Title of Invention	A COMPOUND
Abstract	Compound of formula I wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, -C(0)R5, -N02- -ORS, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -Cio alkyl, C2 -Cio alkenyl, Ci-Cio alkoxy, C3 -Cio cycloalkyl, Ce-Ci4 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -Cio alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3-Cio cycloalkyl, and -Y-Ar, wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -Cio alkenyl, C3-C10 cycloalkyl up to per halosubstituted Ci-C10 alkyl, up to per halo substituted C2-C10 alkenyl, up to per-halosubstituted C3 -Cio cycloalkyl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5NR5'-. NR5C(0)-, -C(0)NR5-, -(CHa)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX^, -CHX«2-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN =0, -CO2R5, -C(0)NR5R5', -C(O)- NR5, -N02> -OR5, -SR5, -NR5R5', -NR5C(0)OR5', -C(0)R5. 3JR5C(0)R5', -S02R5, S02NR5R5', Ci -C10 alkyl, C1-C10 alkoxyl, C3 -C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, and A is a heteroaryl moiety selected from the group consisting of wherein R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-C10 cycloalkyl, C1-C13 heteroaryl, Ce-naryl, C7-24 alkaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C1-C13 heteroaryl, up to per-halosubstituted C6-14 aryl, and up to per-halosubstituted C7-24 alkaryl; R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, C1-C10 alkyl C3-C10 cycloalkyl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, substituted C7-C24 alkaryl, and substituted C4-C23 alkheteroaryl; where R2 is a substituted group, it is substituted by one or more substitutents independently selected from the group consisting of -CN, -CO2R4, -C(0)-NR3R3', _NO2, -OR4, -SR4, and halogen up to per-halosubstitution, wherein R3 and R3' are independently selected from the group consisting of H, -OR4- -SR4- -NR4R4', -C(0)R4, -CO2R4- -C(0)NR4R4> Ci -Cio alkyl, C3-Cio cycloalkyl, C6-Ci4aryl, C3-C13 heteroaryl, up to per per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3 -Cio

Title of Invention

A COMPOUND

Abstract

Compound of formula I wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, -C(0)R5, -N02- -ORS, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -Cio alkyl, C2 -Cio alkenyl, Ci-Cio alkoxy, C3 -Cio cycloalkyl, Ce-Ci4 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -Cio alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3-Cio cycloalkyl, and -Y-Ar, wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -Cio alkenyl, C3-C10 cycloalkyl up to per halosubstituted Ci-C10 alkyl, up to per halo substituted C2-C10 alkenyl, up to per-halosubstituted C3 -Cio cycloalkyl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5NR5'-. NR5C(0)-, -C(0)NR5-, -(CHa)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX^, -CHX«2-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN =0, -CO2R5, -C(0)NR5R5', -C(O)- NR5, -N02> -OR5, -SR5, -NR5R5', -NR5C(0)OR5', -C(0)R5. 3JR5C(0)R5', -S02R5, S02NR5R5', Ci -C10 alkyl, C1-C10 alkoxyl, C3 -C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, and A is a heteroaryl moiety selected from the group consisting of wherein R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-C10 cycloalkyl, C1-C13 heteroaryl, Ce-naryl, C7-24 alkaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C1-C13 heteroaryl, up to per-halosubstituted C6-14 aryl, and up to per-halosubstituted C7-24 alkaryl; R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, C1-C10 alkyl C3-C10 cycloalkyl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, substituted C7-C24 alkaryl, and substituted C4-C23 alkheteroaryl; where R2 is a substituted group, it is substituted by one or more substitutents independently selected from the group consisting of -CN, -CO2R4, -C(0)-NR3R3', _NO2, -OR4, -SR4, and halogen up to per-halosubstitution, wherein R3 and R3' are independently selected from the group consisting of H, -OR4- -SR4- -NR4R4', -C(0)R4, -CO2R4- -C(0)NR4R4> Ci -Cio alkyl, C3-Cio cycloalkyl, C6-Ci4aryl, C3-C13 heteroaryl, up to per per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3 -Cio

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10, rule 13] "A COMPOUND" BAYER CORPORATION, of 100 Bayer Road, Pittsburgh Pennsylvania 15205, United States of America, The following specification particularly describes and ascertain the nature of the invention and the manner in which it is to be performed:- ©R\U\K"FM_ ^3o\|mum^pf ^o^> INHIBITION OF RAF KINASE USING SUBSTITUTED HETEROCYCLIC UREAS Field of the Invention This invention relates to the us eof a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy. Background of the Invention The p21ru oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton'et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by 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. Chem. 1994,269, 30105-8. Kolch et al. {Nature 1991, 349,426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense ohgodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2,668-75). Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21n,I 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 compounds 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 compounds 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 compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds and methods for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula I: O II A-NH-C-NH-B I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below. The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below. Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of which is a 5-6 member aromatic ring. One or more of these rings may have 1-4 carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms. Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, isoquinoline, phthalimidinyl and combinations thereof, such as, diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenylamine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pyridinylnaphthyl thioether, and phthalimidylmethylphenyl. Examples of suitable heteroaryl groups include, but are not limited to, 5-12 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 replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 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-l-, -4- or-5-yl, 1,2,4-triazol-l-, -3- or-5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4-or-5-yl, l,2,4-oxadiazol-3-or-5-yl, l,3,4-thiadiazol-2-or-5-yl, l,2,4-oxadiazol-3- or-5-yl, l,3,4-thiadiazol-2-or-5-yl, l,3,4-thiadiazol-3-or-5-yl, l,2,3-thiadiazoI-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-indolyI, 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-benz-l,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-thjazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyI-2-thienyl, 4-methyU2-thienyl, l-methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyM,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 branched isomers such as isopropyl, isobutyl, sec-butyl, ter/-butyl, etc. Suitable aryl groups include, 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 substituents such that, for example, "C4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups. Suitable halogens include F, CI, Br, and/or I, from one to persubstitution (i.e., all H atoms on the group are replaced by halogen atom), being possible, mixed substitution of halogen atom types also being possible on a given moiety. As indicated above, these ring systems can be unsubstituted or substituted by substituents such a$ halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CM, -C02R5, -C(0)NR5Rr, -C(0)R5, N02, -OR1, -SRS, -NR5Ry, -NR5C(0)OR5', -NR5C(0)R5', C,-CIO alkyl, C2-C10 alkenyl, C,-CI0 alkoxy* Cj-C10 cycloalkyl, C6-C, 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, -C02R5, -C(0)R5, -C(0)NR5R5', -ORs, -SR5, -NR'R5", -N02, -NR5C(0)R5', -NR5C(0)0R5' and halogen up to per-halo substitution. The moieties R5 and R5' are preferably independently selected from H, C,-C10 alkyl, Cj-C,0 alkenyl, C3-C10 cycloalkyl, C6-Cu aryl, C3-CI3 heteroaryl, C7-C24 alkaryl, C4-C23 ilkheteroaryl, up to per-halosubstituted C,-C10 alkyl, up to per-halosubstituted C2-C10 ilkenyl, up to per-halosubstituted C3-CI0 cycloalkyl, up to per-halosubstituted C6-Cu iryl and up to per-halosubstituted C3-C,3 heteroaryl. rhe bridging group Y is preferably -0-, -S-, -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, (CH2)mO-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX\ -CX2-, -S-(CH2)m- and N(Rs)(CH2)m-, where m = 1-3, and X is halogen. fhe moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 nembers of the group consisting of nitrogen, oxygen and sulfur which is tnsubstituted or substituted by halogen up to per-halosubstitucion and optionally ubstituted by ZDl, wherein nl is 0 to 3. iach Z substituent is preferably independently selected from the group consisting of CN, -C02R5, -C(0)NR5R5', -C(O)- NR5, -N02, -OR5, - SR5, - NR5R5', -NR5C(0)0R5', 0, -NR5C(0)R5', -S02R5, -S02NR5R5', C,-C10 alkyl, CrC10 alkoxy, C3-C10 ycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, CTCU alkaryl, C4-CJ3 alkheteroaryl, ubstituted C,-C,0 alkyl, substituted C3-C,0 cycloalkyl, substituted C7~C24 alkaryj and ubstituted C4-C23 alkheteroaryl. If Z is a substituted group, it is substituted by the ne or more substituents independently selected from the group consisting of-CN, :02R5, -C(0)NR5R5', -ORs, -SR5, -NO,, -NR^5, =0, -NR5C(0)Rs', sJR5C(0)ORr, C,-CI0 alkyl, C,-C10 alkoxy, C3-Cl0 cycloalkyl, C3-C13 heteroaryl, C6-14 aryl, C7-C24 alkaryl. he aryl and heteroaryl moieties of B of Formula I are preferably selected from the which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n = 0-3. The aryl and heteroaryl moieties 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)-, -CX2, -CXlH-, -CH20- and -OCH2- and X* is halogen. Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4 members of the group consisting of N, 0 and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution. X, Z, n and nl are as defined above and s = 0 or 1. In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution and Q1 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-Q1 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 R* is hydrogen, C,-C10-alkyl or C3-CI0-cycloalkyl and R7 is preferably selected from the group consisting of hydrogen, C3- CI0-alkyl, CrC6-cycloalkyl and C6-C10-aryl, wherein R* and R7 can be substituted by halogen or up to per-halosubstifution. 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-C,0 alkyl, Cj-C10 cycloalkyl, C,-C,j heteroaryl, C6-C,3 aryl, C,-C24 alkaryl,_up to per-halosubstituted C,-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C,-C13 heteroaryl, up to per-halosubstituted C6-C13 aryl and up to per-halosubstituted C1-C24 alkaryl. The substituent R2 is preferably selected from the group consisting of H, -C(0)R\ -C02R\ -C(0)NR3R3', C,-C10 alkyl, C3-C10 cycloalkyl, C7-C24 alkaryl, CrC» alkheteroaryl, substituted C,-C10 alkyl, substituted Cj-Cl0 cycloalkyl, substituted C7-C24 alkaryl and substituted C4-C2J alkheteroaryl. Where R2 is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, - C02R4, -C(0)-NR3R3', -N02, -OR4, -SR\ and halogen up to per-halosubstitution. R3 and R3' are preferably independently selected from the group consisting of H, -OR4, -SR\ -NR4R4', -C(0)R\ -C02R4, -C(0)NR4R4', C,-C10 alkyl, CrClo cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C,-C10 alkyl, up to per-halosubstituted C3-CI0 cycloalkyl, up to per-halosubstituted C6-C,4 aryl and up to per-halosubstituted C3-C13 heteroaryl. R4 and R4' are preferably independently selected from the group consisting of H, C,-C,0 alkyl, C3-C10 cycloalkyl, C6-Cl4 aryl, C3-C13 heteroaryl; C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C^C^ alkyl, up to per-halosubstituted C3-C,0 cycloalkyl, up to per-halosubstituted C6-C,4 aryl and up to per-halosubstituted C3-CI3 heteroaryl. R" is preferably C,-C,0 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C^C^ alkyl and up to per-halosubstituted C3-Ci0 cycloalkyl. Rbis preferably hydrogen or halogen. Rc is hydrogen, halogen, C,-C,0 alkyl, up to per-halosubstituted C,-CI0 alkyl or combines with R1 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 0, NandS; wherein R2, R1 and B are as defined above; and both 5,3- and 3,5- isoxazolyl ureas of the formulae The invention also relates to compounds of general formula I described above and includes pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula and wherein R1 and B are also as defined above. Component B for these compounds is a 1-3 ring aromatic ring structure selected from the group consisting of: X' which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here R5 and R5' are as defined above, n = 0-2 and each X1 substituent is independently selected from the group of X or from the group consisting of-CN, -C02R5, -C(0)R5, -C(0)NR5R5', -OR5, - N02, -NR5R5', C,-C10 alkyl, C2.10-alkenyl, C,.1(ralkoxy, Cj-C,0 cycloalkyl, C6-Cu aryl and C7-CM alkaryl. The substituent X is selected from the group consisting of -SR5, NR5C(0)OR5', NR5C(0)R5', C3-Cl3 heteroaryl, C«-C2J alkheteroaryl, substituted CrC10 alkyl, substituted C2.10-alkenyl, substituted C,.I0-alkoxy, substituted C,-C10 cycloalkyl, substituted C6-Cu aryl, substituted C7-C2« alkaryl, substituted C^-C^ 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, -C02R5, -C(0)R5, -C(0)NRsRr, -OR5, -SR5, -NR'R5, N02, -NR5C(0)R5, -NR5C(0)OR5' 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 R1 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(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or -0-CH2 -phenyl. Where R' is t-butyl for the' 3,5-isoxazole ureas, B is not and where R' is -CH2 -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, Q1 is pyridinyl, phenyl or benzothiazolyl, Y is -0-, -S-, -CHjS-, -SCH2-, -CH;0-, -OCH2- or-CHr, and Z is H, -SCH3, or-NH-C(0)-CpH2p+I, wherein p is 1-4, n = 0, s = 1 and nl = 0-1. Specific examples of preferred pyrazolyl ureas are: Ar-(3-/e/-/-Butyl-5-pyrazolyl)-Ar-(4-phenyloxyphenyl)urea; Ar-(3-fe^Buryl-5-pyrazolyl)-Ar'-(3-(3-memylaminocarbonylphenyl)-oxyphenyl)urea; //-(3-/er/-Butyl-5-pyrazolyl)-7/'-(3-(4-pyridinyl)thiophenyl)urea; A'-(3-fert-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea; Ar-(3-rerr-Butyl-5-pyrazolyl)-Ar'»(4-(4-pyridinyl)oxyphenyl)urea; Ar-(3-rer/-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea; N-(1 -Methyl-S-fert-butyl-S-pyrazolyl)-// '-(4-phenyloxyphenyl)urea; Ar-(l-Methyl-3-^rt-butyl-5-pyrazolyl)Ar'-(3-(4-pyridinyI)thiophenyl)urea; Ar-(l-Methyl-3-rerr-butyl-5-pyrazolyl)-Ar,-((4-(4-pyridinyl)thiomethyl)-phenyl)urea; N-( 1 -Methyl-3-rerf-butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; N-{ 1 -Methyl-3-terf-butyl-5-pyrazolyl)-iV '-(4-(4-pyridinyl)oxyphenyl)urea; //-(l-Methyl-3-rert-butyl-5-pyrazolyl)-JV'-((4-(4-pyridinyl)methyloxy)phenyl)-urea; Ar-(l-Methyl-3-ferr-butyl-5-pyrazolyl)-7\lf'-(3-(2-benzothiazolyl)oxyphenyl)-urea; //-(3-/er/-butyl-5-pyrazolyl)-//'-(3-(4-pyridyl)thiophenyl)urea; A^-(3-fert-butyl-5-pyrazolyl)-Ar'-(4-(4-pyridyl)thiophenyl)urea; Ar-(3-/err-butyl-5-pyrazolyl)-Ar'-(3-(4-pyridyl)oxyphenyl)urea; //-(3-/crr-butyl-5-pyrazolyl)-//'-(4-(4-pyridyl)oxyphenyl)urea; N-(\ -methyl-3-/er/-butyl-5-pyrazolyl)-A^'-(3-(4-pyridyl)thiophenyl) urea; N-( 1 -methyl-3 -rerr-butyl-S-pyrazolyl)-/^ '-(4-(4-pyridyl)thiophenyl) urea; N-(l -methyl-3-rert-butyl-5-pyrazolyl)-Ar'-(3-(4-pyridyl)oxyphenyl) urea; and iV-(l-methyl-3-rer/-butyl-5-pyrazolyl)-Ar-(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 -0-, -S- or -CH2-, Z is -CH3, CI, -OCH3 or -C(0)-CH3> n = 0, s - 1, and nl = 0-1. Specific examples of preferred 3,5-isoxazolyl ureas are: Ar-(3-Isopropyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea; A'-(3-fert-Butyl-5-isoxazolyl)-Ar'-(4-(4-methoxyphenyl)oxyphenyl)urea; Ar-(3-rerf-Butyl-5-isoxazolyl)-Ar'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea; Ar-(3-rerr-Butyl-5-isoxazolyl)-Ar'-(3-(4-pyridinyl)thiophenyl)urea; M Ar-(3-ferr-Butyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea; Ar-(3-rerr-Butyl-5-isoxazolyl)-Ar-(4-(4-pyridinyl)oxyphenyl)urea.; Ar-(3-ferr-Butyl-5-isoxazolyl)-Ar'-(4-(4-methyl-3-pyridinyl)oxyphenyl)urea; Ar-(3-fer/-Butyl-5-isoxazolyl)-Ar-(3-(2-benzothiazolyl)oxyphenyl)urea; Ar-(3-( 1,1 -DimethylpropyO-S-isoxazolyl)-^ '-(4-(4-methylphenyl)oxyphenyl)-urea; ^-(S-Cl.l-DimethylpropyO-S-isoxazolyO-^'^^-pyridinylJthiopheny^urea; Ar-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)oxyphenyl)urea; ^-(S^ljl-DimethylpropyO-S-isoxazolyO-^'^^-pyridinyOthiophenyOurea; Ar-(3-(l,l-Dimethylpropyl-5-isoxazolyl)-jV'-(5-(2-(4-methoxyphenyl)oxy)-pyridinyl)urea; jV-tS-Cl-Methyl-l-ethylpropyO-S-isoxazolyO-A^'-^^-pyridinyOoxyphenyl)-urea; Ar-(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-Ar-(3-(4-pyridinyl)thiophenyl)-urea; Ar-(3-isopropyl-5-isoxazolyl)-Ar'-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; Ar-(3-isopropyl-5-isoxazolyl)-//'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; //-(3-/ert-butyl-5-isoxazolyl)-A^-(3-(4-(2-methylcarbamoyl)-pyridyl)oxyphenyl) urea; Af-(3-/err-butyl-5-isoxazolyl)-Ar'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; Ar-(3-/er/-butyl-5-isoxazolyl)-Ar'-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea; //-(3-(l, 1 -dimethylprop-1 -yO-S-isoxazolylJ-N '-(3-(4-(2-methylcarbamoyl)-yridyl)oxyphenyl) urea; A'-(3-(lJl-dimethylprop-l-yl)-5-isoxazolyl)-Ar-(4-(4-(2-methylcarbamoyl)-pyridyl)oxyphenyl) urea; and Ar-(3-rert-butyl-5-isoxazolyl)-Ar'-(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, Q1 is phenyl, benzothiazolyl or pyridinyl, Y is -0-, -S- or -CH2-, X is CH3 and Z is -C(0)NH-, CpH2p+1, wherein p = 1-4, -C(0)CH3, -CH3, -OH, -0C2H5, -CN, phenyl, or -OCH3, n = 0 or 1, s = 0 or 1, and nl = 0 or 1. Specific examples of preferred 5,3-isoxazolyl ureas are: //-(5-/er/-Butyl-3-isoxazolyl)-Ar-(4-(4-hydroxyphenyl)oxyphenyl)urea; //-(5-/ert-Butyl-3-isoxazolyl)-Ar'-(4-(3-hydroxyphenyl)oxyphenyl)urea; Ar-(5-rert-Butyl-3-isoxazolyl)-Ar'-(4-(4-acetylphenyl)oxyphenyl)urea; Ar-(5-/ert-Butyl-3-isoxazolyl)-Ar'-(3-benzoylphenyl)urea; M(5-rerr-Butyl-3-isoxazolyl)-Ar'-(4-phenyloxyphenyl)urea; //-(5-fer/-Butyl-3-isoxazolyl)-Ar-(4-(3-methylaminocarbonylphenyl)-thiophenyl)urea; A^-(5-/er/-Butyl-3-isoxazolyl)-A^'-(4-(4-(l,2-methylenedioxy)phenyl)-oxyphenyl)urea; jV-(5-i'er/-Butyl-3-isoxazolyl)-Ar'-(4-(3-pyridinyl)oxyphenyl)urea; //-(5-fert-Butyl-3-isoxazolyl)-A^,-(4-(4-pyridinyl)oxyphenyl)urea; //-(5-/er/-Butyl-3-isoxazolyl)-//'-(4-(4-pyridyl)thiophenyl)urea; A^-(5-/er/-Butyl-3-isoxazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea; Ar-(5-/err-Butyl-3-isoxazolyl)-Ar'-(3-(4-pyridinyl)oxyphenyl)urea; N~(5-tert-B\ityl-3-isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; • ' iV-(5-terf-Butyl-3-isoxazolyl)-//'-(3-(3-methyl-4-pyridinyl)oxyphenyl)urea; //-(5-^rr-Butyl-3-isoxazolyl)-//'-(3-(3-methyl-4-pyridinyl)thiophenyl)urea; /^-(S-^rt-Butyl^-isoxazolyO-A^'^-CS-methyM-pyridinyOthiophenyOurea; iV-(5-rer/-Butyl-3-isoxazolyl)-A^-(3-(4-methyl-3-pyridinyl)oxyphenyl)urea; ^-(i-^nr-Bu^J-isox^o^-^-^-^-meChyW-pyricfmy^oxypheny^urea,' ?/-(5-rerr-Butyl-3-isoxazolyl)-iV-(3-(2-benzothiazolyl)oxyphenyl)urea; //-(5-/er/-butyl-3isoxazolyl)-//'-(3-chloro-4-(4-(2-methyIcarbamoyI)pyridyl)-oxyphenyl) urea; Ar-(5-^rt-butyl-3-isoxazolyl)-Af-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; A/^-(5-rerf-butyl-3-isoxazolyl)-iV-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea; //-(5-rer/-butyl-3-isoxazolyl)-//'-(2-niethyl-4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; //-(5-ter/-butyl-3-isoxazolyI)~// -(4-(4-(2-carbamoyI)pyridyl)oxyphenyI) urea; Ar-(5-rerr-butyl-3-isoxa2olyl)-//'-(3-(4-(2-carbamoyl)pyridyl)oxyphenyl)urea; ^-(S-rerr-butylO-isoxazolyO-jV'^^^-methylcarbamoylJpyridyl)-oxyphenyl) urea; A'-(5-rerr-butyl-3isoxazoIyl)-Ar-(4-(4-(2-methyIcarbamoyl)pyridyl)-thiophenyl) urea; A'-(5-rerf-butyl-3-isoxazolyl)-A'"-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; and Ar-(5-/e/"/-butyl3-isoxazolyl)-//'-(4-(3-methylcarbamoyl)phenyl)oxyphenyl) urea. Additionally included are thienyl ureas of the formulae R1 S' wherein R1 , Rb and B are as defined above. Preferred B components for the thienyl ureas of this invention have aromatic ring structures selected from the group consisting of: These aromatic ring structures can be substituted or unsubstituted by halogen, up to per-halosubstitution. The X1 substiruents are independently selected from the group consisting of X or from the group consisting of, -CN, -OR5, -NR5R5', C,-C10 alkyl. The X substiruents are independently selected from the group consisting of -C02R5, -C(0)NR5R5', -C(0)R5, -N02, -SR5, -NR5C(0)0R5', -NR5C(0)R5', C3-C10 cycloalkyl, C6-CM aryl, C7-C2 The components for B are subject to the proviso that where R1 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, Q1 is phenyl or pyridinyl, Y is -O- or -S-, Z is -CI, -CH3, -OH or -OCH3, n = 0, s - 0 or 1, and nl = 0-2. Specific examples of preferred thienyl ureas are: //-(S-Isopropyl-S-isoxazolyO-^'-C^A-pyridinylJthiophenylJurea; 7/-(3-/err-Butyl-5-isoxazolyl)-7vr'-(4-(4-methoxyphenyl)oxyphenyl)urea; 7V-(3-rerf-Butyl-5-isoxazolyl)-A^'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea; ^-(S-Zerz-Butyl-S-isoxazolyO-A^'^S^-pyridinyOthiophenylJurea; Ar-(3-rerNButyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea; //-(3-/er/-Butyl-5-isoxazolyl)-A'"-(4-(4-pyridinyI)thiophenyI)urea; A^-fe^Butyl-S-isoxazolyty-N'-^-^-pyridinytyoxyphenytyurea; Af-(3-^r/-Butyl-5'isoxa2olyl)-Ar'-(4-(4-methyl-3-pyridinyI)oxyphenyl)urea; Ar-(3-/err-Butyl-5-isoxa2olyl)-//'-(3-(2-benzothia2olyl)oxyphcnyl)urea; N-(3-( 1,1 -Dimethylpropyl)-5-isoxazoIyl)-Ar'-(4-(4-methylphenyl)-oxyphenyl)urea; //-(S-fl.l-DimethylpropyO-S-isoxazolylJ-A^'^^-pyridinylJthiophenyOurea; iV-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-iV'-(4-(4-pyridinyl)oxyphenyl)urea; 7V-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea; JV-(3-( 1,1 -Dimethylpropyl-5-isoxazolyl)-A^'-(5-(2-(4-methoxyphenyl)-oxy)pyridinyl)urea; Ar-(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-^'-(4-(4-pyridinyl)-oxyphenyl)urea; and Af-(3-(l -Methyl-1 -ethylpropylJ-S-isoxazolyl)-^-(3-(4-pyridinyl)thio-phenyl)urea. Preferred thiophenes include: //-(5-ter/-butyl-3-thienyl)-//'-(4-(4-methoxyphenyl)oxyphenyl) urea; Ar-(5-ren-butyl-3-thienyl)-Ar'-(4-(4-hydroxyphenyl)oxyphenyl)urea; 7l/-(5-/er/-butyl-3-thienyl)-Ar'-(4-(3-methylphenyl)oxyphenyl) urea; and Ar-(5-/er/-butyl-3-thienyl)-//'-(4-(4-pyridyl)thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: wherein R, Rb, R1 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 X1 subsrituent is independently selected from the group consisting of X or from the group consisting of -CN, -N02 ,-OR5 and 0,-0,0 alkyl. The X substituents are selected from the group consisting of-SR$, -C02R5, -C(0)R5, -C(0)NR5R5', -NRSR5', -NR5C(0)OR5', -NR5C(0)R5', substituted C2.10-alkenyl, substituted C,.10-alkoxy, -C3-C10 cycloalkyl, -C6-C14 aryl, -C7-C2 This invention also includes pharmaceutical compositions that include compounds described above and a physiologically acceptable carrier. Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula and Q, Q\ X, Y, Z, n, s, and nl are as defined above. The preferred thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q1 is phenyl or pyridinyl, Y is -0- or -S-, n = 0, s = 1 and nl = 0. Specific examples of preferred thiadiazolyl ureas are: ^-(S-rerr-Butyl^-fl-thia-a^-diazolyOJ-Z/'^S-fA-pyridinyOthiophenyOurea; Ar-(5-fert-Butyl-2-(l-thia-3,4-diazolyl))-A^'-(4-(4-pyridinyl)oxyphenyl)urea; A^-(5-rerr-butyl-2-(l-thia-3,4-diazolyl))-A^'-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; //-(5-/frr-butyl-2-(l-thia-3,4-diazolyl))-^'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; ^-(5-/ert-butyl-2-(l-thia-3,4-diazolyl))-A^.(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; //-(5-^r/-butyl-2-(l-thia-3,4-diazolyl))-A^-(2-chloro-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl)urea; //-(S-rerr-butyl^-Cl-thia-S^-diazolylJJ-Af'-CS^-pyridylJthiophenyOurea; W-(5-rerf-butyl-2-( 1 -tbia-3,4-diazolyl))-^'-(2-methyl-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; and N-(5-(\, 1 -dimethylprop-1 -yl)-2-( 1 -thia-3,4-diazolyl))-AT -(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 -CI or -OCH3, s = 0 or 1, n = 0 and nl = 0-2. The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the 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 Na+ or K+), alkaline earth cations (e.g., Mg2, Ca2 or Ba2), 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, MN-diethylamine, //.N-dicycIohexylamine, pyridine, A^A^dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene(DBU). A number of the compounds 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 compounds described in Formula I which possess Raf kinase inhibitory activity. General Preparative Methods The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some of which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, with more detailed examples being presented in the experimental section describing the working examples. Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3"1 Ed.; John Wiley: New York (1985)). For example, 3-substitutcd-5-aminoisoxazoIes (3) are available by the reaction of hydroxylamine with an a-cyanoketone (2), as shown in Scheme I. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an -cyanoketone with hydrazine (R2=H) or a monosubstituted hydrazine affords the 3-substituted- or l,3-disubstituted-5-aminopyrazole (5). Pyrazoles unsubstituted at N-l (R2=H) may be acylated at //-l, for example using di-ter/-butyl dicarbonate, to give pyrazole 7. Similarly, reaction 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-bntoxy (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. Scheme I. 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 LiAlH4 (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)). Scheme II Reduction of Nitroaryls to Aryl Amines Nitroaiyls are commonly formed by electrophilic aromatic nitration using HN03, or an alternative N02+ source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with HN03 Ar-H ► ArN02 potential leaving groups (eg. F, CI, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme HI) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine (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 A^A^'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 21 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (22) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic amine. Scheme rv Selected Methods of Urea Formation (Het = heterocycle) l-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed by treatment with phosgene or a phosgene equivalent. Reaction of anhydride 25 with an aryl amine can generate acid 26 which may spontaneously decarboxylate, or may be isolated. If isolated, decarboxylation of acid 26 may be induced upon heating. Scheme V Urea Formation via Isatoic-Hke Anhydrides Finally, ureas may be further manipulated using methods familiar to those skilled in the art. The invention also includes pharmaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. The compounds may be administered orally, topically, parenterally, by inhalation or spray or sublingually, rectally or vaginally in dosage unit formulations. The 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 compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients. Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl /?-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The compounds may also be in the form of non-aqueous liquid formulations, 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 alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols. Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve. Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons. Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated Cg-C„ fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cg-C„ fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C,-C„ fatty alcohols, saturated or unsaturated C,-C„ fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers. Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix. For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight. It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defuied 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 VI, filed on December 22, 1997, as Serial No. 08/996,343, converted on December 22,1998. The compounds are producible from known compounds (or from starting materials which, in rum, 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 reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. All temperatures are reported uncorrected in degrees Celsius (°C). Unless otfierwise 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-254 250 um 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 Science silica gel. Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHClj S 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCI3 5 77.0; MeOD-d3; 8 49.0; DMSO-d6 5 39.5) as standard. Low resolution mass spectra (MS) and high resolution 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 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept l-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (lxlO"4 torr to 2.5X10"4 torr). The direct insertion desorption chemical ionization (DO) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength 5 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; 2J I 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 assigned structures. List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous BOC /err-butoxycarbonyl cone concentrated dec decomposition DMPU lf3-dimemyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone DMF A^/Z-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate EtOH ethanol(100%) EtjO diethyl ether Et3N triethylamine m-CPBA 3-chIoroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl 5 A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoIes O Step 1. 3-Oxo-4-methylpentanenitrile: A slurry of sodium hydride (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 °C for 15 min., then a ) solution of acetonitrile (13.5 mL, 258 mmol) in benzene (52 mL) was added dropwise via addition funnel followed by a solution of ethyl isobutyrate (15 g, 129 mmol) in benzene (52 mL). The reaction mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water (50 mL) via addition funnel. The organic layer was separated and set aside. EtOAc (100 i mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (cone. HC1) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgSOJ, 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-isopropylisoxazoIe: 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 reaction mixture was immediately extracted with CHClj (3 x 100 mL) without cooling. The combined organic layers were dried (MgSC%), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% CH2C12) to afford the desired isoxazole as a yellow solid (11.3 g, 70%): mp 63-65 "C; TLC R^ (5% acetone/95% CH2C12) 0.19; 'H-NMR (DMSO-d6) d 1.12 (d, .7=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. Genera! Method for the Preparation of 5-Amino-l-alkyI-3-alkylpyrazoles NC 5-Amino-3-tert-butyM-(2-cyanoethyI)pyrazole: A solution of 4,4-dimethyI-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 reaction. 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 (E^O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) R^O.31; 'H-NMR (DMSO-d6) 6 1.13 (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, 1H). A 4. Synthesis of 3-Amino-5-aIkylthiophenes A4a. Synthesis of 3-Amino-5-aIkyIthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids Step 1. 7-/£rf-Butyl-2H-thieno[3,2-d]oxazine-2,4(lH>dione: A mixture of methyl 3-amino-5-te/-/-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 reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 mL). Phosgene (20% in toluene, 70 mL) was added dropwise over a 2 h period. The resulting mixture was stirred at room temperature overnight and the resulting precipitate was triturated (acetone) to afford the desired anhydride (5.78 g, 73%): "H-NMR (CDC13) 6 1.38 (s, 9H), 2.48 (s, 1H), 6.75 (s, 1H); FAB-MS m/z (rel abundance) 226 ((M+H)+, 100%). Step 2. ^-(S-rcrt-Butyl^-carboxy-S-thienyO-A^'^^-pyridinylmethyOphenyl)-urea: A solution of 7-rerf-butyl-2H-thieno[3,2-d]oxazine-2,4(lH)-dione (0.176 g, 0.78 mmol) and 4-(4-pyridinylmethyI)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 EtjO to afford the desired urea (0.25 g, 78%): mp 187-189 °C; TLC (50% EtOAc/50% pet. ether) R^O.04; 'H-NMR (DMSO-d6) 6 1.34 (s, 9H), 3.90 (s, 2H), 7.15 (d, J=THz, 2H), 7.20 (d, J=3 Hz, 2H), 7.40 (d, J=l 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. Ar-(5-rert-Butyl-3-thienyl)-Ar'-(4-(4-pyridinyImethyl)phenyI)urea: A vial containing A^-(5-/ert-butyl-2-carboxy-3-thienyl)-iV(4-(4-pyridinyImethyl)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 purified by preparative HPLC (C-18 column; gradient from 20% CH3CN/79.9% H2O/0.1% TFA to 99.9% H2O/0.1% TFA) to give the desired product (0.024 g, 43%): TLC (50% EtOAc/50% pet. ether) R, 0.18; 'H-NMR (DMSO-d6) 8 1.33 (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, >7 Hz, 1H), 8.58 (s, 1H), 8.68 (d, >7 Hz, 2H), 8.75 (s, 1H); EI-MS m/z 365 (M+). A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-aIkyI-2-thiophene-carboxylate esters 5-te/Y-Butyl-3-thiopheneammonium Chloride: To a solution of methyl 3-amino-5-ferr-butyl-2-thiophcne-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp, for 2.25 h. A cone. HC1 solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 mL) and a saturated NaHC03 solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCl solution (150 mL), dried (NajSOJ, and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification. A4c Synthesis 3-Amino-5-aIkylthiophenes from A'-BOC 3-Amino-5-aIky]-2-thiophenecarboxylate esters Step 1. Methyl 3-(terf-ButoxycarbonyIamino)-5-tert-butyl-2-thiophenecarboxy-late: To a solution of methyl 3-amino-5-terf-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 °C was added di-terM>utyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and Ar1Ar-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 dissolved in CH2C12 (3 L) and sequentially washed with a 1 M H3P04 solution (2 x 750 mL), a saturated NaHCOj solution (800 mL) and a saturated NaCl solution (2 x 800 mL), dried (NajSOJ and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 °C, then treated with water (500 mL) to afford the desired product as an off-white solid (163 g, 74%): 'H-NMR (CDC13) 8 1.38 (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-(^rr-Butoxycarbonylamino)-5-ferf-butyI-2-thiophenecarboxyIic Acid: To a solution of methyl 3-(/er/-butoxycarbonylamino)-5-/er/-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 HC1 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 HC1 solution (500 mL). The organic phase was washed with a saturated NaCl solution (4 x 1.5 L), dried (Na^O,), and 5 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, 93% total yield): 'H-NMR (CDC1,) 6 1.94 (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-terf-BuryI-3-tbiopheneammonium Chloride: A solution of 3-(tert-butoxycarbonylamino)-5-rer/-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HC1 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 collected and dried overnight under reduced pressure to give the desired salt as an off-white solid (1.72 g, 90%): 'H-NMR (DMSO-d6) 6 1.31 (s, 9H), 6.84 (d, 7=1.48 Hz, 1H), 7.31 (d, 7=1.47 Hz, 1H), 10.27 (brs, 3H). A5. General Method for the Synthesis of BOC-Protected Pyrazoles S-Amino-3-/crt-butyl-Ar/'(tert-butoxycarbonyI)pyra2ole: To a solution of 5-amino-3-ter/-butylpyrazole (3.93 g, 28.2 mmol) in CH2C12 (140 mL) was added di-terf-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp, for 13 h, then diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO 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 reaction mixture was heated at 85 °C for 7 h, then cooled to room temperature, and treated with a concentrated NH4OHsolution until basic. The resulting solids were filtered to afford 2-amino-5-(l-(l-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) IV 0.14; 'JLNMR (DMSO-d6) 5 0.80 (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 m/z 172 ((M+H)+). A7. GeneralMetbod for the Synthesis of 2-AminooxadiazoIes \- 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-isopropyI oxadiazole: To a mixture of isobutyric hydrazide (0.093 g), KHCOj (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 CHjCl2 (5 mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO^ and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+). A8. General Method for the Synthesis of 2-Aminooxazoles O ,OH Step 1. 3,3-Dimethyl-l-hydroxy-2-butanone: A neat sample of l-bromo-3,3-dimethyl-2-butanone (33.3 g) at 0 °C was treated with a IN NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (NajSOJ and concentrated under reduced pressure to -3- give 3,3-dimethyl-l-hydroxy-2-butanone (19 g, 100%), which was used inb the next step withour further purification. Step 2. 2-Amino-4-isopropyI-l,3-oxazoIe: To a solution of 3,3-dimethyI-l-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-ij-butylammonium hydroxide (0.4 M, 3.6 mL), then a IN NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with E^O (3 x 25 mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure to afford 2-Amino-4-isopropyM,3-oxazole (1.94 g, 41%): HPLC ES-MS m/z 141 ((M+H)+). A9. Method for the Synthesis of Substituted-S-aminotetrazoIes : 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 CHjCl2 (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1- and 2-isopropyl-5-aminotetrazole (50%), which was used without further purification: HPLC ES-MS m/z 128 ((M+H)+). B. General Methods for Synthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene 4-(4-PyridinylmethyI)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 H2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 'H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%): 'H-NMR (DMSO-d6) 5 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, >8.46 Hz, 2H), 6.86 (d, 7=8.09 Hz, 2H), 7.16 (d, 7=5.88 Hz, 2H), 8.40 (d, 7=5.88 Hz, 2H); EI-MS m/z 184 (NT). This material was used in urea formation reactions without further purification. General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH ( 5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL), basified to pH 10 by adding solid K2COj in portions {Caution: foaming). The organic layer was washed with a saturated NaCl solution, dried (MgS04), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) fy 0.20. B3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. l-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 reaction was stirred 1 h, then a solution of l-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then cooled to room temp., quenched with H20, and concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and H20 (200 mL) . The organic layer was sequentially washed with H20 (2 x 200 mL), a saturated NaHCO, solution (200 mL), and a saturated NaCl solution (200 mL), dried (Na^O,), and concentrated in vacuo. The residue was triturated (Et20/hexane) to afford 1- methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDC13) 5 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, .7=9.2 Hz, 2H); EI-MS m/z 245 (M+). Step 2. 4-(4-Methoxypbenoxy)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 reaction mixture was filtered through a pad of Celite with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR (CDC13) 5 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, .7=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215 (Ml. >. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction tep 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-lercaptopyridine (2.8 g, 24 mmoles), 2-fiuoro-5-nitrobenzotrifIuoride (5 g, 23:5-omoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) r'as stirred at room temperature and under argon overnight. TLC showed complete taction. The mixture was diluted with E^O (100 mL) and water (100 mL) and the queous layer was back-extracted with E^O (2 x 100 mL). The organic layers were fashed with a saturated NaCl solution (100 mL), dried (MgSOJ, and concentrated nder reduced pressure. The solid residue was triturated with E^O to afford the esired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) R^O.06; 1-NMR (DMSO-d6) 8 7.33 (dd, >1.2,4.2 Hz, 2H), 7.78 (d, >8.7 Hz, 1H), 8.46 (dd, =2.4, 8.7Hz, 1H), 8.54-8.56 (m, 3H). tep 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline; A slurry of 3-ifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp, for h. The mixture was diluted with E^O (100 mL) and water (100 mL). The aqueous lase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers ere washed with a saturated NaCl solution (100 mL), dried (MgS04), and mcentrated under reduced pressure. The residue was filtered through a pad of silica radient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the sired product (3.3 g): TLC (50% EtOAc/50% hexane) R,0.10; 'H-NMR (DMSO-d6) 5.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, ^=8.4 Hz, 1H), 8.29 ,7=6.3 Hz, 2H). jneral Method for Substituted Aniline Formation via Nitroarene Formation trough Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(2-(4-Phenyl)thiazoIyl)thio-l-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2C03 (3.18 g, 23 mmol), and the mixture was heated at approximately 65 °C overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO«) and concentrated under reduced pressure. The solid residue was triturated with a E^O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) R^ 0.49; 'H-NMR (CDC13) 5 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, 7=6.9 Hz, 2H), 8.19 (d, y=9.0 Hz, 2H). Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio-l-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) RjrO.18; 'H-NMR (CDC13) 8 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H). General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(6-Methyl-3-pyridinyIoxy)-l -nitrobenzene: To a solution of 5-hydroxy-2-methylpyridine (5.0 g, 45.8 mmol) and l-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K2C03 (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 (>* 130 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na^O,), 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)-l-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 H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, 92%): EI-MS m/z 200 (M). General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4-dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 uL, 6.4 mmol) in anh DMF (20 mL) was added K2C03 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (NajSOJ, 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)-!-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 (balloon) and was allowed^to^stir for 18 h at room temp. The mixture was then filtered through a pad of Celite and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z 245 (M+)- f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K2C03 (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NajSOJ, and concentrated in vacuo. The resulting oil was purified 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)-l- 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 (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (1.6 g, 94%): EI-MS m/z 186 (M+). . General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 3-(5-MethyI-3-pyridinyIoxy)-l-nitrobenzene: To a solution of 3-hydroxy-5-methylpyridine (5.0 g, 45.8 mmol), l-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 K2C03 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (N^SOJ, and concentrated in vacuo . The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%). Step 2. 3-(5-MethyI-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3-pyridinyIoxy)-l-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 H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H)+). i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 5-Nitro-2-(4-methyIphenoxy)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 K2C03 (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 (30% EtOAc/70% pet ether) R^O.79; 'H-NMR (DMSO-dJ 8 2.31 (s, 3H), 7.08 (d, 7=8.46 Hz, 2H), 7.19 (d, 7=9.20 Hz, 1H), 7.24 (d, 7=8.09 Hz, 2H), 8.58 (dd, 7=2.94, 8.82 Hz, 1H), 8.99 (d, 7=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 ((M+H)+), 100%). Step 2. 5-Anuno-2'(4-niethyIphenoxy)pyridine Dihydrochloride: A solution 5-nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 xnmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The reaction mixture was then placed under a H2 atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celite®. A solution of HCI in Et20 was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, 92%): mp 208-210 °C (dec); TLC (50% EtOAc/50% pet ether) R, 0.42; 'H-NMR (DMSO-d6) 8 2.25 (s, 3H), 6.98 (d, 7=8.45 Hz, 2H), 7.04 (d, 7=8.82 Hz, 1H), 7.19 (d, .7=8.09 Hz, 2H), 8.46 (dd, 7=2.57, 8.46 Hz, 1H), 8.63 (d, 7=2.57 Hz, 1H); EI-MS m/z (rel abundance) (M\ 100%). General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1. 4-(3~Thienylthio)~l-nitrobenzene: To a solution of 4-nitrothiophenol (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 reaction mixture was then poured into a mixture of ice and a 6N HCI solution (200 mL) and the resulting aqueous mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a 1M NaOH solution (2 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (MgSO«), and concentrated in vacuo . The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS m/z 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 Bl. B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 4-(5-Pyrimininyloxy)aniIine: 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC-MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp, and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCl solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%). 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 reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (N^SOJ and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90% hexane)Rj-0.57. 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 reaction 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 reaction mixture was warmed to room temp, for 30 min and then heated to the reflux temp, for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a IN HC1 solution then extracted with Et20 (2 x 100 mL). The combined organic layers were dried (NajSOJ and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%). Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-l-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 reaction mnixture was heated to 95 °C overnight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSOJ and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%). -So- Step 4. 4-(5-(2-Methoxy)pyridyI)oxyaniline: 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2. a. 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 K2C03 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp, for 1.5 h, then diluted with EtOAc (100 mL) and water (lOOmL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSOJ, and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et20/hexane solution to afford the desired product (4,6 g, 66%): TLC (100 % ethyl acetate) R, 0.29; 'H-NMR (DMSO-dJ 5 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8,2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8,2H). t>. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine 4-(2-MethyI-4-pyridinyIoxy)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 /er/-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction 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 combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NajSC^), and concentrated in vacuo. The resulting oil was purified by flash chromatography (50 % EtOAc/50% hexane) to afford the desired product as a yellow oil (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. MethyI(4-nitrophenyl)-4-pyridylaniine: To a suspension of N-methyl-4-nitroaniline (2.0 g, 13.2 mmol) and K2C03 (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried (NajSOJ and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine (0.42 g) Step 2. Methyl(4-amuiophenyl)-4-pyridyIamine: Methyl(4-nitrophenyl)-4-pyridylamine was reduced in a manner analogous to that described in Method Bl. B5. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene Step 1. 4-(4-Butoiyphenyl)thio-l-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 reaction was stirred at room temp, for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with EtjO (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 purified by silica gel chromatography (gradient from 20% EtOAc/80% hexane to 50% EtOAc/50% hexane) to give the product as a yellow solid (1.24 g, 67%): TLC (20% EtOAc/80% hexane) fyO.75; 'H-NMR (DMSO-dj) 8 0.92 (t, J= 7.5 Hz, 3H), 1.42 (apphex,>7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, >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-ButoxyphenyI)thioaniIine: 4-(4-Butoxyphenyl)thio-l -nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step 2): TLC (33% EtOAc/77% hexane) RyO.38. B6. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes 4-(4-terf-ButoxycarbamoyIbenzyl)aniline: To a solution of 4,4'-methyIenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di-rerr-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp, for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-ferf-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp, for 16 h. The resulting mixture was diluted with EtjO (200 mL), sequentially washed with a r saturated NaHC03 solution (100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a white solid ( 2.09 g, 46%): TLC (50% EtOAc/50% hexane) R, 0.45; 'H-NMR (DMSO-d,) 5 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, 7=8.4 Hz, 2H), 6.80 (d, 7=8.1 Hz, 2H), 7.00 (d, 7=8.4 Hz, 2H), 7.28 (d, 7=8.1 Hz, 2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M). 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 IN NaOH solution, then extracted with Et20 (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NajSOJ, and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC-MS m/z 214 (M). Step 2. 3-(4-Pyridinyl)methyIaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method Bl. Genera] Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction Step 1. 4-(l-ImidazolyImethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K2C03 (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 combined organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, 91%): EI-MS m/z 203 (M+). Step 2. 4-(l-ImidazolyImetbyl)aniline: 4-(l-Imidazolylmethyl)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction Step 1. 4-(l-Hydroxy-l-(4-pyridyI)methyl-l-nitrobenzene: To a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH2C12 (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 6C, and the mixture was stirred at room temp, overnight. The reaction mixture was successively washed with a 10% NaHSO, solution (50 mL), a saturated K2C03 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgS04) and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous 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 CH2C12 (50 mL). The organic layer was dried (MgSOJ, concentrated under reduced pressure, and purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired product as a white solid. (0.53 g, 8%): mp 110-118 °C; TLC (80% EtOAc/20% hexane) R^O.12; FAB-MS m/z 367 ((M+H)+, 100%). Step 2. 4-(l-Hydroxy-l-(4-pyridyI)methyIaniIine: 4-(l-Hydroxy-l-(4-pyridyI)-m ethyl-1 -nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2. BIO. Formation of 2-(7V-methyIcarbamoyl)pyridines via the Menisci reaction step 1. 2-(iV-methyIcarbamoyI)-4-chIoropyridine. (Caution: this is a highly lazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) n //-methylformamide (250 mL) under argon at ambient temp was added cone. H2S04 3.55 mL) (exotherm). To this was added H202 (17 mL, 30% wt in H20) followed >y FeS04 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark it ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling ubsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was liluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The queous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were /ashed separately with a saturated NaCl solution (3 x 150 mlL. The combined rganics were dried (MgS04) and filtered through a pad of silica gel eluting with itOAc. The solvent was removed in vacuo and the brown residue was purified by ilica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 0% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(N-iethylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% exane) fy0.50; MS; 'H NMR (CDC13): 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, C1CHCN), 3.04 (d 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+). Bll. Generalmethod for the Synthesis of ©-Sulfonylphenyl Anilines Step 1. 4-(4-MethyIsulfonyIphenoxy)-l-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH2C12 (75 mL) at 0 °C was slowly added mCPBA (57-86%, 4 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSOJ, and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene as a solid (2.1 g). Step 2. 4-(4-MethyIsulfonyIpbenoxy)-l-aniIine: 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 o-Alkoxy-o-carboxyphenyl Anilines Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of -(3 -carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added K2C03 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat the reflux tempoerature overnight, then cooled to room temperature and filtered through a pad of Celite. The resulting solution was concentrrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115 118 °C. Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-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 dissolved in water (50 mL), and the aqueous mixture was made acidic with a lN'HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g). C. General Methods of Urea Formation CI a. Reaction of a Heterocyclic Amine with an Isocyanate A'-(S-rerr-Butyl-3-thienyl)-Ar'-(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 H20 (200 mL), a 1 N HC1 solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajS04), 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-phenoxyphenyI)urea. A portion of this material (4.67 g) was purified by flash chromatography (9% EtOAc/27% CHjCl^^o cyclohexane) to afforded the desired product as a white solid (3.17 g). Clb. Reaction of a Heterocyclic Amine with an Isocyanate AH3-f^ButyI-5-isoxazolyl)-A^(4-phenojcyphenyl)urea: To a solution of 5-amino-3-rert-butylisoxazole (8.93 g, 63.7 mmol, 1 eq.) in CHjClj (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 CH2C12 (80 mL). The resulting mixture was poured into water (500 mL) and extracted with EtjO (3 x 200 mL). The organic layer was dried (MgS04) 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^0.27; 'H-NMR (DMSO-d«) 5 1.23 (s, 9H), 6.02 (s, 1H), 6.97 (dd, 7=0.2, 8.8 Hz, 2H), 6.93 (d, .7=8.8 Hz, 2H), 7.08 (t, .7=7.4 Hz, 1H), 7.34 (m, 2H), 7.45 (dd, .7=2.2, 6.6 Hz, 2H) , 8.80 (s, 1H), 10.04 (s, 1H); FAB-MS m/z (rel abundance) 352 ((M+H),70%). Clc. Reaction of a Heterocyclic Amine with an Isocyanate ^-(3-/ffrt-ButyI-5-pyrazoIyI)-7V'-(4-(4-methyiphenyl)oxyphenyI)urea: A solution of 5-amino-3-ter/-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4-(4-methyIphenoxy)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 rain, the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, 33%): mp 204 °C; TLC (5% acetone/95% CH2C12) R^O.92; 'H-NMR (DMSO-d6) 6 L22 (s, 9H), 2.24 (s, 3H), 5.92 (s, 1H), 6.83 (d, 7=8.4 Hz, 2H), 6.90 (d, .7=8.8 Hz, 2H), 7.13 (d, 7=8.4 Hz, 2H), 7.40 (d, 7=8.8 Hz, 2H), 8.85 (s, 1H), 9.20 (br s, 1H), 11.94 (br s, 1H); EI-MS m/z 364 (M+). Cld. Reaction of a Heterocyclic Amine with an Isocyanate A^-(5-^rf-Butyl-3-thienyl)-JV'-(2,3-dichlorophenyI)urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-fcr/-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL, 2.02 mmol) in CH2C12 (10 mL) to clarify the mixture and the resulting solution was stirred at room temp, overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHCOj solution (15 mL), a IN HC1 solution (15 mL) and a saturated NaCl solution (15 mL), dried (NajSOJ, 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) R, 0.57; 'H-NMR (DMSO-d6) 5 1.31 (s, 9H), 6.79 (s, 1H), 7.03 (s, 1H), 7.24-7.33 (m, 2H), 8.16 (dd, 7=1.84, 7.72 Hz, 1H), 8.35 (s, 1H), 9.60 (s, 1H); "C-NMR (DMSO-d6) 8 31.9 (3C), 34.0,103.4,116.1,119.3,120.0,123.4,128.1,131.6,135.6,138.1,151.7,155.2; FAB-MS m/z (rel abundance) 343 ((M+H)+, 83%), 345 ((M+H+2)\ 56%), 347 ((M+H+4)\ 12%). Cle. Reaction of a Heterocyclic Amine with an Isocyanate A,-(3-rerf-Butyl-5-pyrazolyl)-Ar'-(3,4-dichlorophenyl)urea: A solution of 5-amino-3-/err-butyl-Ar/-(rer/-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 CH2C12 (3 mL) and TFA (1.5 mL). After 30 min, the solvent was removed in vacuo and the residue was taken up in EtOAc (10 mL). The resulting mixture was sequentially washed with a saturated NaHCO, solution (10 mL) and a NaCl solution (5 mL), dried (NajSOJ, and concentrated in vacuo. The residue was purified 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) fyO.05, FAB-MS m/z 327 ((M+H)+). Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline Step 1. 3-te/?-Butyl-5-isoxazoIyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CH2C12 (20 mL) at 0 °C was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-/ert-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. Ar-(3-/erf-Butyl-5-isoxazolyl)-A^'-(4-(4-pyridinylthio)phenyl)urea: The crude 3-terf-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4-(4-pyridinylthio)aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 °C for 2 h then cooled to room temp, and diluted with an EtOAc/CH2Cl2 solution (4:1, 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CH2C12 to 4% MeOH/6% CH2C12) to afford a foam, which was triturated (EtjO/hexane) in combination with sonication to give the product as a white powder (0.18 g, 49%): TLC (5% MeOH/95% CH2C12) R, 0.21; 'H-NMR (DMSO-dJ 5 1.23 (s, 9H), 6.06 (s, 1H), 6.95 (d, /=5 Hz, 2H), 7.51 (d, 7=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 «/r 369 ((M+H)+). C2b. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline Step 1. 5-terf-Butyl-3-isoxazoIyl 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-terf-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 dissolved in anh. THF (350 mL) and stirred for 10 min. The orange precipitate (pyridinium hydrochloride) was removed and the isocyanate-containing filtrate (approximately 0.2 M in THF) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) m/z 166 (M+). Step 2. Ar-(5-^rt-Butyl-3-isoxazolyI)-Ar'-(4-(4-pyridinylthlo)phenyl)urea: To a solution of 5-fer/-butyI-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 NaCl solution (100 mL), a saturated NaHC03 solution (100 mL), and a saturated NaCl solution (100 mL), dried (MgS04), and concentrated m vacuo. The resulting material was purified by MPLC (2 x 300 g silica gel, 30 % EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 %): mp 178-179 °C; 'H-NMR (DMSO-d6) 8 1.28 (s, 9H), 6.51 (s, 1H), 6.96 (d, 7=6.25 Hz, 2H), 7.52 (d, 7=8.82 Hz, 2H), 7.62 (d, 7=8.83 Hz, 2H), 8.33 (d, 7=6.25 Hz, 2H), 9.10 (s, 1H), 9.61 (s, 1H); EI-MS m/z 368 (M+). C2c Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline iV-(3-/crt-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyloxy)phenyl)urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH2C12 (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 1 h, then was allowed to warm to room temp, over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-fer?-butyl-Af'-(terr-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 °C for 12 h forming a white precipitate. The solids were dissolved in a IN HC1 solution and allowed to stir at room temp, for 1 h to form a new precipitate. The white solid was washed (50% £^0/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 °C dec; TLC (10% MeOH/ 90% CHC13) R, 0.239; 'H-NMR (DMSO-d6) 8 1.24 (s, 9H), 5.97 (s, 1H), 6.88 (d, 7=6.25 Hz, 2H), 7.10 (d, 7=8.82 Hz, 2H), 7.53 (d, 7=9.2 Hz, 2H), 8.43 (d, 7=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%). Reaction of a Heterocyclic Amine with iVyV'-Carbonyldiiniidazole Followed by Reaction with a Substituted Aniline A^3-te/t-ButyI-l-methyl-5-pyrazolyI)-7V'-(4-(4-pyridinyloxy)phenyI)urea: To a solution of 5-amino-3-ferf-butyl-1-methylpyrazole (189 g, 1.24 mol) in anh. CH2C12 (2.3 L) was added //.W-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 reaction mixture was heated to 36 °C for 16 h. The resulting mixture was cooled to room temp, diluted with EtOAc (2 L) and washed with H20 (8 L) and a saturated NaCl solution (4 L). The organic layer was dried (Na^SO,,) and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et20/11.2% hexane, 2.5 L) to afford the desired urea as a white solid (230 g, 51%): mp 149-152 °C; 'H-NMR (DMSO-d6) 8 1.18 (s, 9H), 3.57 (s, 3H), 6.02 (s, 1H), 6.85 (d, .7=6.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.52 (d, .7=9.0 Hz, 2H), 8.40 (d, .7=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H); FAB-LSIMS m/z 366 ((M+H)+). b. Reaction of a Heterocyclic Amine with tyTV'-CarbonyldiimidazoIe Followed by Reaction with a Substituted Aniline ^-(S-rert-Butyl-S-pyrazoIyO-A^'-p-C^-py'dinylthioJphenyOurea: To a solution of 5-amino-3-/crr-butyl-7/'-(/er/-butoxycarbonyl)pyrazole (0.282 g, 1.18 mmol) in CHjClj (1.2 mL) was added N,N -carbonyldiimidazole (0.200 g, 1.24. mmol) and the mixture was allowed to stir at room temp, for 1 day. 3-(4-Pyridinylthio)aniline (0.239 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp, for 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 (MgSO224 °C dec; TLC (5% MeOH/ 95% CHC13) R, 0.067; 'H-NMR ,(DMSO-d6) 6 1.23 (s, 9H), 5.98 (s, 1H), 7.04 (dm, .7=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, 7=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%). Reaction of Substituted Aniline with fyW-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine Ar-(3-^rt-Butyl-l-methyl-5-pyrazolyl)-Ar'-(4-(4-pyridinylmethyI)phenyl)urea: To a solution of 4-(4-pyridinylmethyl)aniline (0.200 g, 1.08 mmol) in CH2C12 (10 mL) was added Af.AT-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for I h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-amino-3-tert-butyM-methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 °C overnight. The reaction mixture was cooled to room temp and purified by column chromatography (gradient from 20% acetone/80% CH2C12 to 60% acctone/40% CH2C12) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, 58%): TLC (4% MeOH/96% CH2C12) R^O.15; 'H-NMR (DMSO-d6) 5 1.19 (s, 9H), 3.57 (s, 3H), 3.89 (s, 2H), 6.02 (s, 1H), 7.14 (d, 7=8.4 Hz, 2H), 7.21 (d, >6 Hz, 2H), 7.37 (d, 7=8.4 Hz, 2H), 8.45-8.42 (m, 3H), 8.81 (s, 1H); FAB-MS m/z 364 (M+H)+). - CnS- C4b. Reaction of Substituted Aniline with A^W-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine Ar-(3-/err-ButyI-S-pyra2oIyI)-7V-(3-(2-benzothia2o!yIoxy)phenyI)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-/er/-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 CH2C12 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CH2C12. 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% CHjCl2) R, 0.05; 'H-NMR (DMSO-d6) 6 1.24 (s, 9H), 5.97 (s, 1H), 7.00-7.04 (m, 1H), 7.21-7.44 (m, 4H), 7.68 (d, 7=5.5 Hz, 1H), 7.92 (d, .7=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+). :. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline SL H H Ar-(5-rcrt-Butyl-3-thienyI)-Ar,-(4-(4-pyridinyloxy)pbenyl)urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH2C12 (5 mL) was added a solution of 4-(4-pyridinyloxy)aniIine (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH2C12 (5 mL). The resulting mixture was allowed to warm to room temp, and was stirred for 1 h, then was concentrated under reduced pressure. The residue was dissolved in CH2C12 (5 mL), then treated with S-tert-butylthiopheneammoniurn chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h, then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHCO, solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajSOJ, 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% EtOAc/50% hexane) i^-0.13; 'H-NMR (CDC13) 8 1.26 (s, 9H), 6.65 (d, >1.48 Hz, 1H), 6.76 (dd, .7=1.47, 4.24 Hz, 2H), 6.86 (d, .7=1.47 Hz, 1H), 6.91 (d, .7=8.82 Hz, 2H), 7.31 (d, .7=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, .7=1.47 Hz, 2H); "C-NMR (CDC13) 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%). !. General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine iV-(3-rerf-ButyI-4-methyl-5-isoxazolyI)-AT-(2-fluorenyl)urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (l.OmL) was added a solution of 5-amino-4-methyl-3-/err-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 70 °C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 40 °C for 3 h and then at RT for 17 h to produce a precipitate. The solids were washed with Et20 and hexanes to give the desired urea as a beige solid (25 mg, 14%): mp 179-181 °C; 'H-NMR (DMSO-d6) 6 1.28 (s, 9H), 2.47 (s, 3H), 3.86 (s, 2H), 7.22 (t, >7.3 Hz, 1H), 7.34 (m, 2H), 7.51 (d, 7=7.3 Hz, IH), 7.76 (m, 3H), 8.89 (s, IH), 9.03 (s, IH); HPLC ES-MS m/z 362 ((M+H)+). C6. General Method for Urea Formation by Curtius Rearrangement and 5 Carbamate Trapping Step 1. 5-MethyI-2-(azidocarbonyI)thiophene: To a solution of 5-Methyl-2-I 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 internal temperature below 5 °C. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the reaction mixture was stirred for 2 h at 0 °C. The resulting mixture was diluted with CH2C12 (10 mL) and washed with a saturated NaCl solution (10 mL). The aqueous layer was back-extracted with CH2C13 (10 mL), ind the combined organic layers were dried (MgS04) and concentrated in vacuo. The esidue was purified by column chromatography (10% EtOAc/ 90% hexanes) to give :he 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 reactions. Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp, for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions. H H Step 3. ^-(S-rerf-Butyl-S-isoxazoIyO-^'-fS-methyl^-thienyOurea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp. was added 3-amino-5-ferr-butyIisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a 1 N HC1 solution (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSOJ, and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, 93%): mp 200-201 °C; TLC (20% EtOAc/80% hexane) R, 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: POCl3 (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 reaction mixture was then to 55 °C for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCl solution (200 mL), dried (Na^SOJ and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH2C12) to give the desired aldehyde as an orange oil (15.5 g, 35%): TLC (5% EtOAc/95% hexane) R^O.54; 'H NMR (CDCI3) d 1.26 (s, 9H), 6.15 (d, 7=7.0 Hz, 1H), 10.05 (d,J"=6.6 Hz, 1H). Step 2. Methyl 5-ferr-butyl-2-thiophenecarboxyIate: 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 Na^S (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 reaction mixture was stirred at room temp, for 1.5 h, then treated with a 1 N HC1 solution (200 mL) and stirred for 1 h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HC1 solution (200 mL), water (2 x 200 mL) and a saturated NaCl solution (200 mL), dried (Na^OJ and concentrated under reduced pressure. The residue was purified using column chromatography (5% EtOAc/95% hexane) to afford the desired product (0.95 g, 36%): TLC (20% EtOAc/80% hexane) R^O.79; 'H NMR (CDC1,) 5 1.39 (s, 9H), 3.85 (s, 3H), 6.84 (d, 7=3.7 Hz, 1H), 7.62 (d, .7=4.1 Hz, 1H); GC-MS m/z (rel abundance) 198 (M+, 25%). Step 3. 5-/«rt'-BuryI-2-thiophenecarboxylic acid: Methyl 5-/erf-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 reaction mixture, then the pH was adjusted to approximately 3 using a 1 N HC1 solution. The resulting organic phase was washed with water (5 mL), dried (NajSOJ, 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) R/ 0.29; 'H NMR (CDC13) 8 1.41 (s, 9H), 6.89 (d, .7=3.7 Hz, 1H), 7.73 (d, 7=3.7 Hz, 1H), 12.30 (br s, 1H); UC NMR (CDC13) 8 32.1 (3C), 35.2,122.9,129.2,135.1,167.5,168.2. Step 4. ^-(S-Zcrt-Butyl-l-thienylJ-^'^^-dichlorophenyOurea: A mixture of 5-ferf-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 reaction mixture was heated to 80°C for an additional 2 h. The resulting mixture was allowed to cool to room temp, and treated with EtOAc (50 mL). The organic layer was washed with a 1 N HC1 solution (3 x 50 mL), a saturated NaHC03 solution (50 mL), and a saturated NaCl solution (50 mL), dried (Na^OJ, and concentrated under reduced pressure. The residue was purified 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) iyo.28; 'H NMR (CDCL.) 5 1.34 (s, 9H), 6.59 (br s, 2H), 7.10-7.13 (m, 2H), 7.66 (br s, 1H), 8.13 (dd, J=2$, 7.8 Hz, 1H); ,3C NMR (CDC13) 5 32.2 (3C), 34.6, 117.4, 119.07, 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 dissolved 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 purified by reverse phase HPLC. D. Misc. Methods of Urea Synthesis Dl. Electrophylic Halogenation Af-(2-Bromo-5-fcrt-butyI-3-thienyl)-Ar'-(4-methylphenyl)urea: To a slurry of N-(5-ferr-butyl-3-thienyl)-/>/ '-(4-methylphenyl)urea (0.50 g, 1.7 mmol) in CHC13 (20 mL) at room temp was slowly added a solution of Br2 (0.09 mL, 1.7 mmol) in CHC13 (10 mL) via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure, and the residue triturated (2 x Et20/hexane) to give the brominated product as a tan powder (0.43 g, 76%): mp 161-163 °C; TLC (20% EtOAc/ 80% hexane) fyO.71; 'H NMR (DMSO-d6) 5 1.29 (s, 9H), 2.22 (s, 3H), 7.07 (d, 7=8.46 Hz, 2H), 7.31 (d, 7=8.46 Hz, 2H), 7.38 (s, 1H), 8.19 (s, 1H), 9.02 (s, 1H); 13C NMR (DMSO-d6) 6 20.3, 31.6 (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. Synthesis of co-Alkoxy Ureas Step 1. AHS-re/t-Butyl-S-thienyO-N^-^-hydroxyphenyOoxypbenylJurea: A solution of//-(5-/er/-butyl-3-thienyl)-//'-(4-(4-methoxyphenyl)oxyphenyl)urea (1.2 g, 3 mmol) in CH2C12 (50 mL) was cooled to -78 °C and treated with BBr3 (1.0 M in CH2C12, 4.5 mL, 4.5 mmol, 1.5 equiv) dropwise via syringe. The resulting bright yellow mixture was warmed slowly to room temp and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), then washed with a saturated NaHC03 solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajS04), and concentrated under reduced pressure. The residue was purified via flash chromatography (gradient from 10% EtOAc/90% hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan foam (1.1 g, 92%): TLC (20% EtOAc/80% hexane) R, 0.23; 'H NMR (DMSO-d6) & 1.30 (s, 9H), 6.72-6.84 (m, 7H), 6.97 (d, >1.47 Hz, 1H), 7.37 (dm, 7=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. A'-(5-/crt-ButyI-3-thienyl)-Ar'-(4-(4-ethoxyphenyl)oxyphenyl)urea: To a mixture of Ar-(5-/err-butyl-3-thienyl)-//'-(4-(4-hydroxyphenyl)oxyphenyl)urea (0.20 g, 0.5 mmol) and Cs2COj (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 reaction was cooled, filtered, and the solids were washed with EtOAc. The combined organics were concentrated under reduced pressure, and the residue was purified via preparative HPLC (60% CHjCN/40% H2O/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, 73%): mp 155-156 °C; TLC (20% EtOAC/ 80% hexane) F^O.40; 'H-NMR (DMSO-d6) 5 1.30 (s, 9H), 1.30 (t, J=6S9 Hz, 3H), 3.97 (q, 7=6.99 Hz, 2H), 6.80 (d, 7=1.47 Hz, 1H), 6.86 (dm, 7=8.82 Hz, 2H), 6.90 (s, 4H), 6.98 (d, .7=1.47, 1H), 7.40 (dm, 7=8.83 Hz, 2H), 8.54 (s, 1H), 8.73 (s, 1H); 13C-NMR (DMSO-d6) 5 14.7, 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%). D3. Synthesis of ©-Carbamoyl Ureas AK3-tert-Butyl-l-methyl-5-pyrazoIyl)-Ar,-(4-(4- acetaminophenyI)methylphenyI)urea: To a solution of //-(3-terf-butyl-l-methyl-5-pyrazolyO-A^'^^-aminophenylJmethylphenylJurea (0.300 g, 0.795 mmol) in CH2C12 (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 HC1 solution (125 mL) then water (100 mL), dried (MgS04), and concentrated under reduced pressure. The resulting residue was > purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid (0.160 g, 48%): TLC (EtOAc) R^O.33; 'H-NMR (DMSO-d6) 8 1.17 (s, 9H), 1.98 (s, 3H), 3.55 (s, 3H), 3.78 (s, 2H), 6.00 (s, 1H), 7.07 (d, 7=8.5 Hz, 2H), 7.09 (d, .7=8.5 Hz, 2H), 7.32 (d, J=S.S Hz, 2H), 7.44 (d, 7=8.5 Hz, 2H), 8.38 (s, 1H), 8.75 (s, 1H), 9.82 (s, 1H); FAB-MS m/z 420 ((M+H)+). )4. General Method for the Conversion of Ester-Containing Ureas into Alcohol-Containing Ureas N-N-HydroxyethyOO-rcrt-butyl-S-pyrazolyO-iV'^^-dichlorophenylJurea: A solution of A'-(///-(2-(2,3-dichlorophenylamino)carbonyloxyethyl)-3-rerr-butyl-5-pyrazoIyl)-Ar'-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH ( 0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at -65 °C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1 solution (3 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (Et20) to afford the desired product as a white solid (0.17 g, 64 %): TLC (60% EtOAc/40% hexane) R,0.16; 'H-NMR (DMSO- D5a. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas Step 1. A4A^CarboxymethyI)-3-terf-butyl-5-pyrazolyl)-jV'-(2,3- dichlorophenyl)urea: A solution of AT-(///-(ethoxycarbonylmethyl)-3-/er/-butyl-5-pyrazolyl)-^/'-(2,3'dichlorophenyl)urea (prepared as described in Method A3, 0.46 g, 1.11 mmoles) and NaOH (1.2 mL, 5N in water, 6.0 mmoles) in EtOH (7 mL) was stirred at room temp, for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1 solution (4 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (EtjO/hexane) to afford the desired product as a white solid (0.38 g, 89%): TLC (10% MeOH/90% CH2CI2) R^O.04; 'H-NMR (DMSO-d6) 8 1.21 (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, 1H); FAB-MS m/z (rel abundance) 385 ((M+H)+, 100%). Step 2. ^-(^'-((MethylcarbamoyOmethyO-S-^rt-butyl-S-pyrazolyO-^Mi^" dichIorophenyl)urea: A solution of A^A^carboxymethyl)-3-terf-butyl-5-pyrazolyl)-Ar'-(2,3-dichlorophenyl)urea (100 mg, 0.26 mmole) and N,N'-carbonyldiimidazole (45 mg, 0.28 mmole) in CH2C12 (10 mL) was stirred, at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CH2CI2) R^O.81). Dry methylamine hydrochloride (28 mg, 0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The reaction mixture was stirred at room temp, overnight, then diluted with CH2C12, washed with water (30 mL), a saturated NaCl solution (30 mL), dried (MgSOJ and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% acetone/90% CH2C12 to 40% acetone/60% CH2C12) and the residue was crystallized (EtjO/hexane) to afford the desired product (47 mg, 46%): TLC (60% acetone/40% CH2C12) R, 0.59; 'H-NMR (DMSO-d6) 5 1.20 (s, 9H), 2.63 (d, >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, 1H), 9.20 (br s, 1H); 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. ^-(S-rerr-Butyl-S-isoxazolyO-A^'^^-carboxyphenyOoxyphenylJurea: To a solution of A^S-te^butyl-S-isoxazolylJ-N^-^-emoxyoxycarbonylphenyl)-oxyphenyl)urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added a 1M NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HC1 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. Ar-(5-rcrt-Butyl-3-isoxazoIyl)-Ar'-(4-(4-(Ar-methyIcarbamoyl)- phenyI)oxyphenyl)urea: A solution of N-(5-tert-buty\~3-isoxazoly\yN'-(4-(4-carboxyphenyl)oxyphenyI)urea (0.100 g, 0.25 mmol), methylamine (2.0 M in THF; 0.140 mL, 0.278 mmol), l-emyl-3-(3-dimemylaminopropyl)carbodiimide hydrochloride (76 mg, 0.39 mmol), and W-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 1M citric acid solution (20 mL) and extracted widi EtOAc (3x15 mL). The combined extracts were sequentially washed with water (3 x 10 mL) and a saturated NaCl solution (2 x 10 mL), dried (NajSO,), filtered, and concentrated in vacuo . The resulting crude oil was purified by flash chromatography i (60 % EtOAc/40% hexane) to afford the desired product as a white solid (42 mg, 40%): EI-MS m/z 409 ((M+H)). General Method for the Conversion of o-Amine-Containing Ureas into Amide-Containing Ureas A'-(5-rerr-Butyl-3-isoxazolyl)-Ar'-(4-(4-aminophenyl)oxyphenyl)urea: To a solution of -(5-/e^butyl-3-isoxazolyl)-Ar'-(4-(4-rert-butoxycarbonylaminophenyI)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 cone HC1 solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp . The mixture was then poured into water (10 mL) and EtOAc(10 mL) and made basic using a 1M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na^OJ, and concentrated in vacuo to afford the desired product as a white solid (26 mg, 66%). EI-MS m/z 361 ((M+ H)+). D7. General Method for the Oxidation of Pyridine-Containing Ureas A'-(5-/frt'-Butyl-3-isoxazolyl)-Ar'-(4-(A'-oxo-4-pyridinyl)methylphenyI)urea: To a solution of N-(5-tert-b\xty\-3 -isoxazolyl)-N '-(4-(4-pyridinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHC13 (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated K2C03 solution (10 mL). After 5 min, the solution was diluted with CHC13 (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 (MgSO«), and concentrated in vacuo. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the W-oxide (0.082 g, 79%). General Method for the Acylation of a Hydroxy-Containing Urea Ar-(5-/ert-Butyl-3-isoxazolyl)-iV'-(4-(4-acetoxypheiiyloxy)phenyl)urea: To a solution of N-(5-tert-b\ity\-3-isoxazoly\)-N '-(4-(4-hydroxyphenyloxy)phenyl)urea (0,100 g, 0.272 mmol), Wtf-dimemylarninopyridine (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 dissolved in EtOAc (10 mL). The resulting solution was sequentially washed with a 5% citric acid solution (10 mL), a saturated NaHC03 solution (10 mL) and a saturated NaCl solution (10 mL), dried (NajS04), and concentrated under reduced pressure to give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmHg): TLC (40% EtOAc/60% hexane) Ry 0.55; FAB-MS m/z 410 ((M+H)+). D9. Synthesis of to-Alkoxypyridines Stepl. Ar-(5-/crf-Butyl-3-isoxazolyI)-A^-(4-(2(ljH)-pyridinon-5-yl)oxyphenyl)-urea: A solution of A'-(5-fer/-butyl-3-isoxazolyl)-Ar'-(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 CH2C12 (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 purified 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) R^O.05; FAB-MS m/z 369 ((M+H)+, 100%). Step 2. A^^S-^rt-Butyl-a-isoxazoIyO-Af'^-tS^-Etho^pyridyOoxyphenyOurea: A slurry of iV-(5-rerM)Utyl-3-isoxazolyl)-//^4-(2(l^-pyridinon-5-yl)oxyphenyl)urea (0.1 g, 0.27 mmol) and Ag2C03 (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 reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, 38%): mp 146 °C; TLC (40% EtOAc/60% hexane) R^O.49; FAB-MS m/z 397 ((M+H)+, 100%). D10. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide-Containing Urea Ar-(5-rert-Butyl-3-isoxazolyl)-7V'-(4-(4-(l-hydroxyethyI)phenyl)oxyphenyI)urea: To a solution of Ar-(5-terf-butyl-3-isoxazolyl)-Jv'-(4-(4-(l- acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods Bl 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 HC1 solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCl solution (2x10 mL), dried (MgSO«), and concentrated in vacuo . The resulting white solid was purified by trituration (EtjO/hexane) to afford the desired product (0.021 g, 32 %): mp 80-85 °C; 'H NMR (DMSO-d6) 6 1.26 (s, 9H), 2.50 (s, 3H), 4.67 (m, 1H), 5.10 (br s, 1H), 6.45 (s, 1H), 6.90 (m, 4H), 7.29 (d, 7=9.0 Hz, 2H), 7.42 (d, 7=9.0 Hz, 2H), 8.76 (s, 1H), 9.44 (s, 1H); HPLC ES-MS m/z 396 ((M+H)+). Bll. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy-Substituted Ureas Ar-(5-/£rt-ButyI-3-isoxazoIyI)-Ar'-(4-(3-(ben2yIo3cycarbonyIamino)phenyI)-oxyphenyl)urea: To a solution of the //-(5-ter/-butyl-3-isoxazolyl)-W-(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% HC1 solution (50 mL) and teh resulting solution extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCl (2 x 50 mL), dried (NaaSOJ, and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 %): mp 73-75 °C; 'H NMR (DMSO-d6) 5 1.26 (s, 9H), 5.10 (s, 2H), 6.46 (s, 1H), 6.55 (d, 7=7.0 Hz, 1H), 6.94 (d, 7=7.0 Hz, 2H), 7.70 (m, 7H), 8.78 (s, 1H), 9.46 (s, 1H), 9.81 (s, 1H); HPLC ES-MS m/z 501 ((M+H)+). listed above; Table 1. 5-Substituted-3-isoxazolyl Ureas R1 - I CO - TaDie :>.5-suDstitute -\|M- BIOLOGICAL EXAMPLES In Vitro raf Kinase Assay: In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCI, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20 (iL) is mixed with water (5 uL) or with compounds diluted with distilled water from 10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 uL [y-"P]ATP (10003000 dpm/pmol) in 80 mM Tris-HCI, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCl2. The reaction mixtures are incubated at 32 °C, usually for 22 min. Incorporation of "P into protein is assayed by harvesting the reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 jiM ATP and 0.4 jiM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by -M^L~ electrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging Analyzer System. All compounds exemplified displayed ICJ0s of between 1 nM and 10 p.M. Cellular Assay: For in vitro growth assay, human tumor cell lines, including but not limited to HCT116 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage independent growth in soft agar. Human tumor cell lines were obtained from ATCC (Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X 103 cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% C02 incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring 3H-thymidine incorporation into DNA following an 8 h culture with 1 fiCu 3H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 3H-thymidine incorporation by liquid scintillant counting. For anchorage independent cell growth, cells are plated at 1 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 compounds are added to wells and incubated at 37 °C in a 5% C02 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 compounds of Formula I are active to inhibit raf kinase activity and to inhibit oncogenic cell growth. In Vivo Assay: An in vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid cancers) mediated by raf kinase can be performed as follows: CDI nu/nu mice (6-8 weeks old) are injected 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 calipers twice a week. The inhibitory effect of the compounds 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. WE CLAIM: Compound of formula I wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, -C(0)R5, -N02- -ORS, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -Cio alkyl, C2 -Cio alkenyl, Ci-Cio alkoxy, C3 -Cio cycloalkyl, Ce-Ci4 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -Cio alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3-Cio cycloalkyl, and -Y-Ar, wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -Cio alkenyl, C3-C10 cycloalkyl up to per halosubstituted Ci-C10 alkyl, up to per halo substituted C2-C10 alkenyl, up to per-halosubstituted C3 -Cio cycloalkyl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5NR5'-. NR5C(0)-, -C(0)NR5-, -(CHa)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX^, -CHX«2-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN =0, -CO2R5, -C(0)NR5R5', -C(O)- NR5, -N02> -OR5, -SR5, -NR5R5', -NR5C(0)OR5', -C(0)R5. 3JR5C(0)R5', -S02R5, S02NR5R5', Ci -C10 alkyl, C1-C10 alkoxyl, C3 -C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, and A is a heteroaryl moiety selected from the group consisting of wherein R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-C10 cycloalkyl, C1-C13 heteroaryl, Ce-naryl, C7-24 alkaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C1-C13 heteroaryl, up to per-halosubstituted C6-14 aryl, and up to per-halosubstituted C7-24 alkaryl; R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, C1-C10 alkyl C3-C10 cycloalkyl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, substituted C7-C24 alkaryl, and substituted C4-C23 alkheteroaryl; where R2 is a substituted group, it is substituted by one or more substitutents independently selected from the group consisting of -CN, -CO2R4, -C(0)-NR3R3', _NO2, -OR4, -SR4, and halogen up to per-halosubstitution, wherein R3 and R3' are independently selected from the group consisting of H, -OR4- -SR4- -NR4R4', -C(0)R4, -CO2R4- -C(0)NR4R4> Ci -Cio alkyl, C3-Cio cycloalkyl, C6-Ci4aryl, C3-C13 heteroaryl, up to per per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3 -Cio cycloalkyl and up to per-halosubstituted C6 -CM aryl or C3 -C13 Jgeteiparyl; and wherein R4 and R4' are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, C6C14 aryl, C3-C13 heteroaryl; up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl and up to per-halosubstituted Ce-CH aryl or C3-C13 heteroaryl, R4 is C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-Cio alkyl and up to per-halosubstituted C3-C10 cycloalkyl; and Rb is hydrogen or halogen, Rc is hydrogen, halogen, C1-C10 alkyl, up to per-halosubstituted C1-C10 alkyl or combines with R1 and the ring carbon atoms to which R1 and Rc are bound to form a 5- or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 memebrs selected from O, N and S; subject to the proviso that where A is 2. A compound of formula I as claimed in claim 1 wherein said compound is of the formula wherein R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, Ci-Cio alkyl C3-C10 cycloalkyl, substituted Ci-C10 alkyl, substituted C3-C10 cycloalkyl wherein R2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R4, -C(0)-NR3R3, -NO2, -OR4, -SR4, and halogen up to per-halosubstitution, wherein R3 and R3' are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, and up to per-halosubstituted C3-Cio cycloalkyl, and wherein R4 and R4" are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, and up to per-halosubstituted C3-C10 cycloalkyl, wherein R1 is selected from the group consisting of C3-C6 alkyl, C3-C8 cycloalkyl, up to per-halosubstituted C3-C6 alkyl and up to per-halosubstituted C3 -Ce cycloalkyl, B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl; substituted by C6-C14 aryl, C3-C13 heteroaryl or -Y-Ar wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X1 n and wherein n = 0.2, each X1 is independently selected from the group of -CN, -C02R5, -C-[0]R5, -C(0)-NR5 R5, -OR5, -NO2, -NR5 R5, Ci -Cio alkyl, C2-io alkenyl, Ci-io alkoxy, C3 -Cio cycloalkyl, -SR5, -NR5C(0)OR5, NR5C(0)R5, substituted C1-C10 alkyl, substituted C2-10 alkenyl, substituted C1-10 alkoxy, substituted C3-C10 cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5' -C(0)R5> -C(0)-NR5R5, -OR5- -SR5- -NR5R5, -NO2, -NR5C(0)OR5, -NR5 C(0)OR5 and halogen up to per-halosubstitution, wherein R5 and R5' are independently selected from H, Ci -Cio alkyl, C2 -Cio alkenyl, C3 -Cio cycloalkyl, C6 -CM aryl, C3 -C13 heteroaryl, C7-C24 alkaryl, C4 -C23 alkheteroaryl, up to per-halosubstituted Ci -Cio alkyl, up to per-halosubstituted C2-10 alkenyl and up to per-halosubstituted C3 -Cio cycloalkyl wherein Y is -O-, -S-, -N(R5)-, -(CH2)m„ -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5R5--NR5C(0), -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa, -CHX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m=1.3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is optionally by halogen up to per-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C02R5 -C(0)R5, =0, -C(0)-NR5R5', -C(0)R5, -N02, -OR5, -SR5, -NR5 R5, -NR5 C(0)OR5, -NR5 C(0)R5, -SO2R5, - S02R5R5', Ci -Cio alkyl, C1-C10 alkoxy, C3 -C10 cycloalkyl, substituted Ci -Cio alkyl, Ci -Cio alkoxy, C3 -Cio cycloalkyl, susbstituted Ci -Cio alkyl and substituted C3 -Cio cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)NR5R5, -O, -OR5, -SR5, -N02> -NR5 R5', -NR5 C(0)R5', -NR5C(0)OR5, Ci -Cio alkyl, C1-C10 alkoxy, C3 -Cio cycloalkyl. 3. A compound as claimed in claim 2 wherein B is wherein Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2-, -CHaS-, -CH(OH)-, -C(O)-, -CXa 2> -CXH-, -CH2O-, and -OCH2-, Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 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, optionally substituted by halogen up to per-halosubstitution, X1 is Ci -C4 alkyl or halosubstituted Ci -C4 alkyl up to per halo, Z, n and nl as defined in claim 2. 4. A compound as claimed in claim 3, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, and X1 is as defined in claim 3, and Z is selected from the group consisting of -R6, -OR6 and -NHR7 wherein R6 is hydrogen, Ci -Cio alkyl, or C3 -Cio cycloalkyl and R7 is selected from the group consisting of hydrogen, C3 -Cio alkyl and C3 -Ce cycloalkyl, wherein R6 and R7 can be substituted substituted by halogen or up to per-halosubstitution. 5. A compound as claimed in claim 3, wherein Q is phenyl or j^ridinyl optionally substituted by halogen up to per-halosubstitution Q1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -O-, -S-, -CH2S-, -SCH2-, -CH2O-, -OCH2-or -CH2-, X1 is as claimed in claim 3, and Z is -SCH3-, or -NH-C(0)-CP-H2p+l, wherein p is 1-4, n=0 or 1 and nl =0-1. 6. A compound of formula I as claimed in claim 1 wherein said compound is of the formula wherein R2 is as claimed in claim 2 and B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -CO2R5, -C(0)NR5R5, -C(0)R5, -N02- -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -C10 alkyl, C2 -C10 alkenyl, C1-C10 alkoxy, C3 -C10 cycloalkyl, C6-C14 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -C10 alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3 -C10 cycloalkyl, and -Y-Ar, wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -C10 alkenyl, C3 -C10 cycloalkyl, C6 -C14 aryl, C3-C13 heteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per halo substituted C^-Cio alkenyl, up to per-halosubstituted C3 -C10 cycloalkyl, and up to per-halosubstituted C6-Ci4 aryl and C3 -C13 toroaryl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5R5'-. NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX, -CHX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, =0, -C02R5, -C(0)NR5R5', -C(O)- NR5. -N02- -OR5, -SR5, NR5R5', NR5C(0)OR5', -C(0)R5> NR5C(0)R5', -S02R5, -S02NR5R5', Ci-Cioalkyl, Ci-Cioalkoxyl, C3-C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, subject to the proviso that where R4 is methyl B is not 7. A compound as claimed in claim 2 selected from the group consisting of: N-(3-tert-Butyl- 5-pyrazolyl)-N '-(4-phenyloxyphenyl)urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(3- methylaminocarbonylphenyl)oxyphenyl)urea; N-(3 -tert-Butyl-5 -pyrazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; N-(3-tert-Butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5 -pyrazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; N-(3-tert-Butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)methylphenyl)urea; N-( 1 -Methyl-3-tert-butyl-5 -pyrazolyl)-N'-(4-phenyloxyphenyl)urea; N-(l-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-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4- pyridinyl)thiophenyl)urea; N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4- pyridinyl)oxyphenyl)urea; N-(l-Methyl-3-tert-buryl-5-pyrazolyl)-N'-((4-(4- pyridinyl)methyloxy)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)thiophenyl) urea; N-(3-tert-butyl- 5-pyrazolyl)-N'-(4-(4-pyridyl)thiophenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N,-(4-(4-pyridyl)oxyphenyl) urea; N-(l-methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)thiophenyl) urea; N-(l-methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)thiophenyl) urea; N-( 1 -methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl) urea; N-( 1 -methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof. 8. A compound of the formula wherein R1 is selected from the group consisting of C3-C10 alkyl,C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl B is phenyl pyridinyl, indolinyl, isoquinolinyl, qinolinyl or napthyl which is substituted by phenyl, pyndinyl or Y-Ar. wherein the cyclic structures of B are optionally substituted by ogen, up to per-halosubstition, and optionally substituted by X1!! wherein N=0-2; each X1 is independently selected from the group consisting of -CN,-C02R5, -C(0)R5, -C(0)NR5R5, _0R5? . N02) -NR5R5,CI-CIO alkyl, C2-10- alkenyl, Ci-10-alkoxy, C3-C10 cycloalkyl, and C6-C14 aryl, -SR5,-NR5C(0)OR5, NR5C(0)R5', C3-C13 heteroaryl, substituted C1-C10 alkyl, substituted C2-io-alkenyl, substituted Ci-10-alkoxy, substituted C3-C10 cycloalkyl, substituted C6-C14 aryl, substituted C3-C13 heteroaryl, and wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN,-C02R5, -C(0)R5, -C(0)NR5R5, -OR5, -SR5,-NR5R5, } N02,-NR5C(0)R5, -NR5C(0)OR5 and halogen up to per-halosubstitution; wherein R5 and R5', are independently selected from H, C1-C10 alkyl, C2-io alkenyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl, wherein Y is - O-, -S-, -N(R5)-, -(CH2)m-, -C(Q).-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5,-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXvCX^-, -S-(CH2)m, -and -N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and Ar is 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, =0, -C(0)NR5R5, -C(0)R5, -N02,-OR5, - SRV NR5R5, -NR5C(0)OR5, -NR5C(0)R5-, S02R5, -S02 R5R5, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5, -C(0)NR5R5, =0, -OR5, -SR5, -NO2, -NR5R5 , JfR5C(0)R5', -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl, subject to the proviso that where R1 is t-butyl, B is not wherein R6 is -NHC(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or -0-CH£ >—O 9. A compound as claimed in claim 8, wherein B is Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2-, -CH2S, -CH(OH)-, -C(O)-, -CX«2, -CXH-, -CH2O- and -OCH2-, Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution; Q1 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 substituted or unsubstituted by halogen up to per-halosubstitution, X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per halo, and Z, n and nl are as claimed in claim 8. 10. A compound as claimed in claim 9, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per halosubstitution, Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as claimed in claim 9 and Z is selected from the group consisting of-R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl, C3-C6-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. 11. A compound as claimed in claim 9, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution Q1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -O-, -S-, -C(0)-or -CH2-, X1 is as claimed in claim 8 and Z is-NH-C(0)-CpH2p+i, wherein p is 1-4, -CH3, -OH, -OCH3, -OC2H5, -CN or -C(0)CH3, n= 0 or 1, and nl = 0 or 1. 12. A compound as claimed in claim 8 selected from the group consisting of: N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3- hydroxyphenyl) oxyphenyljurea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4- acetylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyi)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3- methylaminocarbonylphenyl) thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(l,2- methylenedioxy)phenyl)- oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridyl)thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4- pyridinyl)methylphenyl)urea; N~(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-pyridinyl)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)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-pyridinyl)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- methylcarbamoyl) pyridyl)-oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(2- methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3-(4-(2- methylcarbamoyl)pyridyl) thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(2-methyl-4-(4-(2- methylcarbamoyl) 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)pyridyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)pyridyl) thiophenyl) urea; N-(5-tert-buryl-3-isoxazolyl)-N'-(3-chloro-4-(4-(2-methylcarbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxa2olyl)-N'-(4-(3-methylcarbamoyl)phenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof. 13. A compound of the formula wherein B is 5-methyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrizinyl, pyndazinyl, naphthyl, quinolinyl, isoquinolinyl, phthaimidinyl, turyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothia- zolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn, wherein n is 0.3 and each X is independently selected from the group consisting of -CN, -CO2R5, C(0)NR5R5, -C(0)R5, -NO2, -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C3-C10 cycloalkyl, Ce-Ci4 aryl, C3-C13 heteroaiyl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2-C10 alkenyl, up to per halo-substituted C1-C10 alko?«y and, up to per halo-substituted C3-C10 cycloalkyl, wherein R5 and R5> are independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, Ce-Ci4 aryl, C3-C13 heteroaiyl, up to per-halosubstituted Ci-Cioalkyl, up to per-halosubstituted C2-Cip alkenyl, and up to per-halosubstituted C3-Ciocycloalkyl, wherein Y is -O-, -S- -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5, NR5-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, CHXS -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-. m= 1-3, and Xa is halogen: Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zm, wherein m is 0 to 3 and each Z is independently selected from the group consisting of -CN, =0, -CO2R5, -C(0)NR5 R5, -C(0)-NR5, -N02, -OR5, -SR5, -NR5 R5, -NR5C(0)OR5, -C(0)R5, -NR5C(0)R5, -S02R5, S02NR5 R5, C1-C10 alkyl Ci-Cioalkoxy, C3-C10 cycloalkyl, up to per halo-substituted C1-C10 alkyl and up to per halo-substituted C3-C10 cycloalkyl, subject to the proviso that B is not wherein R6 is -NHC(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or -O-CH l~V/ 14. A compound of the formula wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl, and up to per-halosubstituted C3-C10 cycloalkyl, and B is phenyl, pyridinyl, indolinyl, isoquindinyl, quindinyl or napthyl which is substituted by X, optionally substituted by halogen, up to per- halosubstitution, and optionally substituted by Xln, wherein n = 0-2, each X1 is independently selected from the group of X or from the group consisting of -CN, -CO2R5, -C(0)R5, -C(0)NR5R5, _0R5} -N02, -NR5R5, C1-C10 alkyl, C2-io-alkenyl, Ci-10-alkoxy, C3-C10 cycloalkyl, C6-C14 aryl and C7-C24 alkaryl, and X is selected from the group consisting of -SR5, -NR5C(0)OR5', -NR5C(0)R5', C3-C13 heteroaryl, substituted C1-C10 alkyl, substituted C2-C10- alkenyl, substituted Ci-Cio-alkoxy, substituted C3-C10 cyclolkyl, substituted Ce-Cn aryl, substituted C3-C13 heteroaryl, and -Y-Ar, and wherein if X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)Rs, -C(0)NR5R5? -OR5, -SR5, -NR5R5, NO2, -NR5C(0)R5, -NR5C(0)OR5' and halogen up to per-halo substitution; wherein R5 and R5 are independently selected from H, C1-C10 alkyl, C2-ioalkenyl, C3-C10 cycloalkyl, Ce-Ci4 aryl, substituted C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per- halosubstituted C3-C10 cycloalkyl wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m, -C{0)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NRSC(O)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa, -CX^-, -S-(CH2)m- and -N(R5)(CH2)m- m=l-3, and Xa is halogen; and Ar is 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-halo and 15. A compound as claimed in claim 14 wherein B is optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R5, ^(O)R5, =0, -C(0)NR5R5, -C(0)R5, -NO2, OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5, -S02 R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, =0, -OR5, -SR5, -NO2, -NR5R5, NR5C(0)R5 and -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl, and C3-C10 cycloalkyl, and where R1 is -CH2-I -butyl. B is not wherein Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(0)-, CX^, -CXH-, -CH2O- and -OCH2-, Xa is halogen; Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution; Q1 is a mono- or bicyclic aromatic structure of 3-10 carbon atoms and 0-4 members of the group consisting of N, O and S substituted or unsubstituted by halogen up to per-halosubstitution, Z, n and nl are as defined in claim 14 and X1 is C1-C4 alkyl or tialosubstituted C1-C4 alkyl up to per halo. 16. A compound as claimed in claim 15, wherein ^ Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution; Ql is selected from the group consisting or phenyl, pyridinyl, naphthyl, pyrimidinyl quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 15 and Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R 7 is selected from the group consisting of hydrogen C3-Cio-alkyl, and C3-C6-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. 17. A compound of the formula wherein B is as defined in claim 1. 18. A compound as claimed in claim 15, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per halosubstitution, Q1 is phenyl benzothiazolyl or pyridinyl optionally substituted by halogen up to per halosubstitution, Y is-O, -S- or -CH2-, X1 is as claimed in claim 14, n = 0 or 1, Z is -CH3, -C1-, OC2H5 or -OCH3, and n 1=0 or 1. 19. A compound as claimed in claim 14 selected from the group consisting of: N-(3-Isopropyl-5 -isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(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)thiophenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4- pyridinyl)methylphenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea; 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- (4methylphenyl)oxyphenyl)urea; N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4- pyridinyl) thiophenyl)urea; N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4- pyridinyl)oxyphenyl)urea; N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4- pyridinyl) thiophenyl) urea; N-(3-(l, l-Dimethylpropyl-5-isoxazolyl)-N'-(5-(2- 4methoxyphenyl)oxy)pyridinyl)urea; N-(3-(l-Methyl-1 -ethylpropyl)-5-isoxazolyl)-N'-(4- (4pyridinyl)oxyphenyl)urea; N-(3-( 1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'-(3- (4pyridinyl) thiophenyl)urea; N-(3-isopropyl-5-isoxazolyl)-N'-(3-(4-(2- methylcarbamoyl)pyridyl)-oxyphenyl)urea; N-(3-isopropyl-5-isoxazolyl)-N'-(4-(4-(2- methylcarbamoyl)pyridyls)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- methyIcarbamoyl)pyridyl)-oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'-(3-(4-(2- methylcarbamoyl)pyridyl)thiophenyl) urea; N-(3-(l,l-dimethylprop-l-yl)-5-isoxazolyl)-N'-(3-(4-(2- methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(3 -(l,l-dimethylprop-l-yl)-5 -isoxazolyl)-N '-(4 -(4 -(2- methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'-(3-chloro-4-(4-(2- methylcarbamoyl)pyridyl)thiophenyl) urea; and pharmaceutically acceptable salts thereof. 20. A compound of the formula wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl Rb is hydrogen or halogen and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl substituted by phenyl, pyridinyl or -Y- Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo and optionally substituted by Xxn and wherein n = 0 - 2; each X1 is independently selected from the group consisting of CN, -OR5, -NR5R5, CVC10 alkyl, -CO2R5, -C(0)NR5R5 , -C(0)R5, -NO2, -SR5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl, substituted Ci-10-alkyl, substituted C2io-alkenyl, substituted Ci-10-alkoxy, and substituted C3-C10 cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5 -C(0)R5, -C(0)NR5R5, _OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5', ^IR5C(0)OR5' and halogen up to per-halo substitution; wherein R5 and R5' are independently selected from H, Ci - C10 alkyl, C2-10 alkenyl, C3-C10 cycloalkyl, up to per halo-substituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3 - C10 cycloalkyl. wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5'-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX ,-CX^-, -S-(CH2)m- and-N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and Ar is 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C02R5, -C(0)R5, =0,-C(0)NR5R5„ -C(O)- NR5, -N02,-OR5, - SR5,-NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5,-S02R5R5, Ci - C10 alkyl, C1-C10 alkoxy,C3 - C10 cycloalkyl, substituted C1-C10 alkyl and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of- CN, -CO2R5. -C(0)NR5R5, =0, -OR5, -SR5, -N02,-NR5R5, -NR5C(0)R5,-NR5C(O)OR5, Ci- C10 alkyl, C1-C10 alkoxyl and C3 - C10 cycloalkyl, 21. A compound as claimed in claim 20, wherein B is wherein subject to the proviso that where R1 is t-butyl and R10 is H, B is not of the formula. Y is selected from the group consisting of -0-, -S-, -CH2-, -^H2-,-CH2S-, -CH(OH)-, -qOh-CX^ , -CXaH-, -CH2O- and -OCH2- Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution, 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, optionally substituted by halogen up to per-halosubstitution, X1 is Ci - C4 alkyl or halosubstituted Ci- C4 alkyl upto per halo, and Z, n and nl are as claimed in claim 20. 22. A compound as claimed in claim 21, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 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, X1 is as defined in claim 21, and Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci - Cio alkyl or C3- Cio cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-C10 alkyl, and C3-Ce -cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. wherein B is as defined in claim 1 subject to the proviso that B is not of the formula 23. A compound of the formula 24. A compound as claimed in claim 21, wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, and Y is -O-or -S-, Z is -CI, -CH3, -OH or -OCH3, X1 is as defined in claim 21, n = o or 1 and nl = 0-2. 25. A compound as claimed in claim 20 selected from the group consisting of: N-(5-tert-Butyl-3-thienyl)-N'-(4-(3- methylphenyl) oxypheny 1) urea; N-(5-tert-Butyl-3-thienyl)-N'-(4-(4- hydroxyphenyl)oxyphenyl)urea; N-( 5-tert-Butyl-3 -thienyl)-N'-(4-(4- methoxyphenyl)oxyphenyl)urea; N-(5 -tert-Butyl-3-thienyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; and pharmaceutically acceptable salts thereof. 26. A compound of the formula wherein R3 is C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted, C1-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl, and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or napthyl, substituted by phenyl, pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by ogen, up to per halo, and optionally substituted by Xln wherein n = 0-2 each X1 is independently selected from the group consisting of -CN,-N02 ,-OR5 and C1-C10 alkyl, -SR5,-C02R5, -C(0)R5, -C(0)NR5R5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C2-10 -alkenyl, substituted C1-10 -alkoxy and substitutedC3-Cio Cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, -C(0)NR5R5, -OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5, -NR5C(0)OR5 and halogen up to per-halosubstitution; wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 -alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl, wherein Y is -0-, -S-, _N(R5)-, -(CH2)-m- -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, NR5C(Oj-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa , -CX«2-, -S-(CH2)m- and -N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and Ar is a 5-10 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN,-CO2R5, -C(0)R5, ^O, -C(0)NR5R5', -C(0)R5, -N02,-OR5, - SRV NR5R5', -NR5C(0)OR5', -NR5C(0)R5', -SO2R5, -S02R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN. 27. A compound as claimed in claim 26, wherein B is wherein Y is selected from the group consisting of-O, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(O)-, -CX«2, -CXaH-, -CH2O-, -OCH2-, Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution: Q1 is phenyl, pyridinyl, naphthyl, parimidinyl, quinoline, isoquinoline, imidazolyl or benzothiazolyl, optionally substituted by halogen up to per-halosubstitution X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per-halo, Z, n and nl are as defined in claim 26 and s is 0 or 1. 28. A compound as claimed in claim 27, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 27 and Z is selected form the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl, C3-C6-cycloalkyl and wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. 29. A compound as claimed in claim 27, wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, Y is -O- or -S-, X1 is as defined in claim 27, n = 0 or ljind nl = 0. 30. A compound as claimed in claim 26, of the formula wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl substituted by phenyl, pyridinyl or -Y-Ar optionally substituted by halogen up to per halo and wherein each cyclic structure of B is optionally substituted by Xin wherein n=0-2, each X1 is independently selected from the group consisting of-CN, -OR5, -NR5R5, Ci-Cioalkyl, -CO2R5, -C(0)NR5R5', -C(0)R5, -N02, -SR5, -NR5C(0)OR5, -NR5C(0)R5', C3-C10 cycloalkyl, and substituted C1-C10 alkyl, substituted C2-Q0 alkenyl, substituted Cno alkoxy, and substituted C3-C10 cycloalkyl, wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 -alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-C10 alkyl, up to per-halosubstituted C2-io-alkenyl up to per-halosubstituted C3-C10 cycloalkyl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m- -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NR5C(0)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX* , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and Ar is a 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN,-CO2R5, -C(0)R5, =0, -C(0)NR5R5', -C(0)-NRS, -N02,-OR5, - SR5,- NR5R5', JJR5C(0)OR5', -NR5C(0)R5', -S02R5, -S02R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, -C(0)NR5R5', =0, -OR5, - SR5,-N02, -NR5R5', -NR5C(0)R5, -NRsC(0)OR5', C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl. 31. A compound as claimed in claim 30 selected from the group consisting of: N-(5-tert-Butyl-2-(l-thia-3 ,4-diazolyl))-N'-(3-(4- pyridinyl)thiophenyl)urea; N-(5-tert-Butyl-2-(l-thia-3 ,4- diazolyl))-N'-(4-(4-pyridinyl)-oxyphenyl)urea; N-(5-tert-Butyl-2-( 1 -thia-3 ,4-diazolyl))-N'-(3-(4-(2- methylcarbamoyl) pyridyl]- oxyphenyljurea; N-(5-tert-Butyl-2-(l-thia-3,4-diazolyl))-N'-(4-(4-(2- methylcarbamoyl) pyridyl]- oxyphenyl)urea; N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(-4-(4-(2- methylcarbamoyl)pyridyl) -oxyphenyl) urea; N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(3-chloro-4-(4- (2methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(2-chloro-4-(4-(2- methylcarbamoyl)pyridyl) -oxyphenyl) urea; N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(3-(4- pyridyl)thiophenyl) urea; N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(2-methyl-4-(4-(2- methylcarbamoyl)pyridyl)oxyphenyl) urea; N-( 5 -(1,1 -dimethylprop-l-yl)-2-(l-thia-3,4-diazolyl))-N'-(4- (3carbamoylphenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof. 32. A compound of one of the formulae R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-i3-heteroaryl, C6-i4-aryl, C7-24-alkaryl, C3-C10 cycloalkyl, up to per-halosubstituted CMO alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstitutedCi-13-heteroaryl, up to per-halosubstituted Ce-M-aryl, and up to per-halosubstituted C7-24-alkaryl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolynil or napthyl; substituted by phenyl, pyridinyl, or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by Xn wherein n=0-2 each X1 is independently selected from the group consisting of -CN, -OR5, -NR5R5, C1-C10 alkyl; -CO2, R5, -C (0)NR5R5, _c(0)R5 =0 -NO2-SR5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C2-io-alkenyl, substituted C1-10 alkoxy, substituted C3-C10 cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -C02R5,-C(0)R5, -C(0)NR5R5, -OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5, -NR5C(0)OR5, and halogen up to per-halo substitution. wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-io-alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl, wherein Y is O, S-, -N(R5)-, -(CH2)m-C(0), -CH(OH)-, -(CH2)mO-, -MR5C(0)NR5R5-, -NR5C(0)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen and Ar is 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN,-C02R5, =0, -C(0)R5, -C(0)NR5R5, -C(O)- NR5, N02, -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5, -S02R5R5, Ci-Cio alkyl, Ci-Cio alkoxy, C3-C10 cycloalkyl substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, C02R5 C(0)NR5 R5', =0, -OR5, -SR5, -N02, -NR5R5', -NR5C(0)R5', -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl. 33. A compound of one of the formulae t-Bu tjBu wherein B is defined in claim 1. 34. A compound as claimed in claim 32, wherein B is wherein Y is selected from the group consisting of-O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(O)-, -CX«2,-CXaH-, -CH20- and -OCH2-, Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 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 substituted by halogen up to per-halosubstitution. X1 is Ci C4 alkyl or halosubstituted C1-C4 alkyl up to per halo, Z, n and nl are as defined in claim 32 or 1. 35. A compound as claimed in claim 34 wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 33 and Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl and C3-Ce-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. 36. A compound as claimed in claim 34 wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, and Y is -O-, or -S- X1 is as claimed in claim 34, n=0 or 1, Z is -CI, -CH3, OH or OCH3 and nl = 0-2. 37. A compound of the formula wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3 -C10 cycloalkyl, R6 is hydrogen or halogen, and wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl substituted by phenyl, pyridinyl or -Y-Ar wherein the cyclic structure of B are optionally substituted by halogen, up to per halo, and optionally substituted by X1!! n = 0-3 and each X1 is independently selected from the group consisting of -CN, -CO2R5, C(0)NR5R5', -C(0)R5, -N02, -OR5, -SR5, -NR5R5', - NR5C(0)OR5', -NR5C(0)R5', C1-C10 alkyl, C2-10 alkenyl, C1-10 alkoxy, C3-C10 cycloalkyl substituted C1-C10 alkyl, substituted C2-C10 alkenyl, substituted C1-10 alkoxy, and substituted C3-C10 cycloalkyl wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C02R5' -C(0)R5, C(0)NR5R5, -OR5, -SR5, -NR5R5', -NO2, -NR5C(0)R5', -NR5C(0)R5' and halogen up to per-halosubstitution wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl, wherein Y is -O-, -S-, -N(R5)-, -(CH2)m,-C(0)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NRSC(O)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m=l-3, and Xa is halogen and Ar is 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R5, -C(0)R5 =0, -C(0)NR5R5, -C(0)R5, -NO2, -OR5, -SR5, -NR5R5, -NR5C(0)OR5', -NR5C(0)R5, -SO2R5, -S02R5R5', C1-C10 alkyl, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)-NR5R5' =0, -OR5, -SR5, -NO2, -NR5R5', - NR5C(0)R5, -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl. 38. A compound as claimed in claim 37, wherein B is wherein Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2, -CH2S-, -CH(OH)-, -C(O), -CX2, -CXH-, -CH2O- and-OCH2-, Xa is halogen Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 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, substituted or unsubstituted by halogen up to per-halosubstitution, X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per halo, and Z, n and nl are as defined in claim 37. 39. A compound as claimed in claim 38, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution, Q1 is selected from the group consisting of phenyl, pyridinyl, aephthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per halo, X1 is as claimed in claim 38 and Z is selected from the group consisting of -R6 , -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl and C3-C6-cycloalkyl, wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution. 40. A compound of the formula wherein B is as defined in claim 1. 41. A compound as claimed in claim 38, wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl, optionally substituted by halogen up to per-halosubstitution, and Y is-O- or -S-, X1 is as claimed in claim 38, Z is -CI or -OCH3, n = 0, s = 0 and nl = 0-2. 42. A pharmaceutical composition having a compound as claimed in claim 2 and a physiologically acceptable carrier. 43. A pharmaceutical composition having a compound as claimed in claim 8 and a physiologically acceptable carrier. 44. A pharmaceutical composition having a compound as claimed in claim 14 and a physiologically acceptable carrier. 45. A pharmaceutical composition having a compound as claimed in Jaini 20 and a physiologically acceptable carrier. 46. A pharmaceutical composition having a compound as claimed in claim 26 and a physiologically acceptable carrier. 47. A pharmaceutical composition having a compound as claimed in claim 32 and a physiologically acceptable carrier. 48. A pharmaceutical composition having a compound as claimed in claim 37 and a physiologically acceptable carrier. Dated this 24th day of October, 2003 [ RITUSHKA NEGI ] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
COMPLETE SPECIFICATION
[See Section 10, rule 13]
"A COMPOUND"
BAYER CORPORATION, of 100 Bayer Road, Pittsburgh Pennsylvania 15205, United States of America,

The following specification particularly describes and ascertain the nature of the invention and the manner in which it is to be performed:-
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INHIBITION OF RAF KINASE USING SUBSTITUTED HETEROCYCLIC UREAS
Field of the Invention
This invention relates to the us eof a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Background of the Invention
The p21ru oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton'et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by 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. Chem. 1994,269, 30105-8. Kolch et al. {Nature 1991, 349,426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense ohgodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2,668-75).

Summary of the Invention
The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21n,I 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 compounds 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 compounds 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 compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds and methods for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula I:
O
II
A-NH-C-NH-B I
wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below.
The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.

Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of which is a 5-6 member aromatic ring. One or more of these rings may have 1-4 carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms.
Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, isoquinoline, phthalimidinyl and combinations thereof, such as, diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenylamine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pyridinylnaphthyl thioether, and phthalimidylmethylphenyl.
Examples of suitable heteroaryl groups include, but are not limited to, 5-12 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 replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 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-l-, -4- or-5-yl, 1,2,4-triazol-l-, -3- or-5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4-or-5-yl, l,2,4-oxadiazol-3-or-5-yl, l,3,4-thiadiazol-2-or-5-yl, l,2,4-oxadiazol-3- or-5-yl, l,3,4-thiadiazol-2-or-5-yl, l,3,4-thiadiazol-3-or-5-yl, l,2,3-thiadiazoI-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-indolyI, 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-benz-l,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-thjazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyI-2-thienyl, 4-methyU2-thienyl, l-methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyM,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 branched isomers such as isopropyl, isobutyl, sec-butyl, ter/-butyl, etc.
Suitable aryl groups include, 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 substituents such that, for example, "C4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups.
Suitable halogens include F, CI, Br, and/or I, from one to persubstitution (i.e., all H atoms on the group are replaced by halogen atom), being possible, mixed substitution of halogen atom types also being possible on a given moiety.
As indicated above, these ring systems can be unsubstituted or substituted by substituents such a$ halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CM, -C02R5, -C(0)NR5Rr, -C(0)R5, *N02, -OR1, -SRS, -NR5Ry, -NR5C(0)OR5', -NR5C(0)R5', C,-CIO alkyl, C2-C10 alkenyl, C,-CI0 alkoxy* Cj-C10 cycloalkyl, C6-C, 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, -C02R5, -C(0)R5, -C(0)NR5R5', -ORs, -SR5, -NR'R5", -N02, -NR5C(0)R5', -NR5C(0)0R5' and halogen up to per-halo substitution.

The moieties R5 and R5' are preferably independently selected from H, C,-C10 alkyl, Cj-C,0 alkenyl, C3-C10 cycloalkyl, C6-Cu aryl, C3-CI3 heteroaryl, C7-C24 alkaryl, C4-C23 ilkheteroaryl, up to per-halosubstituted C,-C10 alkyl, up to per-halosubstituted C2-C10 ilkenyl, up to per-halosubstituted C3-CI0 cycloalkyl, up to per-halosubstituted C6-Cu iryl and up to per-halosubstituted C3-C,3 heteroaryl.
rhe bridging group Y is preferably -0-, -S-, -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, (CH2)mO-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX\ -CX*2-, -S-(CH2)m- and N(Rs)(CH2)m-, where m = 1-3, and X* is halogen.
fhe moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 nembers of the group consisting of nitrogen, oxygen and sulfur which is tnsubstituted or substituted by halogen up to per-halosubstitucion and optionally ubstituted by ZDl, wherein nl is 0 to 3.
iach Z substituent is preferably independently selected from the group consisting of CN, -C02R5, -C(0)NR5R5', -C(O)- NR5, -N02, -OR5, - SR5, - NR5R5', -NR5C(0)0R5', 0, -NR5C(0)R5', -S02R5, -S02NR5R5', C,-C10 alkyl, CrC10 alkoxy, C3-C10 ycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, CTCU alkaryl, C4-CJ3 alkheteroaryl, ubstituted C,-C,0 alkyl, substituted C3-C,0 cycloalkyl, substituted C7~C24 alkaryj and ubstituted C4-C23 alkheteroaryl. If Z is a substituted group, it is substituted by the ne or more substituents independently selected from the group consisting of-CN, :02R5, -C(0)NR5R5', -ORs, -SR5, -NO,, -NR^5*, =0, -NR5C(0)Rs', sJR5C(0)ORr, C,-CI0 alkyl, C,-C10 alkoxy, C3-Cl0 cycloalkyl, C3-C13 heteroaryl, C6-14 aryl, C7-C24 alkaryl.
he aryl and heteroaryl moieties of B of Formula I are preferably selected from the

which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n = 0-3.
The aryl and heteroaryl moieties 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)-, -CX*2, -CXlH-, -CH20- and -OCH2- and X* is halogen.
Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4 members of the group consisting of N, 0 and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution. X, Z, n and nl are as defined above and s = 0 or 1.
In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution and Q1 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-Q1 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 R* is hydrogen, C,-C10-alkyl or C3-CI0-cycloalkyl and R7 is preferably selected from the group consisting of hydrogen, C3-

CI0-alkyl, CrC6-cycloalkyl and C6-C10-aryl, wherein R* and R7 can be substituted by halogen or up to per-halosubstifution.
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-C,0 alkyl, Cj-C10 cycloalkyl, C,-C,j heteroaryl, C6-C,3 aryl, C,-C24 alkaryl,_up to per-halosubstituted C,-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C,-C13 heteroaryl, up to per-halosubstituted C6-C13 aryl and up to per-halosubstituted C1-C24 alkaryl.
The substituent R2 is preferably selected from the group consisting of H, -C(0)R\ -C02R\ -C(0)NR3R3', C,-C10 alkyl, C3-C10 cycloalkyl, C7-C24 alkaryl, CrC» alkheteroaryl, substituted C,-C10 alkyl, substituted Cj-Cl0 cycloalkyl, substituted C7-C24 alkaryl and substituted C4-C2J alkheteroaryl. Where R2 is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, - C02R4, -C(0)-NR3R3', -N02, -OR4, -SR\ and halogen up to per-halosubstitution.

R3 and R3' are preferably independently selected from the group consisting of H, -OR4, -SR\ -NR4R4', -C(0)R\ -C02R4, -C(0)NR4R4', C,-C10 alkyl, CrClo cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C,-C10 alkyl, up to per-halosubstituted C3-CI0 cycloalkyl, up to per-halosubstituted C6-C,4 aryl and up to per-halosubstituted C3-C13 heteroaryl.
R4 and R4' are preferably independently selected from the group consisting of H, C,-C,0 alkyl, C3-C10 cycloalkyl, C6-Cl4 aryl, C3-C13 heteroaryl; C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C^C^ alkyl, up to per-halosubstituted C3-C,0 cycloalkyl, up to per-halosubstituted C6-C,4 aryl and up to per-halosubstituted C3-CI3 heteroaryl.
R" is preferably C,-C,0 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C^C^ alkyl and up to per-halosubstituted C3-Ci0 cycloalkyl.
Rbis preferably hydrogen or halogen.
Rc is hydrogen, halogen, C,-C,0 alkyl, up to per-halosubstituted C,-CI0 alkyl or combines with R1 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 0, NandS;
wherein R2, R1 and B are as defined above;
and both 5,3- and 3,5- isoxazolyl ureas of the formulae
The invention also relates to compounds of general formula I described above and includes pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula

and

wherein R1 and B are also as defined above.
Component B for these compounds is a 1-3 ring aromatic ring structure selected from the group consisting of:
X'

which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here R5 and R5' are as defined above, n = 0-2 and each X1 substituent is independently selected from the group of X or from the group consisting of-CN, -C02R5, -C(0)R5, -C(0)NR5R5', -OR5, - N02, -NR5R5', C,-C10 alkyl, C2.10-alkenyl, C,.1(ralkoxy, Cj-C,0 cycloalkyl, C6-Cu aryl and C7-CM alkaryl.

The substituent X is selected from the group consisting of -SR5, *NR5C(0)OR5', NR5C(0)R5', C3-Cl3 heteroaryl, C«-C2J alkheteroaryl, substituted CrC10 alkyl, substituted C2.10-alkenyl, substituted C,.I0-alkoxy, substituted C,-C10 cycloalkyl, substituted C6-Cu aryl, substituted C7-C2« alkaryl, substituted C^-C^ 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, -C02R5, -C(0)R5, -C(0)NRsRr, -OR5, -SR5, -NR'R5*, N02, -NR5C(0)R5*, -NR5C(0)OR5' 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 R1 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(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or -0-CH2 -phenyl. Where R' is t-butyl for the' 3,5-isoxazole ureas, B is not

and where R' is -CH2 -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, Q1 is pyridinyl, phenyl or benzothiazolyl, Y is -0-, -S-, -CHjS-, -SCH2-,
-CH;0-, -OCH2- or-CHr, and Z is H, -SCH3, or-NH-C(0)-CpH2p+I, wherein p is 1-4, n = 0, s = 1 and nl = 0-1. Specific examples of preferred pyrazolyl ureas are:
Ar-(3-/e/-/-Butyl-5-pyrazolyl)-Ar-(4-phenyloxyphenyl)urea;
Ar-(3-fe^Buryl-5-pyrazolyl)-Ar'-(3-(3-memylaminocarbonylphenyl)-oxyphenyl)urea;
//-(3-/er/-Butyl-5-pyrazolyl)-7/'-(3-(4-pyridinyl)thiophenyl)urea;
A'-(3-fert-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea;
Ar-(3-rerr-Butyl-5-pyrazolyl)-Ar'»(4-(4-pyridinyl)oxyphenyl)urea;
Ar-(3-rer/-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea;
N-(1 -Methyl-S-fert-butyl-S-pyrazolyl)-// '-(4-phenyloxyphenyl)urea;
Ar-(l-Methyl-3-^rt-butyl-5-pyrazolyl)*Ar'-(3-(4-pyridinyI)thiophenyl)urea;
Ar-(l-Methyl-3-rerr-butyl-5-pyrazolyl)-Ar,-((4-(4-pyridinyl)thiomethyl)-phenyl)urea;
N-( 1 -Methyl-3-rerf-butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea;
N-{ 1 -Methyl-3-terf-butyl-5-pyrazolyl)-iV '-(4-(4-pyridinyl)oxyphenyl)urea;
//-(l-Methyl-3-rert-butyl-5-pyrazolyl)-JV'-((4-(4-pyridinyl)methyloxy)phenyl)-urea;
Ar-(l-Methyl-3-ferr-butyl-5-pyrazolyl)-7\lf'-(3-(2-benzothiazolyl)oxyphenyl)-urea;
//-(3-/er/-butyl-5-pyrazolyl)-//'-(3-(4-pyridyl)thiophenyl)urea;
A^-(3-fert-butyl-5-pyrazolyl)-Ar'-(4-(4-pyridyl)thiophenyl)urea;
Ar-(3-/err-butyl-5-pyrazolyl)-Ar'-(3-(4-pyridyl)oxyphenyl)urea;
//-(3-/crr-butyl-5-pyrazolyl)-//'-(4-(4-pyridyl)oxyphenyl)urea;
N-(\ -methyl-3-/er/-butyl-5-pyrazolyl)-A^'-(3-(4-pyridyl)thiophenyl) urea;
N-( 1 -methyl-3 -rerr-butyl-S-pyrazolyl)-/^ '-(4-(4-pyridyl)thiophenyl) urea;
N-(l -methyl-3-rert-butyl-5-pyrazolyl)-Ar'-(3-(4-pyridyl)oxyphenyl) urea; and
iV-(l-methyl-3-rer/-butyl-5-pyrazolyl)-Ar-(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 -0-, -S- or -CH2-, Z is -CH3,

CI, -OCH3 or -C(0)-CH3> n = 0, s - 1, and nl = 0-1. Specific examples of preferred 3,5-isoxazolyl ureas are:
Ar-(3-Isopropyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea;
A'-(3-fert-Butyl-5-isoxazolyl)-Ar'-(4-(4-methoxyphenyl)oxyphenyl)urea;
Ar-(3-rerf-Butyl-5-isoxazolyl)-Ar'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea;
Ar-(3-rerr-Butyl-5-isoxazolyl)-Ar'-(3-(4-pyridinyl)thiophenyl)urea;
M Ar-(3-ferr-Butyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea;
Ar-(3-rerr-Butyl-5-isoxazolyl)-Ar-(4-(4-pyridinyl)oxyphenyl)urea.;
Ar-(3-ferr-Butyl-5-isoxazolyl)-Ar'-(4-(4-methyl-3-pyridinyl)oxyphenyl)urea;
Ar-(3-fer/-Butyl-5-isoxazolyl)-Ar-(3-(2-benzothiazolyl)oxyphenyl)urea;
Ar-(3-( 1,1 -DimethylpropyO-S-isoxazolyl)-^ '-(4-(4-methylphenyl)oxyphenyl)-urea;
^-(S-Cl.l-DimethylpropyO-S-isoxazolyO-^'^^-pyridinylJthiopheny^urea;
Ar-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)oxyphenyl)urea;
^-(S^ljl-DimethylpropyO-S-isoxazolyO-^'^^-pyridinyOthiophenyOurea;
Ar-(3-(l,l-Dimethylpropyl-5-isoxazolyl)-jV'-(5-(2-(4-methoxyphenyl)oxy)-pyridinyl)urea;
jV-tS-Cl-Methyl-l-ethylpropyO-S-isoxazolyO-A^'-^^-pyridinyOoxyphenyl)-urea;
Ar-(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-Ar-(3-(4-pyridinyl)thiophenyl)-urea;
Ar-(3-isopropyl-5-isoxazolyl)-Ar'-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
Ar-(3-isopropyl-5-isoxazolyl)-//'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
//-(3-/ert-butyl-5-isoxazolyl)-A^*-(3-(4-(2-methylcarbamoyl)-pyridyl)oxyphenyl) urea;
Af-(3-/err-butyl-5-isoxazolyl)-Ar'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
Ar-(3-/er/-butyl-5-isoxazolyl)-Ar'-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea;
//-(3-(l, 1 -dimethylprop-1 -yO-S-isoxazolylJ-N '-(3-(4-(2-methylcarbamoyl)-yridyl)oxyphenyl) urea;
A'-(3-(lJl-dimethylprop-l-yl)-5-isoxazolyl)-Ar-(4-(4-(2-methylcarbamoyl)-pyridyl)oxyphenyl) urea; and

Ar-(3-rert-butyl-5-isoxazolyl)-Ar'-(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, Q1 is phenyl, benzothiazolyl or pyridinyl, Y is -0-, -S- or -CH2-, X is CH3 and Z is -C(0)NH-, CpH2p+1, wherein p = 1-4, -C(0)CH3, -CH3, -OH, -0C2H5,
-CN, phenyl, or -OCH3, n = 0 or 1, s = 0 or 1, and nl = 0 or 1. Specific examples of preferred 5,3-isoxazolyl ureas are:
//-(5-/er/-Butyl-3-isoxazolyl)-Ar-(4-(4-hydroxyphenyl)oxyphenyl)urea;
//-(5-/ert-Butyl-3-isoxazolyl)-Ar'-(4-(3-hydroxyphenyl)oxyphenyl)urea;
Ar-(5-rert-Butyl-3-isoxazolyl)-Ar'-(4-(4-acetylphenyl)oxyphenyl)urea;
Ar-(5-/ert-Butyl-3-isoxazolyl)-Ar'-(3-benzoylphenyl)urea;
M(5-rerr-Butyl-3-isoxazolyl)-Ar'-(4-phenyloxyphenyl)urea;
//-(5-fer/-Butyl-3-isoxazolyl)-Ar-(4-(3-methylaminocarbonylphenyl)-thiophenyl)urea;
A^-(5-/er/-Butyl-3-isoxazolyl)-A^'-(4-(4-(l,2-methylenedioxy)phenyl)-oxyphenyl)urea;
jV-(5-i'er/-Butyl-3-isoxazolyl)-Ar'-(4-(3-pyridinyl)oxyphenyl)urea; //-(5-fert-Butyl-3-isoxazolyl)-A^,-(4-(4-pyridinyl)oxyphenyl)urea; //-(5-/er/-Butyl-3-isoxazolyl)-//'-(4-(4-pyridyl)thiophenyl)urea; A^-(5-/er/-Butyl-3-isoxazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea; Ar-(5-/err-Butyl-3-isoxazolyl)-Ar'-(3-(4-pyridinyl)oxyphenyl)urea; N~(5-tert-B\ityl-3-isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; • ' iV-(5-terf-Butyl-3-isoxazolyl)-//'-(3-(3-methyl-4-pyridinyl)oxyphenyl)urea; //-(5-^rr-Butyl-3-isoxazolyl)-//'-(3-(3-methyl-4-pyridinyl)thiophenyl)urea; /^-(S-^rt-Butyl^-isoxazolyO-A^'^-CS-methyM-pyridinyOthiophenyOurea; iV-(5-rer/-Butyl-3-isoxazolyl)-A^-(3-(4-methyl-3-pyridinyl)oxyphenyl)urea; ^-(i-^nr-Bu^J-isox^o^-^-^-^-meChyW-pyricfmy^oxypheny^urea,' ?/-(5-rerr-Butyl-3-isoxazolyl)-iV-(3-(2-benzothiazolyl)oxyphenyl)urea; //-(5-/er/-butyl-3*isoxazolyl)-//'-(3-chloro-4-(4-(2-methyIcarbamoyI)pyridyl)-oxyphenyl) urea;
Ar-(5-^rt-butyl-3-isoxazolyl)-Af-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
A/^-(5-rerf-butyl-3-isoxazolyl)-iV-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea;
//-(5-rer/-butyl-3-isoxazolyl)-//'-(2-niethyl-4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;

//-(5-ter/-butyl-3-isoxazolyI)~// -(4-(4-(2-carbamoyI)pyridyl)oxyphenyI) urea;
Ar-(5-rerr-butyl-3-isoxa2olyl)-//'-(3-(4-(2-carbamoyl)pyridyl)oxyphenyl)urea;
^-(S-rerr-butylO-isoxazolyO-jV'^^^-methylcarbamoylJpyridyl)-oxyphenyl) urea;
A'-(5-rerr-butyl-3*isoxazoIyl)-Ar-(4-(4-(2-methyIcarbamoyl)pyridyl)-thiophenyl) urea;
A'-(5-rerf-butyl-3-isoxazolyl)-A'"-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; and
Ar-(5-/e/"/-butyl*3-isoxazolyl)-//'-(4-(3-methylcarbamoyl)phenyl)oxyphenyl) urea.

Additionally included are thienyl ureas of the formulae

R1 S'

wherein R1 , Rb and B are as defined above. Preferred B components for the thienyl ureas of this invention have aromatic ring structures selected from the group consisting of:

These aromatic ring structures can be substituted or unsubstituted by halogen, up to per-halosubstitution. The X1 substiruents are independently selected from the group consisting of X or from the group consisting of, -CN, -OR5, -NR5R5', C,-C10 alkyl. The X substiruents are independently selected from the group consisting of -C02R5, -C(0)NR5R5', -C(0)R5, -N02, -SR5, -NR5C(0)0R5', -NR5C(0)R5', C3-C10 cycloalkyl, C6-CM aryl, C7-C2 The components for B are subject to the proviso that where R1 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, Q1 is phenyl or pyridinyl, Y is
-O- or -S-, Z is -CI, -CH3, -OH or -OCH3, n = 0, s - 0 or 1, and nl = 0-2. Specific examples of preferred thienyl ureas are:
//-(S-Isopropyl-S-isoxazolyO-^'-C^A-pyridinylJthiophenylJurea;
7/-(3-/err-Butyl-5-isoxazolyl)-7vr'-(4-(4-methoxyphenyl)oxyphenyl)urea;
7V-(3-rerf-Butyl-5-isoxazolyl)-A^'-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea;
^-(S-Zerz-Butyl-S-isoxazolyO-A^'^S^-pyridinyOthiophenylJurea;
Ar-(3-rerNButyl-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)methylphenyl)urea;

//-(3-/er/-Butyl-5-isoxazolyl)-A'"-(4-(4-pyridinyI)thiophenyI)urea;
A^-fe^Butyl-S-isoxazolyty-N'-^-^-pyridinytyoxyphenytyurea;
Af-(3-^r/-Butyl-5'isoxa2olyl)-Ar'-(4-(4-methyl-3-pyridinyI)oxyphenyl)urea;
Ar-(3-/err-Butyl-5-isoxa2olyl)-//'-(3-(2-benzothia2olyl)oxyphcnyl)urea;
N-(3-( 1,1 -Dimethylpropyl)-5-isoxazoIyl)-Ar'-(4-(4-methylphenyl)-oxyphenyl)urea;
//-(S-fl.l-DimethylpropyO-S-isoxazolylJ-A^'^^-pyridinylJthiophenyOurea;
iV-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-iV'-(4-(4-pyridinyl)oxyphenyl)urea;
7V-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-Ar'-(4-(4-pyridinyl)thiophenyl)urea;
JV-(3-( 1,1 -Dimethylpropyl-5-isoxazolyl)-A^'-(5-(2-(4-methoxyphenyl)-oxy)pyridinyl)urea;
Ar-(3-(l-Methyl-l-ethylpropyl)-5-isoxazolyl)-^'-(4-(4-pyridinyl)-oxyphenyl)urea; and
Af-(3-(l -Methyl-1 -ethylpropylJ-S-isoxazolyl)-^-(3-(4-pyridinyl)thio-phenyl)urea.
Preferred thiophenes include:
//-(5-ter/-butyl-3-thienyl)-//'-(4-(4-methoxyphenyl)oxyphenyl) urea; Ar-(5-ren-butyl-3-thienyl)-Ar'-(4-(4-hydroxyphenyl)oxyphenyl)urea; 7l/-(5-/er/-butyl-3-thienyl)-Ar'-(4-(3-methylphenyl)oxyphenyl) urea; and Ar-(5-/er/-butyl-3-thienyl)-//'-(4-(4-pyridyl)thiophenyl) urea; and
Also included are the thiadiazolyl and furyl ureas of the formulae:

wherein R*, Rb, R1 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 X1 subsrituent is independently selected from the group consisting of X or from the group consisting of -CN, -N02 ,-OR5 and 0,-0,0 alkyl. The X substituents are selected from the group consisting of-SR$, -C02R5, -C(0)R5, -C(0)NR5R5', -NRSR5', -NR5C(0)OR5',

-NR5C(0)R5', substituted C2.10-alkenyl, substituted C,.10-alkoxy, -C3-C10 cycloalkyl, -C6-C14 aryl, -C7-C2 This invention also includes pharmaceutical compositions that include compounds described above and a physiologically acceptable carrier.
Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula

and Q, Q\ X, Y, Z, n, s, and nl are as defined above. The preferred thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q1 is phenyl or pyridinyl, Y is -0- or -S-, n = 0, s = 1 and nl = 0. Specific examples of preferred thiadiazolyl ureas are:
^-(S-rerr-Butyl^-fl-thia-a^-diazolyOJ-Z/'^S-fA-pyridinyOthiophenyOurea;
Ar-(5-fert-Butyl-2-(l-thia-3,4-diazolyl))-A^'-(4-(4-pyridinyl)oxyphenyl)urea;
A^-(5-rerr-butyl-2-(l-thia-3,4-diazolyl))-A^'-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
//-(5-/frr-butyl-2-(l-thia-3,4-diazolyl))-^'-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea;
^-(5-/ert-butyl-2-(l-thia-3,4-diazolyl))-A^*.(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea;
//-(5-^r/-butyl-2-(l-thia-3,4-diazolyl))-A^-(2-chloro-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl)urea;
//-(S-rerr-butyl^-Cl-thia-S^-diazolylJJ-Af'-CS^-pyridylJthiophenyOurea;
W-(5-rerf-butyl-2-( 1 -tbia-3,4-diazolyl))-^'-(2-methyl-4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; and
N-(5-(\, 1 -dimethylprop-1 -yl)-2-( 1 -thia-3,4-diazolyl))-AT *-(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 -CI or -OCH3, s = 0 or 1, n = 0 and nl = 0-2.

The present invention is also directed to pharmaceutically acceptable salts of formula
I. Suitable pharmaceutically acceptable salts are well known to those skilled in the 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*
Na+ or K+), alkaline earth cations (e.g., Mg*2, Ca*2 or Ba*2), the ammonium cation, as
well as acid salts of organic bases, including aliphatic and aromatic substituted
ammonium, and quaternary ammonium cations such as those arising from protonation
or peralkylation of triethylamine, MN-diethylamine, //.N-dicycIohexylamine,
pyridine, A^A^dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane
(DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene(DBU).
A number of the compounds 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 compounds described in Formula I which possess Raf kinase inhibitory activity.
General Preparative Methods
The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some of which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, with more detailed examples being presented in the experimental section describing the working examples.
Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984). March. Advanced Organic Chemistry, 3"1 Ed.; John Wiley: New York (1985)). For

example, 3-substitutcd-5-aminoisoxazoIes (3) are available by the reaction of hydroxylamine with an a-cyanoketone (2), as shown in Scheme I. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an -cyanoketone with hydrazine (R2=H) or a monosubstituted hydrazine affords the 3-substituted- or l,3-disubstituted-5-aminopyrazole (5). Pyrazoles unsubstituted at N-l (R2=H) may be acylated at //-l, for example using di-ter/-butyl dicarbonate, to give pyrazole 7. Similarly, reaction 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-bntoxy (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.

Scheme I. 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 LiAlH4 (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)).

Scheme II Reduction of Nitroaryls to Aryl Amines
Nitroaiyls are commonly formed by electrophilic aromatic nitration using HN03, or an alternative N02+ source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with
HN03
Ar-H ► ArN02
potential leaving groups (eg. F, CI, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme HI) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme

Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls
As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine (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 A^A^'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 21 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (22) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic amine.

Scheme rv Selected Methods of Urea Formation (Het = heterocycle)
l-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed by treatment with phosgene or a phosgene equivalent. Reaction of anhydride 25 with an aryl amine can generate acid 26 which may spontaneously decarboxylate, or may be isolated. If isolated, decarboxylation of acid 26 may be induced upon heating.

Scheme V Urea Formation via Isatoic-Hke Anhydrides
Finally, ureas may be further manipulated using methods familiar to those skilled in the art.
The invention also includes pharmaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or sublingually, rectally or vaginally in dosage unit formulations. The 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 compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in

order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl /?-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, 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 alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing

the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated Cg-C„ fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cg-C„ fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic

acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C,-C„ fatty alcohols, saturated or unsaturated C,-C„ fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics.
It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defuied 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 VI, filed on December 22, 1997, as Serial No. 08/996,343, converted on December 22,1998.
The compounds are producible from known compounds (or from starting materials which, in rum, 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 reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg.
All temperatures are reported uncorrected in degrees Celsius (°C). Unless otfierwise 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-254 250 um 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 Science* silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHClj S 7.26; MeOH 5 3.30; DMSO 5 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCI3 5 77.0; MeOD-d3; 8 49.0; DMSO-d6 5 39.5) as standard. Low resolution mass spectra (MS) and high resolution 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 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept l-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (lxlO"4 torr to 2.5X10"4 torr). The direct insertion desorption chemical ionization (DO) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength
5 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; 2J
I 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 assigned structures.
List of Abbreviations and Acronyms:
AcOH acetic acid
anh anhydrous
BOC /err-butoxycarbonyl
cone concentrated
dec decomposition
DMPU lf3-dimemyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone

DMF A^/Z-dimethylformamide
DMSO dimethylsulfoxide
DPPA diphenylphosphoryl azide
EtOAc ethyl acetate
EtOH ethanol(100%)
EtjO diethyl ether
Et3N triethylamine
m-CPBA 3-chIoroperoxybenzoic acid
MeOH methanol
pet. ether petroleum ether (boiling range 30-60 °C)
THF tetrahydrofuran
TFA trifluoroacetic acid
Tf trifluoromethanesulfonyl
5 A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoIes
O
Step 1. 3-Oxo-4-methylpentanenitrile: A slurry of sodium hydride (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 °C for 15 min., then a
) solution of acetonitrile (13.5 mL, 258 mmol) in benzene (52 mL) was added dropwise via addition funnel followed by a solution of ethyl isobutyrate (15 g, 129 mmol) in benzene (52 mL). The reaction mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water (50 mL) via addition funnel. The organic layer was separated and set aside. EtOAc (100
i mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (cone. HC1) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgSOJ, 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-isopropylisoxazoIe: 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 reaction mixture was immediately extracted with CHClj (3 x 100 mL) without cooling. The combined organic layers were dried (MgSC%), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% CH2C12) to afford the desired isoxazole as a yellow solid (11.3 g, 70%): mp 63-65 "C; TLC R^ (5% acetone/95% CH2C12) 0.19; 'H-NMR (DMSO-d6) d 1.12 (d, .7=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. Genera! Method for the Preparation of 5-Amino-l-alkyI-3-alkylpyrazoles

NC 5-Amino-3-tert-butyM-(2-cyanoethyI)pyrazole: A solution of 4,4-dimethyI-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 reaction. 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 (E^O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) R^O.31; 'H-NMR (DMSO-d6) 6 1.13 (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, 1H).

A 4. Synthesis of 3-Amino-5-aIkylthiophenes A4a. Synthesis of 3-Amino-5-aIkyIthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids

Step 1. 7-/£rf-Butyl-2H-thieno[3,2-d]oxazine-2,4(lH>dione: A mixture of methyl 3-amino-5-te/-/-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 reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 mL). Phosgene (20% in toluene, 70 mL) was added dropwise over a 2 h period. The resulting mixture was stirred at room temperature overnight and the resulting precipitate was triturated (acetone) to afford the desired anhydride (5.78 g, 73%): "H-NMR (CDC13) 6 1.38 (s, 9H), 2.48 (s, 1H), 6.75 (s, 1H); FAB-MS m/z (rel abundance) 226 ((M+H)+, 100%).
Step 2. ^-(S-rcrt-Butyl^-carboxy-S-thienyO-A^'^^-pyridinylmethyOphenyl)-urea: A solution of 7-rerf-butyl-2H-thieno[3,2-d]oxazine-2,4(lH)-dione (0.176 g, 0.78 mmol) and 4-(4-pyridinylmethyI)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 EtjO to afford the desired urea (0.25 g, 78%): mp 187-189 °C; TLC (50% EtOAc/50% pet. ether) R^O.04; 'H-NMR (DMSO-d6) 6 1.34 (s, 9H), 3.90 (s, 2H), 7.15 (d, J=THz, 2H), 7.20 (d, J=3 Hz, 2H), 7.40 (d, J=l 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. Ar-(5-rert-Butyl-3-thienyl)-Ar'-(4-(4-pyridinyImethyl)phenyI)urea: A vial containing A^-(5-/ert-butyl-2-carboxy-3-thienyl)-iV*(4-(4-pyridinyImethyl)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 purified by preparative HPLC (C-18 column; gradient from 20% CH3CN/79.9% H2O/0.1% TFA to 99.9% H2O/0.1% TFA) to give the desired product (0.024 g, 43%): TLC (50% EtOAc/50% pet. ether) R, 0.18; 'H-NMR (DMSO-d6) 8 1.33 (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, >7 Hz, 1H), 8.58 (s, 1H), 8.68 (d, >7 Hz, 2H), 8.75 (s, 1H); EI-MS m/z 365 (M+).
A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-aIkyI-2-thiophene-carboxylate esters

5-te/Y-Butyl-3-thiopheneammonium Chloride: To a solution of methyl 3-amino-5-ferr-butyl-2-thiophcne-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp, for 2.25 h. A cone. HC1 solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 mL) and a saturated NaHC03 solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCl solution (150 mL), dried (NajSOJ, and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification.

A4c Synthesis 3-Amino-5-aIkylthiophenes from A'-BOC 3-Amino-5-aIky]-2-thiophenecarboxylate esters

Step 1. Methyl 3-(terf-ButoxycarbonyIamino)-5-tert-butyl-2-thiophenecarboxy-late: To a solution of methyl 3-amino-5-terf-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 °C was added di-terM>utyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and Ar1Ar-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 dissolved in CH2C12 (3 L) and sequentially washed with a 1 M H3P04 solution (2 x 750 mL), a saturated NaHCOj solution (800 mL) and a saturated NaCl solution (2 x 800 mL), dried (NajSOJ and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 °C, then treated with water (500 mL) to afford the desired product as an off-white solid (163 g, 74%): 'H-NMR (CDC13) 8 1.38 (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-(^rr-Butoxycarbonylamino)-5-ferf-butyI-2-thiophenecarboxyIic Acid:
To a solution of methyl 3-(/er/-butoxycarbonylamino)-5-/er/-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 HC1 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 HC1 solution (500 mL). The organic phase was washed with a saturated NaCl solution (4 x 1.5 L), dried (Na^O,), and 5 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, 93% total yield): 'H-NMR (CDC1,) 6 1.94 (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-terf-BuryI-3-tbiopheneammonium Chloride: A solution of 3-(tert-butoxycarbonylamino)-5-rer/-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HC1 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 collected and dried overnight under reduced pressure to give the desired salt as an off-white solid (1.72 g, 90%): 'H-NMR (DMSO-d6) 6 1.31 (s, 9H), 6.84 (d, 7=1.48 Hz, 1H), 7.31 (d, 7=1.47 Hz, 1H), 10.27 (brs, 3H).

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

S-Amino-3-/crt-butyl-Ar/'(tert-butoxycarbonyI)pyra2ole: To a solution of 5-amino-3-ter/-butylpyrazole (3.93 g, 28.2 mmol) in CH2C12 (140 mL) was added di-terf-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp, for 13 h, then diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO 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 reaction mixture was heated at 85 °C for 7 h, then cooled to room temperature, and treated with a concentrated NH4OHsolution until basic. The resulting solids were filtered to afford 2-amino-5-(l-(l-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) IV 0.14; 'JLNMR (DMSO-d6) 5 0.80 (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 m/z 172 ((M+H)+).
A7. GeneralMetbod for the Synthesis of 2-AminooxadiazoIes

\-
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-isopropyI oxadiazole: To a mixture of isobutyric hydrazide (0.093 g), KHCOj (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 CHjCl2 (5 mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO^ and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H)+).
A8. General Method for the Synthesis of 2-Aminooxazoles
O
,OH

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

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

Step 2. 2-Amino-4-isopropyI-l,3-oxazoIe: To a solution of 3,3-dimethyI-l-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-ij-butylammonium hydroxide (0.4 M, 3.6 mL), then a IN NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with E^O (3 x 25 mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure to afford 2-Amino-4-isopropyM,3-oxazole (1.94 g, 41%): HPLC ES-MS m/z 141 ((M+H)+).
A9. Method for the Synthesis of Substituted-S-aminotetrazoIes

: 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 CHjCl2 (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1- and 2-isopropyl-5-aminotetrazole (50%), which was used without further purification: HPLC ES-MS m/z 128 ((M+H)+).

B. General Methods for Synthesis of Substituted Anilines
Bl. General Method for Substituted Aniline Formation via Hydrogenation of
a Nitroarene

4-(4-PyridinylmethyI)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 H2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 'H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite*. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%): 'H-NMR (DMSO-d6) 5 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, >8.46 Hz, 2H), 6.86 (d, 7=8.09 Hz, 2H), 7.16 (d, 7=5.88 Hz, 2H), 8.40 (d, 7=5.88 Hz, 2H); EI-MS m/z 184 (NT). This material was used in urea formation reactions without further purification.
General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene

4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH ( 5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL), basified to pH 10 by adding solid K2COj in portions {Caution: foaming). The organic layer was washed with a saturated NaCl solution, dried (MgS04), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) fy 0.20.

B3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. l-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 reaction was stirred 1 h,
then a solution of l-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was
added dropwise to form a dark green solution. The reaction was heated at 95 °C
overnight, then cooled to room temp., quenched with H20, and concentrated in vacuo.
The residue was partitioned between EtOAc (200 mL) and H20 (200 mL) . The
organic layer was sequentially washed with H20 (2 x 200 mL), a saturated NaHCO,
solution (200 mL), and a saturated NaCl solution (200 mL), dried (Na^O,), and
concentrated in vacuo. The residue was triturated (Et20/hexane) to afford 1-
methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDC13) 5 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, .7=9.2 Hz, 2H); EI-MS m/z 245 (M+).

Step 2. 4-(4-Methoxypbenoxy)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 reaction mixture was filtered through a pad of Celite* with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR (CDC13) 5 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, .7=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215 (Ml.
>. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

tep 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-lercaptopyridine (2.8 g, 24 mmoles), 2-fiuoro-5-nitrobenzotrifIuoride (5 g, 23:5-omoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) r'as stirred at room temperature and under argon overnight. TLC showed complete taction. The mixture was diluted with E^O (100 mL) and water (100 mL) and the queous layer was back-extracted with E^O (2 x 100 mL). The organic layers were fashed with a saturated NaCl solution (100 mL), dried (MgSOJ, and concentrated nder reduced pressure. The solid residue was triturated with E^O to afford the esired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) R^O.06; 1-NMR (DMSO-d6) 8 7.33 (dd, >1.2,4.2 Hz, 2H), 7.78 (d, >8.7 Hz, 1H), 8.46 (dd, =2.4, 8.7Hz, 1H), 8.54-8.56 (m, 3H).

tep 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline; A slurry of 3-ifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp, for h. The mixture was diluted with E^O (100 mL) and water (100 mL). The aqueous lase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers ere washed with a saturated NaCl solution (100 mL), dried (MgS04), and mcentrated under reduced pressure. The residue was filtered through a pad of silica radient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the sired product (3.3 g): TLC (50% EtOAc/50% hexane) R,0.10; 'H-NMR (DMSO-d6) 5.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, ^=8.4 Hz, 1H), 8.29 ,7=6.3 Hz, 2H).
jneral Method for Substituted Aniline Formation via Nitroarene Formation trough Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(2-(4-Phenyl)thiazoIyl)thio-l-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2C03 (3.18 g, 23 mmol), and the mixture was heated at approximately 65 °C overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO«) and concentrated under reduced pressure. The solid residue was triturated with a E^O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) R^ 0.49; 'H-NMR (CDC13) 5 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, 7=6.9 Hz, 2H), 8.19 (d, y=9.0 Hz, 2H).

Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio-l-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) RjrO.18; 'H-NMR (CDC13) 8 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H).
General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(6-Methyl-3-pyridinyIoxy)-l -nitrobenzene: To a solution of 5-hydroxy-2-methylpyridine (5.0 g, 45.8 mmol) and l-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K2C03 (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 (>* 130 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na^O,), 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)-l-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 H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, 92%): EI-MS m/z 200 (M*).
General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4-dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 uL, 6.4 mmol) in anh DMF (20 mL) was added K2C03 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (NajSOJ, 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)-!-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 (balloon) and was allowed^to^stir for 18 h at room temp. The mixture was then filtered through a pad of Celite* and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z 245 (M+)-
f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K2C03 (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NajSOJ, and concentrated in vacuo. The resulting oil was purified 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)-l-
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 (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (1.6 g, 94%): EI-MS m/z 186 (M+).
. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 3-(5-MethyI-3-pyridinyIoxy)-l-nitrobenzene: To a solution of 3-hydroxy-5-methylpyridine (5.0 g, 45.8 mmol), l-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 K2C03 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (N^SOJ, and concentrated in vacuo . The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%).
Step 2. 3-(5-MethyI-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3-pyridinyIoxy)-l-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 H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H)+).
i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 5-Nitro-2-(4-methyIphenoxy)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 K2C03 (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 (30% EtOAc/70% pet ether) R^O.79; 'H-NMR (DMSO-dJ 8 2.31 (s, 3H), 7.08 (d, 7=8.46 Hz, 2H), 7.19 (d, 7=9.20 Hz, 1H), 7.24 (d, 7=8.09 Hz, 2H), 8.58 (dd, 7=2.94, 8.82 Hz, 1H), 8.99 (d, 7=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 ((M+H)+), 100%).

Step 2. 5-Anuno-2'(4-niethyIphenoxy)pyridine Dihydrochloride: A solution 5-nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 xnmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The reaction mixture was then placed under a H2 atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celite®. A solution of HCI in Et20 was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, 92%): mp 208-210 °C (dec); TLC (50% EtOAc/50% pet ether) R, 0.42; 'H-NMR (DMSO-d6) 8 2.25 (s, 3H), 6.98 (d, 7=8.45 Hz, 2H), 7.04 (d, 7=8.82 Hz, 1H), 7.19 (d, .7=8.09 Hz, 2H), 8.46 (dd, 7=2.57, 8.46 Hz, 1H), 8.63 (d, 7=2.57 Hz, 1H); EI-MS m/z (rel abundance) (M\ 100%).
General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1. 4-(3~Thienylthio)~l-nitrobenzene: To a solution of 4-nitrothiophenol (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 reaction mixture was then poured into a mixture of ice and a 6N HCI solution (200 mL) and the resulting aqueous mixture was

extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a 1M NaOH solution (2 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (MgSO«), and concentrated in vacuo . The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS m/z 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 Bl.
B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

4-(5-Pyrimininyloxy)aniIine: 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC-MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp, and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCl solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).
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 reaction vessel for 42 h, then allowed to cool to room temp. The reaction

mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (N^SOJ and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90% hexane)Rj-0.57.

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 reaction 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 reaction mixture was warmed to room temp, for 30 min and then heated to the reflux temp, for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a IN HC1 solution then extracted with Et20 (2 x 100 mL). The combined organic layers were dried (NajSOJ and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%).

Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-l-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 reaction mnixture was heated to 95 °C overnight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSOJ and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).

-So-

Step 4. 4-(5-(2-Methoxy)pyridyI)oxyaniline: 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
a. 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 K2C03 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp, for 1.5 h, then diluted with EtOAc (100 mL) and water (lOOmL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSOJ, and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et20/hexane solution to afford the desired product (4,6 g, 66%): TLC (100 % ethyl acetate) R, 0.29; 'H-NMR (DMSO-dJ 5 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8,2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8,2H).
t>. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine

4-(2-MethyI-4-pyridinyIoxy)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 /er/-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction 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 combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NajSC^), and concentrated in vacuo.

The resulting oil was purified by flash chromatography (50 % EtOAc/50% hexane) to afford the desired product as a yellow oil (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. MethyI(4-nitrophenyl)-4-pyridylaniine: To a suspension of N-methyl-4-nitroaniline (2.0 g, 13.2 mmol) and K2C03 (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried (NajSOJ and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4-nitrophenyl)-4-pyridylamine (0.42 g)

Step 2. Methyl(4-amuiophenyl)-4-pyridyIamine: Methyl(4-nitrophenyl)-4-pyridylamine was reduced in a manner analogous to that described in Method Bl.
B5. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene

Step 1. 4-(4-Butoiyphenyl)thio-l-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 reaction was stirred at room temp, for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with EtjO (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 purified by silica gel chromatography (gradient from 20% EtOAc/80% hexane to 50% EtOAc/50% hexane) to give the product as a yellow solid (1.24 g, 67%): TLC (20% EtOAc/80% hexane) fyO.75; 'H-NMR (DMSO-dj) 8 0.92 (t, J= 7.5 Hz, 3H), 1.42 (apphex,>7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, >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-ButoxyphenyI)thioaniIine: 4-(4-Butoxyphenyl)thio-l -nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step 2): TLC (33% EtOAc/77% hexane) RyO.38.
B6. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes

4-(4-terf-ButoxycarbamoyIbenzyl)aniline: To a solution of 4,4'-methyIenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di-rerr-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp, for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-ferf-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp, for 16 h. The resulting mixture was diluted with EtjO (200 mL), sequentially washed with a

r

saturated NaHC03 solution (100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a white solid ( 2.09 g, 46%): TLC (50% EtOAc/50% hexane) R, 0.45; 'H-NMR (DMSO-d,) 5 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, 7=8.4 Hz, 2H), 6.80 (d, 7=8.1 Hz, 2H), 7.00 (d, 7=8.4 Hz, 2H), 7.28 (d, 7=8.1 Hz, 2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M*).
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 IN NaOH solution, then extracted with Et20 (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NajSOJ, and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC-MS m/z 214 (M*).

Step 2. 3-(4-Pyridinyl)methyIaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method Bl.
Genera] Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction

Step 1. 4-(l-ImidazolyImethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K2C03 (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 combined organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, 91%): EI-MS m/z 203 (M+).

Step 2. 4-(l-ImidazolyImetbyl)aniline: 4-(l-Imidazolylmethyl)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.
Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction

Step 1. 4-(l-Hydroxy-l-(4-pyridyI)methyl-l-nitrobenzene: To a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH2C12 (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 6C, and the mixture was stirred at room temp, overnight. The reaction mixture was successively washed with a 10% NaHSO, solution (50 mL), a saturated K2C03 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgS04) and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous 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 CH2C12 (50

mL). The organic layer was dried (MgSOJ, concentrated under reduced pressure, and purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired product as a white solid. (0.53 g, 8%): mp 110-118 °C; TLC (80% EtOAc/20% hexane) R^O.12; FAB-MS m/z 367 ((M+H)+, 100%).

Step 2. 4-(l-Hydroxy-l-(4-pyridyI)methyIaniIine: 4-(l-Hydroxy-l-(4-pyridyI)-m ethyl-1 -nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
BIO. Formation of 2-(7V-methyIcarbamoyl)pyridines via the Menisci reaction

step 1. 2-(iV-methyIcarbamoyI)-4-chIoropyridine. (Caution: this is a highly lazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) n //-methylformamide (250 mL) under argon at ambient temp was added cone. H2S04 3.55 mL) (exotherm). To this was added H202 (17 mL, 30% wt in H20) followed >y FeS04 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark it ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling ubsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was liluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The queous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were /ashed separately with a saturated NaCl solution (3 x 150 mlL. The combined rganics were dried (MgS04) and filtered through a pad of silica gel eluting with itOAc. The solvent was removed in vacuo and the brown residue was purified by ilica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 0% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(N-iethylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% exane) fy0.50; MS; 'H NMR (CDC13): 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, C1CHCN), 3.04 (d 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+).
Bll. Generalmethod for the Synthesis of ©-Sulfonylphenyl Anilines

Step 1. 4-(4-MethyIsulfonyIphenoxy)-l-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH2C12 (75 mL) at 0 °C was slowly added mCPBA (57-86%, 4 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSOJ, and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-MethyIsulfonyIpbenoxy)-l-aniIine: 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 o-Alkoxy-o-carboxyphenyl Anilines

Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of -(3 -carboxy-4-hydroxyphenoxy)-l -nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added K2C03 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat the reflux tempoerature overnight, then cooled to room temperature and filtered through a pad of Celite*. The resulting solution was concentrrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115 118 °C.

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-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 dissolved in water (50 mL), and the aqueous mixture was made acidic with a lN'HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g).
C. General Methods of Urea Formation
CI a. Reaction of a Heterocyclic Amine with an Isocyanate

A'-(S-rerr-Butyl-3-thienyl)-Ar'-(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 H20 (200 mL), a 1 N HC1 solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajS04), 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-phenoxyphenyI)urea. A portion of this material (4.67 g) was purified by flash chromatography (9% EtOAc/27% CHjCl^^o cyclohexane) to afforded the desired product as a white solid (3.17 g).
Clb. Reaction of a Heterocyclic Amine with an Isocyanate

AH3-f^ButyI-5-isoxazolyl)-A^(4-phenojcyphenyl)urea: To a solution of 5-amino-3-rert-butylisoxazole (8.93 g, 63.7 mmol, 1 eq.) in CHjClj (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 CH2C12 (80 mL). The resulting mixture was poured into water (500 mL) and extracted with EtjO (3 x 200 mL). The organic layer was dried (MgS04) 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^0.27; 'H-NMR (DMSO-d«) 5 1.23 (s, 9H), 6.02 (s, 1H), 6.97 (dd, 7=0.2, 8.8 Hz, 2H), 6.93 (d, .7=8.8 Hz, 2H), 7.08 (t, .7=7.4 Hz, 1H), 7.34 (m, 2H), 7.45 (dd, .7=2.2, 6.6 Hz, 2H) , 8.80 (s, 1H), 10.04 (s, 1H); FAB-MS m/z (rel abundance) 352 ((M+H)*,70%).
Clc. Reaction of a Heterocyclic Amine with an Isocyanate

^-(3-/ffrt-ButyI-5-pyrazoIyI)-7V'-(4-(4-methyiphenyl)oxyphenyI)urea: A solution of 5-amino-3-ter/-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4-(4-methyIphenoxy)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 rain, the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, 33%): mp 204 °C; TLC (5% acetone/95% CH2C12) R^O.92; 'H-NMR (DMSO-d6) 6 L22 (s, 9H), 2.24 (s, 3H), 5.92 (s, 1H), 6.83 (d, 7=8.4 Hz, 2H), 6.90 (d, .7=8.8 Hz, 2H), 7.13 (d, 7=8.4 Hz, 2H), 7.40 (d, 7=8.8 Hz, 2H), 8.85 (s, 1H), 9.20 (br s, 1H), 11.94 (br s, 1H); EI-MS m/z 364 (M+).

Cld. Reaction of a Heterocyclic Amine with an Isocyanate

A^-(5-^rf-Butyl-3-thienyl)-JV'-(2,3-dichlorophenyI)urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-fcr/-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL, 2.02 mmol) in CH2C12 (10 mL) to clarify the mixture and the resulting solution was stirred at room temp, overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHCOj solution (15 mL), a IN HC1 solution (15 mL) and a saturated NaCl solution (15 mL), dried (NajSOJ, 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) R, 0.57; 'H-NMR (DMSO-d6) 5 1.31 (s, 9H), 6.79 (s, 1H), 7.03 (s, 1H), 7.24-7.33 (m, 2H), 8.16 (dd, 7=1.84, 7.72 Hz, 1H), 8.35 (s, 1H), 9.60 (s, 1H); "C-NMR (DMSO-d6) 8 31.9 (3C), 34.0,103.4,116.1,119.3,120.0,123.4,128.1,131.6,135.6,138.1,151.7,155.2; FAB-MS m/z (rel abundance) 343 ((M+H)+, 83%), 345 ((M+H+2)\ 56%), 347 ((M+H+4)\ 12%).
Cle. Reaction of a Heterocyclic Amine with an Isocyanate

A,-(3-rerf-Butyl-5-pyrazolyl)-Ar'-(3,4-dichlorophenyl)urea: A solution of 5-amino-3-/err-butyl-Ar/-(rer/-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 CH2C12 (3 mL) and TFA (1.5 mL). After 30 min, the solvent was removed in vacuo and the residue was taken up in EtOAc (10 mL). The resulting mixture was sequentially washed with a saturated NaHCO, solution (10 mL) and a NaCl solution (5 mL), dried (NajSOJ, and concentrated in vacuo. The residue was purified 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) fyO.05, FAB-MS m/z 327 ((M+H)+).
Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline

Step 1. 3-te/?-Butyl-5-isoxazoIyl Isocyanate: To a solution of phosgene (20% in toluene, 1.1*3 mL, 2.18 mmol) in CH2C12 (20 mL) at 0 °C was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-/ert-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. Ar-(3-/erf-Butyl-5-isoxazolyl)-A^'-(4-(4-pyridinylthio)phenyl)urea: The
crude 3-terf-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4-(4-pyridinylthio)aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 °C for 2 h then cooled to room temp, and diluted with an EtOAc/CH2Cl2 solution (4:1, 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CH2C12 to 4% MeOH/6% CH2C12) to afford a foam, which was triturated (EtjO/hexane) in combination with sonication to give the product as a white powder (0.18 g, 49%): TLC (5% MeOH/95% CH2C12) R, 0.21; 'H-NMR (DMSO-dJ 5 1.23 (s, 9H), 6.06 (s, 1H), 6.95

(d, /=5 Hz, 2H), 7.51 (d, 7=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 «/r 369 ((M+H)+).
C2b. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline
Step 1. 5-terf-Butyl-3-isoxazoIyl 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-terf-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 dissolved in anh. THF (350 mL) and stirred for 10 min. The orange precipitate (pyridinium hydrochloride) was removed and the isocyanate-containing filtrate (approximately 0.2 M in THF) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) m/z 166 (M+).

Step 2. Ar-(5-^rt-Butyl-3-isoxazolyI)-Ar'-(4-(4-pyridinylthlo)phenyl)urea: To a solution of 5-fer/-butyI-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 NaCl solution (100 mL), a saturated NaHC03 solution (100 mL), and a saturated NaCl solution (100 mL), dried (MgS04), and concentrated m vacuo. The resulting material was purified by MPLC (2 x 300 g silica gel, 30 % EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 %): mp 178-179 °C; 'H-NMR (DMSO-d6) 8 1.28 (s, 9H), 6.51

(s, 1H), 6.96 (d, 7=6.25 Hz, 2H), 7.52 (d, 7=8.82 Hz, 2H), 7.62 (d, 7=8.83 Hz, 2H), 8.33 (d, 7=6.25 Hz, 2H), 9.10 (s, 1H), 9.61 (s, 1H); EI-MS m/z 368 (M+).
C2c Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline

iV-(3-/crt-Butyl-5-pyrazolyl)-Ar'-(4-(4-pyridinyloxy)phenyl)urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH2C12 (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 1 h, then was allowed to warm to room temp, over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-fer?-butyl-Af'-(terr-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 °C for 12 h forming a white precipitate. The solids were dissolved in a IN HC1 solution and allowed to stir at room temp, for 1 h to form a new precipitate. The white solid was washed (50% £^0/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 °C dec; TLC (10% MeOH/ 90% CHC13) R, 0.239; 'H-NMR (DMSO-d6) 8 1.24 (s, 9H), 5.97 (s, 1H), 6.88 (d, 7=6.25 Hz, 2H), 7.10 (d, 7=8.82 Hz, 2H), 7.53 (d, 7=9.2 Hz, 2H), 8.43 (d, 7=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%).
Reaction of a Heterocyclic Amine with iVyV'-Carbonyldiiniidazole Followed by Reaction with a Substituted Aniline

A^3-te/t-ButyI-l-methyl-5-pyrazolyI)-7V'-(4-(4-pyridinyloxy)phenyI)urea: To a solution of 5-amino-3-ferf-butyl-1-methylpyrazole (189 g, 1.24 mol) in anh. CH2C12 (2.3 L) was added //.W-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 reaction mixture was heated to 36 °C for 16 h. The resulting mixture was cooled to room temp, diluted with EtOAc (2 L) and washed with H20 (8 L) and a saturated NaCl solution (4 L). The organic layer was dried (Na^SO,,) and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et20/11.2% hexane, 2.5 L) to afford the desired urea as a white solid (230 g, 51%): mp 149-152 °C; 'H-NMR (DMSO-d6) 8 1.18 (s, 9H), 3.57 (s, 3H), 6.02 (s, 1H), 6.85 (d, .7=6.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.52 (d, .7=9.0 Hz, 2H), 8.40 (d, .7=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H); FAB-LSIMS m/z 366 ((M+H)+).
b. Reaction of a Heterocyclic Amine with tyTV'-CarbonyldiimidazoIe Followed by Reaction with a Substituted Aniline

^-(S-rert-Butyl-S-pyrazoIyO-A^'-p-C^-py'dinylthioJphenyOurea: To a solution of 5-amino-3-/crr-butyl-7/'-(/er/-butoxycarbonyl)pyrazole (0.282 g, 1.18 mmol) in CHjClj (1.2 mL) was added N,N -carbonyldiimidazole (0.200 g, 1.24. mmol) and the mixture was allowed to stir at room temp, for 1 day. 3-(4-Pyridinylthio)aniline (0.239 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp, for 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 (MgSO224 °C dec; TLC (5% MeOH/ 95% CHC13) R, 0.067; 'H-NMR ,(DMSO-d6) 6 1.23 (s, 9H), 5.98 (s, 1H), 7.04 (dm, .7=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, 7=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%).
Reaction of Substituted Aniline with fyW-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine

Ar-(3-^rt-Butyl-l-methyl-5-pyrazolyl)-Ar'-(4-(4-pyridinylmethyI)phenyl)urea: To
a solution of 4-(4-pyridinylmethyl)aniline (0.200 g, 1.08 mmol) in CH2C12 (10 mL) was added Af.AT-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for I h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-amino-3-tert-butyM-methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 °C overnight. The reaction mixture was cooled to room temp and purified by column chromatography (gradient from 20% acetone/80% CH2C12 to 60% acctone/40% CH2C12) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, 58%): TLC (4% MeOH/96% CH2C12) R^O.15; 'H-NMR (DMSO-d6) 5 1.19 (s, 9H), 3.57 (s, 3H), 3.89 (s, 2H), 6.02 (s, 1H), 7.14 (d, 7=8.4 Hz, 2H), 7.21 (d, >6 Hz, 2H), 7.37 (d, 7=8.4 Hz, 2H), 8.45-8.42 (m, 3H), 8.81 (s, 1H); FAB-MS m/z 364 (M+H)+).
- CnS-

C4b. Reaction of Substituted Aniline with A^W-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine

Ar-(3-/err-ButyI-S-pyra2oIyI)-7V-(3-(2-benzothia2o!yIoxy)phenyI)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-/er/-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 CH2C12 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CH2C12. 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% CHjCl2) R, 0.05; 'H-NMR (DMSO-d6) 6 1.24 (s, 9H), 5.97 (s, 1H), 7.00-7.04 (m, 1H), 7.21-7.44 (m, 4H), 7.68 (d, 7=5.5 Hz, 1H), 7.92 (d, .7=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+).
:. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline
SL
H H Ar-(5-rcrt-Butyl-3-thienyI)-Ar,-(4-(4-pyridinyloxy)pbenyl)urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH2C12 (5 mL) was added a solution of 4-(4-pyridinyloxy)aniIine (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH2C12 (5 mL). The resulting mixture was allowed to warm to room temp, and was stirred for 1 h, then was concentrated under reduced pressure. The

residue was dissolved in CH2C12 (5 mL), then treated with S-tert-butylthiopheneammoniurn chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h, then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHCO, solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajSOJ, 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% EtOAc/50% hexane) i^-0.13; 'H-NMR (CDC13) 8 1.26 (s, 9H), 6.65 (d, >1.48 Hz, 1H), 6.76 (dd, .7=1.47, 4.24 Hz, 2H), 6.86 (d, .7=1.47 Hz, 1H), 6.91 (d, .7=8.82 Hz, 2H), 7.31 (d, .7=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, .7=1.47 Hz, 2H); "C-NMR (CDC13) 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%).
!. General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine

iV-(3-rerf-ButyI-4-methyl-5-isoxazolyI)-AT-(2-fluorenyl)urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (l.OmL) was added a solution of 5-amino-4-methyl-3-/err-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 70 °C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 40 °C for 3 h and then at RT for 17 h to produce a precipitate. The solids were washed with Et20 and hexanes to give the desired urea as a beige solid (25 mg, 14%): mp 179-181 °C; 'H-NMR (DMSO-d6) 6 1.28 (s, 9H), 2.47

(s, 3H), 3.86 (s, 2H), 7.22 (t, >7.3 Hz, 1H), 7.34 (m, 2H), 7.51 (d, 7=7.3 Hz, IH), 7.76 (m, 3H), 8.89 (s, IH), 9.03 (s, IH); HPLC ES-MS m/z 362 ((M+H)+).
C6. General Method for Urea Formation by Curtius Rearrangement and 5 Carbamate Trapping

Step 1. 5-MethyI-2-(azidocarbonyI)thiophene: To a solution of 5-Methyl-2-I 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 internal temperature below 5 °C. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the reaction mixture was stirred for 2 h at 0 °C. The resulting mixture was diluted with CH2C12 (10 mL) and washed with a saturated NaCl solution (10 mL). The aqueous layer was back-extracted with CH2C13 (10 mL), ind the combined organic layers were dried (MgS04) and concentrated in vacuo. The esidue was purified by column chromatography (10% EtOAc/ 90% hexanes) to give :he 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 reactions.

Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp, for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions.
H H Step 3. ^-(S-rerf-Butyl-S-isoxazoIyO-^'-fS-methyl^-thienyOurea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp.

was added 3-amino-5-ferr-butyIisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a 1 N HC1 solution (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSOJ, and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, 93%): mp 200-201 °C; TLC (20% EtOAc/80% hexane) R, 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: POCl3 (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 reaction mixture was then to 55 °C for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCl solution (200 mL), dried (Na^SOJ and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH2C12) to give the desired aldehyde as an orange oil (15.5 g, 35%): TLC (5% EtOAc/95% hexane) R^O.54; 'H NMR (CDCI3) d 1.26 (s, 9H), 6.15 (d, 7=7.0 Hz, 1H), 10.05 (d,J"=6.6 Hz, 1H).

Step 2. Methyl 5-ferr-butyl-2-thiophenecarboxyIate: 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 Na^S (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 reaction mixture was stirred at room temp, for 1.5 h, then treated with a 1 N HC1 solution (200 mL) and stirred for 1 h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HC1 solution (200 mL), water (2 x 200 mL) and a saturated NaCl solution (200 mL), dried (Na^OJ and concentrated under reduced pressure. The residue was purified using column chromatography (5% EtOAc/95% hexane) to afford the desired product (0.95 g, 36%): TLC (20% EtOAc/80% hexane) R^O.79; 'H NMR (CDC1,) 5 1.39 (s, 9H), 3.85 (s, 3H), 6.84 (d, 7=3.7 Hz, 1H), 7.62 (d, .7=4.1 Hz, 1H); GC-MS m/z (rel abundance) 198 (M+, 25%).

Step 3. 5-/«rt'-BuryI-2-thiophenecarboxylic acid: Methyl 5-/erf-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 reaction mixture, then the pH was adjusted to approximately 3 using a 1 N HC1 solution. The resulting organic phase was washed with water (5 mL), dried (NajSOJ, 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) R/ 0.29; 'H NMR (CDC13) 8 1.41 (s, 9H), 6.89 (d, .7=3.7 Hz, 1H), 7.73 (d, 7=3.7 Hz, 1H), 12.30 (br s, 1H); UC NMR (CDC13) 8 32.1 (3C), 35.2,122.9,129.2,135.1,167.5,168.2.

Step 4. ^-(S-Zcrt-Butyl-l-thienylJ-^'^^-dichlorophenyOurea: A mixture of 5-ferf-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 reaction mixture was heated to 80°C for an additional 2 h. The resulting mixture was allowed to cool to

room temp, and treated with EtOAc (50 mL). The organic layer was washed with a 1 N HC1 solution (3 x 50 mL), a saturated NaHC03 solution (50 mL), and a saturated NaCl solution (50 mL), dried (Na^OJ, and concentrated under reduced pressure. The residue was purified 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) iyo.28; 'H NMR (CDCL.) 5 1.34 (s, 9H), 6.59 (br s, 2H), 7.10-7.13 (m, 2H), 7.66 (br s, 1H), 8.13 (dd, J=2$, 7.8 Hz, 1H); ,3C NMR (CDC13) 5 32.2 (3C), 34.6, 117.4, 119.07, 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 dissolved 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 purified by reverse phase HPLC.
D. Misc. Methods of Urea Synthesis Dl. Electrophylic Halogenation

Af-(2-Bromo-5-fcrt-butyI-3-thienyl)-Ar'-(4-methylphenyl)urea: To a slurry of N-(5-ferr-butyl-3-thienyl)-/>/ '-(4-methylphenyl)urea (0.50 g, 1.7 mmol) in CHC13 (20 mL) at

room temp was slowly added a solution of Br2 (0.09 mL, 1.7 mmol) in CHC13 (10 mL) via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure, and the residue triturated (2 x Et20/hexane) to give the brominated product as a tan powder (0.43 g, 76%): mp 161-163 °C; TLC (20% EtOAc/ 80% hexane) fyO.71; 'H NMR (DMSO-d6) 5 1.29 (s, 9H), 2.22 (s, 3H), 7.07 (d, 7=8.46 Hz, 2H), 7.31 (d, 7=8.46 Hz, 2H), 7.38 (s, 1H), 8.19 (s, 1H), 9.02 (s, 1H); 13C NMR (DMSO-d6) 6 20.3, 31.6 (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. Synthesis of co-Alkoxy Ureas

Step 1. AHS-re/t-Butyl-S-thienyO-N^-^-hydroxyphenyOoxypbenylJurea: A
solution of//-(5-/er/-butyl-3-thienyl)-//'-(4-(4-methoxyphenyl)oxyphenyl)urea (1.2 g, 3 mmol) in CH2C12 (50 mL) was cooled to -78 °C and treated with BBr3 (1.0 M in CH2C12, 4.5 mL, 4.5 mmol, 1.5 equiv) dropwise via syringe. The resulting bright yellow mixture was warmed slowly to room temp and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), then washed with a saturated NaHC03 solution (50 mL) and a saturated NaCl solution (50 mL), dried (NajS04), and concentrated under reduced pressure. The residue was purified via flash chromatography (gradient from 10% EtOAc/90% hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan foam (1.1 g, 92%): TLC (20% EtOAc/80% hexane) R, 0.23; 'H NMR (DMSO-d6) & 1.30 (s, 9H), 6.72-6.84 (m, 7H), 6.97 (d, >1.47 Hz, 1H), 7.37 (dm, 7=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. A'-(5-/crt-ButyI-3-thienyl)-Ar'-(4-(4-ethoxyphenyl)oxyphenyl)urea: To a
mixture of Ar-(5-/err-butyl-3-thienyl)-//'-(4-(4-hydroxyphenyl)oxyphenyl)urea (0.20 g, 0.5 mmol) and Cs2COj (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 reaction was cooled, filtered, and the solids were washed with EtOAc. The combined organics were concentrated under reduced pressure, and the residue was purified via preparative HPLC (60% CHjCN/40% H2O/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, 73%): mp 155-156 °C; TLC (20% EtOAC/ 80% hexane) F^O.40; 'H-NMR (DMSO-d6) 5 1.30 (s, 9H), 1.30 (t, J=6S9 Hz, 3H), 3.97 (q, 7=6.99 Hz, 2H), 6.80 (d, 7=1.47 Hz, 1H), 6.86 (dm, 7=8.82 Hz, 2H), 6.90 (s, 4H), 6.98 (d, .7=1.47, 1H), 7.40 (dm, 7=8.83 Hz, 2H), 8.54 (s, 1H), 8.73 (s, 1H); 13C-NMR (DMSO-d6) 5 14.7, 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%).
D3. Synthesis of ©-Carbamoyl Ureas

AK3-tert-Butyl-l-methyl-5-pyrazoIyl)-Ar,-(4-(4-
acetaminophenyI)methylphenyI)urea: To a solution of //-(3-terf-butyl-l-methyl-5-pyrazolyO-A^'^^-aminophenylJmethylphenylJurea (0.300 g, 0.795 mmol) in CH2C12 (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 HC1 solution (125 mL) then water (100 mL), dried (MgS04), and concentrated under reduced pressure. The resulting residue was

>

purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid (0.160 g, 48%): TLC (EtOAc) R^O.33; 'H-NMR (DMSO-d6) 8 1.17 (s, 9H), 1.98 (s, 3H), 3.55 (s, 3H), 3.78 (s, 2H), 6.00 (s, 1H), 7.07 (d, 7=8.5 Hz, 2H), 7.09 (d, .7=8.5 Hz, 2H), 7.32 (d, J=S.S Hz, 2H), 7.44 (d, 7=8.5 Hz, 2H), 8.38 (s, 1H), 8.75 (s, 1H), 9.82 (s, 1H); FAB-MS m/z 420 ((M+H)+).

)4. General Method for the Conversion of Ester-Containing Ureas into Alcohol-Containing Ureas
N-N-HydroxyethyOO-rcrt-butyl-S-pyrazolyO-iV'^^-dichlorophenylJurea: A
solution of A'-(///-(2-(2,3-dichlorophenylamino)carbonyloxyethyl)-3-rerr-butyl-5-pyrazoIyl)-Ar'-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH ( 0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at -65 °C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1 solution (3 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (Et20) to afford the desired product as a white solid (0.17 g, 64 %): TLC (60% EtOAc/40% hexane) R,0.16; 'H-NMR (DMSO- D5a. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas

Step 1. A4A^CarboxymethyI)-3-terf-butyl-5-pyrazolyl)-jV'-(2,3-
dichlorophenyl)urea: A solution of AT-(///-(ethoxycarbonylmethyl)-3-/er/-butyl-5-pyrazolyl)-^/'-(2,3'dichlorophenyl)urea (prepared as described in Method A3, 0.46 g, 1.11 mmoles) and NaOH (1.2 mL, 5N in water, 6.0 mmoles) in EtOH (7 mL) was stirred at room temp, for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1 solution (4 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (EtjO/hexane) to afford the desired product as a white solid (0.38 g, 89%): TLC (10% MeOH/90% CH2CI2) R^O.04; 'H-NMR (DMSO-d6) 8 1.21 (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, 1H); FAB-MS m/z (rel abundance) 385 ((M+H)+, 100%).

Step 2. ^-(^'-((MethylcarbamoyOmethyO-S-^rt-butyl-S-pyrazolyO-^Mi^"
dichIorophenyl)urea: A solution of A^A^carboxymethyl)-3-terf-butyl-5-pyrazolyl)-Ar'-(2,3-dichlorophenyl)urea (100 mg, 0.26 mmole) and N,N'-carbonyldiimidazole (45 mg, 0.28 mmole) in CH2C12 (10 mL) was stirred, at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CH2CI2) R^O.81). Dry methylamine hydrochloride (28 mg, 0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The reaction mixture was stirred at room temp, overnight, then diluted with CH2C12, washed with water (30 mL), a saturated NaCl solution (30 mL), dried (MgSOJ and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% acetone/90% CH2C12 to 40% acetone/60% CH2C12) and the residue was crystallized (EtjO/hexane) to afford the desired product (47 mg, 46%): TLC (60% acetone/40% CH2C12) R, 0.59; 'H-NMR (DMSO-d6) 5 1.20 (s, 9H), 2.63 (d, >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, 1H), 9.20 (br s, 1H); 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. ^-(S-rerr-Butyl-S-isoxazolyO-A^'^^-carboxyphenyOoxyphenylJurea:
To a solution of A^S-te^butyl-S-isoxazolylJ-N^-^-emoxyoxycarbonylphenyl)-oxyphenyl)urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added a 1M NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HC1 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. Ar-(5-rcrt-Butyl-3-isoxazoIyl)-Ar'-(4-(4-(Ar-methyIcarbamoyl)-
phenyI)oxyphenyl)urea: A solution of N-(5-tert-buty\~3-isoxazoly\yN'-(4-(4-carboxyphenyl)oxyphenyI)urea (0.100 g, 0.25 mmol), methylamine (2.0 M in THF; 0.140 mL, 0.278 mmol), l-emyl-3-(3-dimemylaminopropyl)carbodiimide hydrochloride (76 mg, 0.39 mmol), and W-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 1M citric acid solution (20 mL) and extracted widi EtOAc (3x15 mL). The combined extracts were sequentially washed with water (3 x 10 mL) and a saturated NaCl solution (2 x 10 mL), dried (NajSO,), filtered, and concentrated in vacuo . The resulting crude oil was purified by flash chromatography

i

(60 % EtOAc/40% hexane) to afford the desired product as a white solid (42 mg, 40%): EI-MS m/z 409 ((M+H)*).
General Method for the Conversion of o-Amine-Containing Ureas into Amide-Containing Ureas

A'-(5-rerr-Butyl-3-isoxazolyl)-Ar'-(4-(4-aminophenyl)oxyphenyl)urea: To a solution
of -(5-/e^butyl-3-isoxazolyl)-Ar'-(4-(4-rert-butoxycarbonylaminophenyI)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 cone HC1 solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp . The mixture was then poured into water (10 mL) and EtOAc(10 mL) and made basic using a 1M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na^OJ, and concentrated in vacuo to afford the desired product as a white solid (26 mg, 66%). EI-MS m/z 361 ((M+ H)+).
D7. General Method for the Oxidation of Pyridine-Containing Ureas

A'-(5-/frt'-Butyl-3-isoxazolyl)-Ar'-(4-(A'-oxo-4-pyridinyl)methylphenyI)urea: To a
solution of N-(5-tert-b\xty\-3 -isoxazolyl)-N '-(4-(4-pyridinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHC13 (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated K2C03 solution (10 mL). After 5 min, the solution was diluted with CHC13 (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 (MgSO«), and concentrated in

vacuo. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the W-oxide (0.082 g, 79%).
General Method for the Acylation of a Hydroxy-Containing Urea

Ar-(5-/ert-Butyl-3-isoxazolyl)-iV'-(4-(4-acetoxypheiiyloxy)phenyl)urea: To a solution of N-(5-tert-b\ity\-3-isoxazoly\)-N '-(4-(4-hydroxyphenyloxy)phenyl)urea (0,100 g, 0.272 mmol), Wtf-dimemylarninopyridine (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 dissolved in EtOAc (10 mL). The resulting solution was sequentially washed with a 5% citric acid solution (10 mL), a saturated NaHC03 solution (10 mL) and a saturated NaCl solution (10 mL), dried (NajS04), and concentrated under reduced pressure to give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmHg): TLC (40% EtOAc/60% hexane) Ry 0.55; FAB-MS m/z 410 ((M+H)+).
D9. Synthesis of to-Alkoxypyridines

Stepl. Ar-(5-/crf-Butyl-3-isoxazolyI)-A^-(4-(2(ljH)-pyridinon-5-yl)oxyphenyl)-urea: A solution of A'-(5-fer/-butyl-3-isoxazolyl)-Ar'-(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 CH2C12 (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 purified 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) R^O.05; FAB-MS m/z 369 ((M+H)+, 100%).
Step 2. A^^S-^rt-Butyl-a-isoxazoIyO-Af'^-tS^-Etho^pyridyOoxyphenyOurea:
A slurry of iV-(5-rerM)Utyl-3-isoxazolyl)-//^4-(2(l^-pyridinon-5-yl)oxyphenyl)urea (0.1 g, 0.27 mmol) and Ag2C03 (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 reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite* then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, 38%): mp 146 °C; TLC (40% EtOAc/60% hexane) R^O.49; FAB-MS m/z 397 ((M+H)+, 100%).
D10. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide-Containing Urea

Ar-(5-rert-Butyl-3-isoxazolyl)-7V'-(4-(4-(l-hydroxyethyI)phenyl)oxyphenyI)urea:
To a solution of Ar-(5-terf-butyl-3-isoxazolyl)-Jv*'-(4-(4-(l-
acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods Bl 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 HC1 solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCl solution (2x10 mL), dried (MgSO«), and concentrated in vacuo . The resulting white solid was purified by trituration (EtjO/hexane) to afford the desired product (0.021 g,

32 %): mp 80-85 °C; 'H NMR (DMSO-d6) 6 1.26 (s, 9H), 2.50 (s, 3H), 4.67 (m, 1H), 5.10 (br s, 1H), 6.45 (s, 1H), 6.90 (m, 4H), 7.29 (d, 7=9.0 Hz, 2H), 7.42 (d, 7=9.0 Hz, 2H), 8.76 (s, 1H), 9.44 (s, 1H); HPLC ES-MS m/z 396 ((M+H)+).
Bll. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy-Substituted Ureas

Ar-(5-/£rt-ButyI-3-isoxazoIyI)-Ar'-(4-(3-(ben2yIo3cycarbonyIamino)phenyI)-oxyphenyl)urea: To a solution of the //-(5-ter/-butyl-3-isoxazolyl)-W-(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% HC1 solution (50 mL) and teh resulting solution extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCl (2 x 50 mL), dried (NaaSOJ, and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 %): mp 73-75 °C; 'H NMR (DMSO-d6) 5 1.26 (s, 9H), 5.10 (s, 2H), 6.46 (s, 1H), 6.55 (d, 7=7.0 Hz, 1H), 6.94 (d, 7=7.0 Hz, 2H), 7.70 (m, 7H), 8.78 (s, 1H), 9.46 (s, 1H), 9.81 (s, 1H); HPLC ES-MS m/z 501 ((M+H)+).

listed above;

Table 1.

5-Substituted-3-isoxazolyl Ureas R1

- I CO -

TaDie :>.5-suDstitute

-|M-

BIOLOGICAL EXAMPLES
In Vitro raf Kinase Assay:
In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HCI, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20 (iL) is mixed with water (5 uL) or with compounds diluted with distilled water from 10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 uL [y-"P]ATP (1000*3000 dpm/pmol) in 80 mM Tris-HCI, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCl2. The reaction mixtures are incubated at 32 °C, usually for 22 min. Incorporation of "P into protein is assayed by harvesting the reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 jiM ATP and 0.4 jiM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by
-M^L~

electrophoresis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging Analyzer System.
All compounds exemplified displayed ICJ0s of between 1 nM and 10 p.M.
Cellular Assay:
For in vitro growth assay, human tumor cell lines, including but not limited to HCT116 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage independent growth in soft agar. Human tumor cell lines were obtained from ATCC (Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X 103 cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% C02 incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring 3H-thymidine incorporation into DNA following an 8 h culture with 1 fiCu 3H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 3H-thymidine incorporation by liquid scintillant counting.
For anchorage independent cell growth, cells are plated at 1 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 compounds are added to wells and incubated at 37 °C in a 5% C02 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 compounds of Formula I are active to inhibit raf kinase activity and to inhibit oncogenic cell growth.
In Vivo Assay:
An in vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid cancers) mediated by raf kinase can be performed as follows:
CDI nu/nu mice (6-8 weeks old) are injected 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 calipers twice a week.
The inhibitory effect of the compounds 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.

WE CLAIM:
Compound of formula I

wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, -C(0)R5, -N02- -ORS, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -Cio alkyl, C2 -Cio alkenyl, Ci-Cio alkoxy, C3 -Cio cycloalkyl, Ce-Ci4 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -Cio alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3-Cio cycloalkyl, and -Y-Ar,
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -Cio alkenyl, C3-C10 cycloalkyl up to per halosubstituted Ci-C10 alkyl, up to per halo substituted C2-C10 alkenyl, up to per-halosubstituted C3 -Cio cycloalkyl,
wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5NR5'-. NR5C(0)-, -C(0)NR5-, -(CHa)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX^, -CHX«2-, -S-(CH2)m- and
-N(R5)(CH2)m-,
m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN =0, -CO2R5, -C(0)NR5R5',

-C(O)- NR5, -N02> -OR5, -SR5, -NR5R5', -NR5C(0)OR5', -C(0)R5. 3JR5C(0)R5', -S02R5, S02NR5R5', Ci -C10 alkyl, C1-C10 alkoxyl, C3 -C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, and A is a heteroaryl moiety selected from the group consisting of

wherein R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-C10 cycloalkyl, C1-C13 heteroaryl, Ce-naryl, C7-24 alkaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C1-C13 heteroaryl, up to per-halosubstituted C6-14 aryl, and up to per-halosubstituted C7-24 alkaryl;
R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, C1-C10 alkyl C3-C10 cycloalkyl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, substituted C7-C24 alkaryl, and substituted C4-C23 alkheteroaryl;
where R2 is a substituted group, it is substituted by one or more substitutents independently selected from the group consisting of -CN, -CO2R4, -C(0)-NR3R3', _NO2, -OR4, -SR4, and halogen up to per-halosubstitution,
wherein R3 and R3' are independently selected from the group consisting of H, -OR4- -SR4- -NR4R4', -C(0)R4, -CO2R4- -C(0)NR4R4> Ci -Cio alkyl, C3-Cio cycloalkyl, C6-Ci4aryl, C3-C13 heteroaryl, up to per per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3 -Cio

cycloalkyl and up to per-halosubstituted C6 -CM aryl or C3 -C13 Jgeteiparyl; and
wherein R4 and R4' are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, C6C14 aryl, C3-C13 heteroaryl; up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl and up to per-halosubstituted Ce-CH aryl or C3-C13 heteroaryl,
R4 is C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-Cio alkyl and up to per-halosubstituted C3-C10 cycloalkyl; and
Rb is hydrogen or halogen,
Rc is hydrogen, halogen, C1-C10 alkyl, up to per-halosubstituted C1-C10 alkyl or combines with R1 and the ring carbon atoms to which R1 and Rc are bound to form a 5- or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 memebrs selected from O, N and S;
subject to the proviso that where A is

2. A compound of formula I as claimed in claim 1 wherein said compound is of the formula

wherein R2 is selected from the group consisting of H-C(0)R4, -C(0)2R4, -C(0)NR3R3, Ci-Cio alkyl C3-C10 cycloalkyl, substituted Ci-C10 alkyl, substituted C3-C10 cycloalkyl wherein R2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN,
-CO2R4, -C(0)-NR3R3, -NO2, -OR4, -SR4, and halogen up to per-halosubstitution,
wherein R3 and R3' are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, and up to per-halosubstituted C3-Cio cycloalkyl, and
wherein R4 and R4" are independently selected from the group consisting of H, C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, and up to per-halosubstituted C3-C10 cycloalkyl,
wherein R1 is selected from the group consisting of C3-C6 alkyl, C3-C8 cycloalkyl, up to per-halosubstituted C3-C6 alkyl and up to per-halosubstituted C3 -Ce cycloalkyl,
B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl;
substituted by C6-C14 aryl, C3-C13 heteroaryl or -Y-Ar
wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X1 n
and wherein n = 0.2, each X1 is independently selected from the group of -CN, -C02R5, -C-[0]R5, -C(0)-NR5 R5, -OR5, -NO2, -NR5 R5, Ci -Cio alkyl,

C2-io alkenyl, Ci-io alkoxy, C3 -Cio cycloalkyl, -SR5, -NR5C(0)OR5, NR5C(0)R5, substituted C1-C10 alkyl, substituted C2-10 alkenyl, substituted C1-10 alkoxy, substituted C3-C10 cycloalkyl,
wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5'
-C(0)R5> -C(0)-NR5R5, -OR5- -SR5- -NR5R5, -NO2, -NR5C(0)OR5, -NR5 C(0)OR5 and halogen up to per-halosubstitution,
wherein R5 and R5' are independently selected from H, Ci -Cio alkyl, C2 -Cio alkenyl, C3 -Cio cycloalkyl, C6 -CM aryl, C3 -C13 heteroaryl, C7-C24 alkaryl, C4 -C23 alkheteroaryl, up to per-halosubstituted Ci -Cio alkyl, up to per-halosubstituted C2-10 alkenyl and up to per-halosubstituted C3 -Cio cycloalkyl wherein Y is -O-, -S-, -N(R5)-, -(CH2)m„ -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5R5--NR5C(0), -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa, -CHX^-, -S-(CH2)m- and -N(R5)(CH2)m-,
m=1.3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is optionally by halogen up to per-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C02R5 -C(0)R5, =0, -C(0)-NR5R5', -C(0)R5, -N02, -OR5, -SR5, -NR5 R5, -NR5 C(0)OR5, -NR5 C(0)R5, -SO2R5, - S02R5R5', Ci -Cio alkyl, C1-C10 alkoxy, C3 -C10 cycloalkyl, substituted Ci -Cio alkyl, Ci -Cio alkoxy, C3 -Cio cycloalkyl, susbstituted Ci -Cio alkyl and substituted C3 -Cio cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)NR5R5, -O, -OR5, -SR5, -N02> -NR5 R5', -NR5 C(0)R5', -NR5C(0)OR5, Ci -Cio alkyl, C1-C10 alkoxy, C3 -Cio cycloalkyl.

3. A compound as claimed in claim 2 wherein B is

wherein
Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2-, -CHaS-, -CH(OH)-, -C(O)-, -CXa 2> -CX*H-, -CH2O-, and -OCH2-,
Xa is halogen,
Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution,
Q1 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, optionally substituted by halogen up to per-halosubstitution, X1 is Ci -C4 alkyl or halosubstituted Ci -C4 alkyl up to per halo,
Z, n and nl as defined in claim 2.
4. A compound as claimed in claim 3, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by
halogen, up to per-halosubstitution,
Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, and X1 is as defined in claim 3, and
Z is selected from the group consisting of -R6, -OR6 and -NHR7 wherein R6 is hydrogen, Ci -Cio alkyl, or C3 -Cio cycloalkyl and R7 is selected from the group consisting of hydrogen, C3 -Cio alkyl and C3 -Ce cycloalkyl, wherein R6 and R7 can be substituted substituted by halogen or up to per-halosubstitution.

5. A compound as claimed in claim 3, wherein Q is phenyl or j^ridinyl optionally substituted by halogen up to per-halosubstitution Q1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -O-, -S-, -CH2S-, -SCH2-, -CH2O-, -OCH2-or -CH2-, X1 is as claimed in claim 3, and Z is -SCH3-, or -NH-C(0)-CP-H2p+l, wherein p is 1-4, n=0 or 1 and nl =0-1.
6. A compound of formula I as claimed in claim 1 wherein said compound is of the formula

wherein R2 is as claimed in claim 2 and B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn' wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -CO2R5, -C(0)NR5R5, -C(0)R5, -N02- -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, Ci -C10 alkyl, C2 -C10 alkenyl, C1-C10 alkoxy, C3 -C10 cycloalkyl, C6-C14 aryl, C3 -C13 heteroaryl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2 -C10 alkenyl, up to per halo-substituted C1-C10 alkoxy, up to per halo-substituted C3 -C10 cycloalkyl, and -Y-Ar,
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2 -C10 alkenyl, C3 -C10 cycloalkyl, C6 -C14 aryl, C3-C13 heteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per halo substituted C^-Cio alkenyl, up to per-halosubstituted C3 -C10

cycloalkyl, and up to per-halosubstituted C6-Ci4 aryl and C3 -C13 toroaryl,
wherein Y is -O-, -S-, -N(R5)-, -(CH2)m, -C(O), -CH(OH)-, -(CH2)mO, -NR5C(0)NR5R5'-. NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX*, -CHX^-, -S-(CH2)m- and -N(R5)(CH2)m-,
m=l-3, and Xa is halogen, and Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, =0, -C02R5, -C(0)NR5R5', -C(O)- NR5. -N02- -OR5, -SR5, NR5R5', NR5C(0)OR5', -C(0)R5> NR5C(0)R5', -S02R5, -S02NR5R5', Ci-Cioalkyl, Ci-Cioalkoxyl, C3-C10 cycloalkyl, up to per halo-suibstituted Ci -C10 alkyl, and up to per halo-substituted C3-C10 cycloalkyl, subject to the proviso that where R4 is methyl
B is not

7. A compound as claimed in claim 2 selected from the group consisting of:
N-(3-tert-Butyl- 5-pyrazolyl)-N '-(4-phenyloxyphenyl)urea;
N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(3-
methylaminocarbonylphenyl)oxyphenyl)urea;
N-(3 -tert-Butyl-5 -pyrazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea;
N-(3-tert-Butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea;
N-(3 -tert-Butyl-5 -pyrazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea;
N-(3-tert-Butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)methylphenyl)urea;
N-( 1 -Methyl-3-tert-butyl-5 -pyrazolyl)-N'-(4-phenyloxyphenyl)urea;
N-(l-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-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-
pyridinyl)thiophenyl)urea;
N-(l-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-
pyridinyl)oxyphenyl)urea;
N-(l-Methyl-3-tert-buryl-5-pyrazolyl)-N'-((4-(4-
pyridinyl)methyloxy)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)thiophenyl) urea;
N-(3-tert-butyl- 5-pyrazolyl)-N'-(4-(4-pyridyl)thiophenyl) urea;
N-(3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl) urea;
N-(3-tert-butyl-5-pyrazolyl)-N,-(4-(4-pyridyl)oxyphenyl) urea;
N-(l-methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)thiophenyl)
urea;
N-(l-methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)thiophenyl)
urea;
N-( 1 -methyl-3-tert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl)
urea;
N-( 1 -methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)oxyphenyl)
urea;
and pharmaceutically acceptable salts thereof.
8. A compound of the formula

wherein R1 is selected from the group consisting of C3-C10 alkyl,C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl
B is phenyl pyridinyl, indolinyl, isoquinolinyl, qinolinyl or napthyl which is substituted by phenyl, pyndinyl or Y-Ar.

wherein the cyclic structures of B are optionally substituted by ogen, up to per-halosubstition, and optionally substituted by X1!! wherein N=0-2;
each X1 is independently selected from the group consisting of -CN,-C02R5, -C(0)R5, -C(0)NR5R5, _0R5? . N02) -NR5R5,CI-CIO alkyl, C2-10- alkenyl, Ci-10-alkoxy, C3-C10 cycloalkyl, and C6-C14 aryl,
-SR5,-NR5C(0)OR5, NR5C(0)R5', C3-C13 heteroaryl, substituted C1-C10 alkyl, substituted C2-io-alkenyl, substituted Ci-10-alkoxy, substituted C3-C10 cycloalkyl, substituted C6-C14 aryl, substituted C3-C13 heteroaryl, and
wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN,-C02R5,
-C(0)R5, -C(0)NR5R5, -OR5, -SR5,-NR5R5, } N02,-NR5C(0)R5, -NR5C(0)OR5 and halogen up to per-halosubstitution;
wherein R5 and R5', are independently selected from H, C1-C10 alkyl, C2-io alkenyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl,
wherein Y is - O-, -S-, -N(R5)-, -(CH2)m-, -C(Q).-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5,-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXvCX^-, -S-(CH2)m, -and -N(R5)(CH2)m-,
m = 1-3, and Xa is halogen; and
Ar is 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, =0, -C(0)NR5R5, -C(0)R5, -N02,-OR5, - SRV NR5R5, -NR5C(0)OR5, -NR5C(0)R5-, S02R5, -S02 R5R5, C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group

consisting of-CN, -CO2R5, -C(0)NR5R5, =0, -OR5, -SR5, -NO2, -NR5R5 , JfR5C(0)R5', -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl, subject to the proviso that where R1 is t-butyl, B is not

wherein R6 is -NHC(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or

-0-CH£
>—O

9. A compound as claimed in claim 8, wherein B is

Y is selected from the group consisting of -O-, -S-, -CH2-,
-SCH2-,
-CH2S, -CH(OH)-, -C(O)-, -CX«2, -CX*H-, -CH2O- and -OCH2-,
Xa is halogen,
Q is phenyl or pyridinyl substituted or unsubstituted by
halogen, up to per-halosubstitution;
Q1 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 substituted or unsubstituted by halogen up to per-halosubstitution, X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per halo, and
Z, n and nl are as claimed in claim 8.

10. A compound as claimed in claim 9, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per halosubstitution,
Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as claimed in claim 9 and
Z is selected from the group consisting of-R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl, C3-C6-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
11. A compound as claimed in claim 9, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution Q1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -O-, -S-, -C(0)-or -CH2-, X1 is as claimed in claim 8 and Z is-NH-C(0)-CpH2p+i, wherein p is 1-4, -CH3, -OH, -OCH3, -OC2H5, -CN or -C(0)CH3, n= 0 or 1, and nl = 0 or 1.
12. A compound as claimed in claim 8 selected from the group consisting of:
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyl)
oxyphenyl) urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-
hydroxyphenyl) oxyphenyljurea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-
acetylphenyl)oxyphenyl)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyi)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-
methylaminocarbonylphenyl) thiophenyl) urea;

N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(l,2-
methylenedioxy)phenyl)- oxyphenyl) urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-pyridinyl)oxyphenyl)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridyl)thiophenyl)urea;
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-
pyridinyl)methylphenyl)urea;
N~(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-pyridinyl)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)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-pyridinyl)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-
methylcarbamoyl) pyridyl)-oxyphenyl) urea;
N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(2-
methylcarbamoyl)pyridyl)- oxyphenyl) urea;
N-(5-tert-butyl-3-isoxazolyl)-N'-(3-(4-(2-
methylcarbamoyl)pyridyl) thiophenyl) urea;
N-(5-tert-butyl-3-isoxazolyl)-N'-(2-methyl-4-(4-(2-
methylcarbamoyl) 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)pyridyl) oxyphenyl) urea;

N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)pyridyl) thiophenyl) urea; N-(5-tert-buryl-3-isoxazolyl)-N'-(3-chloro-4-(4-(2-methylcarbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxa2olyl)-N'-(4-(3-methylcarbamoyl)phenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof.
13. A compound of the formula

wherein B is 5-methyl-2-thienyl or
selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrizinyl, pyndazinyl, naphthyl, quinolinyl, isoquinolinyl, phthaimidinyl, turyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothia- zolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn, wherein n is 0.3 and each X is independently selected from the group consisting of -CN, -CO2R5, C(0)NR5R5, -C(0)R5, -NO2, -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C3-C10 cycloalkyl, Ce-Ci4 aryl, C3-C13 heteroaiyl, up to per halo-substituted C1-C10 alkyl, up to per halo-substituted C2-C10 alkenyl, up to per halo-substituted C1-C10 alko?«y and, up to per halo-substituted C3-C10 cycloalkyl,
wherein R5 and R5> are independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, Ce-Ci4 aryl, C3-C13 heteroaiyl,

up to per-halosubstituted Ci-Cioalkyl, up to per-halosubstituted C2-Cip alkenyl, and up to per-halosubstituted C3-Ciocycloalkyl,
wherein Y is -O-, -S- -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5, NR5-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, CHXS -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-.
m= 1-3, and Xa is halogen: Ar is a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zm, wherein m is 0 to 3 and each Z is independently selected from the group consisting of -CN, =0, -CO2R5, -C(0)NR5 R5, -C(0)-NR5, -N02, -OR5, -SR5, -NR5 R5, -NR5C(0)OR5, -C(0)R5, -NR5C(0)R5, -S02R5, S02NR5 R5, C1-C10 alkyl Ci-Cioalkoxy, C3-C10 cycloalkyl, up to per halo-substituted C1-C10 alkyl and up to per halo-substituted C3-C10 cycloalkyl, subject to the proviso that B is not

wherein R6 is -NHC(0)-0-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, -C(0)NH-(CH3)2, -OCH2CH(CH3)2, or

-O-CH
l~V/

14. A compound of the formula

wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl, and up to per-halosubstituted C3-C10 cycloalkyl, and
B is phenyl, pyridinyl, indolinyl, isoquindinyl, quindinyl or napthyl
which is substituted by X, optionally substituted by halogen, up to per- halosubstitution, and optionally substituted by Xln, wherein n = 0-2,
each X1 is independently selected from the group of X or from the group consisting of -CN, -CO2R5, -C(0)R5, -C(0)NR5R5, _0R5} -N02, -NR5R5, C1-C10 alkyl, C2-io-alkenyl, Ci-10-alkoxy, C3-C10 cycloalkyl, C6-C14 aryl and C7-C24 alkaryl, and
X is selected from the group consisting of -SR5, -NR5C(0)OR5', -NR5C(0)R5', C3-C13 heteroaryl, substituted C1-C10 alkyl, substituted C2-C10- alkenyl, substituted Ci-Cio-alkoxy, substituted C3-C10 cyclolkyl, substituted Ce-Cn aryl, substituted C3-C13 heteroaryl, and -Y-Ar, and wherein if X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)Rs, -C(0)NR5R5? -OR5, -SR5, -NR5R5, NO2, -NR5C(0)R5, -NR5C(0)OR5' and halogen up to per-halo substitution;
wherein R5 and R5 are independently selected from H, C1-C10 alkyl, C2-ioalkenyl, C3-C10 cycloalkyl, Ce-Ci4 aryl, substituted C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per- halosubstituted C3-C10 cycloalkyl
wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m, -C{0)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NRSC(O)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa, -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-
m=l-3, and Xa is halogen; and Ar is 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-halo and

15. A compound as claimed in claim 14 wherein B is
optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R5, ^(O)R5, =0, -C(0)NR5R5, -C(0)R5, -NO2, OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5, -S02 R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C02R5, -C(0)NR5R5, =0, -OR5, -SR5, -NO2, -NR5R5, NR5C(0)R5 and -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl, and C3-C10 cycloalkyl, and where R1 is -CH2-I -butyl. B is not

wherein
Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2-, -CH2S-, -CH(OH)-, -C(0)-, CX^, -CX*H-, -CH2O- and -OCH2-,
Xa is halogen;
Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution;
Q1 is a mono- or bicyclic aromatic structure of 3-10 carbon atoms and 0-4 members of the group consisting of N, O and S substituted or unsubstituted by halogen up to per-halosubstitution,
Z, n and nl are as defined in claim 14 and X1 is C1-C4 alkyl or tialosubstituted C1-C4 alkyl up to per halo.

16. A compound as claimed in claim 15, wherein
^ Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution;
Ql is selected from the group consisting or phenyl, pyridinyl, naphthyl, pyrimidinyl quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 15 and
Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R 7 is selected from the group consisting of hydrogen C3-Cio-alkyl, and C3-C6-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
17. A compound of the formula

wherein B is as defined in claim 1.
18. A compound as claimed in claim 15, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per halosubstitution, Q1 is phenyl benzothiazolyl or pyridinyl optionally substituted by halogen up to per halosubstitution, Y is-O, -S- or -CH2-, X1 is as claimed in claim 14, n = 0 or 1, Z is -CH3, -C1-, OC2H5 or -OCH3, and n 1=0 or 1.
19. A compound as claimed in claim 14 selected from the group consisting of:
N-(3-Isopropyl-5 -isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(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)thiophenyl)urea;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-
pyridinyl)methylphenyl)urea;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea;
N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenyl)urea;
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-
(4methylphenyl)oxyphenyl)urea;
N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-
pyridinyl) thiophenyl)urea;
N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-
pyridinyl)oxyphenyl)urea;
N-(3-(l,l-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-
pyridinyl) thiophenyl) urea;
N-(3-(l, l-Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-
4methoxyphenyl)oxy)pyridinyl)urea;
N-(3-(l-Methyl-1 -ethylpropyl)-5-isoxazolyl)-N'-(4-
(4pyridinyl)oxyphenyl)urea;
N-(3-( 1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'-(3-
(4pyridinyl) thiophenyl)urea;
N-(3-isopropyl-5-isoxazolyl)-N'-(3-(4-(2-
methylcarbamoyl)pyridyl)-oxyphenyl)urea;
N-(3-isopropyl-5-isoxazolyl)-N'-(4-(4-(2-
methylcarbamoyl)pyridyls)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-
methyIcarbamoyl)pyridyl)-oxyphenyl) urea;
N-(3-tert-butyl-5-isoxazolyl)-N'-(3-(4-(2-
methylcarbamoyl)pyridyl)thiophenyl) urea;

N-(3-(l,l-dimethylprop-l-yl)-5-isoxazolyl)-N'-(3-(4-(2-
methylcarbamoyl)pyridyl)oxyphenyl) urea;
N-(3 -(l,l-dimethylprop-l-yl)-5 -isoxazolyl)-N '-(4 -(4 -(2-
methylcarbamoyl)pyridyl)oxyphenyl) urea;
N-(3-tert-butyl-5-isoxazolyl)-N'-(3-chloro-4-(4-(2-
methylcarbamoyl)pyridyl)thiophenyl) urea;
and pharmaceutically acceptable salts thereof.
20. A compound of the formula

wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl
Rb is hydrogen or halogen and
B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or
napthyl substituted by phenyl, pyridinyl or -Y- Ar,
wherein the cyclic structures of B are optionally substituted by
halogen, up to per halo and optionally substituted by Xxn
and
wherein n = 0 - 2; each X1 is independently selected from the
group consisting of CN, -OR5, -NR5R5, CVC10 alkyl,
-CO2R5, -C(0)NR5R5 , -C(0)R5,
-NO2, -SR5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl,
substituted Ci-10-alkyl, substituted C2io-alkenyl, substituted
Ci-10-alkoxy, and substituted C3-C10 cycloalkyl,
wherein if X1 is a substituted group, it is substituted by one or
more substituents independently selected from the group
consisting of-CN, -CO2R5

-C(0)R5, -C(0)NR5R5, _OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5', ^IR5C(0)OR5' and halogen up to per-halo substitution;
wherein R5 and R5' are independently selected from H, Ci - C10 alkyl, C2-10 alkenyl, C3-C10 cycloalkyl, up to per halo-substituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3 - C10 cycloalkyl.
wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m, -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5'-, -NR5C(0)-, -C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX* ,-CX^-, -S-(CH2)m- and-N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and
Ar is 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C02R5, -C(0)R5, =0,-C(0)NR5R5„ -C(O)- NR5, -N02,-OR5, - SR5,-NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5,-S02R5R5, Ci - C10 alkyl, C1-C10 alkoxy,C3 - C10 cycloalkyl, substituted C1-C10 alkyl and substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of- CN, -CO2R5.
-C(0)NR5R5, =0, -OR5, -SR5, -N02,-NR5R5, -NR5C(0)R5,-NR5C(O)OR5, Ci- C10 alkyl, C1-C10 alkoxyl and C3 - C10 cycloalkyl,
21. A compound as claimed in claim 20, wherein B is
wherein
subject to the proviso that where R1 is t-butyl and R10 is H, B is not of the formula.

Y is selected from the group consisting of -0-, -S-, -CH2-, -^H2-,-CH2S-, -CH(OH)-, -qOh-CX^ , -CXaH-, -CH2O- and -OCH2-
Xa is halogen,
Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution,
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, optionally substituted by halogen up to per-halosubstitution,
X1 is Ci - C4 alkyl or halosubstituted Ci- C4 alkyl upto per halo, and
Z, n and nl are as claimed in claim 20.
22. A compound as claimed in claim 21, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution,
Q1 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, X1 is as defined in claim 21, and
Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci - Cio alkyl or C3- Cio cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-C10 alkyl, and C3-Ce -cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
wherein B is as defined in claim 1
subject to the proviso that B is not of the formula
23. A compound of the formula

24. A compound as claimed in claim 21, wherein Q is phenyl
optionally substituted by halogen up to per-halosubstitution, Q1 is
phenyl or pyridinyl optionally substituted by halogen up to per-
halosubstitution, and Y is -O-or -S-, Z is -CI, -CH3, -OH or -OCH3,
X1 is as defined in claim 21, n = o or 1 and nl = 0-2.
25. A compound as claimed in claim 20 selected from the group
consisting of:
N-(5-tert-Butyl-3-thienyl)-N'-(4-(3-
methylphenyl) oxypheny 1) urea;
N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-
hydroxyphenyl)oxyphenyl)urea;
N-( 5-tert-Butyl-3 -thienyl)-N'-(4-(4-
methoxyphenyl)oxyphenyl)urea;
N-(5 -tert-Butyl-3-thienyl)-N '-(4-(4-pyridinyl)thiophenyl)urea;
and pharmaceutically acceptable salts thereof.
26. A compound of the formula

wherein R3 is C1-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted, C1-C10 alkyl and up to per-halosubstituted C3-C10 cycloalkyl,
and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or napthyl, substituted by phenyl, pyridinyl or -Y-Ar,

wherein the cyclic structures of B are optionally substituted by ogen, up to per halo, and optionally substituted by Xln wherein n = 0-2
each X1 is independently selected from the group consisting of -CN,-N02 ,-OR5 and C1-C10 alkyl,
-SR5,-C02R5, -C(0)R5, -C(0)NR5R5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C2-10 -alkenyl, substituted C1-10 -alkoxy and substitutedC3-Cio Cycloalkyl,
wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, -C(0)NR5R5, -OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5, -NR5C(0)OR5 and halogen up to per-halosubstitution;
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 -alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl,
wherein Y is -0-, -S-, _N(R5)-, -(CH2)-m- -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, NR5C(Oj-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa , -CX«2-, -S-(CH2)m- and -N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and
Ar is a 5-10 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN,-CO2R5, -C(0)R5, ^O, -C(0)NR5R5', -C(0)R5, -N02,-OR5, - SRV NR5R5', -NR5C(0)OR5', -NR5C(0)R5', -SO2R5, -S02R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN.

27. A compound as claimed in claim 26, wherein B is

wherein
Y is selected from the group consisting of-O, -S-, -CH2-,
-SCH2-, -CH2S-, -CH(OH)-, -C(O)-, -CX«2, -CXaH-, -CH2O-,
-OCH2-,
Xa is halogen,
Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution:
Q1 is phenyl, pyridinyl, naphthyl, parimidinyl, quinoline, isoquinoline, imidazolyl or benzothiazolyl, optionally substituted by halogen up to per-halosubstitution
X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per-halo,
Z, n and nl are as defined in claim 26 and s is 0 or 1.
28. A compound as claimed in claim 27, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution,
Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 27 and
Z is selected form the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl, C3-C6-cycloalkyl and wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
29. A compound as claimed in claim 27, wherein Q is phenyl
optionally substituted by halogen up to per-halosubstitution, Q1 is
phenyl or pyridinyl optionally substituted by halogen up to per-

halosubstitution, Y is -O- or -S-, X1 is as defined in claim 27, n = 0 or ljind nl = 0.
30. A compound as claimed in claim 26, of the formula

wherein B is
phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl substituted by phenyl, pyridinyl or -Y-Ar optionally substituted by halogen up to per halo and wherein each cyclic structure of B is optionally substituted by Xin
wherein n=0-2, each X1 is independently selected from the group consisting of-CN, -OR5, -NR5R5, Ci-Cioalkyl, -CO2R5, -C(0)NR5R5', -C(0)R5, -N02, -SR5, -NR5C(0)OR5, -NR5C(0)R5', C3-C10 cycloalkyl, and substituted C1-C10 alkyl, substituted C2-Q0 alkenyl, substituted Cno alkoxy, and substituted C3-C10 cycloalkyl,
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 -alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted Ci-C10 alkyl, up to per-halosubstituted C2-io-alkenyl up to per-halosubstituted C3-C10 cycloalkyl,
wherein Y is -O-, -S-, -N(R5)-, -(CH2)-m- -C(O)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NR5C(0)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX* , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-, m = 1-3, and Xa is halogen; and
Ar is a 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN,-CO2R5,

-C(0)R5, =0, -C(0)NR5R5', -C(0)-NRS, -N02,-OR5, - SR5,- NR5R5', JJR5C(0)OR5', -NR5C(0)R5', -S02R5, -S02R5R5', C1-C10 alkyl, C1-C10 alkoxy, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of-CN, -CO2R5, -C(0)R5, -C(0)NR5R5', =0, -OR5, - SR5,-N02, -NR5R5', -NR5C(0)R5, -NRsC(0)OR5', C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl.
31. A compound as claimed in claim 30 selected from the group consisting of:
N-(5-tert-Butyl-2-(l-thia-3 ,4-diazolyl))-N'-(3-(4-
pyridinyl)thiophenyl)urea; N-(5-tert-Butyl-2-(l-thia-3 ,4-
diazolyl))-N'-(4-(4-pyridinyl)-oxyphenyl)urea;
N-(5-tert-Butyl-2-( 1 -thia-3 ,4-diazolyl))-N'-(3-(4-(2-
methylcarbamoyl) pyridyl]- oxyphenyljurea;
N-(5-tert-Butyl-2-(l-thia-3,4-diazolyl))-N'-(4-(4-(2-
methylcarbamoyl) pyridyl]- oxyphenyl)urea;
N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(-4-(4-(2-
methylcarbamoyl)pyridyl) -oxyphenyl) urea;
N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(3-chloro-4-(4-
(2methylcarbamoyl)pyridyl)-oxyphenyl) urea;
N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(2-chloro-4-(4-(2-
methylcarbamoyl)pyridyl) -oxyphenyl) urea;
N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(3-(4-
pyridyl)thiophenyl) urea;
N-(5-tert-butyl-2-(l-thia-3,4-diazolyl))-N'-(2-methyl-4-(4-(2-
methylcarbamoyl)pyridyl)oxyphenyl) urea;
N-( 5 -(1,1 -dimethylprop-l-yl)-2-(l-thia-3,4-diazolyl))-N'-(4-
(3carbamoylphenyl)oxyphenyl) urea;
and pharmaceutically acceptable salts thereof.

32. A compound of one of the formulae

R1 is selected from the group consisting of halogen, C3-C10 alkyl, C3-i3-heteroaryl, C6-i4-aryl, C7-24-alkaryl, C3-C10 cycloalkyl, up to per-halosubstituted CMO alkyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstitutedCi-13-heteroaryl, up to per-halosubstituted Ce-M-aryl, and up to per-halosubstituted C7-24-alkaryl;
B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolynil or napthyl;
substituted by phenyl, pyridinyl, or -Y-Ar,
wherein the cyclic structures of B are optionally substituted by
halogen, up to per halo, and
optionally substituted by X*n wherein n=0-2
each X1 is independently selected from the group consisting of
-CN, -OR5, -NR5R5, C1-C10 alkyl;
-CO2, R5, -C (0)NR5R5, _c(0)R5 =0 -NO2-SR5, -NR5C(0)OR5, -NR5C(0)R5, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C2-io-alkenyl, substituted C1-10 alkoxy, substituted C3-C10 cycloalkyl,
wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -C02R5,-C(0)R5, -C(0)NR5R5, -OR5, -SR5, -NR5R5, -NO2, -NR5C(0)R5, -NR5C(0)OR5, and halogen up to per-halo substitution.
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-io-alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-io-alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl,

wherein Y is O, S-, -N(R5)-, -(CH2)m-C(0), -CH(OH)-, -(CH2)mO-, -MR5C(0)NR5R5-, -NR5C(0)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHXa , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-,
m=l-3, and Xa is halogen and
Ar is 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 Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN,-C02R5, =0, -C(0)R5, -C(0)NR5R5, -C(O)- NR5, N02, -OR5, -SR5, -NR5R5, -NR5C(0)OR5, -NR5C(0)R5, -S02R5, -S02R5R5, Ci-Cio alkyl, Ci-Cio alkoxy, C3-C10 cycloalkyl substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, C02R5 C(0)NR5 R5', =0, -OR5, -SR5, -N02, -NR5R5', -NR5C(0)R5', -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl.

33. A compound of one of the formulae
t-Bu tjBu
wherein B is defined in claim 1.
34. A compound as claimed in claim 32, wherein B is

wherein
Y is selected from the group consisting of-O-, -S-, -CH2-, -SCH2-,

-CH2S-, -CH(OH)-, -C(O)-, -CX«2,-CXaH-, -CH20- and -OCH2-,
Xa is halogen,
Q is phenyl or pyridinyl substituted or unsubstituted by
halogen, up to per-halosubstitution,
Q1 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 substituted by halogen up to per-halosubstitution.
X1 is Ci C4 alkyl or halosubstituted C1-C4 alkyl up to per halo,
Z, n and nl are as defined in claim 32 or 1.
35. A compound as claimed in claim 34 wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by
halogen, up to per-halosubstitution,
Q1 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X1 is as defined in claim 33 and
Z is selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl and C3-Ce-cycloalkyl wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
36. A compound as claimed in claim 34
wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, and Y is -O-, or -S- X1 is as claimed in claim 34, n=0 or 1, Z is -CI, -CH3, OH or OCH3 and nl = 0-2.

37. A compound of the formula

wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C3-C10 alkyl and up to per-halosubstituted C3 -C10 cycloalkyl, R6 is hydrogen or halogen, and
wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or napthyl
substituted by phenyl, pyridinyl or -Y-Ar
wherein the cyclic structure of B are optionally substituted by halogen, up to per halo, and
optionally substituted by X1!!
n = 0-3 and each X1 is independently selected from the group consisting of -CN, -CO2R5, C(0)NR5R5', -C(0)R5, -N02, -OR5, -SR5, -NR5R5', - NR5C(0)OR5', -NR5C(0)R5', C1-C10 alkyl, C2-10 alkenyl, C1-10 alkoxy, C3-C10 cycloalkyl substituted C1-C10 alkyl, substituted C2-C10 alkenyl, substituted C1-10 alkoxy, and substituted C3-C10 cycloalkyl
wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C02R5'
-C(0)R5, C(0)NR5R5, -OR5, -SR5, -NR5R5', -NO2, -NR5C(0)R5', -NR5C(0)R5' and halogen up to per-halosubstitution
wherein R5 and R5' are independently selected from H, C1-C10 alkyl, C2-10 alkenyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, and up to per-halosubstituted C3-C10 cycloalkyl,
wherein Y is -O-, -S-, -N(R5)-, -(CH2)m,-C(0)-, -CH(OH)-, -(CH2)mO-, -NR5C(0)NR5R5-, -NRSC(O)-, C(0)NR5-, -(CH2)mS-, -(CH2)mN(R5)-, -0(CH2)m-, -CHX* , -CX^-, -S-(CH2)m- and -N(R5)(CH2)m-,

m=l-3, and Xa is halogen and
Ar is 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-halo and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R5, -C(0)R5 =0, -C(0)NR5R5, -C(0)R5, -NO2, -OR5, -SR5, -NR5R5, -NR5C(0)OR5', -NR5C(0)R5, -SO2R5, -S02R5R5', C1-C10 alkyl, C3-C10 cycloalkyl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(0)-NR5R5' =0, -OR5, -SR5, -NO2, -NR5R5', - NR5C(0)R5, -NR5C(0)OR5, C1-C10 alkyl, C1-C10 alkoxyl and C3-C10 cycloalkyl.
38. A compound as claimed in claim 37, wherein B is

wherein
Y is selected from the group consisting of -O-, -S-, -CH2-, -SCH2, -CH2S-, -CH(OH)-, -C(O), -CX*2, -CX*H-, -CH2O- and-OCH2-,
Xa is halogen
Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per-halosubstitution,
Q1 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, substituted or unsubstituted by halogen up to per-halosubstitution,
X1 is C1-C4 alkyl or halosubstituted C1-C4 alkyl up to per halo, and
Z, n and nl are as defined in claim 37.
39. A compound as claimed in claim 38, wherein
Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution,

Q1 is selected from the group consisting of phenyl, pyridinyl, aephthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per halo, X1 is as claimed in claim 38 and
Z is selected from the group consisting of -R6 , -OR6 and -NHR7, wherein R6 is hydrogen, Ci-Cio-alkyl or C3-Cio-cycloalkyl and R7 is selected from the group consisting of hydrogen, C3-Cio-alkyl and C3-C6-cycloalkyl, wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.
40. A compound of the formula

wherein B is as defined in claim 1.
41. A compound as claimed in claim 38,
wherein Q is phenyl optionally substituted by halogen up to
per-halosubstitution, Q1 is phenyl or pyridinyl, optionally substituted by halogen up to per-halosubstitution, and Y is-O- or -S-, X1 is as claimed in claim 38, Z is -CI or -OCH3, n = 0, s = 0 and nl = 0-2.
42. A pharmaceutical composition having a compound as claimed in claim 2 and a physiologically acceptable carrier.
43. A pharmaceutical composition having a compound as claimed in claim 8 and a physiologically acceptable carrier.
44. A pharmaceutical composition having a compound as claimed in claim 14 and a physiologically acceptable carrier.

45. A pharmaceutical composition having a compound as claimed in
Jaini 20 and a physiologically acceptable carrier.
46. A pharmaceutical composition having a compound as claimed in claim 26 and a physiologically acceptable carrier.
47. A pharmaceutical composition having a compound as claimed in claim 32 and a physiologically acceptable carrier.
48. A pharmaceutical composition having a compound as claimed in claim 37 and a physiologically acceptable carrier.
Dated this 24th day of October, 2003
[ RITUSHKA NEGI ]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

Documents:

990-mumnp-2003-(diagram).doc

990-MUMNP-2003-ASSIGNMENT(1-9-2009).pdf

990-mumnp-2003-cancelled pages(08-05-2006).pdf

990-mumnp-2003-claims(granted)-(08-05-2006).doc

990-mumnp-2003-claims(granted)-(08-05-2006).pdf

990-mumnp-2003-claims.pdf

990-mumnp-2003-correspondence(14-03-2007).pdf

990-MUMNP-2003-CORRESPONDENCE(28-8-2009).pdf

990-MUMNP-2003-CORRESPONDENCE(4-4-2012).pdf

990-mumnp-2003-correspondence(ipo)-(19-04-2007).pdf

990-mumnp-2003-description (complete).pdf

990-mumnp-2003-form 1(24-10-2003).pdf

990-MUMNP-2003-FORM 16(1-9-2009).pdf

990-mumnp-2003-form 18(14-06-2005).pdf

990-mumnp-2003-form 2(granted)-(08-05-2006).doc

990-mumnp-2003-form 2(granted)-(08-05-2006).pdf

990-mumnp-2003-form 3(08-05-2006).pdf

990-mumnp-2003-form 3(23-10-2003).pdf

990-mumnp-2003-form 5(23-10-2003).pdf

990-mumnp-2003-form-1.pdf

990-mumnp-2003-form-18.pdf

990-mumnp-2003-form-2.pdf

990-mumnp-2003-form-26.pdf

990-mumnp-2003-form-3-231003.pdf

990-mumnp-2003-form-3.pdf

990-MUMNP-2003-MUM-CORRESPONDENCE(13-2-2012).pdf

990-MUMNP-2003-MUM-POWER OF AUTHORITY(13-2-2012).pdf

990-mumnp-2003-petition under rule 137(08-05-2006).pdf

990-mumnp-2003-petition under rule 138(08-05-2006).pdf

990-mumnp-2003-petition under rule 138(23-03-2004).pdf

990-mumnp-2003-petition under rule 138(30-01-2004).pdf

990-MUMNP-2003-POWER OF ATTORNEY(4-4-2012).pdf

990-mumnp-2003-power of authority(08-05-2006).pdf

990-mumnp-2003-power of authority(24-10-2003).pdf

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Patent Number

206231

Indian Patent Application Number

990/MUMNP/2003

PG Journal Number

N/A

Publication Date

15-Mar-2007

Grant Date

19-Apr-2007

Date of Filing

24-Oct-2003

Name of Patentee

BAYER CORPORATION

Applicant Address

100 BAYER ROAD, PITTSBURGH PENNSYLVANIA 15205, UNITED STATES OF AMERICA

Inventors:

#	Inventor's Name	Inventor's Address
1	UDAY KHIRE	101 TANGLEWOOD DRIVE, HAMDEN, CONNECTICUTE 06518.
2	TIMOTHY B. LOWINGER,	CANADA, #203, 5-7 CHITOSE-CHO, NISHINOMIYA CITY, HYOGO 662-0046, JAPAN.
3	HOLGER PAULSEN	PAHLKESTRASSE 5, 42115 WUPPERTAL.
4	BERND RIEDL	VON DER GOLTZ STRASSE 7, 42329 WUPPERTAL.
5	WILLIAM J. SCOTT	210 SADDLE HILL DRIVE, GUILFORD, CONNECTICUT 06437. USA.
6	ROGER A SMITH	65 WINTERHILL ROAD, MADISON, CONNECTICUTE 06443.
7	JILL E. WOOD	72 PICKWICK ROAD, HAMDEN, CONNECTICUT 06517.
8	HOLIA HATOUM MOKDAD	43 JOSEPH LANE, HAMDEN CONNECTICUTE 06514.
9	JEFFREY JOHNSON	213 LEETES ISLAND ROAD, BRANDFORD, CONNECTICUT 06405, USA.
10	WENDAY LEE	282 EVERGREEN AVENUE, HAMDEN, CONNECTICUT 06418, USA.
11	ROBERT SIBLEY	1187 MT. CARMEL AVENUE, NORTH HAVEN, CONNECTICUT 06473, USA.
12	JACQUES DUMAS	821 BEECHWOOD ROAD, ORANGE, CONNECTICUT 06477, UNITED STATES OF AMERICA
13	WENDAY LEE	282 EVERGREEN AVENUE, HAMDEN, CONNECTICUT 06418, USA.
14	ANIKO REDMAN	66 E. STREET, DERBY, CONNECTICUT 06418, USA.
15	JOEL RENICK	4275 MORAGA AVENUE, SAN SIEGO, CALIFORNIA 92177, USA.

PCT International Classification Number

C 07 D 241/18

PCT International Application Number

N/A

PCT International Filing date

1998-12-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	08 / 996,343	1997-12-22	U.S.A.