100 2, C2a o--O, o 115 t-Bu N 0 135-B 10, B4b, NHMe 138 C2a 116 t-Bu O 219-0.78 80% 437 C3a, D5b -OMe 221 EtOAc/ (M+H) + step 2 hexane [HPLC ES-MU 117 t-Bu 0 step ru NH step 2, C3a 118 t-Bu O 124 0.39 5% C l c, D5b N H Me MeOH/ 0-\eN 45% EtOAc/ Cl 50% hexane 119 t-Bu no 73-75 0.41 100% 479 B3a, C4a, EtOAc (M+H)-DSb ,O-NH [HPLC O ES-MS] o°4 120 t-Bu 0 NHME 0.32 100% 436 Clb, D5b EtOAc (M+H) + step 1, [HPLC step 2 l ES-MSl 121 t-Bu N 0.23 10% 506 B3a, C4a, MeOH/ (M+H) + D5b 0 90% [HPLC 4 4 CH2C12 ES-MS] 122 t-Bu 0.18 10% 506 B3a, C4a, MeOH/ (M+H) + D5b Et je 90% [HPLC t° CH2C12 ES-MS] /\ O \/ 123 t-Bu 0 229-0.37 40% 435 D5b step 231 EtOAc/ (M+H) + I, B3d N-Me 60% [HPLC step 2, O hexane ES-MU C3a 124 t-Bu n 0.21 5% 508 B3a, C4a, ONq MeOH/ (M+H) + D5b 0 95% [HPLC -CH2C12 ES-MS] O 125 t-Bu 167-0.34 5% 424 C3b, D5b eNHEt 170 MeOH/ (M+H) + eO<N 45% [HPLC EtOAc/ES-MS] 50% hexane 126 t-Bu 124 0.26 5% C3b, D5b CI NHMe MeOH/ 0-\eN 45% EtOAc/ 50% hexane 127 t-Bu 125-0.28 5% C3b, D5b 128 MeOH/ tO<N 45% EtOAc/ 50% hexane 128 t-Bu 0.37 50% 426 C3b NHMe EtOAc/ (M+H) + Meus 50% pet [HPLC ether ES-MS 129 t-Bu 0 0.10 50% 424 C3b NMe2 EtOAc/ (M+H) + nO<N 50% pet [HPLC ether ES-MS 130 t-Bu N 0. 18 70% 472 D5b step2 --NH EtOAc : 30% [HPLC hexane ES-MS] 131 t-Bu O 325820. C3b Me (M+H) + [HPLC ES-MS] N d304 /\ O \/ 132 t-Bu F 0.57 558 C3b (M+H) + 0 [HPLC ES-MS) Hz N O 133 t-Bu r 0 0.21 598 C3b p/\ (M+H) + [HPLC ES-MS] N 0-6 0 134 t-Bu F. 86 489 C3b (M+H) + - [HPLC O ES-MS] 135 t-Bu 0.64 514 C3b \\ (M+H) + [HPLC NH ES-MS] o04 136 t-Bu MeO 0.29 453 C3b NH (M+H) + [HPLC ES-MS] 137 t-Bu N 0.70 502 C3b < ? ° M+H+ [HPLC ES-MS] 138 t-Bu 0.50 556 C3b (M+H) + - [HPLC O ES-MS] 139 t-Bu 0.27 541 C3b (M+H) + N [HPLC ES-MS] c N /\ O \/ 140 t-Bu 0 211-0.27 50% 426 C3b NHME 212 EtOAc/ (M+H) + S N SO% pet [HPLC ether ES-MS 141 t-Bu H2 ra 195-B8, C2a wC-NO 198 142 t-Bu CF3 170-C3a 171 /\ O \/ 143 t-Bu Me 141-0.63 5% 382 B3b step 144 acetone/ (M+H) + 1,2, Cld 95% [FAB] CH2C12 144 t-Bu F 0.57 5% 386 B3b step acetone/ (M+H) + 1,2, Cld 95% [FAB] CH2C12 145 t-Bu F 145-0.44 5% 370 B3b step 148 acetone/ (M+H) + 1,2, Cld 95% [FAB] CH2C12 146 t-Bu F 197-0.50 5% 404 B3b step 202 acetone/ (M+H) + 1,2, C I d 95% [FAB] CI CH2C12 147 t-Bu F 0.60 5% 404 B3b step acetone/ (M+H) + 1,2. C I d 95% [FAB] CH2CI2 148 t-Bu Me 126-0.17 30% 366 B4c, C4a vNt, N 129 MeOH/ (M+H) + 70% [FAB] EtOAc 149 t-Bu HZ 383 C3b /\ C_SN (M+H) + [HPLC ES-MU 150 t-Bu H 156-0.48 40% 395 C3a. D2 N OEt 159 EtOAc/ (M+H) + stepl, step hexane [HPLC 2 ES-MU 151 t-Bu 0. 51 409 C3a, D9 N OPr-n 159 (M+H) step 1) [HPLC step2 ES-MU 152 t-Bu H_& 130-0.60 437 C3a, D9 132 (M+H) + step 1, [HPLC step2 ES-MS 153 t-Bu Xx H > 146-0.54 40% °l49 !'"C3a, D2 N OPr-i 150 EtOAc/ (A1-H)-step I, step hexane [HPLC 2 ES-MU 154 t-Bu n H m 145-0.57 40% 423 C3a, D2 ~ MNtOBu-s 148 EtOAc ! (MtH) + stepl, step hexane [HPLC 2 ES-MISS 155 t-Bu H= 175-0.51 40% 457 C3a, D2 , >Ntr On 178 EtOAc/ (M+H)-step l, step hexane [HPLC 2 ES-MS] 156 t-Bu H 149-0.48 40% 407 C3a, Dl N 0 152 EtOAc/ (M+H) + step I, hexane [HPLC step 2 ES-MU 157 t-Bu Et 146-036 40% 409 C3a N OMe 147 EtOAc/ (M+H) + hexane [HPLC ES-MU 158 t-Bu me 156-0.43 40% 395 C3a N OMe 158 EtOAc/ (M+H) + hexane FAB 159 t-Bu 164-0.52 5% 396 B3b step 168 acetone/ (M+H) + 1,2, Cld Me Me 95% [HPLC CH2C12 ES-MS 160 t-Bu 0. 36 5% 380 B3b step acetonel (M+H) + 1,2, Cld Me Me 95% [FAB] CH2CI2 161 t-Bu-169-368 C3b ON Me 171 (M+H) + FAT 162 t-Bu ex 168 0.11 50% C3b EtOAc/ 50% pet éther 163 t-Bu eS 4SMe 146 C3b N 164 t-Bu < 0.45 100% 369 C2b EtOAc (M+H) + [FAB] F 165 t-bru 0.20 100% 367 B9, C2b EtOAc (M+H) + [FAB] HA 166 t-Bu 0 ci 187-0.46 30% 421 C3b 188 EtOAc/ (M+H) + Cl hexane [FAB] 167 t-Bu 133 0. 36 409 C3a, D9 (M+H) + step 1, [FAB] step2 168 t-Bu OPr-i 0.39 40% 411 C3a. D9 EtOAc/ (M+H) + step 1, = FOt"N 60% [FAB] step2 hexane 169 t-Bu OEt 0.32 5% 397 B3k, C8 acetone/ (M+H) + 95% [HPLC CH2C12 ES-MSl 170 t-Bu OMe 0.21 5% 383 B3k, C8 acetone/ (M+H) + 95% [HPLC CH2C12 ES-MSl 171 t-Bu 0.60 100% 365 C2b EtOAc (M+H) + [FAB] 0 172 t-Bu \9S/=\ 0. 16 30% 369 C8 EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 173 t-Bu 125-0.09 5% C3b N 129 MeOH/ 45% EtOAc/ 50% hexane 174 t-Bu 147-B3b) C2a O SMe 149 175 t-Bu H 0 0.30 100% 380 C3a, D5b NN EtOAc (M+H) + step2 [HPLC ES-MU 176 t-Bu 0 0.50 25% 353 MS EtOAc/ (M+H) + B F3C 75% [CI] 4b, C8 hexane

Table 2.3-Substituted-5-isoxazolyl Ureas Mass Spec. mp TLC Solvent [Source] Synth. En R'R2 (OC) R, System Method 177 Me Me 169-0.25 5% 324 Clb 0 170 acetone/ (M+H) + 95% [FAB] CH2CI2 178 i-Pr 153-0.54 50% 338 Clb 156 EtOAc/ (M+H) + 50% pet [FAB] ether 179 i-Pr 166-0.54 50% 352 Clb 170 EtOAc/ (M+H)- 50% pet [FABJ ether 180 i-Pr 112-0.29 5% 355 A2. = S <, 117 MeOH/ (M+H) + B4a, 95% [FAB] C3a CH2C12 181 i-Pr O 0.08 50% 395 C8 -NHMe EtOAc/ (M+H) + -0 50% [HPLC hexane ES-MS 182 i-Pr O 169-0.20 50% 396 C3b NHME 170 EtOAc/ (M+H) + O N 50% pet [HPLC ether ES-MS 183 i-Pr N 0.10 50 % 353 C8 \\,-O Me EtOAc/ (M+H) + 50% [HPLC hexane ES-MU 184 i-Pr 0.09 50 % 389 C8 EtOAc/ (M+H) + N-50% [HPLC hexane ES-MU 185 i-Pr Me 0.23 30% 352 C8 EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 186 i-Pr fi5 O 194-0.29 50% 396 C3b NHME 195 EtOAc/ (M+H) + 0-\eN 50% pet [HPLC ether ES-MS 187 0.03 50% 401 C8 EtOAc/ (M+H) + 50% [FAB] hexane 188 0-\CN 351 C8 (M+H)+ [HPLC ES-MU 189 Me 175-0.43 50% 364 Clb --P O Me 1g EtOAc/ (M+H) + Me 50% pet [FAB] ether 190 t-Bu 0.21 5% 369 B4a, MeOH/ (M+H) + C2a 95% [FAB] CH2C12 191 t-Bu S OPr-n 0.52 50% 426 B5, C4a EtOAc/ (M+H) + 50% [FAB] hexane 192 t-Bu O 182-352 Clb 184 (M+H) + FAB 193 t-Bu n/=\ 165 0.34 60% 366 Clb dec EtOAc (M+H) + 40% pet [FAB] ether 194 t-Bu 0-\CN 210 0.05 5% 353 C3a dec acetone/ (M+H) + 95% [FAB] CH2C12 195 t-Bu 25 5% 382 C3a O OMe 15 acetone% (M+H) + 95% [FAB] CH2CI2 196 t-Bu 90-92 0.16 5% 409 C2a \_/acetone/ (M+H) + 95% [FAB] S CH2C12 197 t-Bu n Nmß 221 0.14 5% 409 C2a dec acetone/ (M+H) + 95% [FAB) CH2C12 198 t-Bu N 196-0.17 5% 368 A2, O Me 198 MeOH/ (M+H) + B3h, 95% [FAB) C3a CH2C12 199 t-Bu 204-0.27 50% 383 A2, 206 EtOAc/ (M+H) + B3a, 50% pet [FAB] C3a ether 200 t-Bu H2 179-351 A2, C3a /\ CN 180 (M+H) + FAB 201 t-Bu/ 0. 33 50% 414 (M+) A2, _a EtOAc/ [EI] B4a, 50% pet C3a ether 202 t-Bu 188-0.49 50% 399 A2, O SMe I g9 EtOAc ;' (M+H) + B4a, 50% pet [HPLC C3a ether ES-MS1 203 t-Bu O 179-0.14 5% 395 A2, \/180 MeOH/ (M+H) + B4a, N Me 95% [FABJ C3a CH2CI2 204 t-Bu N 197-0.08 10% 353 A2, \/199 acetone ; (M+H) + B3h, N 90% [FAB] C3a CH2C12 205 t-Bu ci 136-0.33 50% 421 A2, 139 EtOAc% (M+H) + B3h, 50% pet [FAB] C3a ether 206 t-Bu 213 0.05 5% 369 C3a ,-, de acetone/ (M+H) + 95% [FAB] CH2C12 207 t-Bu Me 605%2740. C2a MeOH/ (M+H) + 95% [FAB] CH2C12 208 t-Bu @ 118-0.19 5% 387 A2, \ :-)/ 121 MeOH/ (M+H) T B4a, 95% [FABJ C3a CH2C12 209 t-Bu 0 NHME 217-0.18 5% A2, C3b NHMe 219 MeOH/ O \/95% CHC13 210 t-Bu 0 0.48 50% 394 C8 O \/EtOAc/ (M+H) + Me 50% [HPLC hexane ES-MU 211 t-Bu 0 0.17 30% 364 C8 EtOAc/ (M+H) + 70% [HPLC hexane ES-MU 212 t-Bu \-p 0.79 70% 421 B3a EtOAc/ (M+H) + step 1, NH 30% [HPLC B3d O hexane ES-MS) step 2, C3a 213 t-Bu-0.50 50% 407 B3a EtOAc/ (M+H) + step I, 50% [HPLC B3d O hexane ES-MS] step 2, C3a 214 t-Bu 0 182-0.25 5% 424 C3b, NHET 185 MeOH/ (M+H) + D5b 0-\eN 45% [HPLC EtOAc/ES-MS] 50% hexane 215 t-Bu 0 198-0.20 5% 444 C3b, f NHMe 200 MeOH/ (M+H) + D5b N 45% [HPLC EtOAc/ES-MS] 50% hexane 216 t-Bu fi5 O 0.24 50% 426 C3b NHMe EtOAc/ (M+H) + 50% pet [HPLC ether ES-MS 217 t-Bu 0 215-426 C3b 8 NH Me 217 (M+H) + /\ S N [HPLC ES-MU 218 t-Bu 0 188-0.22 50% 410 C3b 9 NH Me 200 EtOAc/ (M+H) + 50% pet [HPLC ether ES-MS 219 t-Bu 214-0. 3 5% :2. C2b ci 95% CH2C12 220 t-Bu 0-aMe 180 C3b -CN 221 t-Bu 160-0. 58 50% 336 (M+) C3b 162 EtOAc ! [CI] 50°/a pet ether 222 t-Bu 0.18 50% C3b EtOAc/ N 50% pet ether 223 t-Bu p SCF 163-0.21 5% 453 C3b 165 MeOH/ (M+H) + 95% [HPLC CH2C12 ES-MSl 224 t-Bu 0-0 208-0.17 5% 353 C3b 2 212 MeOH/ (M+H) + 95% [FABJ CH2C12 225 t-Bu 109-0.17 5% 369 C3b 112 MeOH/ (M+H) + 95% [FAB] CH2C12 226 t-Bu S OCF 155-0. 57 10% 453 C3b 156 MeOH/ (M+H) + CH2Cl2 FAB 227 t-Bu N-O 231-0.54 10% 534 C3b NH 234 MeOH/ (M+H) + CH2C12 [FAB] --O NH NU 228 t-bru 179-0.24 5% A2. C3b 180 MeOH/ O Me 95% CHC13 229 t-Bu 030 5% 370 A2, C3b /\ O \/F MeOH/ (M+H) + 95% [FAB] CHC13 230 t-Bu 178-0.20 5% A2, C3b 180 MeOH/ N 95% CHC13 231 t-Bu 186-0.20 5°/a r12, C3b -Q-SN 18 MeOH/ Me 95% CHC13 232 t-Bu 149-0.28 5% A2. C3b 152 MeOH/ 95% CHC13 233 t-Bu 210-0.06 10% 421 C3b N O CF3 213 MeOH/ (M+H) + CH2C12 FAB 2'4 t-Bu OMe 132-0.43 5% A2. C3b 133 MeOH/ ; O-- 95% CHC13 235 t-Bu 71-73 0.27 S% A2, C3b , ^ MeOH ; 95% CHC13 236 t-Bu Cl 176-0.44 10% 437 C3b 177 MeOH/ (M+H) + Y=NFs</¢cl CH2C12 [FAB] 237 t-Bu H 0.09 50 % 351 C8 c EtOAc/ (M+H) + N 50% [HPLC hexane ES-MU 238 t-Bu 0 0.16 50% 403 C8 EtOAc/ (M+H) + 50% [HPLC hexane ES-MU 239 t-Bu 0.15 50 % 381 C8 ----O-N EtOAc/ (M+H) + Me 50% [HPLC hexane ES-MU 240 t-Bu A 19100%370215-0. C3b 216 EtOAc (M+H) + [HPLC ES-MU 241 t-Bu 42 5% N=N MeOH/ 95% CH2C12 242 t-Bu hX \ 0.74 100% 366 B4b, C8 EtOAc (M+H) + Me [HPLC ES-MU 243 t-Bu 0 0. 12 30% 421 C8 EtOAc/ (M+H) + F3C 70% [HPLC hexane ES-MU 245 t-Bu 0.68 100% 368 B4b, C8 EtOAc (M+H) + HO [HPLC ES-MSl 246 t-Bu 0 142-0.13 5% A2, C3b N 144 MeOH/ 45% EtOAc/ 50% hexane 247 t-Bu n O 205-0.31 50% 410 C3b NHMe 207 EtOAc/ (M+H) + 50% pet [HPLC ether ES-MS 248 Me 154-0.50 50% 365 (M+) Clb ---Me 155 EtOAc/ [EI] Et 50% pet ether 249 Me 160-0.37 5% 380 Clb nfMe FO<Me 162 acetone/ (M+H) e Et 95% [FAB] CH2CI2 250 Me Cl Cl 196-0.58 5% 342 Clb -Me 199 acetone/ (M+H) + Et 95% [FAB] CH2C12 251 Me 137-0.25 5% 396 A2, nf Me wO t OMe 138 acetone/ (M+H) + B3a, Et 95% [FAB] C3a CH2C12 252 Me H 0.18 5% 364 (M+) A2, C3a ---Me N \ N MeOH/ [EI] Et CHC13 253 Me 215-383 A2, , ^ 221 (M+H) + B4a, Et SN dec [FABJ c3a 254 Me 0. 42 10% 383 A2, ' 188 MeOH/ (M+H) + B4a, Et CHC13 [FAB] C3a 255 Me 90-92 0.19 30% 366 (M+) A2, C3a --Me---O-N EtOAc/ [EI] Et 70% pet ether 257 Me N 199-0.33 70% 423 A2, 200 EtOAc/ (M+H) + B3e, Et 30% pet [FAB] C3a ether 258 Me O 117-0.14 5% A2, C3b Me NHMe 119 MeOH/ Et 95% CHC13 259 Me z F O 0.37 75% 409 C8 /EtOAc/ (M+H) + Et N Me 25% [HPLC hexane ES-MS 260 Me 0 94-0.25 50% 424 C3b ---Me NHME 195 EtOAc/ (M+H) + Et 50% pet [HPLC O N ether ES-MS 261 Me O 216-0.20 50% 424 C3b .Me NHMe 217 EtOAc/ (M+H) + Et 3O<N 50% pet [HPLC ether ES-MU 262 Me 62-65 0.18 5% A2, C3b Me MeOH/ Et-N s 95% 263 Me 86-89 0.16 5% _ A2, C3b Et StN 95% Et s _/N 95% CHC13 264 Me 14s-0.32 5% A2. C3b nf Me OO U F 146 MeOH/ Et 95% CHC13 265 Me \\/=\ 0.23 5% 381 A2, C3b Me O N Me MeOFI,' (M+H) + Et 95% [FAB] CHC13 266 Me OMe 0.20 5% 396 A2, C3b .Me acetone' (M+H) + Et wOt 95% [FAB] CH2C12 267 Me 0.38 50 % 366 C8 Me EtOAci (M+H) + Et 0 \/50% [HPLC hexane ES-MS 268 Me 0 0.14 50 % 367 C8 ---Me EtOAc/ (M+H) + Et 50% [HPLC hexane ES-MU 269 Me n S/=\ 0.21 50 % 383 C8 EtOAc/ (M+H) + Et N 50% [HPLC hexane ES-MU 270 Me H2/=\ o io 50 % 365 C8 EtOAc/ (M+H) + Et N 50% [HPLC hexane ES-MU 271 Me H2 0.14 50 % 365 C8 nf Me tC\ j EtOAc/ (M+H) + Et N 50% [HPLC hexane ES-MU 272 Me n/=\ 0. 35 50% 382 C8 EtOAc ! (M+H) + HO SO/o [HPLC hexane ES-MU 273 Me 0 0.48 50% 382 C8 Me vOa EtoAc/ (M+H) + OH 50% [HPLC hexane ES-MU 274 Me 0. 20 100% 367 B4b, C8 Et EtOAc (M+H) + O N [HPLC ES-MU me 275 Me N 0.56 100% 435 B4b, C8 EtOAc (M+H) + Et [HPLC F3C ES-MU 276 Me 5 S/=\ 0.57 75% 383 C8 Me N S \/EtOAc/ (M+H) + Et 25% [HPLC hexane ES-MU 277 Me 0.40 100% B3f, C8 ---Me EtOAc Et O 278 MEt O i OMe 63'65 410 H) + A2. C3a (M Et FAT 279 Me 84 0.16 5% 381 A2, C3a ---Et 0 N MEOH, : (M+H) + Et 95% [FABJ CHOC13 280 Me @nL = 189-0.16 5% 397 A2, . Et--C S-N 192 MeOH/ (M+H) + B4a, Et 95% [HPLC C3a CHC13 ES-MU 281 Me \\ 189 0.17 5% 397 A2. Et 191 MeOH/ (M+H) + B4a, Et SN 95% [FAB] C3a CHC13 1 282 Mu 123-414 A2, C3a Et 125 (M+H) + A2, C3a Et FAB 283 Me H2 175-0.16 5% 379 A2, C3a ----Et C-\N 177 MeOH/ (M+H) + Et 95°/a [FAB) CHC13 284 Me 135-0.33 5% A2, C3b -Et 0 \/137 MeOH/ Et 95% CHC13 285 Me 67 0.41 5% A2, C3b --\-Et-0-0-&Me MeOH/ Et 95% CHC13 286 155-0. 38 50% 377 (M+) Clb 156 EtOAc/ [EI] 50% pet ether 287 O h) 0.18 5% 379 A2. C3b \SN MeOH ! (M+H) + 95% [FAB] CHC13 I I

Table 3. N'-Substituted-3-tert-butyl-5-pyrazolyl Ureas Mass Spec. mp TLC Solvent [Source] Synth. Ex. R'R= (°C R, System Method 289 H 0 0.07 50% 393 C8 EtOAc/ (M+H) + 50% [HPLC hexane ES-MU 290 H 0 ome 181-381 C2b 183 (M+H) + FAT 291 H Me 0.30 50 % 365 C8 0 EtOAc. (M+H)- 50% [HPLC hexane ES-MU 292 H N 366 C8 --a 0-\aMe (M+H)-i- FAB 293 H 0.53 50% 398 C8 EtOAc/ (M+H) + 50% [HPLC hexane ES-MS 294 H 369 C8 O F (M+H) + [HPLC ES-MU 295 H 0.27 50% 351 Clc EtOAc/ (M+H) + 50% [FAB] hexane 296 H Cl Cl 0.59 50% 327 Clc EtOAc/ (M+H) + 50% [FAB] hexane 297 H HZ 0.30 60% 350 C4a CLCN acetone/ (M+H) + 40% [FAB] CH2CI2 298 H < 0.07 5% 368 B4a, MeOH/ (M+H) + C4a S N 95% [FAB] u CHC13 299 H hR/= 0.18 5% 367 (M+) B4a, MeOH/ [EI] C4a 95% CHC13 300 H O 160-408 A5, B6, HO CF3 O 161 (M+H) + C3b NHMe [FAB] isolated at TFA salt 301 H 24 10% 351 (M+) C3a < O<N 232 MeOH/ [EI] dec CHC13 302 H n/=\ 204 0.06 5% 364 (M+) C3b acetone/ [EI] 95% CH2CI2 303 H 110-0.05 5% 408 C3b III acetone/ (M+H+) 0<'Yq 95% S v CH2C12 304 Me H2 0.10 20% 380 C4a wO-Ct, N acetone/ (M+H) + 80% [FAB] CH2CI2 305 Me 7 19100%452 B3a99-0. » 19HMe 101 EtOAc (M+H) T step 1, [HPLC B12, ES-MS] DSb step 2, C3a 306 Me H, H,, 0.48 30% 378 Bl, C3a tC-C<, N acetone! (M+H) + 70% [FAB] CH2C12 307 Me Me 135-0.03 30% 408 C3a N OMe 137 EtOAci (M+H) + 70% [HPLC hexane ES-MU 308 Me 0.35 70% 382 B4a, acetone/ (M+H) + C4a 30% [FAB] CH2C12 309 Me 0.46 70% 382 B4a, acetonei (M+H) + C4a S<N 30% [FAB] CH2C12 310 Me CF3 0.32 70% 450 B3b, acetone/ (M+H) + C4a SN 30% [FAB] CH2C12 311 Me 0.09 50% 381 C4a EtOAc ! (M+H) + 50% [FAB] hexane 312 Me 0.61 100% 397 B3c, EtOAc (M+H) + C4a FAB 313 Me 0. 25 50% 453 B5, C4a vS< OBu-n EtOAci (M+H) + 50% [FAB] hexane 314 Me, H2 = 0.65 100% 462 B6, C4a C NH EtOAc (M+H) + O i-B FAB 315 Me HZ 0.67 100% 478 B6, C4a C--\/NH EtOAc (M+H) + [FAB] t-BuO 316 Me 0.50 100% 378 C4a tC <NH2 EtOAc (M+H) + FAB 317 Me H 033 100% 420 C4a, D3 +/\>CC NH EtOAc (M+H) + Me/ [FAB] 318 Me H2 0.60 10% 478 C4a, D3 nCoNH water/ (M+H) + 90% [FABJ H02C CH3CN 319 Me H 0.55 100% 434 C4a. D3 NH EtOAc (M+H)- Et [FAB] 320 M e<° o N H 2 0. 52 EOt O°Å c (3M0+ H) + C 4 al FAB1320 Me 0. 52 100% 380 C4a O NHZ EtOAc (M+H) + FAT 321 Me 0. 2 60% 366 C4a acétone/ (M+H) + 40% [FAB] CH2C12 322 Me 0.52 100% 452 C4a, D3 \/ EtOAc (M+H) + Et0 [FAB] 323 Me HZ 0.34 60% 396 C4a w S-CtZN acetone/ (M+H) + 40% [FAB] CH2C12 324 Me Hz 036 60% 396 C4a C-acetone/ (M+H) + 40% [FAB] CH2CI2 325 Me 147-365 Clc \=/U 149 (M+H) + FAB 326 Me HZ 161-0.15 4% 364 C2b -\ N 162 MeOH/ (M+H) + 96% [FAB] CH2CI2 327 Me 228 379 C2b 0 Me FAT 328 Me 0.30 5% 422 C2b MeOH/ (M+H) + O-- (I \ 95% [FAB] S~< CH2C12 329 Me i I 0.46 100% 464 B3c, EtOAc (M+H) + C4a _ 3S eS 3 [FAB] S 330 Me N-0 0.52 100% 506 B3c, EtOAc (M+H) + C4a CF3 [FAB) 331 Me 0 0.75 100% 421 B3c, EtOAc (M+H) + C4a FAB 332 Mye 0.50 100% 465 B3c, O SCF3 EtOAc (M+H) + C4a FAT 333 M e 50100%3490. C4a EtOAc (M+H) + [FAB] 334 Me 0.60 100% 4-1 B2. C4a EtOAc (i-H)- [FAB] 335 Me 0.52 100% 466 C4a. D3 EtOAc (4H) + i-Bu [FAB] 336 Me s OPr-n 0.42 100% 439 BS, C4a EtOAc (M-H) + FAB 337-CH :-CF, O \/+H) + C3a FAB 338- (CH,) 2CN 0.37 50% 404 A3, Clb EtOAc/ (M+H) + 50% (HPLC hexane ES-MU 339 ° Me-NH 159-_ 508 A5, B6, -161 (I+I) + C2b t-Bu p [FAB] Table 4. 5-Substituted-2-thiadiazolyl Ureas Mass Spec. mp TLC Solvent [Source] Synth. En R'R= (°C) R, S stem Method 340 t-Bu 0.37 5% 399 B3a, C3a O OMe MeOH/ (M+H) + 95% [FAB] CH2C12 341 t-Bu 0.26 5% 370 C3a /\, ON MeOH ; (M+H) + 95% [FAB) CH2CI2 342 t-Bu 386 B4a, C3a (M+H) + SON [FAB] 343 t-Bu \9/=\ 0.30 5% 383 Clb acétone/ (M+H) + 95% [FAB] CH2CI2 344 t-Bu 0 0.60 10% 412 C3b \/Me MeOH ! (M+H) + CH2C12 FAB 345 t-Bu 0 245-0.23 100% 456 B3a step NHME 250 EtOAc (M+H) + 1, B 12, O OMe [HPLC DSb step ES-MU 2, C3a 346 t-Bu 0 0.10 50% C3b NHMe EtOAc/ 50°/ « pe éther 347 t-Bu 0.13 50% 441 C3b fume2 EtOAc/ (M+H) + nOz'N 50% pe [HPLC ether ES-MS 348 t-Bu O 0.14 5% 441 C3b, f NHEt MeOH/ (M+H) + DSb 0-\eN 45% [HPLC EtOAc/ES-MS] 50% hexane 349 t-Bu O 0.23 5% 461 C3b, Cl NHMe MeOH/ (M+H) + DSb 45% [HPLC EtOAc/ES-MS] 50% hexane 350 t-Bu O 0.09 5% 461 C3b, Cl eNHMe MeOH/ (M+H) + DSb 45% [HPLC EtOAc/ES-MS] 50% hexane 351 t-Bu O 0.13 5% 441 C3b. Me NHMe MeOH, % (M+H)-Db 4 ON 45% [HPLC EtOAc/ES-MS] 50% hexane 352 t-Bu O 159-0.10 50% 427 C3b NHME 160 EtOAc/ (M+H) + O N 50% pe [HPLC ether ES-MU 353 t-Bu Cl 0.47 10% 438 C3b MeOH ! (M+H) + N O Cl CH2C12 [FAB] 354 t-Bu 0.31 10% 371 C3b MeOH/ (M+H) + CH2C12 FAB 355 t-Bu Cl 0.51 10% 400 C3b MeOH/ (M+H) + N O CI CH2C12 [FAB] 356 t-Bu 0 0.43 10% 385 C3b MeOH/ (M+H) + CH2CI2 FAB 357 t-Bu 0.70 10% 416 C3b O SMe MeOH/ (M+H) + CH2C12 FAB 358 t-Bu vhon 0.11 50 °/438 C8 EtOAc/ (M+H) + 50% [HPLC hexane ES-MS 359 t-Bu 0.06 5% 432 C3b S SMe MeOH/ (M+H) + 95% [FAB] CH2C12 360 t-Bu--ao-Q 0.20 50% 385 C8 EtOAc/ (M+H) + HO 50% [HPLC hexane ES-MU 361 t-Bu Me 107-0.05 30% 412 C3a vNOMe 110 EtOAc/ (M+H) + 70% [HPLC hexane ES-MS1 362 t-Bu 0.16 100% 370 C8 EtOAc (M+H) + 0-\CS [HPLC ES-MU 363 Me 0.12 100% C4a, D5b Me eNHEt EtOAc Et fi5/=\ w°Y 364 Me O 183-B3d step nfMe eNH2 185 2, C3a Et- /\ O \/ w°t 365 Me Me OMe 0.19 6% 413 A6, C3b MeOH/ (M+H) + Et 94% [FABJ CHC13 366 Me 248-0.34 6°/a A6, C3b Me -O- !N 249 MeOH% Et 94% CHOC13 367 M e 0.20 400 A6. C3b Me Et (M+H) + s, r [FAB] 368 Et 182-0.33 5% A6, C3b O Cl 183 MeOH/ Et 95% CHC13 369 Et S N 180-0.19 5% A6) C3b Et 181 MeOH/ Et 95% CHC13 370 Et 168-0.24 5% A6, C3b - ( O OMe 169 MeOH/ Et 95 °/a CHC13 371 Et 168-0. 17 6°/a A6, C3b 0 \con Et 94°/a CHC13 372 Et 156 0.19 6% A6, C3b SN 158 MeOH/ Et 94% _ CHC13 Table 5. 5-Substituted-3-thienyl Ureas mp TLC Solvent Mass Synth. Entrv R'R2 (OC) R, System Spec. Method 373 t-Bu O 144-0.68 5% A4b. 145 acetone/C 1 a 95% CH2Cl2 374 t-Bu Me 0.52 30% 381 Et20/ (M+H) + 70% pet [HPLC ether ES-MU 375 t-Bu 0.26 30% 397 need Et20/ (M+H) + recipie 70% pet [HPLC ether ES-MS 376 t-Bu N 0.28 50% 368 need 0 Et20/ (M+H) + recipie 50% pet [HPLC ether ES-MU 377 t-Bu 57 381 A4a (M+H) + FAB 378 t-Bu H, 0.15 50% 365 (M+ A4a c EtOAc/ [EI] 50% pet ether 379 t-Bu 0.44 50% 383 A4a O OH EtOAc/ (M+H) + 50% pet [FAB] ether 380 t-Bu 384 A4a /\ (M+H) + FAT 381 t-Bu 176-0.45 20% 425 D2 O OPr-n 1 EtOAc/ (M+H) + D2 80% [FAB] hexane

Table 5. Additional Ureas Mass Spec. mp TLC Solvent [Source] Synth. En R= °C) R S stem ethod 382 _ 161-0.71 20% 367-dol \ Me 163 EtOAc/ (M+H) +, 0, Me 80% 369 hexane (M+3) + Br H H FAB 383 145-0.57 5% A2 Cl p 147 MeOH :' C3b N'1 I I 95% -01 N N CHC13 H H 384 132-0.33 5% 339 A9, N-N 0 0 135 acetone. (M+H)-Cld 95% [HPLC ES- T1 H H CH2C12 MS] 385 0.60 50% 462 C8 EtOAci (M+H) N O 50% HPLC ES- NN, NN I I SCF hexane MS) H H H 386 0.28 5% 339 A7, ) rO O YOo acetone. (M+H) + Cld 95% [FAB] N N N CH2C12 H H 387 340 B3b O (M+H) + step O O [FAB] 1, 2 NNNN N Cld H H 388 174-5 424 B4b, C8 h-O O (M+H) + [HPLC ES- N H H MS 0 NHET 389 198-C3b, O 200 DSb N NANJJ N N N H H O NHPr-i 390 169-0.23 100% B4b, C8 0 0 170 EtOAc N,N-, J, NAN H H O NHMe 391 167-0.12 100% B4b, C8 -o 0 0 171 EtOAc N,NNN H H 392 0.08 50% 400 C8 EtOAc/ (M+H) + 50% [HPLC ES- NN NN N hexane MS] i H H 393 0.55 90% 443 BIO, EtOAc/ (M+H)--B4b, 0 0 10% [FAB] C2b N N hexane H H O NHMe 394 OEt 230 377 C5 dec (M+H) + [HPLC ES- ONNNON ms) H H 395 0.48 50% 383 C8 EtOAc/ (M+H) + (I 50% [FAB] N N Me hexane H H 396"/= 417 C8 \P/', (M+H) + r S O'N [HPLC ES- NNJ. IN MSl H H 397 155-0.44 5% 380 Clb 157 acetone/ (M+H) + 95% [FAB) N I O \ I I j CH2C12 , O NJN H H

BIOLOGICAL EXAMPLES In Vitro raf Kinase Assai: In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCl, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCL This protein solution (20 µL is mixed with water (5 1L) or with compound diluted with distille water from 10 mM stock solutions of compound dissolve in DMSO. The kinase rection is initiated by adding 25 pL [y-33P] ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH 7.5,120 mM NaCl, 1.6 mM DTT, 16 mM MgCI,. The rection mixtures are incubated at 32 °C, usually for 22 min. Incorporation of 33P into protein is assayed by harvesting the rection onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10iM ATP and 0.4 tM MEK are used. In some experiments, the kinase rection is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by

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 compound exemplified displaved ICSOs of between I nM and 10 iM.

Cellular Assav: For in vitro growth assay, human tumor cell lines, including but not limited to HCTI 16 and DLD-I, 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 10'cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% CO2 incubator. Compound 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 3H-thymidine incorporation into DNA following an 8 h culture with 1 tCu 3H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring'H-thymidine incorporation by liquid scintillant counting.

For anchorage independent cell growth, cells are plated at I x 103 to 3 x 103 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 compound are added to wells and incubated at 37 °C in a 5% CO2 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).

These assays establish that the compound of Formula I are active to inhibit raf kinase activity and to inhibit oncogenic cell growth.

InVivo Assay: An in vivo assay of the inhibitory effect of the compound on tumors (e. g., solid cancers) mediated by raf kinase can be performed as follows: CDI nu/nu mice (6-8 weeks old) are injecte subcutaneously into the flank at 1 x 106 cells with human colon adenocarcinoma cell line. The mice are dosed i. p., i. v. or p. 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 caliers twice a week.

The inhibitory effect of the compound on raf kinase and therefore on tumors (e. g., 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.