AU2008252068B2 - Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas - Google Patents
Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas Download PDFInfo
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Description
I AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Bayer Corporation Address for Service: CULLEN & CO Patent & Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia Invention Title: Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas The following statement is a full description of this invention, including the best method of performing it, known to us: la 5 INHIBITION OF RAF KINASE USING SUBSTITUTED HETEROCYCLIC UREAS Field of the Invention This invention relates to the us eof a group of arvl ureas in treating raf mediated 10 diseases. and pharmaceutical compositions for use in such therapy. Background of the Invention The p2l'" 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. 15 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 20 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 25 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 Biochen. Sci. 1994, 19, 474-80; Fridman et al. J 30 Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991. 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly. inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2. 668-75).
Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21", the instant inhibitors are 5 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 10 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). 15 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 20 treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula I: 0 A-NH-C-NH-B I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, 25 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, 30 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.
3 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 5 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 10 (phenylthiophenyl), diphenylamine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenyinaphthyl ether, pyridinylnapthyl ether, 15 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 20 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-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5 25 tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2 or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5 30 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-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8 quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally 4 optionally substituted phenyl, 2 - or 3-thienyl, 1.3.4-thiadiazol - r, 2 . zoyl, 3-pyrry l 3-pyrazolyl. 2-thiazolyl or 5-thiazolyl, etc. For example. B can be 4 -methyl-phenyl, 5-methyl-2 thienyl, 4 -methyl-2-thienyl, 1-methyl-3-pyrryl. 1-methyl-3-pyrazoly]. 5-methyl-2 thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl. 5 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, tert-butyl, etc. 10 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,
"C
4 cycloalkyl" includes methyl substituted 15 cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups. Suitable halogens include F, Cl, Br, and/or 1, from one to persubstitution (i.e., all H atoms on the group are replaced by halogen atom), being possible, mixed substitution 20 of halogen atom types also being possible on a given moiety. As indicated above, these ring systems can be unsubstituted or substituted by substituents such as halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, 25 hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CN, -COR', -C(O)NR'R", -C(O)R', -NO., -OR', -SR', -NR'R 5 , -NR'C(0)OR, -NR'C(O)R", C,-C,, alkyl,
C,-C,
0 alkenyl, C,-C,, alkoxy,
C
3 rCI 0 cycloalkyl, Cb-CII aryl,
C
7
-C
2 , alkaryl, C-C, heteroaryl,
C-C,
3 alkheteroaryl substituted C,-Co alkyl, substituted CrC, 0 alkenyl, substituted C,-C,o alkoxy, 30 substituted
C
3 -C,, cycloalkyl, substituted C-C, alkheteroaryl and -Y-Ar. Where a substituent, X or X', is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, -COR', -C(O)R', -C(O)NR'R", -OR', -SR', -NR'R , -NO 2 , -NR 5 C(O)R, 35
-NR
5 C(O)OR" and halogen up to per-halo substitution.
5 The moieties R5 and R' are preferably independently selected from H. C,-C, alkyl, C2-C,, alkenyl, C-C, cycloalkyl,
C-C,
4 aryl, C,-C 3 heteroaryl, C,-C, alkaryl, C 4 -C,, alkheteroaryl, up to per-halosubstituted C,-Co alkyl, up to per-halosubstituted C,-C, alkenyl, up to per-halosubstituted
C
3 -Co cycloalkyl, up to per-halosubstituted
C
6
-C
14 5 aryl and up to per-halosubstituted
C
3
-C
3 heteroaryl. The bridging group Y is preferably -0-, -S-, -N(R 5 )-, -(CH,)-,, -C(O)-, -CH(OH)-, -(CH,)mO-, -(CH,)mS-, -(CH,)mN(R)-,
-O(CH
2 )m-, -CHX', -CX',-, -S-(CH,)m- and -N(R')(CH,)m-, where m = 1-3, and X' is halogen. 10 The moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by Z,, wherein nI is 0 to 3. 15 Each Z substituent is preferably independently selected from the group consisting of -CN, -COR', -C(O)NRR *, -C(O)- NR', -NO 2 , -OR', - SR', - NRR, -NR'C(O)OR, =0, -NR 5 C(O)R', -SOR', -SONR'R , C,-C, 0 alkyl, C,-C,, alkoxy,
C
3 rC 10 cycloalkyl, C,-C, aryl, C-C, heteroaryl, Cr-C 24 alkaryl, C-C,, alkheteroaryl, 20 substituted C,-C,, alkyl, substituted
C
3
C
0 cycloalkyl, substituted C,-C,, alkaryl and substituted
C,-C,
3 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, -COR, -C(O)NR'R", -OR', -SR', -NO, -NR 5 R", =0, -NR'C(O)R ,
-NR
5 C(O)OR",
C,-C,
0 alkyl, C,-C,o alkoxy,
C
3
C,
0 cycloalkyl,
C
3
-C,
3 heteroaryl,
C,
25 C, aryl, C-C,, alkaryl. The aryl and heteroaryl moieties of B of Formula I are preferably selected from the group consisting of 30 6 O00
R
5
R
5 NN and N 5 which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n = 0-3. Xn -Q Y-- Qa, Zn, The aryl and heteroaryl moieties of B are more preferably of the formula: 10 wherein Y is selected from the group consisting of -O-, -S-, -CH,-, -SCH.-, -CHS-, -CH(OH)-, -C(O)-, -CX',, -CX'H-, -CH0- and -OCH,- and X' is halogen. Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is a mono- or bicyclic 15 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 20 halogen, up to per-halosubstitution and Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, or Y-Q' is phthalimidinyl substituted or unsubstituted by halogen up to per-halo substitution. Z and X are preferably independently selected from the group consisting 7 of -R". -OR", -SR*, and -NHR , wherein R* is hydrogen, C,-Co-alkyl or C-Co cvcloalkyl and R' is preferably selected from the group consisting of hydrogen, C, C,-alkyl, C,-C,-cycloalkyl and C-C 0 -aryl, wherein R* and R can be substituted by halogen or up to per-halosubstitution. 5 The heteroaryl moiety A of formula I is preferably selected from the group consisting of: R c 1 Ra RI N R 1 R1 R R R N O N N N N N S N N S 0 NRb R and S 10 The substituent R' is preferably selected from the group consisting of halogen,C-C, alkyl, C-C, 0 cycloalkyl, C,-C 3 heteroaryl, C,-C,, aryl, C,-C,, alkaryl,_up to per halosubstituted C,-C, alkyl and up to per-halosubstituted
C
3 -C,, cycloalkyl, up to per halosubstituted Cr-C 3 heteroaryl, up to per-halosubstituted
C
6
-C,
3 aryl and up to per halosubstituted C,-C,, alkaryl. 15 The substituent R 2 is preferably selected from the group consisting of H. -C(O)R 4 , -CO,R4, -C(O)NR 3 R 3 , C-C, 0 alkyl, C 3 rCI 0 cycloalkyl, C-C, alkaryl, C.,-C, alkheteroaryl, substituted C-C, alkyl, substituted C 3 C, cycloalkyl, substituted C, C, alkaryl and substituted CC.
3 alkheteroaryl. Where R 2 is a substituted group, it is 20 preferably substituted by one or more substituents independently selected from the group consisting of -CN, - COR', -C(O)-NR 3 RV , -NO 2 , -OR', -SR 4 , and halogen up to per-halosubstitution.
8
R
3 and R' are preferably independently selected from the group consisting of H, -OR 4 ,
-SR
4 . -NR 4 R', -C(O)R 4 , -COR 4 , -C(O)NR 4
R
4 , C,-C,o alkyl, C.-C, 0 cycloalkyl, C,-C 4 aryl, C,-C 3 heteroaryl, C,-C,, alkaryl, C,-C, 3 alkheteroaryl, up to per-halosubstituted 5 C-C,o alkyl, up to per-halosubstituted C-C, cycloalkyl, up to per-halosubstituted
C,
C,, aryl and up to per-halosubstituted C-C,, heteroaryl.
R
4 and R are preferably independently selected from the group consisting of H, C,
C,
0 alkyl, C-C,o cycloalkyl, C,-C,, aryl, C 3 -Ce heteroaryl; C-C, alkaryl, C 4 -C,, 10 alkheteroaryl, up to per-halosubstituted
C,-C,
0 alkyl, up to per-halosubstituted C-C,, cycloalkyl, up to per-halosubstituted C,-C,, aryl and up to per-halosubstituted
C
3
-C,
3 heteroaryl. R'is preferably C,-C, alkyl, C-Co cycloalkyl, up to per-halosubstituted C,-C,, alkyl 15 and up to per-halosubstituted C 3
C
0 cycloalkyl. Rb is preferably hydrogen or halogen. R' is hydrogen, halogen, C,-C,o alkyl, up to per-halosubstituted C,-C,o alkyl or 20 combines with R' and the ring carbon atoms to which R' and R' are bound to form a 5- or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from 0, N and S; The invention also relates to compounds of general formula I described above and 25 includes pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula R1 ,N I 1 0 R 2 NH-C-NH-B wherein R 2 , R' and B are as defined above; 9 and both 5.3- and 3.5- isoxazolyl ureas of the formulae R' 0 N 1 0 N 1 NH-C-NH-B and R' N I 1 NH-C-NH-B 5 wherein R' and B are also as defined above. Component B for these compounds is a 1-3 ring aromatic ring structure selected from 10 the group consisting of: X1 X nX N. N R5 R 5 or , which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here R' and R are as defined above, n = 0-2 and each X' substituent is independently - selected from the group of X or from the group consisting of-CN, -COR5, -C(O)R5, 15 -C(O)NR'R". -OR', - NO,, -NR 5
R
5 , C,-C, 0 alkyl, C,_,-alkenyl, C,.,,-alkoxy, 10 C,-C,, cycloalkyl, C,-C,, aryl and C--C,, alkaryl. The substituent X is selected from the group consisting of -SR, -NR 5 C(0)OR', NRC(O)R , C 3
C
13 heteroaryl, C 4
-C,
3 alkheteroaryl, substituted C,-C,o alkyl, 5 substituted C,.
1 -alkenyl, substituted C,.,O-alkoxy, substituted C-C, 0 cycloalkyl, substituted C,-C,., aryl, substituted C-C,, alkaryl. substituted C 3
-C
3 heteroaryl, substituted C 4 -C,, 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, -COR', 10 C(O)R5, -C(O)NRSR, -OR', -SR', -NR'R' , NO,, -NR'C(O)R5. -NR5C(O)OR ' and halogen up to per-halosubstitution, where R3 and R" are as defined above. The components of B are subject to the following provisos, where R' is t-butyl and R 2 is methyl for the pyrazolyl ureas, B is not C(0)OC 4
H
9 15 Where R' is t-butyl for the 5,3-isoxazolyl ureas, B is not 0 R 6 wherein R* is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -0-propyl, -C(O)NH (CH2),, -OCHCH(CH 3
)
2 , or -O-CH, -phenyl. Where R' is t-butyl for the 3,5 isoxazole ureas, B is not / o0 -0-CH 2 - / and where R' is -CH, -t-butyl for the 3,5 -isoxazolyl ureas, B is not \/ o CH 3 20 Preferred pyrazolyl ureas, 3,5-isoxazolyl ureas and 5,3-isoxazolyl ureas are those wherein B is of the formula Xn -Q-(Y-Qi),-Zl S1I wherein Q. Q', X, Z. Y. n. s and ni are as defined above. Preferred pyrazole ureas more particularly include those wherein Q is phenyl or pyndinyl, Q' is pyndinyl, phenyl or benzothiazolyl, Y is -0-, -S-, -CHS-. -SCH,-, 5 -CH:O-, -OCH,- or -CH,-, and Z is H, -SCH, or -NH-C(O)-C H,, , wherein p is 1-4. n = 0, s = I and nl = 0-1. Specific examples of preferred pyrazolyl ureas are: N-(3-tert-Butyl-5-pyrazolyl)-N'-( 4 -phenyloxyphenyl)urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-( 3
-(
3 -methylaminocarbonylphenyl) oxyphenyl)urea; 10 N-(3-erti-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-lert-Butyl-5-pyrazolyl)-N'-( 4
-(
4 -pyridinyl)methylphenyl)urea; N-(1 -Methyl-3-tert-butyl-5-pyrazolvl)-N'-( 4 -phenyloxyphenvl)urea; 15 N-(I -Methyl-3-tert-butyl-5-pyrazolyl)-N'-( 3
-(
4 -pyridinyl)thiophenyl)urea; N-( -Methyl-3-tert-butyl-5-pyrazolyl)-N'-((4-(4-pyridinyl)thiomethyl) phenyl)urea; N-(I -Methyl-3 -tert-butyl-5-pyrazolyl)-N'-( 4
-(
4 -pyridinyl)thiophenyl)urea; 20 N-( -Methyl-3-tert-butyl-5-pyrazolyl)-N'-( 4
-(
4 -pyridinyl)oxyphenyl )urea; N-(l -Methyl-3-tert-butyl-5-pyrazolyl)-N'-(( 4
-(
4 -pyridinyl)methyloxy)phenyl
)
urea; N-(1 -Methyl-3-tert-butyl-5-pyrazolyl)-N'-( 3
-(
2 -benzothiazolyl)oxyphenyl
)
urea; 25 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-iert-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)oxyphenyl) urea;
N-(
3 -tert-butyl-5-pyrazolyl)-N'-(4-(4-pyridyl)oxyphenyi) urea; N-(I-methyl-3-tert-butyl-5-pyrazolyl)-N'-( 3
-(
4 -pyridyl)thiophenyl) urea; 30 N-(I-methyl-3-tert-butyl-5-pyrazolyl)-N'-( 4
-(
4 -pyridyl)thiophenyl) urea; N-(I -methyl-3-tert-butyl-5-pyrazolyl)-N'-( 3
-(
4 -pyridyl)oxyphenyl) urea; and N-(I-methyl-3-tert-butyl-5-pyrazolyl)-N'-( 4
-(
4 -pyridyl)oxyphenyl) urea. Preferred 3,5-isoxazolyl ureas more particularly include those wherein Q is phenyl or 35 pyridinyl, Q' is phenyl, benzothiazolyl or pyridinyl, Y is -0-, -S- or -CH,-, Z is -CH,, 12 Cl. -OCH, or -C(O)-CH 3 , n = 0. s = 1. and n] = 0- 1. Specific examples of preferred 3.5-isoxazolyl ureas are : N-(3-Isopropyl-5-isoxazolyly-N
-(
4
-(
4 -pyridinyl)thiophenyl)urea, N-(3-tir-Butyl-5-isoxazolyl )-N '-(4-(4-methoxyphenyl )oxyphenvl )urea; 5 N-(3-tert-Butyl-S-isoxazolyl)-N '-(5-( 2
-(
4 -acetylphenyl)oxy)pyridinyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(3-(4-pynidinyl)thiophenyl )urea, N-(3-tirt-Buty1-5-isoxazolyl )-N '-(4-(4-pyridinyl )methylphenvl )urea; N-(3 -tert- Butyl -5 -isox azo ly)N'-(4-(4-pyri di nyl)thiophenyl )urea; N-(3-rerI-Butyl-5-isoxazolyl)-N
-(
4
-(
4 -pyridinyl)oxyphenyl)urea; 10 N-(3-zert-Butyl-5-i soxazolyl)-N '-( 4
-(
4 -methyl- 3 -pyridinyl)oxyphenyl)urea; N-(3-terz-Butyl-5-isoxazolyl )-N '-(3-(2-benzothiazolyl)oxyphenvl )urea;, N-(3-( 1,1 -D imethy lpropyl)-5 -i sox azoIyi I)-N '-(4-(4-m ethylIph envl hox yphenylI) urea; N-(3-( 1,1 -Dimethylpropyl)-5-isoxazolyl)-N'-( 3
-(
4 -pyridinyl)thiophenyl)urea; 15 N-(3-( I, I -Dimethylpropyl)-5 -isox azolIyl)-N'-( 4
-(
4 -pyr d in yl)ox yph enyl) urea; N-(3-( 1,1 -Dimethylpropyl)-5-isoxazolyl)-N
-(
4
-(
4 -pyridinyl)thiophenyl)urea; N-(3-(, 1, -Dimethylpropyl-5-isoxazolyl)-N'-(5-( 2
-(
4 -methoxyphenyl)oxy) pyridinyl)urea; N-(3-( 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N
'-(
4 -(4-pyridinyl )oxyphenyl) 20 urea; N-(3-(] -Methyl- I -ethylpropyl)-5-isoxazolyl)4v '-(3-(4-pyridinyl )thiophenyl) urea; N-(3-isopropyl-5-isoxazolyl)-N'-( 3
-(
4 -(2-methylcarbamoyl)pyridyl) 25 oxyphenyl) urea;
N-(
3 -isopropyJ-5isoxazoy)N'(4(4-(2methylcarbamoyl)pyrdyl) oxyphenyl) urea; N-(3-terl-butyl-5-isoxazolyl).N
-(
3 -(4-(2-methylcarbamoyl
)
pyridyl)oxyphenyl) urea; 30 N-(3-tert-butyl-5 -isox azo ly l)-N'-( 4
-(
4 -(2-methylcarb amoylI)pynidylI) oxyphenyl) urea; N-(3-teri-butyl-5-isoxazolyl)-N
'-(
3
-(
4 -(2-methylcarbamoyl)pynidyl) thiophenyl) urea; N-(3-( 1,1-dimethylprop- 1 -yi)-5-isoxazolyl)-N
'-(
3
-(
4 -(2-methylcarbamoyl) 35 yridyl)oxyphenyl) urea; N-(3-( 1,1 -dimethylprop- I -yl)-5-isoxazolyl)-N
'-(
4
-(
4
-(
2 -methylcarbarnoyl) pyridyl)oxyphenyl) urea; and 13 N-( 3-tert-buty' 1-5- isxzl)--( -clr--4(-ehlabmy~viy) Ihiophenyl) urea. Preferred 5,3-isoxazolyl ureas more paricularly include those wherein Q is is phenyl 5 or pyridinyl, Q' is phenyl, bernzothiazolyl or pyridinyl, Y is -0-, -S- or -CH.-, X is CH3 and Z is -C(O)NH-, CPP, wherein p = 1-4, -C(O)CH 3 , -CH 3 , -OH, -OC,H, -CN, phenyl. or -OCH 3 , n =O0or 1, s =Q0or 1, and n I = 0 or 1. Specific examples of preferred 5.3-isoxazolvl ureas are: N-(5-tert-Butvl-3-i soxazolyl)-N '-( 4
-(
4 -hydroxyphenyl)oxyphenyl)urea; 10 N-(5-tert-Butyl-3-i soxazolyl)-N '-(4-(3 -hydroxyphenyl )oxyphenyl)urea; N-(5-ieri-Butyl-3-isoxazolyl)-N '-(4-(4-acetylphenyl )oxyphenyl)urea; N-(5-iert-Butvl-3 -isoxazolyl)-N '-(3-benzoylphenyl)urea; N-(5 -tert- But 1- 3 -i sox azo lyl)-N '-( 4 -pheny Iox ypheny1) urea; N-(5-irt-Butvl-3-i soxazolyl)-N '-( 4
-(
3 -methylaminocarbonylphenyl
)
15 thiophenvl)urea; N-(5-ieri-Butvl-3)-i soxazolyl)-N '-(4-(4-(1I, 2 -methylenedioxy)phenyl) oxyphenyl )urea; N-(5 -tert-ButylI- 3-1sox azo Iyl)-N '-(4-(3 -pyri din yl )ox yphenylI)urea; N-(5 -Iert-B uty I- 3 - sox azo Iy I)-N '-(4-(4-pyri di nyl )oxyphenyl)urea; 20 N-(5-teri-Butyl-3-isoxazolyl)-N'-( 4
-(
4 -pyridyl)thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N
'-(
4
-(
4 -pyridinyl)methylphenyl )urea; N-(5 -teri-B ut I- 3 -1 sox azolIyl)-N '-(3 -(4-pyri din yl )ox yphenylI)urea; N-(5-reri.Butyl-3-isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl )urea; N-(5 -iert-B uty 1- 3 -1soxazolIyl)-N '-( 3
-(
3 -meth yl -4-pyri d inyl)oxyp hen yl)urea; 25 N-(5-ieri-Butyl-3-isoxazolyl)-N
-(
3
-(
3 -methyl-4-pyridinyl)thiophenyl)urea; N-(5-terr-Butyl-3 -isoxazolyl)-N '-( 4
-(
3 -methyl-4-pyridinyl)thiophenyl)urea; N-( 5-iert-Butyl-3-isoxazolyl)-N
-(
3
-(
4 -methyl-3-pyridinyl)oxyphenyl)urea; N-(5-ierz-Butyl-3-isoxazolyl)-N
-(
4
-(
3 -methyl-4-pyridinyl)oxyphenyl)urea; N-(5-terzi-Butyl-3-isoxazolyl)-N '-(3-(2-benzothiazolyl )oxyphenyl )urea; 30 N-(5-Iert-butyl-3-isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbanoyl)py-idyl) oxyphenyl) urea; N-(5-terr-butyl-3-isoxazolyl)-N
'-(
4 -(4-(2-methvlcarbamoyl)pynidyl) oxyphenyl) urea; N-(5-terzt-butvl -3-i soxazolyl)-N -(3-(4-(2-methylcarbamoyl)pyridyl) 35 thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N
'-(
2 -methyl-4-(4-(2-methylcarbanioyl)pyridyi) oxyphenyl) urea; 14 N-(5-tert-butyl-3-isoxazolyl)-N'-( 4 -(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyi)-N'-( 3
-(
4
-(
2 -carbamoyl)pyridyl)oxyphenyl) urea; N-(S-tert-butyl-3-isoxazolyl)-N'-( 3
-(
4
-(
2 -methylcarbamoyl)pyndyl) oxyphenyl) urea; 5 N-(5-er-butyl-3-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)pyridyl) thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3 -chloro-4-(4-(2-methylcarbamoyl)pyridyl) oxyphenyl) urea; and N-(5-tert-butyl-3-isoxazoyl)-N'-( 4
-(
3 -methylcarbamoyl)phenyl)oxyphenyl) 10 urea. Additionally included are thienyl ureas of the formulae R' A 0 Rb NH-C-NH-B R Ri ? 0 S0|| or S NH-C-NH-B NH-C-NH-B wherein R' , R' and B are as defined above. Preferred B components for the thienyl 15 ureas of this invention have aromatic ring structures selected from the group consisting of: / XX 20 0 R6
-
R
R
5 -~and
I
15 These aromatic ring structures can be substituted or unsubstituted by halogen. up to per-halosubstitution. The X' substituents are independently selected from the group consisting of X or from the group consisting of . -CN, -OR3, -NR'R3, C,-C, 0 alkyl. 5 The X substituents are independently selected from the group consisting of -COR 5 . -C(O)NRR5',
-C(O)R
5 . -NO,, -SR', -NR3C(O)OR3, -NR'C(O)R", C,-C,, cycloalkyl,
C,-C
4 aryl, C,-C,, alkaryl,
C
3 -C, heteroaryl,
C
4
-C.
3 alkheteroaryl, and substituted
C,
C,
0 alkyl, substituted C.,-alkenyl, substituted C.,-alkoxy, substituted
C
3 -CI cycloalkyl, substituted C-C,, aryl, substituted C,-C,, alkaryl, substituted
C
3 -C,, 10 heteroaryl, substituted C,-C,, alkheteroaryl, and -Y-Ar. Where X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO,R', -C(O)R3, -C(O)NR'R", -OR, -SR', -NR'R , -NO,,
-NR
5 C(O)R.
-NR'C(O)OR
5 and halogen up to per-halo substitution. The moieties R', R 5 , Y and Ar are as defined above and n = 0-2. 15 The components for B are subject to the proviso that where R' is t-butyl and Rb is H for the 3-thienyl ureas, B is not of the formula \/ o O/ CH(CH 3
)
2 . Preferred thienyl ureas include those wherein B is of the formula Xn -Q-(Y-Q')s-Zni 20 and Q, Q', Y, X, Z, n, s and nl are as defined above. The preferred thienyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is -0- or -S-, Z is -Cl, -CH 3 , -OH or -OCH,, n = 0, s = 0 or 1. and nI = 0-2. Specific examples of preferred thienyl ureas are: N-(3-Isopropyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; 25 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; 16 N-(3-rerr-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(3-rert-Butyl-5-isoxazolyl)-N'-(4-(4-pyndinyl)oxyphenyl)urea: N-(3-rert-Butyl-5-isoxazolyl)-N'-(4-(4-methyl-3-pyridinyl)oxyphenyl)urea; N-(3-rert-Butyl-5-isoxazolyl)-N'-(3-(2-benzothiazolyl)oxyphenvl)urea; 5 N-(3-(1,1 -Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-methylphenyl) oxyphenyl)urea: N-(3-(1,1 -Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl)thiophenyl)urea; N-(3-(1.1 -Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl)oxyphenvl )urea; N-(3-(1,1 -Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; 10 N-(3-(1,1 -Dimethylpropyl-5-isoxazolyl)-N'-(5-(2-(4-methoxyphenyl) oxy)pyndinyl)urea; N-(3-(l -Methyl-I -ethylpropyl)-5-isoxazolyl)-N'-(4-(4-pyridinyl) oxyphenyl)urea; and N-(3-( 1-Methyl-I -ethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl)thio 15 phenyl)urea. Preferred thiophenes include: N-(5-ierr-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl)oxyphenyl) urea; N-(5-iert-butyl-3-thienyl)-N'-(4-(4-hydroxyphenyl)oxyphenyl) urea; 20 N-(5-iert-butyl-3-thienyl)-N'-(4-(3-methylphenyl)oxyphenyl) urea; and N-(5-ert-butyl-3-thienyl)-N'-(4-(4-pyridyl)thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: RI R' Ni' o 0 0 N S O I1 N 4 14Rb NH-C-NH-B 25 wherein R', R', R' and B are as defined above. The thiadiazolyl and furyl ureas have preferred aromatic ring structures for B identical to those for the pyrazolyl, thienyl and isoxazolyl ureas shown above. Such ring structures can be unsubstituted or substituted by halogen, up to per-halosubstitution, and each X' substituent is independently selected from the group consisting of X or from the groupconsisting of 30 -CN, -NO.,-OR' and C,-C 0 alkyl. The X substituents are selected from the group consisting of -SR', -COR', -C(O)R', -C(O)NR'R 5 , -NR'R 5 , -NR 5
C(O)OR",
17 -NR'C(O)R". substituted C,.,-alkenyl. substituted C.
0 -alkoxy. -C,-C,, cycloalkyl. -C,-C,, aryl, -C,-C,,, alkaryl, C,-C, heteroaryl, C,-C., alkheteroaryl. and substituted C,-C, alkyl, substituted C,-C 0 cycloalkyl, substituted arvl. substituted alkaryl, substituted heteroaryl, substituted C,-C,, alkheteroaryl and -Y-Ar. Each of R3, R" and 5 Ar are as defined above, n = 0-2, and the substituents on X where X is a substituted group are as defined for the pyrazolyl. isoxazolyl and thienyl ureas. This invention also includes pharmaceutical compositions that include compounds described above and a physiologically acceptable carrier. 10 Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula Xn -Q-(Y-Qi),-Zfi and Q, Q', X, Y, Z, n, s, and nI are as defined above. The prefer-red thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is -0- or -S-, n = 0, s = I and nI = 0. Specific examples of prefer-red thiadiazolyl ureas 15 are: N-(5-tert-Butyl-2-(1 -thia-3,4-diazolyl))-N'-( 3
-(
4 -pyridinyl)thiophenyl)urea; N-(5-iert-Butyl-2-(] -thia-3,4-diazolyl))-N'-( 4
-(
4 -pyndinyl)oxyphenyl)urea; N-(5-tert-butyl-2-(1 -thia-3,4-diazolyl))-N'-(3-( 4 -(2-methylcarbamoyl)pyridyl) oxyphenyl) urea; 20 N-(5-iert-butyl-2-(l -thia-3,4-diazolyl))-N'-( 4
-(
4 -(2-methylcarbamoyl)pyridyl) oxyphenyl) urea; N-(5-iert-butyl-2-(I -thia-3,4-diazolyl))-N'-(3-chloro-4-(4-(2 methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-2-(1 -thia-3,4-diazolyl))-N'-(2-chloro-4-(4-(2 25 methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-2-(I-thia-3,4-diazolyl))-N'-( 3 -(4-pyridyl)thiophenyl) urea; N-(5-Iert-butyl-2-(I -thia-3,4-diazolyl))-N'-(2-methyl-4-(4-(2 methylcarbamoyl)pyridyl)oxyphenyl) urea; and N-(5-(1,1 -dimethylprop- I -yl)-2-(1 -thia-3,4-diazolyl))-N -(4-(3 30 carbamoylphenyl)oxyphenyl) urea. The preferred furyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is -0- or -S-, Z is -Cl or -OCH,, s = 0 or 1, n = 0 and n I = 0-2.
18 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, 5 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 0 substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, NN-diethylamine, NN dicyclohexylamine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5 diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 5 A number of the compound of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compound described in Formula I which possess Raf kinase inhibitory activity. 0 Definitions of the specific embodiments of the invention as claimed herein follow. According to a first embodiment of the invention, there is provided a compound of the formula R' 0 _ 0 N II NH-C-NH-B 25 wherein R' is selected from the group consisting of C 3
-C
6 alkyl, C 3
-C
6 cycloalkyl, up to per-halosubstituted C 3
-C
6 alkyl and up to per-halosubstituted C 3 -Cio cycloalkyl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl which is substituted by -Y-Ar and optionally substituted by X, halogen, up to per-halosubstitution, and optionally substituted by X', wherein n = 0-2; 18a each X' is independently selected from the group of X or from the group consisting of -CN, -C0 2
R
5 , -C(O)R', -C(O)NR 5
R
5 , -OR 5 , -NO 2 , -NR 5
R
5 , CI-CI 0 alkyl, C 2
-
1 o-alkenyl, Ci.
10 alkoxy, C 3
-C
10 cycloalkyl, and C 6
-C
14 and X is selected from the group consisting of -SR 5 , -NR 5
C(O)OR
5 , NR 5 C(O)R", C 3
-C
13 5 heteroaryl, substituted CI-CI 0 alkyl, substituted C 2 -1o-alkenyl, substituted Ci1io-alkoxy, substituted C 3 -CIO cycloalkyl, substituted C 6
-CI
4 aryl, substituted C 3
-C
3 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, -C0 2 R', -C(O)R', -C(O)NRR 5 , 0 -OR', -SR', -NRsR", NO 2 , -NR 5 C(O)R', -NRsC(O)OR 5 and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, CI-CI 0 alkyl, C 2
-
1 o-alkenyl, C 3 C 1 0 cycloalkyl, C 6
-C
1 4 aryl, C 3
-C
1 3 heteroaryl, C 7
-C
24 alkaryl, C4-C 2 3 alkheteroaryl, up to per halosubstituted CI-CI 0 alkyl, up to per-halosubstituted C 2 -io-alkenyl, and up to per halosubstituted C 3 -Cio cycloalkyl, wherein Y is -O-, -S-, -N(R)-, -(CH 2 )-m, -C(O)-, -CH(OH)-, 5 -(CH 2 )mO-, -NR 5
C(O)NR
5
R
5 -, -NR 5 C(O)-, -C(O)NR 5 -, -(CH 2 )mS-, -(CH 2 )mN(R 5 )-, -O(CH 2 )m-, -CHXa, -CXa2-, -S-(CH 2 )m- and -N(R 5
)(CH
2 )m-, m = 1-3, and Xa is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, '0 isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, subject to the proviso that where Y is -(CH 2 )-m or -C(O)-, Ar is not phenyl, wherein Ar 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 25 consisting of -CN, -C0 2 R', -C(O)Rs, =O, -C(O)NRR', -C(O)Rs, -NO 2 , -OR', -SR 5 , -NR 5
R
5 ,
-NR
5 C(0)OR", -NR 5 C(O)Rs, -S0 2
R
5 , -S0 2
R
5 R"', CI-Cio alkyl, Ci-CI 0 alkoxy, C 3 -CIo cycloalkyl, substituted Ci-Cio alkyl, and substituted C 3 -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, -C0 2
R
5 , -C(O)NRR 5 , =0, -OR, -SR', -NO 2 , -NR 5
R
5 , -NR 5 C(O)R , 30 -NR 5 C(0)OR", CI-Cio alkyl, Ci-CIo alkoxyl, and C 3 -CIO cycloalkyl, subject to the proviso that where R' is t-butyl, B is not 18b 0 R 6 wherein R 6 is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl,
-C(O)NH-(CH
3
)
2 , -OCH 2
CH(CH
3
)
2 , or -0-CH 2 5 According to a second embodiment of the invention, there is provided a compound of the formula t-Bu 0_ N I I NH-C-N H-B 0 wherein B is 5-methyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by -Y-Ar and optionally substituted by halogen up to per 15 halosubstitution, and Xn, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 Rs, -C(O)NR 5 R", -C(O)R', -NO 2 , -OR', -SR', -NR 5 R", -NR 5
C(O)OR
5 , -NRsC(O)R', Ci-Cio alkyl, C 2 -Cio alkenyl, CI-Cio alkoxy, C 3
-C
1 O cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl, up to per halo-substituted C 1
-C
10 alkyl, up to per halo 20 substituted C 2 -CIO alkenyl, up to per halo-substituted CI-CIO alkoxy and, up to per halo substituted C 3
-C
10 cycloalkyl, wherein R 5 and R 5 are independently selected from H, Ci-CIO alkyl, C 2 -CIOalkenyl, C 3 CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted 18c CI-Ci 0 alkyl, up to per-halosubstituted C 2 -CIo alkenyl, and up to per-halosubstituted C 3
-C
10 cycloalkyl, wherein Y is - 0-, -S-, -N(R 5 )-, -(CH 2 )-m, -C(O)-, -CH(OH)-, -(CH 2 )mO-,
-NR
5 C(O)NR5 NR 5 -, -NR 5 C(O)-, -C(O)NR 5 -, -(CH 2 )mS-, -(CH 2 )mN(Rs)-, -O(CH 2 )m-, -CHXa, 5 -Cxa 2 -, -S-(CH 2 )m- and -N(R )(CH 2 )m-, m = 1-3, and Xa is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, 0 benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zni, wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, =0, -C0 2 R', -C(O)NRR 5 , -C(O)-NR', -NO 2 , -ORs, -SRs, -NRsR', -NRsC(O)OR 5 , -C(O)R', -NR 5 C(O)Rs, -S0 2
R
5 , SO 2
NR
5
R
5 , CI-CI 0 alkyl, CI-CI 0 alkoxyl, C 3 -Cio cycloalkyl, up 5 to per halo-substituted CI-CI 0 alkyl and up to per halo-substituted C 3 -CIO cycloalkyl; subject to the proviso that B is not 0 R 6 wherein R' is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, 20 -C(O)NH-(CH 3
)
2 , -OCH 2
CH(CH
3
)
2 , or -0-CH 2 / [Text continues on page 19.] 19 General Preparative Methods The compound of Formula I may be prepared by use of known chemical rections and procedures, some of which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, 5 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. 0 Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985)). For example, 3 substituted-5-aminoisoxazoles (3) are available by the rection of hydroxylamine with an a cyanoketone (2), as shown in Scheme 1. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an -cyanoketone with hydrazine (R 2 =H) or a monosubstituted 5 hydrazine affords the 3-substituted- or 1,3-disubstituted-5-aminopyrazole (5). Pyrazoles unsubstituted at N-1 (R 2 =H) may be acylated at N-1, for example using di-tert-butyl dicarbonate, to give pyrazole 7. Similarly, reaction of nitrile 8 with an -thioacetate ester gives the 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 !0 butoxy (BOC) carbamate (10), followed by saponification and treatment with acid. When BOC protection is used, decarboxylation may be accompanied by deprotection giving the substituted 3-thiopheneammonium salt 11. Alternatively, ammonium salt 11 may be directly generated through saponification of ester 9 followed by treatment with acid. 25 20
CH
3 CN R' 1) base O N 2) H2NOH-HCI N H bRe 0 NH 2 1f base R R,0CN R2 NHNH 2 4 N 2NH2 0 RO X 6 R2=H NI R1 N NH 2 R
HS..-CO
2 R 0 OR C1 I S OR CN
-NH
2 8 CO 2 R 9 1) OH' 2) H* O O O R' R1 1) OH' S S
NH
3 * 2) H- NHBOC 11 CO2R 10 Scheme I. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced 5 Organic Chemistry, 3" Ed.; John Wiley: New York (1985); Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H, or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic 10 Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a 21 zero valent metal, such as Fe. Sn or Ca. often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 d Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H
2 / catalyst (eg. Ni, Pd, Pt) ArNO 2 [H') . ArNH 2 M(0) 5 (eg. Fe. Sn, Ca) Scheme II Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO 3 , or an alternative NO, source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with
HNO
3 10 Ar-H o ArNO 2 potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme III). O2N ArSH R base 12 0 2 N R' S-Ar 0 2 NR SH Br-Ar 13 CuO / base 15 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine (16). The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an 5 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 10 amine. Het-NH 2 16
H
2 N-Ar 19 COCl2 COC12
H
2 N-Ar O Het-NH 2 Het-NCO Het,.N N' Ar : OCN-Ar 17 H H 20 18 N3 DPPA N3 DPPA 0 0 00 Het X Het OH X Ar HO' Ar 21 22 23 24 S Scheme IV Selected Methods of Urea Formation (Het = heterocycle) I-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed 15 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.
23 Ri RI 1)0H_ S - - S
NH
2 2) COC1 2 25
RO
2 C NH 9 O
H
2 N-Ar Ri R1 Ar 2 S N Ar S N N'Ar H H HOC 27 26 Scheme V Urea Formation via Isatoic-like Anhydrides Finally, ureas may be further manipulated using methods familiar to those skilled in the art. 5 The invention also includes pharmaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 10 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 15 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 20 compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in 24 order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example. inert diluents, such as calcium carbonate. sodium carbonate, lactose, calcium phosphate or sodium 5 phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid, and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as 10 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, 15 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 20 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 25 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 30 example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
25 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 5 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 10 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 15 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, 20 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 25 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 30 demulcent, a preservative and flavoring and coloring agents. The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing 26 the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols. 5 Compounds of the invention may also be administrated transdermallv using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. W094/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a 10 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 fonrs. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of 15 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, 20 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. 25 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
C
8 C, fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated 30 C.-C, fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic 27 acids with a total of up to 24 carbons such as diisopropyl adipate. diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes. amides, ketones, ureas and their derivatives, and ethers such as 5 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 8
-C,
8 fatty alcohols, saturated or unsaturated C 8
-C
8 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids 10 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, 15 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. 20 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 25 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 30 regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
28 It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. 5 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 seventy of the 10 condition undergoing therapy. It will bc further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of 15 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, 20 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 25 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 turn, are producible from known compounds), e.g., through the general 30 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.
29 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 5 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. 10 All temperatures are reported uncorrected in degrees Celsius (*C). Unless otherwise indicated. all parts and percentages are by weight. Commercial grade reagents and solvents were used without further purification. Thin layer chromatography (TLC) was performed on Whatman* pre-coated glass-backed 15 silica gel 60A F-254 250 gm 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 20 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 25 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 Me 4 Si (6 0.00) or residual protonated solvent (CHC 3 5 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon ( 3 C) NMR spectra were measured with a General Electric 30 GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl, 8 77.0: MeOD-d 3 ; S 49.0; DMSO-d, 8 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass 30 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 5 was performed with electron energy of 70 eV and a trap current of 300 pLA. Liquid cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept I-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (1x10 4 torr to 2.5x10 4 torr). The direct 10 insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength 15 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-I methyl silicone column (0.33 mM coating; 25 20 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 25 consistant with assigned structures. List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous 30 BOC tert-butoxycarbonyl conc concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone 31 DMF N.,N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate 5 EtOH ethanol (100%) Et,O diethyl ether Et 3 N triethylamine rn-CPBA 3-chloroperoxybenzoic acid MeOH methanol 10 pet. ether petroleum ether (boiling range 30-60 *C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl 15 A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoles 0 CN Step 1. 3-Oxo-4-methylpentanenitrile: A slurry of sodium hydnde (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 *C for 15 min.. then a 20 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 25 mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (conc. HCl) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgSO,), and concentrated in vacuo to give the a cyanoketone as a yellow oil which was used in the next step without further 30 purification.
32 N | O
NH
2 Step 2. 5-Amino-3-isopropylisoxazole: Hydroxylamine hydrochloride (10.3 g, 148 mmol) was slowly added to an ice cold solution of NaOH (25.9 g, 645 mmol) in water 5 (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 CHC 3 (3 x 100 mL) without cooling. The combined organic layers were dried (MgSO,), and concentrated in vacuo. The resulting oily 10 yellow solid was filtered through a pad of silica (10% acetone/90% CHCl2) to afford the desired isoxazole as a yellow solid (11.3 g, 70%): mp 63-65 "C; TLC Rf (5% acetone/95% CHCl.) 0.19, 'H-NMR (DMSO-d 6 ) d 1.12 (d, J=7.0 Hz, 6H), 2.72 (sept, J=7.0 Hz, 1H), 4.80 (s, 2H), 6.44 (s, 1H); FAB-MS nilz (rel abundance) 127 ((M+H); 67%). 15 A3. General Method for the Preparation of 5-Amino-I-alkyl-3-alkylpyrazoles NNH N NH2 NC 5-Amino-3-tert-butvl-1-(2-cyanoethyl)pyrazole: A solution of 4,4-dimethyl-3 oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) 20 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 (EtO/hexane) to afford the desired product (2.5 g, 30%): TLC (30% 25 EtOAc/70% hexane) Rf 0.31; 'H-NMR (DMSO-d,) 8 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).
33 A 4. Synthesis of 3-Amino-5-alkylthiophenes A4a. Synthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids S NH 5 0 04 Step 1. 7-tert-Butyl-2H-thieno[3,2-dloxazine-2,4(1H)-dione: A mixture of methyl 3-amino-5-terr-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 10 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
N
T
MR (CDCl 3 ) 6 1.38 (s, 9H), 2.48 (s, IH), 6.75 (s, I H); FAB-MS ni/z (rel abundance) 226 ((M+H)~, 100%). - 0 N N N 15 HOOC H H Step 2. N-(5-tert-Butyl-2-carboxy-3-thienyl)-N'-(4-(4-pyridinylmethyl)phenyl) urea: A solution of 7-tert-butyl-2H-thieno[3,2-d]oxazine-2,4(1H)-dione (0.176 g, 0.78 mrnol) and 4-(4-pyridinylmethyl)aniline (0.144 g, 0.78 nmol) in THF (5 mL) was heated at the reflux temp. for 25 h. After cooling to room temp., the resulting 20 solid was triturated with Et.0 to afford the desired urea (0.25 g, 78%): mp 187-189 OC; TLC (50% EtOAc/50% pet. ether) Rf 0.04; 'H-NMR (DMSO-d) 8 1.34 (s. 9H), 3.90 (s, 2H), 7.15 (d, J=7Hz, 2H), 7.20 (d, J=3 Hz, 2H), 7.40 (d, J=7 Hz, 2H), 7.80 (s 1H), 8.45 (d, J=3 Hz, 2H) 9.55 (s, IH), 9.85 (s, IH), 12.50 (br s, IH); FAB-MS m/z (rel abundance) 410 ((M+H)*; 20%).
34 - 0 N N H H Step 3. N-(5-tert-Butvl-3-thienvl)-N'-(4-(4-p)ridinvlmethy.l)pbenvI)urea: A vial containing N-(5-tert-butyl-2-carboxy-3-thienyl)-N'-( 4 -(4-pyridinylmethyl)phenyl) urea (0.068 g, 0.15 mmol) was heated to 199 *C in an oil bath. After gas evolution 5 ceased, the material was cooled and purified by preparative HPLC (C-18 column; gradient from 20% CH 3 CN/79.9% 1H,0/0.1% TFA to 99.9% H,0/0. I % TFA) to give the desired product (0.024 g, 43%): TLC (50% EtOAc/50% pet. ether) R, 0.18; 'H NMR (DMSO-d,) 5 1.33 (s, 9H), 4.12 (s, 2H), 6.77 (s, I H), 6.95 (s, 1H), 7.17 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.69 (d, J=7 Hz, 1H), 8.58 (s, I H), 8.68 (d, J=7 Hz, 10 2H), 8.75 (s, 1 H); EI-MS m/z 365 (M'). A4b. Synthesis 3 -Amino-5-alkylthiophenes from 3 -Amino-5-alkyl-2-thiophene carboxylate esters S
NH
3 ' CI~ 5-tert-Butyl-3-thiopheneammonium Chloride: To a solution of methyl 3 -amino-5 15 tert-butyl-2-thiophene-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp. for 2.25 h. A conc. HCI solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for I h, then the solution was concentrated under reduced pressure. The white residue 20 was suspended in EtOAc (150 mL) and a saturated NaHCO, solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCI solution (150 mL), dried (NaSO), 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. 25 35 A4c. Synthesis 3-Amino-5-alkylthiophenes from N-BOC 3-Amino-5-alkylI-2 thiophenecarboxy late esters S N0 - N Ik 0 -k MeO 2 C H Step 1. Methyl 3-(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxy 5 late: To a solution of methyl 3-amino-5-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 *C was added di-zert-butyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and N.N-dimethylaminopyridine (86 g, 0.70 mol, 1.00 equiv) and the resulting mixture was stirred at room temp for 7 d. The resulting dark solution was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately 10 20 'C. The resulting red solids were dissolved in CH,Cl, (3 L) and sequentially washed with a I M H 3 PO. solution (2 x 750 mL), a saturated NaHCO 3 solution (800 mL) and a saturated NaCI solution (2 x 800 mL), dried (Na SO 4 ) 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 15 product as an off-white solid (163 g, 74%): 'H-NMR (CDC 3 ) S 1.38 (s, 9H), 1.51 (s, 9H), 3.84 (s, 3H), 7.68 (s, 1H), 9.35 (br s, 1H); FAB-MS n/z (rel abundance) 314 ((M+H)-, 45%). S N0
HO
2 C H Step 2. 3-(tert-Butoxycarbonylamino)-5-terr-butyl-2-thiophenecarboxylic Acid: 20 To a solution of methyl 3-(tert-butoxycarbonylamino)-5-tert-butyl-2 thiophenecarboxylate (90.0 g, 0.287 mol) in THF (630 mL) and MeOH (630 mL) was added a solution of NaOH (42.5 g, 1.06 mL) in water (630 mL). The resulting mixture was heated at 60 *C for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0 *C. The pH was adjusted to approximately 7 with a 36 1.0 N HCI solution (approximately I 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 HCI solution (500 mL). The organic phase was washed with a saturated NaCI solution (4 x 1.5 L), dried (Na.SO4), 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
(CDCI
3 ) S 1.94 (s, 9H), 1.54 (s, 9H), 7.73 (s, IH), 9.19 (br s, I H); FAB-MS m/z (rel abundance) 300 ((M+H)', 50%). S 10
NH
3 ' Cr Step 3. 5-tert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(ter butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HCI solution (4.0 M in dioxane, 12.5 mL, 0.050 mol, 5.0 equiv), and the resulting mixture was heated at 80 *C for 2 h. The resulting 15 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-d,) 8 1.31 (s, 9H), 6.84 (d, J=1.48 Hz, 1H), 7.31 (d, J=1.47 Hz, 1H), 10.27 (br s, 3H).
37 AS. General Method for the Synthesis of BOC-Protected Pyrazoles NI
NH
2 0 5-Amino-3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole: To a solution of 5-amino 5 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CH 2 Cl, (140 mL) was added di-tert-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp. for 13 h, thcn diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired 10 carbamate (6.26 g, 92%): mp 63-64 *C; TLC Rf (5% acetone/95% CH 2 Cl,); 'H-NMR (DMSO-d,) 8 1.15 (s, 9H), 1.54 (s, 9H), 5.22 (s, 1H), 6.11 (s, 2H); FAB-MS m/z ((M+H)'). A6. General Method for the Synthesis of 2-Aminothiadiazoles S N 15 N NH2 2-Amino-5-(1-(1-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, I equiv). The reaction mixture was heated at 85 *C for 7 h, then cooled to room temperature, and treated 20 with a concentrated NH 4 OHsolution until basic. The resulting solids were filtered to afford 2 -amino-5-(I-(1-ethyl)propyl)thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, 51%): mp 155-158 *C; TLC (5% MeOH/ 95% CHCl 3 ) Rf 0.14; 'H-NMR (DMSO-d 6 ) 8 0.80 (t, J=7.35 Hz, 6H), 1.42-1.60 (m. 2H), 38 1.59-1.71 (m. 2H), 2.65-2.74 (m, 1H), 7.00 (br s, 2H); HPLC ES-MS m.: 172 ((M+H)-). A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles 0 N ,NH2 5 H 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 0 C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as 10 a yellow oil (1.0 g, 10%), which was used inb the next step withour further purification. iO N
NH
2 Step 2. 2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 g), KHC0 3 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature 15 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 CHCl, (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)'). 20 A8. General Method for the Synthesis of 2-Aminooxazoles 0 OH Step 1. 3,3-Dimetbyl-1-hydroxy-2-butanone: A neat sample of 1-bromo-3,3 dimethyl-2-butanone (33.3 g) at 0 *C was treated with a IN NaOH solution, then was 25 stirred for I h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (Na:SO 4 ) and concentrated under reduced pressure to 39 give 3.3-dimethyl-I-hydroxy-2-butanone (19 g, 100%), which was used inb the nex! step withour further purification. N 0
NH
2 Step 2. 2-Amino-4-isopropyl-1,3-oxazole: To a solution of 3,3-dimethvl-l 5 hydroxy-2-butanone (4.0 g) and cyanimide (50% w/w, 2.86 g) in THF (10 mL) was added a IN NaOAc solution (8 mL), followed by tetra-n-butylammonium hydroxide (0.4 M, 3.6 mL), then a IN NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with Et,O (3 x 25 10 mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CHC1, (3 x 25 mL). The combined organic layers were dried (NaSO,) and concentrated under reduced pressure to afford 2-Amino-4 isopropyl-1,3-oxazole (1.94 g, 4 1%): HPLC ES-MS n/z 141 ((M+H)'). 15 A9. Method for the Synthesis of Substituted-5-aminotetrazoles N-N N , i N
NH
2 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, 20 and concentrated under reduced pressure. The resulting aqueous mixture was washed with CHCl: (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)-).
40 B. General Methods for Synthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene 5
H
2 N -N 4-(4-Pyridinylmethyl)aniline: To a solution of 4
-(
4 -nitrobenzyl)pyridine (7.0 g, 32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry was shaken under a H, atmosphere (50 psi) using a Parr shaker. After I h, TLC and 'H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a 10 short pad of Celite*. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%): 'H-NMR (DMSO-d 6 ) 6 3.74 (s, 2H), 4.91 (br s, 2H). 6.48 (d, J=8.46 Hz, 2H), 6.86 (d, J=8.09 Hz, 2H). 7.16 (d, J=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); El MS ml: 184 (M). This material was used in urea formation reactions without further purification. 15 B2. General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene
H
2 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-1-nitrobenzene 20 (Menai ST 3355A; 0.220 g, 0.95 mmol) and H20 (0.5 mL) in AcOH ( 5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H20 (50 mL), basified to pH 10 by adding solid KCO, in portions (Caution: foaming). The organic layer was washed with a saturated NaCl solution, dried (MgSO 4 ), concentrated in 25 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) R, 0.20.
41 B3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution. Followed by Reduction 0 I I 0 2 N O OMe Step 1. 1-Methoxy-4-(4-nitrophenoxv)benzene: To a suspension of NaH (95%, - 5 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 I h, then a solution of 1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 *C overnight, then cooled to room temp., quenched with HO, and concentrated in vacuo. 10 The residue was partitioned between EtOAc (200 mL) and H2O (200 mL) . The organic layer was sequentially washed with HO (2 x 200 mL). a saturated NaHCO, solution (200 mL), and a saturated NaCl solution (200 mL), dried (Na.SO,), and concentrated in vacuo. The residue was triturated (EtO/hexane) to afford I methoxy- 4 -(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDC 3 ) S 3.83 (s, 15 3H), 6.93-7.04 (m, 6H), 8.18 (d, J=9.2 Hz, 2H); El-MS m/z 245 (M-).
H
2 N O OMe Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of I-methoxy-4-(4 nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C 20 (1.5 g) and the resulting slurry was shaken under a H. atmosphere (50 psi) for 18 h. The reaction mixture was filtered through a pad of Celite* with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR (CDCIl) 8 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, J=8.8 Hz, 2H), 6.79-6.92 (m, 6H); El MS m/z 215 (M'). 25 B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
CF
3 02NS 0 2 N
N~
42 Step 1. 3 -(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4 mercaptopyridine (2.8 g, 24 mmoles), 2 -fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete 5 reaction. The mixture was diluted with Et,O (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et.O (2 x 100 mL). The organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The solid residue was triturated with Et,O to afford the desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) Rf 0.06; 10 'H-NMR (DMSO-d 6 ) S 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd, J=2.4, 8.7Hz, 1 H), 8.54-8.56 (m, 3H).
CF
3
H
2 N N Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3 trifluoromethyl-4-(4-pyridinvlthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 15 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for 4 h. The mixture was diluted with EtO (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The residue was filtered through a pad of silica 20 (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50% hexane) R 1 0.10; 'H-NMR (DMSO-d,) 5 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz, 2H). 25 B3c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 43 NS S 0 2 N N Step 1. 4
-(
2
-(
4 -Phenyl)thiazolyl)thio-1-nitrobenzene: A solution of 2-mercapto-4 phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4 nitrobenzene (2.3 mL, 21.7 mmoles) followed by K:CO 3 (3.18 g, 23 mmol), and the 5 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 4 ) and concentrated under reduced pressure. The solid residue was triturated with a EtO/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49; 'H-NMR (CDCl 3 ) 6 10 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
H
2 N Step 2. 4
-(
2 -(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio- I -nitro benzene was reduced in a manner analagous to that used in the preparation of 3 (trifluoromethyl)-4-(4-pyndinylthio)aniline: TLC (25% EtOAc/75% hexane) R. 0.18; 15 'H-NMR (CDCI,) 6 3.89 (br s. 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H). B3d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 N 20 0 2 NZ O Step 1. 4
-(
6 -Methvl-3-pyridinyloxy)-1-nitrobenzene: To a solution of 5-hydroxy 2-methylpyridine (5.0 g, 45.8 mmol) and I-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K2 C0 3 (13.0 g, 91.6 mniol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool 44 to room temp. The resulting mixture was poured into water (200 mLj 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 (Na.SOJ, and concentrated in vacuo to afford the desired product (8.7 g, 83%). The this material 5 was carried to the next step without further purification.
H
2 N O Step 2. 4
-(
6 -Methyl-3-pyridinyloxy)aniline: A solution of 4 -(6-methyl-3 pyridinyloxy)-I-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to 10% Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H. 10 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%): El-MS ml: 200 (M'). B3e. General Method for Substituted Aniline Formation via Nitroarene Formation 15 Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N Oe Step 1. 4
-(
3 ,4-Dimethoxyphenoxy)-I-nitrobenzene: To a solution of 3,4 dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 gL, 6.4 mmol) in anh DMF (20 mL) was added K-IC0 3 (1.8 g, 12.9 mmol) in one portion. The 20 mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (NaSO 4 ), and concentrated in vacuo to afford the desired product (0.8 g, 54%). The crude product was carried to 25 the next step without further purification.
H
2 N O OMe Step 2. 4
-(
3
,
4 -Dimethoxyphenoxy)aniline: A solution of 4
-(
3 ,4-dimethoxy phenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10% 45 Pd/C (0.100 g) and the resulting mixture was placed under a H. atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite' and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS ni: 245 (M). 5 B3f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction N 0 2 N 0 Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine 10 (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(l) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K.CO, (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 15 were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2SO 4 ), 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. N I I ' I
H
2 N 0 20 Step 2. 3 -(3-Pyridinyloxy)aniline: A solution of 3-(3-pyridinyloxy)-1 nitrobenzene (2.0 g, 9.2 mnmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite* and concentrated in vacuo to afford the desired product as a red oil (1.6 g, 25 94%): EI-MS n/z 186 (M). B3g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 46 N 0 2 N O Step 1. 3 -(5-Methl-3-pyridinvloxy)-l-nitrobenzene: To a solution of 3-hydroxy 5-methylpyridine (5.0 g, 45.8 mmol), 1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper(l) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added KCO, 5 (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 NaCI solution (2 x 100 mL), dried (NaSO 4 ), and concentrated in vacuo . The resulting oil was purified 10 by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%). N
H
2 N O N Step 2. 3-(5-Methvl-3-pyridinyloxy)-1-nitrobenzene: A solution of 3-(5-methyl-3 pyridinyloxy)-l-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10% 15 Pd/C (0.100 g) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite* and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): Cl-MS m/: 201 ((M+H)'). 2B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N O Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of 2-chloro-5 nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 25 g, 50 mmol, 1.25 equiv) and KCO, (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred overnight at room temp. The resulting mixture was treated with water (600 mL) to generate a precipitate. This mixture was stirred for I h, and the solids were separated and sequentially washed with a I N NaOH solution (25 mL), water (25 mL) 47 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, 0.79; 'H-NMR (DMSO-d,) 8 2.31 (s, 3H). 7.08 (d, J=8.46 Hz. 2H), 7.19 (d, J=9.20 Hz, I H), 7.24 (d, J=8.09 Hz, 2H), 8.58 (dd, J=2.94, 8.82 Hz. IH), 8.99 (d, J=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 ((M+H)~), 5 100%).
N
0 Cr H 3 N. - H C' Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochloride: A solution 5 nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, I eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The 10 reaction mixture was then placed under a H, atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celite*. A solution of HCI in EtO was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, 92%): mp 208-2 10 *C (dec); TLC (50% EtOAc/50% pet ether) Rf 0.42; 'H-NMR (DMSO-d,) 8 15 2.25 (s, 3H), 6.98 (d, J=8.45 Hz, 2H), 7.04 (d, J=8.82 Hz, 1H), 7.19 (d, J=8.09 Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H), 8.63 (d, J=2.57 Hz, 1H); EI-MS n/z (rel abundance) (M~, 100%). B3i. General Method for Substituted Aniline Formation via Nitroarene Formation 20 Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N Step 1. 4-(3-Thienvlthio)-I-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 25 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 48 extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a I M NaOH solution (2 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (MgSO 4 ), and concentrated in vacuo . The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) 5 to afford of the desired product (0.5 g, 34%). GC-MS i/: 237 (M~). S
H
2 N Step 2. 4-(3-Thienylthio)aniline: 4 -(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method BI. 10 B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
H
2 N N 4-(5-Pyrimininvloxy)aniline: 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in 15 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 0 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 20 saturated NaCl solution (2 x 50 mL), dried (MgSO,), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%). B3k. General Method for Substituted Aniline Formation via Nitroarene Formation 25 Through Nucleophilic Aromatic Substitution, Followed by Reduction Br OMe N Step 1. S-Bromo-2-methoxvpyridine: 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 49 mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (NaSO) and concentrated under reduced pressure to give a pale yellow. volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90% hexane) Rf 0.57. HO >-OMe 5 N 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 10 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 15 temp. for I h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a IN HCI solution then extracted with Et,O (2 x 100 mL). The combined organic layers were dried (NaSO.,) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%). 0 0 2 N N OMe 20 Step 3. 4-(5-(2-Methoxy)pyridvl)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 I h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mnixture was heated to 95 *C ovemight, then treated 25 with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).
H
2 N N OMe 50 Step 4. 4 -(5-( 2 -Methoxy)pyridyl)oxyaniline: 4 -(5-(2-Methoxy)pyridyl)oxynitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2. B4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
H
2 N S N 3-(4-Pyridiny lthio)aniline: To a solution of 3-arninothiophenol (3.8 mL, 34 moles) in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) 10 followed by K:CO, (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (1O0mL). 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 (MgSO4), and concentrated under reduced pressure. The residue was filtered through a pad of silica 15 (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et.0/hexane solution to afford the desired product (4.6 g, 66%): TLC (100 % ethyl acetate) Rf 0.29; 'H-NMR (DMSO-d 6 ) 5 5.41 (s, 2H), 6.64-6.74 (im, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, I H), 8.32 (d. J=4.8, 2H). 2B4b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
H
2 N 4-(2-Methyl-4-pyridinvloxy')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 25 potassium tert-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 (NaSO4), and concentrated in vacuo.
51 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 mzl 201 ((M+H)~). B4c. General Method for Substituted Aniline Synthesis via Nucleophilic 5 Aromatic Substitution using a Halopyridine Me 0 2 N N Step 1. Methyl(4-nitrophenvl)-4-pyridylamine: To a suspension of N-methyl-4 nitroaniline (2.0 g, 13.2 mmol) and K.CO, (7.2 g, 52.2 mmol) in DMPU (30mL) was 10 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 (Na.SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 15 gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4 nitrophenyl)-4-pyridylamine (0.42 g) H2NMe
H
2 N
-
/ Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4 pyridylamine was reduced in a manner analogous to that described in Method B 1. 20 B5. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene S 0 2 N O Step 1. 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitrophenyl 25 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 52 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 5 additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with EtO (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL). dried (MgSO 4 ), 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 10 product as a yellow solid (1.24 g, 67%): TLC (20% EtOAc/80% hexane) Rf 0.75; 'H NMR (DMSO-d) 8 0.92 (t, J= 7.5 Hz. 3H), 1.42 (app hex, J=7.5 Hz. 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz. 2H), 8.09 (d, J= 9 Hz, 2H).
H
2 N O 15 Step 2. 4
-(
4 -Butoxyphenyl)thioaniline: 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)
R
1 0.38. 20 B6. General Method for Sy'nthesis of Substituted Anilines by' the Acylation of Diaminoarenes
H
2 N N 0 H 4
-(
4 -tert-Butoxycarbamoylbenzyl)aniline: To a solution of 4
,
4 '-methylenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di 25 tert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp. for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-tert-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp. for 16 h. The resulting mixture was diluted with Et:0 (200 mL), sequentially washed with a 53 saturated NaHCOs solution (100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a 5 white solid ( 2.09 g. 46%): TLC (50% EtOAc/50% hexane) R, 0.45; 'H-NMR (DMSO-d,) 8 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, J=8.4 Hz, 2H), 6.80 (d. J=8.1 Hz. 2H), 7.00 (d, J=8.4 Hz. 21-1), 7.28 (d, J=8.1 Hz. 2H), 9.18 (br s, IH); FAB-MS i/: 298 (M-). 1B7. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction 0 2 N N 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 15 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 Et,O (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 (NaSO.,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane) 20 then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC MS mlz 214 (M'). -N
H
2 N N Step 2. 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method B 1. 25 B8. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction 54 ON 0 2 N KN Step I. 4 -(l-Imidazoly'lmethyl)-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 K2CO 3 (1.0 g, 7.3 rnmol). The resulting mixture was stirred at rooom 5 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 (MgSO 4 ), 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, 10 91%): El-MS m/z 203 (M'). N\
H
2 N N Step 2. 4-(I-Imidazolylmethyl)aniline: 4-(I -Imidazolylmethyl)-i-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2. 1B9. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzvl Compounds Followed by Reduction OH N N 0 2 N &'O Step 1. 4 -(I-Hydroxy-1-(4-pyridyl)methyl-1-nitrobenzene: To a stirred solution of 3 -(4-nitrobenzyl)pynidine (6.0 g, 28 mmol) in CHCl, (90 mL) was added m-CPBA 20 (5.80 g, 33.6 mmol) at 10 *C, and the mixture was stirred at room temp. overnight. The reaction mixture was successively washed with a 10% NaHSO solution (50 mL), a saturated K,C0 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature 25 overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous
NH
3 solution (30 mL). The mixture was stirred at room temp. for I h, then was concentrated under reduced pressure. The residue was poured into a mixture of water (50 mL) and CHCl 2 (50 55 mL). The organic layer was dried (MgSO 4 ). concentrated under reduced pressure. and punfied 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) Rf 0.12; FAB-MS mi 367 ((M+H)~, 100%). 5 OH H2N N Step 2. 4-(1-Hydroxv-l-(4-pyridyl)methylaniline: 4-(I-Hydroxy-I-(4-pyridyl) methyl-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2. 10 BIO. Formation of 2 -(N-methylcarbamoyl)pyridines via the Menisci reaction 0 C'I
NH
2 Step 1. 2 -(N-methvlcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) 15 in N-methylformamide (250 mL) under argon at ambient temp was added conc. H.SO, (3.55 mL) (exotherm). To this was added H,0, (17 mL, 30% wt in H20) followed by FeSO, 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for lh then was heated slowly over 4 h at 45 *C. When bubbling subsided,the reaction was heated at 60 *C for 16 h. The opaque brown solution was 20 diluted with H20 (700 mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCI solution (3 x 150 mlL. The combined organics were dried (MgSO,) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by 25 silica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc / 20% hexane). The resulting yellow oil crystallized at 0 *C over 72 h to give 2-(N methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) R,0.50; MS; 'H NMR (CDCl 3 ): d 8.44 (d, 1 H, J = 5.1 Hz, CHN), 8.21 (s, 56 1H, CHCCO). 7.96 (b s, IH,. NH), 7.43 (dd. 1H .1 = 2.4. 5.4 Hz. CICHCN), 3.04 (d. 3H, J = 5.1 Hz. methyl); CI-MS z/: 171 ((M-H)+). B11. Generalmethod for the Sy~nthesis of o-SulfonylphenyI Anilines 0 0 2 N Me 5 0 '0 Step 1. 4
-(
4 -Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4 methylthiophenoxy)-1-ntirobenzene (2 g, 7.66 mmol) in CHCI, (75 mL) at 0 *C was slowly added nCPBA (57-86%. 4 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a I N NaOH solution (25 10 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 (MgSO.,), and concentrated under reduced pressure to give 4
-(
4 -methylsulfonylphenoxy)-l nitrobenzene as a solid (2.1 g). 15 Step 2. 4-(4-Methylsulfonylpbenoxy)-l -aniline: 4 -(4-Methylsulfonylphenoxy)-1 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 0 Oj) OMe 20 0 2 N OMe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene: To a solution of -( 3 -carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous to that described in Method B3a. step 1, 12 mmol) in acetone (50 mL) was added KCO, (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat 25 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.
57 0 0 N OH O'CN OMe Step 2. 4 -(3-Carboxy-4-methoxy phenoxy)-1-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 5 heated at the reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a IN HCI solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-carboxy-4 10 methoxyphenoxy)- I -nitrobenzene (1.04 g). C. General Methods of Urea Formation C1a. Reaction of a Heterocyclic Amine with an Isocanate N N H H 15 N-(5-tert-Butyl-3-thien y)-N'-(4-phenoxyphenyl)urea: To a solution of 5-terr 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 20 sequentially washed with HO (200 mL), a I N HCI solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na'S0 4 ), and concentrated under reduced pressure. The resulting off-white solid was recrystallized (EtOAc/hexane) to give a white solid (13.7 g, 88%), which was contaminated with approximately 5% of bis(4 phenoxyphenyl)urea. A portion of this material (4.67 g) was purified by flash 25 chromatography (9% EtOAc/27% CHC1,/64% cyclohexane) to afforded the desired product as a white solid (3.17 g). Cib. Reaction of a Heterocyclic Amine with an Isocyanate 58 N N N H H N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-phenoxyphenyl)urea: To a solution of 5 amino-3-rert-butylisoxazole (8.93 g, 63.7 mmol. I eq.) in CHCl, (60 mL) was added 4-phenyloxyphenyl isocyanate (15.47 g, 73.3 mmol, 1.15 eq.) dropwise. The mixture 5 was heated at the reflux temp. for 2 days, eventually adding additional CHCI, (80 mL). The resulting mixture was poured into water (500 mL) and extracted with Et,O (3 x 200 mL). The organic layer was dried (MgSO 4 ) 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) 10 6 1.23 (s, 9H), 6.02 (s, 1 H), 6.97 (dd, J=0.2, 8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.08 (t, J=7.4 Hz, 1 H), 7.34 (m, 2H), 7.45 (dd, J=2.2, 6.6 Hz. 2H) , 8.80 (s, 1 H), 10.04 (s, 1 H); FAB-MS n/z (rel abundance) 352 ((M+H)-,70%). CIc. Reaction of a Heterocyclic Amine with an Isocyanate NI 0 0 N N N H H H 15 N-( 3 -tert-Butyl-5-pyrazoly)-N'-(4-(4-methylphenl)oxyphenyl)urea: A solution of 5-amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4-(4 methylphenoxy)phenyl isocyanate (0.225 g, 1.0 mmol 1.0 equiv) in toluene (10 mL) was heated at the reflux temp. ovemight. The resulting mixture was cooled to room temp and quenched with MeOH (a few mL). After stirring for 30 min, the mixture 20 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%
CHC
2 ) R 1 0.92; 'H-NMR (DMSO-d,) S 1.22 (s, 9H), 2.24 (s, 3H), 5.92 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 8.85 (s, IH), 9.20 (br s, 1H), 11.94 (br s, 1H); El-MS 25 m/z 364 (M').
59 Cid. Reaction of a Heterocyclic Amine with an Isocyanate S 0 1 0 N N C H H C N-(5-rert-Butyl-3-thienyl)-N'-(2,3-dichlorophenyl)urea: Pyridine (0.163 mL, 2.02 5 mmol) was added to a slurry of 5-tert-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL. 2.02 mmol) in CHCl, (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 10 organic layer was sequentially washed with a saturated NaHCO, solution (15 mL), a IN HC solution (15 mL) and a saturated NaCl solution (15 mL), dried (Na.,SO 4 ), and concentrated under reduced pressure. A portion of the residue was by preparative HPLC (C-18 column; 60% acetonitrile/40% water/0.05% TFA) to give the desired urea (0.180 g, 34%): mp 169-170 'C; TLC (20% EtOAc/80% hexane) Rf 0.57; 'H 15 NMR (DMSO-d 6 ) S 1.31 (s, 9H), 6.79 (s, lH), 7.03 (s, IH), 7.24-7.33 (m, 2H), 8.16 (dd, J=1.84, 7.72 Hz, IH), 8.35 (s, IH), 9.60 (s, LH); '"C-NMR (DMSO-d 6 ) S 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 nilz (rel abundance) 343 ((M+H)-, 83%), 345 ((M+H+2)~, 56%), 347 ((M+H+4)', 12%). 20 Cle. Reaction of a Heterocyclic Amine with an Isocyanate N, N N N N C1 H H H
N-(
3 -rert-Butyl-5-pyrazolyl)-N'-(3,4-dichlorophenyl)urea: A solution of 5-amino 3-ter-i-butyl-N'-(iert-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 25 stirred at 55 *C for 2 d. The toluene was removed in vacuo and the solid was 60 redissolved in a mixture of CHCl, (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 3 solution (10 mL) and a NaCl solution (5 mL), dried (Na,SO 4 ). and concentrated in vacuo. The residue 5 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) Rf 0.05, FAB-MS m/: 327 ((M+H)~). C2a. Reaction of a Heterocyclic Amine with Pbosgene to Form an Isocyanate, then 10 Reaction with Substituted Aniline N, 0 N=C=0 Step 1. 3 -tert-Butyl-5-isoxazolyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CH,Cl (20 mL) at 0 *C was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-ter!-butylisoxazole (0.305 g, 2.18 15 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. S N,/ N' 0 N N N H H Step 2. N-( 3 -tert-Butvi-5-isoxazoll)-N'-(4-(4-pyridinyithio)phenyl)urea: The crude 3 -tert-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 20 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/CHCl, solution (4:1, 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting yellow oil was purified by column 25 chromatography (silica gel, gradient from 2% MeOH/98% CHCl, to 4% MeOH/6% CH,C.) to afford a foam, which was triturated (Et.0/hexane) in combination with sonication to give the product as a white powder (0.18 g, 49%): TLC (5% MeOH/95% CHCl,) Rf 0.21; 'H-NMR (DMSO-d,) 8 1.23 (s. 9H), 6.06 (s, IH), 6.95 61 (d, J=5 Hz. 2H), 7.51 (d, J=8 Hz. 2H), 7.62 (d, J=8 Hz. 2H). 8.32 (d, J=5 H z. 2H), 9.13 (s. I H ). 10 .19 (s, 1 H); FAB-MS ml: 369 ((M+H)+). C2b. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed 5 by Reaction with Substituted Aniline 0 N N=C=O Step 1. 5-tert-Butyl-3-isoxazolyl Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CHCl, (1 L) was added 3-amino-5-tert butylisoxazole (10.0 g, 71 mmol) followed by pyridine (46 mL, 569 mmol). The 10 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/: 166 15 (M'). S - 0 N N N H H Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinylthio)phenyl)urea: To a solution of 5-tert-butyl-3-isoxazolyl isocyanate (247 mL, 0.2 M in THF, 49.4 mmol) was added 4-(4-pyridinylthio)aniline (5 g, 24.72 mnol), followed by THF (50 mL) 20 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 NaHCO3 solution (100 mL), and a saturated NaCI solution (100 mL), dried (MgSO4). and concentrated in vacuo. The resulting material was purified by MPLC 25 (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-d,) 8 1.28 (s. 9H), 6.51 62 (s, 1H). 6.96 (d, J=6.25 Hz. 2H), 7.52 (d, J=8.82 Hz. 2H), 7.62 (d. J=8.83 Hz. 2H). 8.33 (d. J=6.25 Hz. 2H), 9.10 (s, I H), 9.61 (s, I H); El-MS i/: 368 (M'). C2c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed 5 by Reaction with Substituted Aniline 00 N N N H H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CHCI, (13 mL) at 0 *C was slowly 10 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 I h, then was allowed to warm to room temp. over I h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-tert-butyl 15 N'-(tert-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 HCI solution and allowed to stir at room temp. for I h to form a new precipitate. The white solid was washed (50% Et,0/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 *C dec; TLC (10% MeOH/ 90% 20 CHC 3 ) Rf 0.239; 'H-NMR (DMSO-d 6 ) S 1.24 (s, 9H), 5.97 (s, IH), 6.88 (d, J=6.25 Hz, 2H), 7.10 (d, J=8.82 Hz, 2H), 7.53 (d, J=9.2 Hz, 2H), 8.43 (d, J=6.25 Hz, 2H), 8.92 (br s, 1H), 9.25 (br s, lH), 12.00 (br s, 1H); EI-MS n/z rel abundance 351 (M', 24%). 25 C3a. Reaction of a Heterocyclic Amine with NN'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline 63 0 0 N,/I I N N N / H H N-(3-tert-Butyl-1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy)pheny l)urea: To a solution of 5-amino-3-tert-butyl-1-methylpyrazole (189 g, 1.24 mol) in anh. CH2CI, 5 (2.3 L) was added NN'-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The mixture was allowed to stir at ambient temperature for 5 h before adding 4-(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 H.0 (8 L) and a saturated NaCl solution (4 L). The organic layer was dried 10 (NaSO,) and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et.0/1 1.2% hexane, 2.5 L) to afford the desired urea as a white solid (230 g, 51%): mp 149-152 *C; 'H-NMR (DMSO-d,) 8 1.18 (s, 9H), 3.57 (s, 3H), 6.02 (s, 1H), 6.85 (d, J=6.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 211), 8.40 (d, J=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H); FAB-LSIMS m/z 366 15 ((M+H)~). C3b. Reaction of a Heterocyclic Amine with NN'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline / 0 N N N H H H 20 N-(3-tert-Butyl-5-pyrazolyl)-N '-(3-(4-pyridinylthio)phenyl)urea: To a solution of 5-amino-3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole (0.282 g, 1.18 mmol) in
CH
2 CI, (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 I day. 3-(4-Pyridinylthio)aniline (0.239 25 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 64 organic layer was extracted with EtOAc (3 x 15 mL), dried (MgSO,), and concentrated in vacuo. The residue was diluted with CHCl. (5 mL) and trifluoroacetic acid (2 mL) and the resulting solution was allowed to stir for 4 h. The trifluoroacetic reaction mixture was made basic with a saturated NaHCO 3 solution, 5 then extracted with CHCl, (3 x 15 mL). The combined organic layers were dried (MgSO, and concentrated in vacuo. The residue was purified by flash chromatography (5% MeOH/95% CHC,). The resulting brown solid was triturated with sonication (50% Et,0/50% pet. ether) to give the desired urea (0.122 g, 28%): mp >224 *C dec; TLC (5% MeOH/ 95% CHCIl) Rf 0.067; 'H-NMR (DMSO-d 6 ) S 10 1.23 (s, 9H), 5.98 (s, 1H), 7.04 (dm, J=13.24 Hz, 2H), 7.15-7.19 (m, IH), 7.40-7.47 (m, 2H), 7.80-7.82 (m, IH), 8.36 (dm, =15.44 Hz, 2H), 8.96 (br s. IH), 9.32 (br s, IH), 11.97 (br s, 1H); FAB-MS m/z (rel abundance) 368 (M', 100%). C4a. Reaction of Substituted Aniline with N,N'-Carbonvldiimidazole Followed by 15 Reaction with a Heterocyclic Amine 0 N N N / H H N-(3-teri-Butyl-I1-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethvl)phenyl)urea: To a solution of 4 -(4-pyridinylmethyl)aniline (0.200 g, 1.08 mmol) in CHCl, (10 mL) was added N,N'-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture 20 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-butyl-l 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% CH.,Cl, to 60% acetone/40% CHCl,) and the resulting solids 25 were crystallized (Et20) to afford the desired urea (0.227 g, 58%): TLC (4% MeOH/96% CHC1,) Rf 0.15; 'H-NMR (DMSO-d 6 ) S 1.19 (s, 911), 3.57 (s, 3H), 3.89 (s, 2H), 6.02 (s, I H), 7.14 (d, J=8.4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 8.45-8.42 (m, 3H), 8.81 (s, I H); FAB-MS n/z 364 (M+H)*).
65 C4b. Reaction of Substituted Aniline with NN'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine N N N O S H H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(2-benzothiazolyloxy)phenyl)urea: A solution 5 of 3-(2-benzothiazolyloxy)aniline (0.24 g, 1.0 mmol, 1.0 equiv) and N.N' carbonyldiimidazole (0.162 g, 1.0 mmol, 1.0 equiv) in toluene (10 mL) was stirred at room temp for 1 h. 5-Amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol) was added and the resulting mixture was heated at the reflux temp. overnight. The resulting mixture was poured into water and extracted with CH2Cl, (3 x 50 mL). The combined organic 10 layers were concentrated under reduced pressure and dissolved in a minimal amount of CHCI. 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% CHC1 2 ) RO.05; 'H-NMR (DMSO-d,) 8 1.24 (s, 9H), 5.97 (s, lH), 7.00-7.04 (m, IH), 7.21-7.44 (m, 4H), 7.68 (d, J=5.5 Hz, 1HI), 15 7.92 (d, J=7.7 Hz, I H), 7.70 (s, I H), 8.95 (s, IH), 9.34 (br s, I H), 11.98 (br s, I H); El MS n/z 408 (M~). C4c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline S 0 0 N N 20 H H N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH.Cl (5 mL) was added a solution of 4-(4-pyridinyloxy)aniline (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CHCl, (5 mL). The resulting mixture was allowed to warm to room 25 temp. and was stirred for I h, then was concentrated under reduced pressure. The 66 residue was dissolved in CHCI: (5 mL), then treated with 5-tert butylthiopheneammonium chloride (Method A4c; 0.206 g, 1.07 mmol). followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for I h. then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp 5 an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL). sequentially washed with a saturated NaHCO 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na.SO 4 ), 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% 10 EtOAc/50% hexane) R, 0.13; 'H-NMR (CDC 3 ) 6 1.26 (s, 9H), 6.65 (d. J=1.48 Hz, 1H), 6.76 (dd, J=1.47, 4.24 Hz, 2H), 6.86 (d, =1.47 Hz, 1H), 6.91 (d, J=8.82 Hz, 2H). 7.31 (d, J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, J=1.47 Hz. 2H); ' 3 C-NMR
(CDC
3 ) 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 ni/z (rel abundance) 368 15 ((M+H)', 100%). C5. General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine N N N H H 20 N-(3-tert-Butyl-4-methyl-5-isoxazolyl)-N'-(2-fluorenyl)urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (1.OmL) was added a solution of 5-amino-4-methyl-3-tert-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 70 *C for 2 h, cooled to room temp., and treated 25 with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylanine (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 EtO and hexanes to give the desired urea as a beige solid (25 mg, 14%): mp 179-181 *C; 'H-NMR (DMSO-d) 6 1.28 (s, 9H), 2.47 67 (s, 3H), 3.86 (s, 2H), 7.22 (t. J=7.3 Hz, IH), 7.34 (m. 2H), 7.51 (d, J=7.3 Hz, I H), 7.76 (m, 3H), 8.89 (s, I H). 9.03 (s, I H); HPLC ES-MS i/z 362 ((M+H)~). C6. General Method for Urea Formation by Curtius Rearrangement and 5 Carbamate Trapping 0
N
3 /' Step 1. 5-Methyl-2-(azidocarbonyl)thiophene: To a solution of 5-Methyl-2 10 thiophenecarboxylic acid (1.06 g, 7.5 mmol) and Et 3 N (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 CHCl, (10 mL) and washed with a saturated 15 NaCl solution (10 mL). The aqueous layer was back-extracted with CHC1, (10 mL), and the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc/ 90% hexanes) to give the azidoester (0.94 g, 75%). Azidoester (100 mg, 0.6 mmol) in anhydrous toluene (10 mL) was heated to reflux for I h then cooled to rt. This solution was used as a 20 stock solution for subsequent reactions. OCN Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp. for I h then cooled to room temp. This solution was used as a stock solution for subsequent 25 reactions. 0 N N N H H Step 3. N-(5-tert-Butyl-3-isoxazoly)-N'-(5-methyl-2-thienyl)urea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp.
68 was added 3 -amino-5-r'ert-butylisoxazole (0.092 g. 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a I N HCI solution (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The 5 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) Rr 0.20; El-MS ml: 368 (M). C7. General Methods for Urea Formation by Curtius Rearrangement and 10 Isocyanate Trapping CI CHO Step 1. 3-Chloro-4,4-dimethylpent-2-enal: POC1 3 (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 15 *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 NaCI solution (200 mL), dried (NaSO 4 ) 20 and concentrated under reduced pressure. The residue was filtered through a pad of silica (CHC.2) to give the desired aldehyde as an orange oil (15.5 g, 35%): TLC (5% EtOAc/95% hexane) R, 0.54; 'H NMR (CDCl3) d 1.26 (s, 9H), 6.15 (d, J=7.0 Hz, I H), 10.05 (d, J=6.6 Hz, 1H). /s3 CO 2 Me 25 Step 2. Methyl 5-tert-butyl-2-thiophenecarboxylate: To a solution of 3-chloro 4,4-dimethylpent-2-enal (1.93 g, 13.2 mmol) in anh. DMF (60 mL) was added a solution of 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 69 treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids. The reaction mixture was stirred at room temp. for 1.5 h, then treated with a I N HCI solution (200 mL) and stirred for I h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HCl 5 solution (200 mL), water (2 x 200 mL) and a saturated NaCl solution (200 mL), dried (NaSO.,) 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) Rf 0.79; 'H NMR (CDCI 3 ) 5 1.39 (s, 9H), 3.85 (s, 3H), 6.84 (d, J=3.7 Hz, 1H), 7.62 (d, J=4.1 Hz, 1H); GC-MS n/z (rel 10 abundance) 198 (M~, 25%). /s3 CO 2 H Step 3. 5-tert-Butyl-2-thiophenecarboxylic acid: Methyl 5-tert-butyl-2 thiophenecarboxylate (0.10 g, 0.51 mmol) was added to a KOH solution (0.33 M in 90% MeOH/10% water, 2.4 mL, 0.80 mmol) and the resulting mixture was heated at 15 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 HCl solution. The resulting organic phase was washed with water (5 mL), dried (Na.SO 4 ), 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) Rf 0.29; 'H NMR 20 (CDCI,) 3 1.41 (s, 9H), 6.89 (d, J=3.7 Hz, 1H), 7.73 (d, J=3.7 Hz, IH), 12.30 (br s, 1H); 3 C NMR (CDCl 3 ) 5 32.1 (3C), 35.2, 122.9, 129.2, 135.1, 167.5, 168.2. N N CI H H CI Step 4. N-(5-tert-Butyl-2-thienyl)-N'-(2,3-dichlorophenyl)urea: A mixture of 5 tert-butyl-2-thiophenecarboxylic acid (0.066 g, 0.036 mmol), DPPA (0.109 g, 0.39 25 mmol) and EtN (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 70 room temp. and treated with EtOAc (50 mL). The organic layer was washed with a I N HCI solution (3 x 50 mL), a saturated NaHC0 3 solution (50 mL), and a saturated NaCl solution (50 mL), dried (Na.SO,), and concentrated under reduced pressure. The residue was purified by column chromatography (5% EtOAc/95% hexane) to 5 afford the desired urea as a purple solid (0.030 g, 24%): TLC (10% EtOAc/90% hexane) Rf0.28; 'H NMR (CDC],) 5 1.34 (s, 9H), 6.59 (br s. 2H), 7.10-7.13 (m, 2H), 7.66 (br s, IH), 8.13 (dd, J=2.9, 7.8 Hz, IH); "C NMR (CDCl 3 ) 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 ml (rel abundance) 343 ((M+H)~, 100%), 345 ((M+H+2)~, 67%), 347 10 ((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 15 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 20 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. 25 D. Misc. Methods of Urea Synthesis D1. Electrophylic Halogenation
-
0 .N N Br H H
N-(
2 -Bromo-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl)urea: To a slurry of N-(5 30 teri-butyl-3-thienyl)-N-(4-methylphenyl)urea (0.50 g, 1.7 mmol) in CHC 3 (20 mL) at 71 room temp was slowly added a solution of Br, (0.09 mL. 1.7 mmol) in CHCl 3 (10 mL) via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure. and the residue triturated (2 x 5 Et,0/hexane) to give the brominated product as a tan powder (0.43 g, 76%): mp 161 163 *C; TLC (20% EtOAc/ 80% hexane) R,0.71; 'H NMR (DMSO-d 6 ) 6 1.29 (s, 9H), 2.22 (s, 3H), 7.07 (d, J=8.46 Hz, 2H), 7.31 (d, J=8.46 Hz, 2H), 7.38 (s, IH), 8.19 (s, 1H), 9.02 (s, 1H); "C NMR (DMSO-d,) 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 i/z (rel abundance) 367 10 ((M+H)~, 98% ), 369 (M+2+H)', 100%). D2. Synthesis of w-Alkoxy Ureas -. 0 0~ N N 0H H H Step 1. N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-hydroxyphenyl)oxyphenyl)urea: A 15 solution of N-(5-tert-butyl-3-thienyl)-N'-( 4
-(
4 -methoxyphenvl)oxyphenyl)urea (1.2 g, 3 mmol) in CH,Cl, (50 mL) was cooled to -78 *C and treated with BBr 3 (1.0 M in CHCl, 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 20 EtOAc (50 mL), then washed with a saturated NaHCO 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO 4 ), 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) Rf 0.23; 'H NMR (DMSO-d,) 8 25 1.30 (s, 9H), 6.72-6.84 (m, 7H), 6.97 (d, ]=1.47 Hz, IH), 7.37 (dm, J=9.19 Hz, 2H), 8.49 (s, IH), 8.69 (s, IH), 9.25 (s, 1H); FAB-MS m/z (rel abundance) 383 ((M+H)', 33%).
72 S 0 N N O H H Step 2. N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-ethoxyphenyl)oxyphenyl)urea: To a mixture of N-(5-tert-butyl-3-thienyl)-N'-( 4
-(
4 -hydroxyphenyl)oxyphenyl)urea (0.20 g, 0.5 mmol) and Cs,CO, (0.18 g, 0.55 mmol, 1.1 equiv) in reagent grade acetone (10 5 mL) was added ethyl iodide (0.08 mL, 1.0 mmol, 2 equiv) via syringe, and the resulting slurry was heated at the reflux temp. for 17 h. The reaction was cooled, filtered, and the solids were washed with EtOAc. The combined organics were concentrated under reduced pressure, and the residue was purified via preparative HPLC (60% CH 3 CN/40% H,0/0.05% TFA) to give the desired urea as a colorless 10 powder (0.16 g, 73%): mp 155-156 *C; TLC (20% EtOAC/ 80% hexane) Rr 0.40; 'H NMR (DMSO-d) 8 1.30 (s, 9H), 1.30 (t, J=6.99 Hz, 3H), 3.97 (q, J=6.99 Hz. 2H), 6.80 (d, J=1 .47 Hz, 1 H), 6.86 (dm, J=8.82 Hz, 2H), 6.90 (s, 4H), 6.98 (d, J=1.47, 1H), 7.40 (dm, J=8.83 Hz, 2H), 8.54 (s, 1H), 8.73 (s, IH); "C-NMR (DMSO-d,) 8 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), 15 135.0, 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 o-Carbamoyl Ureas / 0 -~ ~0 N N N N H H H 20 N-(3-tert-Butyl-1-methyl-5-pyrazolyl)-N'-(4-(4 acetaminophenyl)methylphenyl)urea: To a solution of N-(3-tert-butyl-i-methyl-5 pyrazolyl)-N'-(4-(4-aminophenyl)methylphenyl)urea (0.300 g, 0.795 mmol) in CHCl, (15 mL) at 0 *C was added acetyl chloride (0.057 mL, 0.795 mmol), followed by anhydrous EtN (0.111 mL, 0.795 mmol). The solution was allowed to warm to room 25 temp over 4 h, then was diluted with EtOAc (200 mL). The organic layer was sequentially washed with a IM HCI solution (125 mL) then water (100 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The resulting residue was 73 purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid (0.160 g, 48%): TLC (EtOAc) R, 0.33; 'H-NMR (DMSO-d 6 ) 6 1.17 (s. 9H), 1.98 (s, 3H), 3.55 (s, 3H). 3.78 (s, 2H), 6.00 (s, IH). 7.07 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz. 2H), 8.38 (s. LH), 8.75 5 (s, 1H), 9.82 (s, 1H); FAB-MS i/z 420 ((M+H)'). D4. General Method for the Conversion of Ester-Containing Ureas into Alcohol Containing Ureas N 0 NN N N N CI HO, H H C1 10 N-(N'-(2-Hydroxyethyl)-3-tert-bu tyl-5-pyrazolyl)-N '-(2,3-dich lorophenyl)u rea: A solution of N-(N'-( 2
-(
2 ,3-dichlorophenylamino)carbonyloxyethyl)-3-tert-butyl-5 pyrazolyl)-N'-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH ( 0.8 mL, 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 15 mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (3 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgSO.
1 ) and concentrated under reduced pressure. The residue was crystallized (EtO) to afford the desired product as a white solid (0.17 g, 64 %): TLC (60% EtOAc/40% hexane) R,0.16; 'H-NMR (DMSO-d 6 ) 6 1.23 (s, 9H), 3.70 (t, J=5.7 20 Hz, 2H), 4.10 (t, J=5.7 Hz, 2H), 6.23 (s, IH), 7.29-7.32 (m, 2H), 8.06-8.09 (m, IH), 9.00 (br s, IH), 9.70 (brs, 1H); FAB-MS ni/z (rel abundance) 371 ((M+H)~, 100%). D5a. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas N/ 0 NN N N CI HO j H H CI 25 0 74 Step 1. ( xymethyl)-3-tert-butyl-5-pyrazolyI)-N'-(2.3 dichlorophenyl)urea: A solution of N-(N'-(ethoxycarbonylmethyl)-3-rier,-butvl-5 pyrazolyl)-N'-(2,3-dichlorophenyl)urea (prepared as described in Method A3. 0.46 1.1! mmoles) and NaOH (1.2 mL, 5N in water, 6.0 mmoles) in EtOH (7 mL) was 5 stirred at room temp. for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (4 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was crystallized (EtO/hexane) to afford the desired product as a white solid 10 (0.38 g, 89%): TLC (10% MeOH/90% CH2Cl 2 ) Rr0.04; 'H-NMR (DMSO-d,) 8 1.21 (s, 9H), 4.81 (s. 2H), 6.19 (s, IH), 7.28-7.35 (m, 2H), 8.09-8.12 (m, I H ), 8.76 (br s, IH). 9.52 (br s. I H); FAB-MS i/z (rel abundance) 385 ((M+H)-, 100%). / 0 N N N CI MeHN H H CI 0 Step 2. N-(N'-((Methylcarbamoy)methyI)-3-tert-butyl-5- pyrazoly)-N'-(2,3 15 dichlorophenyl)urea: A solution of N-(N'-(carboxvmethyl)-3-tert-butyl-5 pyrazolyl)-N'-(2,3-dichlorophenyl)urea (100 mo, 0.26 mmole) and
NN'
carbonyldiimidazole (45 mg, 0.28 mmole) in CHCl: (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CHC,) R,0.81). Dry methylamine hydrochloride (28 mg. 20 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 CHCl,, washed with water (30 mL), a saturated NaCI solution (30 mL), dried (MgSO,) and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% acetone/90% CHCl, to 40% 25 acetone/60% CHCl,) and the residue was crystallized (Et,0/hexane) to afford the desired product (47 mg, 46%): TLC (60% acetone/40% CHCl,) Rf 0.59; 'H-NMR (DMSO-d,) 8 1.20 (s, 9H), 2.63 (d, J=4.5 Hz, 3H), 4.59 (s, 2H), 6.15 (s, IH), 7.28- 75 7.34 (m. 2H), 8.02-8.12 (m. 2H), 8.79 (br s, I H), 9.20 (br s, I H): FAB-MS n!: (rel abundance) 398 ((M+H)*, 30%). D5b. General Method for the Conversion of Ester-Containing Ureas into 5 Amide-Containing Ureas 0) 0 N N N C2 H HOCO 2 H Step . N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-carboxyphenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyy)-N'-(4-(4-ethoxyoxycarbonylphenyl) oxyphenvl)urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) 10 was added a I M NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HCI solution (20 mL) to form a white precipitate. The solids were washed with water (50 mL) and hexane (50 mL) , and then dried (approximately 0.4 mmHg) to afford the desired product (0.368 g, 75 %). This material was carried to the 15 next step without further purification. 0, 0 0 N N N NHMe H H I) _ 0 Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(N-methylcar bamoyl) phenyl)oxyphenyl)urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4 carboxyphenyl)oxyphenyl)urea (0.100 g, 0.25 mmol), methylamine (2.0 M in THF; 20 0.140 mL, 0.278 mmol), l-ethyl- 3
-(
3 -dimethylaminopropyl)carbodiimide hydrochloride (76 mg, 0.39 mmol), and N-methylmorpholine (0.030 mL, 0.27 mmol) in a mixture of THF (3 mL) and DMF (3mL) was allowed to stir overnight at room temp. then was poured into a IM citric acid solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined extracts were sequentially washed with water (3 x 25 10 mL) and a saturated NaCl solution (2 x 10 mL), dried (NaSO.,), filtered, and concentrated in vacuo . The resulting crude oil was purified by flash chromatography 76 (60 % EtOAc/40% hexane) to afford the desired product as a white solid (42 mg. 40%): El-MS m/Z 409 ((M+H)~). D6. General Method for the Conversion of o-Amine-Containing Ureas into Amide Containing Ureas 0 0 N N N NH 5 H H 2 N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-aminophenyl)oxy phenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-( 4
-(
4 -tert-butoxycarbonylaminophenyl)oxy phenyl)-urea (prepared in a manner analogous to Methods B6 then C2b; 0.050 g, 0.11 mmol) in anh 1,4-dioxane (3 mL) was added a conc HCI solution (1 mL) in one 10 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 1 M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO), and concentrated in vacuo to 15 afford the desired product as a white solid (26 mg, 66%). EI-MS m/z 367 ((M+ H)-). D7. General Method for the Oxidation of Pyridine-Containing Ureas N N N N H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(N-oxo-4-pyridiny)methylphenyl)urea: To a 20 solution of N-(5-terr-butyl-3-isoxazolyl)-N'-( 4
-(
4 -pyridinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHC 3 (10 mL) was added n-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 KCO, solution (10 mL). After 5 min, the solution was diluted with CHC1 3 (50 mL). The organic layer was washed successively 25 with a saturated aqueous NaHSO, solution (25 mL), a saturated NaHCO 3 solution (25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 ), and concentrated in 77 vacuo. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the N-oxide (0.082 g, 79%). D8. General Method for the Acylation of a Hydroxy-Containing Urea -.- 0 -~0 N N NO 5 H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetoxyphenvioxy)phenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-( 4
-(
4 -hydroxyphenyloxy)phenyl )urea (0.100 g, 0.272 mmol), N,N-dimethylaminopyridine (0.003 g, 0.027 mmol) and Et 3 N (0.075 rnL, 0.544 mmol) in anh THF (5 mL) was added acetic anhydnde (0.028 mL, 10 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 NaHCO 3 solution (10 mL) and a saturated NaCI solution (10 mL), dried (Na 1 SO4), and concentrated under reduced pressure to 15 give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mm.Hg): TLC (40% EtOAc/60% hexane) Rf 0.55: FAB-MS n/z 410 ((M+H)-). D9. Synthesis of o-Alkoxypyridines 01- 0 N N N N O 20 H H H Step 1. N-(5-tert-Bu tyl-3-isoxazolyl)-N'-(4-(2(1H)-pyridinon-5-yI)oxyphenyl) urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(5-(2-methoxy)pyridyl) oxyaniline (prepared in a manner analogous to that described in Methods B3k and C3b; 1.2 g, 3.14 mmol) and trimethylsilyl iodide (0.89 mL, 6.28 mmol) in CHCl, 25 (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% 78 MeOH/85% EtOAc) to give the desired product (0.87 g. 75%): mp 175-180 OC; TLC (80% EtOAc/20% hexane) R,0.05; FAB-MS ml: 369 ((M-H)~, 100%). N N N N OEt H H Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(5-(2-Ethoxy)pyridyl)oxyphenyl)urea: 5 A slurry of N-(5-teri-butvl-3-isoxazolyl)-N'-(4-(2(l H)-pyridinon-5-yl)oxyphenyl)urea (0.1 g, 0.27 mmol) and Ag,C0 3 (0.05 g, 0.18 mmol) in benzene (3 mL) was stirred at room temp. for 10 min. lodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite' 10 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) Rf0.49; FAB-MS m: 397 ((M+H)~, 100%). 15 D1O. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide Containing Urea 0 0 N N N H H OH N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(1-hydroxyethyl)phenyl)oxyphenyl)urea: To a solution of N-(5-er-butyl-3-isoxazolyl)-N-(4-(4-(I 20 acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods BI and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH, (0.008 g, 0.21 mmol) in one portion. The mixture was allowed to stir for 2 h at room temp., then was concentrated in vacuo. Water (20 mL) and a 3M HCI solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The 25 combined organic layers were washed with water (3 x 10 mL) and a saturated NaCl solution (2 x 10 mL), dried (MgSO4), and concentrated in vacuo . The resulting white solid was purified by trituration (Et 2 0/hexane) to afford the desired product (0.021 g, 79 32 %): mp 80-85 *C, 'H NMR (DMSO-d,) 6 1.26 (s. 9H), 2.50 (s, 3H). 4.67 (m. I H), 5.10 (br s. I H), 6.45 (s, I H), 6.90 (m, 4H). 7.29 (d, J=9.0 Hz. 2H), 7.42 (d, J=9.0 Hz. 2H), 8.76 (s, IH), 9.44 (s, IH); HPLC ES-MS i/: 396 ((M+H)~). D1I. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy Substituted Ureas H 0 0 1 0 N 0 N OI'Ph N N N O H H N-(5-:ert-Bu tyl-3-isoxazolyl)-N'-(4-(3-(benzyloxycarbonylamino)phenyl) oxyphenyl)urea: To a solution of the N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(3 10 carboxyphenvl)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 Et 3 N (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 15 stirring for 3 h then allowed to cool to room temp. The resulting mixture was poured into a 10% HCI solution (50 mL) and teh resulting solution extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCl (2 x 50 mL), dried (Na2SO4), and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the 20 desired product as a white solid (0.7 g, 60 %): mp 73-75 *C; 'H NMR (DMSO-de) 6 1.26 (s, 9H), 5.10 (s, 2H), 6.46 (s, 1H), 6.55 (d, J=7.0 Hz, 1H), 6.94 (d, J=7.0 Hz, 2H), 7.70 (m, 7H), 8.78 (s, IH), 9.46 (s, 1H), 9.81 (s, lH); HPLC ES-MS n/z 501 ((M+H)~). 25 80 The following compounds have been synthesized according to the General Methods listed above: Table 1. 5-Substituted-3-isoxazolvl Ureas Ri - 0 O
R
2 N N N 5 H H Mass mp TLC Solvent Spec. Synth. Entrv R' R- (*C) R, System Sourcel Method I I-Bu O 148- 352+) CIc 149 (M+H)4 [FAB] 2 t-Bu \ C1 176- 0.16 5% 386 C2b 177 MeOH/ (M+H)+ 95% [FAB) CH2Cl2 3 t-Bu Cl 0.50 30% 400 C2b EtOAc/ (M+H)+ _ & & Me70% [HPLC hexane ES-MS] 4 t-Bu O Me 156- 0.50 30% 366 C2b 157 EtOAc/ (M+H)+ 70% [HPLC hexane ES-MSl 5 t-Bu Me 0.80 40% 492 C2b / Me EtOAc/ (M+H)+ Me Et 60% (HPLC Me Et hexane ES-MS] 6 t-Bu Ho 190- 0.15 30% 350 (M+) C2b C C N, 191 EtOAc! [Eli 70% hexane 7 t-Bu 0.55 20% 352 C2b EtOAci (M+H)+ 80% [FAB] hexane 8 i-Bu 0.25 20% 367 (M+) C2b EtOAc! [Ell 80% hexane 9 I-Bu O 0.15 20% 363 (M+) C2b - Ph EtOAc/ [EI] 80% hexane 10 t-Bu Me 0.30 20% 381 (M+) C2b S EtOAc/ [El] 80% 81 1 i-Bu - N 0.25 30% 425 B3b. C2b S EtOAc/ (M-H) 70% [HPLC hexane ES-MS1 12 i-Bu 175- 0.25 30% 409 B3a. Step 177 EtOAcI (M+H)- L. B3b o-'< 70% [HPLC Step 2. S hexane ES-MS1 C2b 13 t-Bu 0.35 30% 402 B3b, C2b - EtOAc! (M+H)+ 70% [HPLC hexane ES-MS1 14 i-Bu 0.20 30% 403 B3b, C2b N O .EtOAc/ (M+H)+ 70% [HPLC hexane ES-MS1 15 I-Bu 0.25 30% 419 B3b, C2b EtOAc/ (M+H)+ 70% [HPLC hexane ES-MS1 16 t-Bu 0.20 30% 419 B3b, C2b /N EtOAc/ (M+H)+ 70% [HPLC hexane ES-MS1 17 t-Bu 0.40 30% 352 C2b EtOAc/ (M+H)+ 0 70% [HPLC hexane ES-MS1 18 r-Bu 0.40 30% 365 (M+) C2b EtOAc/ [El] O 70% hexane 19 i-Bu 0.15 30% 367 (M+) E3a. C2b. O EtOAc/ [El) D2 Step 1 70% hexane 20 1-Bu S Me 200- 0.20 20% 280 C6 201 EtOAc/ (M+H)+ 80% [FAB] hexane 21 t-Bu 178- 368 (M+) B4a, C2b S N 179 [El} 22 :-Bu i H 2 N 164- 0.25 30% 351 B1. C2b 165 EtOAc/ (M+H)+ 70% [FAB] hexane II 23 r-Bu H2 N 170- 0.15 30% 351 B7, B1, C 172 EtOAc/ (M+H)+ C2b 70% [FAB} hexane 24 i-Bu \ - 179- 0.20 30% 387 C2b 182 EtOAc/ (M+H)+ 70% [FAB] hexane 82 2e - 0.55 40% 410 B3b, C2b, )"O EtOAci (M+H)- D2 Step 1, Me 60% [FAB] D8 hexane 26 r-Bu Me 176- 0.55 25% 366 B3a, C2b 0 182 EtOAc; (M+H) 75% [FAB) hexane 27 i-Bu Me 0.40 25% 366 B3a. C2b EtOAc/ (M+H)+ 75% [FAB] hexane 28 M Me 750- 0.45 25% 380 B3a. C2b Me 158 EtOAc/ (M+H)+ 75% [FAB] hexane 29 i-Bu HO 0.30 25% 368 C2b 0 EtOAc/ (M+H)+ 75% [FAB] hexane 30 -Bu C I 18- 0.50 25% 420 B3a Step O Cl 122 EtOAc/ (M+H)+ I, B3b 75% [FAB] Step 2, hexane C2b 31 T-Bu NO, 195- 0.30 25% 397 (M-) C2b - 197 EtOAc/ [FAB] 75% hexane 32 t-Bu Me 0.80 25% 366 B3a. C2b / EtOAc/ (M+H)+ 75% [FAB] hexane 33 i-Bu O a Me 155- 0.55 30% 382 B3a, C2b 156 EtOAc/ (M+H)+ 70% [FAB) hexane 34 -uOP- 137- 0.62 25% 410 B3a, C2b, 141 EtOAc/ (M+H)+ D2 75% [FAB] hexane 35 i-Bu 0 OPr-i 164- 0.60 25% 410 B3a, C2b, 166 EtOAc/ (M+H)+ D2 75% [FAB] hexane 36 i-Bu OH 78-80 0.15 25% 368 C2b SOEtOAc/ (M+H)+ 75% [FAB) 37 i-Bu -- & SC 167. hexane 3 7 i- u 6 7 3 7 4 B 3 i, B 1, 169 (M+H)- C2b [FAB] 38 i-fu O 200 0.30 5% 396 B3a Step dec MeOH/ (M+H)+ 2, C2b 0.5% [FAB] AcOH/ 94.5% CH2CI2__
__
83 39 t-Bu
CO
2 H 234 0.30 5% 396 B3a Step dec MeOH (M+H)- 2. C2b \-. 0.5% [FAB] AcOH 94.5%/ CH2Cl2 40 t-Bu H, 203- 0.35 10% 340 BS. B2b. C 206 MeOH (M+H)+ C2b 0.5% [FAB] AcOH/ 89.5% _____ ______ ~EtOAc ________ 41 i-Bu 0 177- 419 B8. B2b. SH, 180 (M+H)+ C2b - C-~j~j[FAB) 42 j-Bu 158- 0.25 30% 369 B4a. C2b 159 EtOAc/ (M+H)+ N 70% [FAB] hexane 43 i-Bu CF 3 180- 0.15 30% 437 B4a. C2b / 1-- \181 EtOAc. (M+H)+ S- N 70% [FAB] hexane 44 :-Bu / OEt 140- 0.25 20% 396 B3a, C2b, - 142 EtOAc/ (M+H)+ D2 80% [FAB) hexane 45 i-Bu N- 68-71 0.30 50% 370 B4a. C2b s EtOAc/ (M+H)+ N 50% [FAB) hexane 46 i-Bu N 183- 0.30 30% 403 C2b S Cl 186 EtOAc/ (M+H)+ 70% [CI] hexane 47 t-Bu / \ - 98- 0.25 10% 454 C2b _ O-x / Cl 101 EtOAc: (M+H)+
F
3 C 90% [FAB] I _hexane 48 t-Bu - O 163- 0.25 20% 394 B1, C2b _ 166 EtOAc/ (M+H)+ Me 80% [FAB] hexane 49 f-Bu / \ - C 144- 0.25 20% 399 C2b -N O - / SMe 147 EtOAc/ (M+H)+ 80% [FAB] I_ hexane 50 r-Bu . / \ -7155- 0.25 40% 383 C2b 157 EtOAc (M+H)+ - 60% [FAB] hexane ... 51 t-Bu \ --- 162- 0.35 25% 386 C2b 164 EtOAc/ (M+H)+ 75% [FAB] hexane I 84 52 i-Bu - 149- 0.15 15% 382 C2b 150 EtOAc! (M-H) 85% [FAB) hexane 53 I-Bu N < 77-80 0.30 30% 40S M-) B3e. C2b O EtOAc! [EI) 70% hexane 54 t-Bu --- N 162- 0.17 40% 354 B3j, C2b O 164 EtOAc/
(M-H)
N 60% [FAB] hexane 55 i-Bu N- 73-76 0.20 30% 368 (M+) B2. C2b \ / EtOAc/ [EI] 70% hexane 56 i-Bu MeO 73-75 0.15 25% 428 B2, C2b EtOAc/ (M+H)+ 75% [FAB] OMe hexane 57 i-Bu S OMe 143- 0.25 30% 398 B3e. C2b 145 EtOAc/ (M-H)+ 70% [FAB) hexane 58 i-Bu S OMe 148- 0.25 30% 428 B3e. C2b - 151 EtOAc/ (M+H)+ OMe 70% [FAB] hexane 59 t-Bu O N 0.30 100% 353 B4b, C3b -N EtOAc (M+H)+ I fFAB) 60 i-Bu O OMe 126- 0.25 30% 412 B3e. C2b x -~ ~e 129 EtOAc/ (M+H)+ OMe 70% [FAB] hexane 61 r-Bu O0 - 201- 0.25 10% 396 B3a. C2b, 204 EtOAc/ (M-H)+ D2 OEt 90% [FAB) I_ hexane 62 z-Bu N 163- 0.30 40% 369 B4a. C2b S 164 EtOAc/ (M+H)+ 60% [FAB] hexane 63 t-Bu 162- 0.20 25% 363 (M+) C2b 163 EtOAc/ [El] 75% O hexane 64 i-Bu N 127- 0.22 40% 353 B3e Step 129 EtOAc/ (M+H)+ 1, B2, 60% [FAB] C2b hexane 65 t-Bu / 85-87 0.20 50% 402 (M+) B3e Step -- NEtOAc/ [EI] 1, B2, 50% C2b hexane 85 66 -Bu NeO 108- 0.25 10% 381 04-) B3e. C2b 110 EtOAc [EI - D 90% hexane 67 :-Bu O NH 186- 0.25 30% 367 B6, C2b, 189 EtOAc. (M+H)-- D6 70% [FAB] hexane 68 t-Bu o0 221- .25 60% 409 B3e, C2b. NHMe 224 EtOAc' (M+H) D5b 40% [FAB) hexane 69 I-Bu O 114- 0.25 60% 409 B3e. C2b, -NHMe 117 EtOAc/ (M+H)+ D5b 0 40% [FAB] -hexane 70 I-Bu 0 201- 0.25 60% 423 B3e, C2b, 2 203 EtOAc/ (M+H)+ D5b / 40% [FAB] hexane 71 t-Bu 148- 0.25 20% 370 B3c. C2b 151 EtOAc (M+H)+ 80% [FAB] ,- -- -- hexane 72 i-Bu OMe 188- 0.25 20% 382 B3e, C2b / 201 EtOAc/ (M+H)+ 80% [FAB] hexane 73 t-Bu O N134- 0.25 20% 367 B3e. C2b a\ e 136 EtOAc! (M+H). 80% [FAB] - hexane 74 t-Bu 0 176- 0.25 50% 403 B3e, C2b \ 178 EtOAc/ (M+H)+ N 50% [FAB] hexane 75 t-Bu -N 132- 0.52 40% 383 B3k. C3b S/OMe 134 EtOAc.' (M+H)' 60% [FAB) hexane 76 t-Bu OHe 160- 0.79 75% 381 C3a N\-0 -Me 162 EtOAc/ (M+H)+ 25% [FAB] hexane 77 t-Bu 140- 0.25 50% 352 (M+) B4b, C3b 143 EtOAc/ [El] 50% CH2CI2 78 I-Bu 147- 0.25 50% 352 (M+) B3f, C3b 150 EtOAc- [El] O- 50% N CH2Cl2 79 i-Bu 166- 0.44 50% 396 C3b - 170 EtOAc! (M+H)+ 0 50% [FAB] hexane 86 80 t-Bu ' 190- 0.25 50% 367 B38. C3b 193 EtOAci (M+H) O Me 50% [FAB) CH2CI2 81 i-Bu Me 136- 0.25 50% 367 B4b. C3b 140 EtOAc/ (M+H)+ O- N 50% [FAB] CH2CI2 82 r-Bu Me 65-67 0.25 50% 367 B4b. C3b \O N EtOAc/ (M+H)+ 50% [FAB] CH2C2 83 t-Bu Me 68-72 0.25 50% 383 B4a, C3b EtOAc/ (M+H)+ 50% [FAB] CH2Cl2 84 t-Bu -N 146 0.49 40% 397 B3k C3b, - &O\ OEt EtOAc/ (M+H)+ D9 60% [FAB] hexane 85 r-Bu Me 164- 0.25 50% 382 (M+) B4a. C3b S N 165 EtOAc/ [El]
-
50% CH2Cl2 86 I-Bu P-NH 175- 0.25 20% 485 B3e. C3b. Ph 0 177 EtOAc/ (M+H)+ D5b \\-O: 80% [FAB] hexane 87 r-Bu H 137- 0.30 50% 366 (M+) C3a. D2 -N& H 141 EtOAc! [El] step I 50% hexane 88 r-Bu Ph-NH 120- 0.25 20% 471 B3e. C3b. 0 122 EtOAc/ (M+H)+ D5b 0 80% [HPLC _\--/ - /hexane ES-MS1 89 t-Bu Et-NH 168- 0.25 50% 423 B3e. C3b. O 170 EtOAc/ (M+H)- D5b O 50% [HPLC hexane ES-MS] 90 t-Bu H - OH 80-85 0.25 50% 396 B1, C2b, / Me EtOAc/ (M+H)- DIO 50% [HPLC hexane ES-MS1 91 t-Bu 0 73-75 0.25 30% 501 B3e. C3b. P - EtOAc/ (M+H)+ DII 70% [HPLC O hexane ES-MS] 92 i-Bu Me 0.50 5% 366 Bla acetone/ (M+H)+ 95% [FAB] CH2CI2 93 t-Bu
CF
3 199- 0.59 5% 419 (M+) Bla 200 acetone/ [FAB] 95% ________________CH2CI2
__
87 94 f-Bu CF., 0.59 5% 419 (M'-) Bla O acetone [FAB] CH2CI2 _ 95 i-Bu Me 78-82 0.25 10% 379 (M-) B3e. C3b EtOAc [El] Me CH2C12 96 i-Bu O NH 214- 0.75 60% 463 C2b. D3 0 217 EtOAci (M+H)+ FIC 40% [FAB] hexane 97 t-Bu O 235 0.35 25% 402 B3b, C2b -0 EtOAc; (M-H)-ev 75% hexane 98 t-Bu 0 153- 0.25 30% 424 B3e, C2b ' OEt 155 EtOAc/ (M+H)+ 0 70% [FAB) N____ -d hexane 99 I-Bu N 100 0.62 40% 411 B3a, BL O OPr-i EtOAc (M+H)- C3b 60% [FAB] I hexane 100 i-Bu OH 110- 0.15 100% 367 115 EtOAc (M+H)+ [FAB1 Table 1. 5-Substituted-3-isoxazolyl Ureas - continued R1 - 0 O ,R2 N N N H H Mass mp TLC Solvent Spec. Synth. Entry R' R2 (*C) R, System [Sourcel Method 101 t-Bu 0 0.50 100% 410 BIO, B4b, EtOAc (M+H)+ C2b O N [FAB] 102 i-Bu O 153- 395 C3b 0_ 155 (+) Me- [FAB] 103 t-Bu 0 0.52 100% 396 BIO, B4b,
NH
2 EtOAc (M+H)+ C2b N [HPLC I _ES-MS] 104 t-Bu 0 0.75 100% 396 BIO, B4b, NH, EtOAc (M+H)+ C2b O\N [HPLC ES-MS1 105 t-Bu O 107- 0.85 100% 410 BIO. B4b. 105 UNHMe 110 EtOAc (M+H)- C2b 0 \*N [FAB] 106 t-Bu 0 132- B3d step NH, 135 2, C3a 107 i-Bu 0 0.58 100% C3a. D5b o NHPr-n EtOAc 108 t-Bu 0 0.58 100% C3a. D5b NHPr-' EtOAc 109 t-Bu 0 137- 0.62 100% 439 B3a step \NHMe 140 EtOAc (M+H)+ 1, B12. O OMe [HPLC D5b step ES-MS1 2. C3a 110 t-Bu 0 163- 0.73 100% 425 B3a step NHMc 166 EtOAc (M+H)+ 1, B12, O OH [HPLC D5b step ES-MS] 2. C3a III t-Bu 1OSOMe 1- B3b step 181 1, BI . B3d step 2. C2a 112 t-Bu 0 135- B3b, C2a Me 139 113 t-Bu Oe 212- B3d step NHe215 2a. C2a 114 -Bu MeHN..O 98- B3d step S.: 100 2, C2a -a~-o-Ki 0 0 115 t-Bu 0 N 135- BIO. B4b, \---' HMe 138 C2a 116 i-Bu 0 219- 0.78 80% 437 C3a, D5b HO O 221 EtOAc/ (M+H)+ step 2 hexane [HPLC - -ES-MS1 117 t-Bu 160- B3a step NNH step 2. C3a 118 i-Bu 0 124 0.39 5% CIc, D5b NHMe MeOH/ 0 N 45% EtOAc/ Cl 50% hexane i 89 119 i-Bu 73-75 0.41 100% 479 B3a. C4a. EtOAc (M+H)- D5b NH [HPLC o ES-MS] 0 120 i-Bu 0 0.32 100% 436 Clb. D5b NHMc EtOAc (M+H)- step I, N /[HPLC step 2 ES-MS] 121 t-Bu 0.23 10% 506 B3a. C4a. N NH MeOH/ (M+H)- D5b o 90% [HPLC O CH2C12 ES-MS] 122 t-Bu 0.18 10% 506 B3a. C4a, N MeOH/ (M+H)+ D5b Et NH 90% [HPLC o CH2C2 ES-MS] 123 i-Bu O O 229- 0.37 40% 435 D5b step 231 EtOAc/ (M+H)- 1, B3d N.Me 60% [HPLC step 2, o hexane ES-MS1 C3a 124 i-Bu /--\ 0.21 5% 508 B3a, C4a, O N NH MeOH/ (M+H)- D5b o 95% [HPLC CH2Cl2 ES-MS) 125 t-Bu 0 167- 0.34 5% 424 C3b, D5b NHEt 170 MeOH/ (M+H)+ N 45% [HPLC EtOAc/ ES-MS) 50% hexane 1 126 I-Bu 0 124 0.26 5% C3b, D5b Ci NHMe MeOH/ N 45% EtOAc/ 50% hexane _ 127 t-Bu 0 125- 0.28 5% C3b. D5b Me NHMe 128 MeOH/ N 45% EtOAc/ 50% hexane 128 t-Bu 0 0.37 50% 426 C3b NHMe EtOAc/ (M+H)+ Me S 50% pet [HPLC ether ES-MS1 129 I-Bu 0 0.10 50% 424 C3b NMe 2 EtOAc/ (M+H)+ O N 50% pet [HPLC ___F _ I1 ether ES-MS1 90 130 t-Bu N NH 0.18 70% 472 D5b step2 - EtOAc (M+H) 30% [HPLC \ hexane ES-MS] 131 r-Bu 0 0.32 582 C3b Me (M+H)+ [HPLC ES-MS) 0 O / 132 t-Bu F 0.57 558 C3b (M+H)+ [HPLC N ES-MS] N 0 O / 133 t-Bu O 0.21 598 C3b 0 /\ (M+H)+ (HPLC N ES-MS] 0 134 r-Bu F NH 0.86 489 C3b O (M+H)+ [HPLC ES-MS) 135 I-Bu 0.64 514 C3b Q (M+H)+ HN-, [HPLC NH ES-MS] 136 t-Bu MeO -\NH 0.29 453 C3b 0 (M+H)+ [HPLC O / ES-MS] 137 I-Bu N 0.70 502 C3b MeO -/' NH (M+H)+ [HPLC \ / ES-MS] 138 -Bu 0 N-F\\ - 05056 0 (M+H)+ [HPLC ____ (.J 0
\/ES-MS]
91 139 0-Bu 0.27 541 C3b C\ N (M+H)+ N [HPLC QN ES-MS) 0 60 140 _-Bu O 211- 0.27 50% 426 C3b NHMe 212 EtOAc/ (M+H)+ S N 50% pet [HPLC ether ES-MS) 141 i-Bu H2 r-\ 195- B8, C2a C-N O 198 142 t-Bu CF 3 170- C3a 0 171 143 t-Bu Me 141- 0.63 5% 382 B3b step / \ /\- 144 acetone/ (M+H)+ 1.2. Cld - 95% [FAB] CH2Cl2 144 i-Bu F 0.57 5% 386 B3b step / \ /\ acetone! (M+H)- 1.2. Cid 95% [FAB] CH2C12 145 t-Bu F 145- 0.44 5% 370 B3b step / \ O \ 148 acetone/ (M+H)+ 1.2. Cld 95% [FAB] CH2C12 146 i-Bu F 197- 0.50 5% 404 B3b step / \ O J 202 acetone/ (M+H)+ 1,2, Cld - 95% [FAB] 7CI CH2C12 147 t-Bu F 0.60 5% 404 B3b step / \ /- acetone/ (M+H)+ 1.2. Cld - 95% [FAB] F CH2Cl2 148 r-Bu Me 126- 0.17 30% 366 B4c. C4a N N 129 MeOH/ (M+H)+ 70% [FAB] EtOAc 149 I-Bu H2 383 C3b C-S (M+H)+ [HPLC ES-MS1 150 i-Bu H - 156- 0.48 40% 395 C3a. D2 N\ Ot 159 EtOAc/ (M+H)+ step 1. step hexane [HPLC 2 -1 ES-MS1 151 _-Bu 157- 0.51 409 C3a. D9 ~N P-n 159 (M+H)+ step 1, (HPLC step2 ES-MS _ 152 :-Bu 130- 0.60 437 C3a, D9 132 (M+H)+ step 1, [HPLC step2 -ES-MS) I 153 _____ 92 153 t-Bu - i 146- 0.54 40% 09 C3a. D2 150 EtOAc (M-H ) step. step hexane [HPLC 2 ES-MS] 154 t-Bu N 145- 0.57 40% 423 C3a, D2 148 EtOAc. (M-H))- step. step hexane (HPLC 2 __ES-MS 1 155 i-Bu H 175- 0.51 40% 457 C3a. D2 \ 178 EtOAc; (M-H)- stepl. step hexane [HPLC 2 6 ES-MS) 156 t-Bu H O 149- 0.48 40% 407 C3a. DI
-
0 152 EtOAc/ (M+H)- step 1, hexane [HPLC step 2 ES-MS _ 157 -Bu Et Oe 146- 0.36 40% 409 C3a
-
147 EtOAc/ (M+H)+ hexane [HPLC ES-MS1 158 I-Bu /- Me O~e 156- 0.43 40% 395 C3a - - & uMe 158 EtOAct (M+H)+ hexane [FAB] 159 t-Bu / 164- 0.52 5% 396 B3b step 168 acetone/ (M+H)+ 1,2, Cld Me Me 95% [HPLC CH2CI2 ES-MS) 160 t-Bu / - 0.36 5% 380 B3b step
-
acetone/ (M+H)+ 1,2. CId Me Me 95% [FAB] CH2Cl2 161 I-Bu / O M 169- 368 C3b Me 171 (M+H)+ [FAB _ 162 I-Bu O 168 0.11 50% C3b EtOAc/ 50% pet ether 163 I-Bu S SM 146 C3b 164 i-Bu 0.45 100% 369 C2b EtOAc (M+H)+ IN [FAB] 165 t-Bu 0.20 100% 367 B9, C2b EtOAc (M+H)+ C N [FAB] HO N 166 I-Bu O Cl 187- 0.46 30% 421 C3b N 188 EtOAc/ (M+H)+ N Q Cl hexane [FAB] 167 i-Bu 1 0 133 0.36 409 C3a, D9 (M+H)+ step 1 O N [FAB] step2 93 168 i-Bu OPr-i 0.39 40% 41 1 C3a. D9 ONEtOAct (M+H)- step , 60% [FAB] step2 hexane 169 t-Bu OEt 0.32 5% 397 B3k. C8 acetone! (M+H)+ 95% [HPLC CH2CI2 ES-MS] 170 f-Bu OMe 0.21 5% 383 B3k, C8 O acetone/
(M+H)
95% [HPLC CH2C2 ES-MS] 171 t-Bu 0.60 100% 365 C2b EtOAc (M+H)+ N [FAB] __ ___0 X__ 172 t-Bu ~ - 0.16 30% 369 C8 N EtOAc/ (M+H)+ 70% (HPLC hexane ES-MS I 173 t-Bu 125- 0.09 5% C3b N 129 MeOH/ 45% EtOAc/ 50% ____hexane 174 i-Bu Oex S 147- B3b, C2a _____ ____ __ -149 175 I-Bu H O 0.30 100% 380 C3a, D5b -- N- \N EtOAc (M+H)+ step2 (HPLC ES-MS] 176 t-Bu / 0-- 0.50 25% 353 MS -N EtOAc/ (M+H)+ B
F
3 C 75% [CI] 4b, C8 hexane Table 2.3-Substituted-5-isoxazolvi Ureas R1 O N N H H Mass Spec. mp TLC Solvent (Source] Synth. Entry R' R2 (*C) R, System Method 177 Me / \ a - 169- 0.25 5% 324 Cib 170 acetone/ (M+H)+ 95% [FAB] CH2Cl2 178 i-Pr \O 153- 0.54 50% 338 Clb 156 EtOAc/ (M+H)+ 50% pet [FAB] ether 94 179 i-Pr O e 166- 0.54 0 352 - C3b 170 EtOAc'
(.M+--I
50% pet [FAB) ether 180 i-Pr N 112- 0.29 5% 355 +2H. 117 MeOH/ (M+4H)- B4a, 95% [FAB] C3a 181 i-Pr CH2C2 FNHMc 0.08 50% 395 C8 EtOAc/
(M+H)
O50% [HPLC hexane ES-MS 182 i-Pr 0 169- 0.20 50% 396 C3b -NHMe 170 EiOAc/ (M+H)+ 0 N 50% pet [HPLC 183 i-Pr ether ES-MS) O N 0.10 50 % 353 C8 0 / me EtOAc/ (M+H)+ 50% [HPLC hexane ES-MS) 0.09 50 % 389 C8 D N H e 195E tO A c/ (M + H )8 N- 50% [HPLC 185 i-Pr hexane ES-MS 187 -K> Me 0.03 50% 401 CS O EtOAc/ (M+H)+ 70% [HPLC 186 iPr hexane i-K> /89 4O NHMe 194- 0.29 50% 396 Cb Me -- 17 EtOAc/ (M+H)+ 50% pet (HPLC ether 190 BN0.2 5% 369 C8 EtOAc/ (M+H)+ 50% [FAB hexane 188 O1N 352 C8 184 (M+H)+ [HPLC 89 O M 17-5 - ' O.4 3 50% 36S4 Cl me 178 EtOAc/ (M+H)+ 50% pet [FAB) ether 19 tBuS-<\ N 0.21 5% 69 B a MeOH/ (M+H)+ C2a 95% [FAB] 191 tBu - CH2Cl2 19 tBuS OPr-n 0.52 50% 426 B5. C4a EtOAc/ (M+H)+ 50% [FAB] 192 -Bu-hexane -92 1-uO82- 352 Clb 184
(M+H)+
95 193 t-Bu Me 165 0.34 60% 366 Clb dec EtOAc (M+H)+ 40% pet (FAB] ether 194 i-Bu 210 0.05 5% 353 C3a dec acetone/ (M+H)+ 95% [FAB] CH2CI2 195 t-Bu - 174- 0.25 5% 382 C3a 175 acetone (M+H)+ 95% [FAB) CH2CI2 196 t-Bu 90-92 0.16 5% 409 C2a N acetone/ (M+H)+ O-T 95% [FAB] s CH2Cl2 197 t-Bu N 0 221 0.14 5% 409 C2a - - dec acetone/ (M+H)+ 95% [FAB] CH2C2 198 t-Bu -N 196- 0.17 5% 368 A2. O/ Me 198 MeOH/' (M+H)- B3h. N 95% [FAB] C3a CH2Cl2 199 t-Bu / \ -204- 0.27 50% 383 A2, 206 EtOAc/ (M+H)+ B3a, 50% pet [FAB] C3a ether 200 t-Bu H2 179- 351 A2, C3a C N 180 (M+H)+ {FAB1 201 r-Bu SMe 0.33 50% 414 (M+) A2. N SeEtOAc: [El) B4a. 50% pet C3a ether 202 t-Bu O SMe 188- 0.49 50% 399 A2, N 189 EtOAc. (M+H)+ B4a, 50% pet [HPLC C3a ether ES-MS) 203 t-Bu - 179- 0.14 5% 395 A2, O \ 180 MeOH/ (M+H)+ B4a, N e 95% [FAB] C3a CH2CI2 204 t-Bu N 197- 0.08 10% 353 A2, O \/ 199 acetone. (M+H)+ B3h, 90% [FAB] C3a CH2Cl2 205 :-Bu Cl 136- 0.33 50% 421 A2, / \1 o--C, 139 EtOAc: (M+H)+ B3h, OCDC- 50% pet [FAB] C3a N_ ether 206 t-Bu 213 0.05 5% 369 C3a dec acetone/ (M+H)+ S N 95% [FAB) I -_ _ I_ _CH2C2 I I 96 207 i-Bu Me 0.60 5% 274 C2a MeOH/ (M+H)+ 95% (FAB) CH2CI2 208 i-Bu - F 118- 0.19 5% 387 A2. \=N 121 MeOH/ (M+H)- B4a. 95% [FAB] C3a CH2CI2 209 I-Bu 0 217- 0.18 5% A2. C3b NHMe 219 MeOH/ O /95% CHCl3 210 i-Bu - 0 0.48 50% 394 C8 0 \ / EtOAc/ (M+H)+ 50% [HPLC hexane ES-MS] 211 i-Bu O,- 0.17 30% 364 C8 EtOAc/ (M+H)+ 70% [HPLC hexane ES-MS _ 212 t-Bu O O 0.79 70% 421 B3a EtOAc/ (M+H)+ step . NH 30% [HPLC B3d o hexane ES-MS] step 2, C3a 213 r-Bu O 0.50 50% 407 B3a - 1 EtOAc/ (M+H)+ step , NH 50% [HPLC B3d o hexane ES-MS] step 2, C3a 214 t-Bu 0 182- 0.25 5% 424 C3b, NHEI 185 MeOH/ (M+H)+ D5b O N 45% [HPLC EtOAc/ ES-MS] 50% hexane 215 i-Bu 0 198- 0.20 5% 444 C3b, NHMe 200 MeOH/ (M+H)+ D5b O N 45% [HPLC EtOAc/ ES-MS] 50% hexane 216 t-Bu 0 0.24 50% 426 C3b NHMe EtOAc/ (M+H)+ S N 50% pet [HPLC _______ether ES-MSI 217 i-Bu 0 215- 426 C3b NHMe 217 (M+H)+ N [HPLC ES-MS1 218 i-Bu O 188- 0.22 50% 410 C3b -NHMe 200 EtOAc/ (M+H)+ O- \N 50% pet [HPLC ether ES-MS1 97 219 i-Bu / 214- 0.35 5% A?. C2b Cl 215 acetone/ 95% CH2C2 220 t-Bu O Me 180 Cb 221 i-Bu - 160- 0.58 50% 336 (M-) C3b 162 EtOAct [CI) 50% pet ether 222 t-Bu 0.18 50% Cb 'N SEtOAc/ 50% pet ether 223 t-Bu O 3 SCF 163- 0.21 5% 453 C3b - 3 165 MeOH/ (M+H)+ 95% [HPLC CH2Cl2 ES-MS] 224 i-Bu / N - 208- 0.17 5% 353 C3b N 212 MeOH/ (M+H)+ 95% [FAB) CH2Cl2 225 i-Bu 109- 0.17 5% 369 C3b 112 MeOH/ (M+H)+ 95% [FAB] CH2Cl2 226 i-Bu / 155- 0.57 10% 453 C3b -N 3 156 MeOH/ (M+H)+ I CH2Cl2 [FABI 1 227 t-Bu N-0 231- 0.54 10% 534 C3b NH 234 MeOH/ (M+H)+ O NHO CH2CI2 [FAB] 228 t-Bu / \ 179- 0.24 5% A2. C3b S N 180 MeOH/ o /Me 95% CHC13 229 t-Bu / 0.30 5% 370 A2, C3b MeOH/ (M+H)+ 95% [FAB] CHC13 230 i-Bu 178- 0.20 5% A2. C3b N180 MeOH/ 95% CHC13 231 I-Bu / 186- 0.20 5% A2. C3b 187 MeOH/ Me 95% _ _CHC13 232 t-Bu 149- 0.28 5% A2. C3b N 152 MeOH/ S 95% CHC13 233 :-Bu - 210- 0.06 10% 421 C3b N O\ CF3 213 MeOH/ (M+H)+ N I I CH2C12 [FAB1 9 8 __7 234 t-Bu OMe 132- 0.43 5%' A2. Cb --\ 133 MeOH/ 95% CHCl3 235 t-Bu \71-73 0.27 5% A2. C3b MeOH/ O- N 95% 236 ____ c I CHC13 236 t-Bu Cl 176- 0.44 10% 437 C3b / C 177 MeOH/
(M+H)-
N CH2C12 [FAB) 237 t-Bu H, 0.09 50 % 351 C8 / EtOAc/ (M+H)+ 50% [HPLC hexane ES-MS1 238 t-Bu 0.16 50% 403 C8 EtOAc/ (M+H)+ 50% [HPLC hexane ES-MS1 239 t-Bu O N 0.15 50 % 381 C8 - X.jEtOAc/ (M+H)± Me 50% [HPLC hexane ES-MS) 240 t-Bu 215- 0.19 100% 370 C3b N 216 EtOAc (M-H)+ [HPLC ES-MS) 241 i-Bu O S\ 0.42 5% N=N SMeOH/ 95% CH2CI2 242 t-Bu O 0.74 100% 366 B4b, C8 - EtOAc (M+H)+ Me [HPLC ES-MS1 243 t-Bu o 0.12 30% 421 C8 N EtOAc/ (M+H)+
F
3 C 70% [HPLC hexane ES-MS1 245 I-Bu O 0.68 100% 368 B4b, C8 EtOAc (M+H)+ HO [HPLC -ES-MS1 ___ 246 t-Bu 142- 0.13 5% A2, C3b 144 MeOH/ 45% N EtOAc/ 50% hexane 247 t-Bu 0 205- 0.31 50% 410 C3b INHMe 207 EtOAc/ (M+H)+ O N 50% pet [HPLC I__ __ __ __ether ES-MS] 248 evMe 154- 0.50 50% 365 (M+) Clb -k-e \~j~'~j 155 EtOAc! [El] Et 50% pet I ether 99 249 e O Me 160- 0.37 5% 380 CIb -I, M- 162 acetone (M+H) 95% [FAB] CH2Cl2 250 Me CI Cl 196- 0.58 5% 342 Clb -A- Me k-K199 acetone. (M+H)+ Et 95% [FAB] CH2CI2 251 Me 137- 0.25 5% 396 A2. 138 acetone/ (M+H)+ B3a. Et 95% [FAB] C3a 2 CH2M2 252 M e N 0.18 5% 364 (M+) A2. C3a Et CHC13 253 m e 215- 383 A2. FM 221 (M+H)- B4a. Edec [FAB) C3a 254 Me ~- - 187. 0.42 10% 383 A2, -.. Me S N 188 MeOH/ (M+H)+ B4a, Et CHC13 [FAB) C3a 255 M e O N 90-92 0.19 30% 366 (M+) A2. C3a Me EtOAc/ [El] Et 70% pet ether 257 Me N 199- 0.33 70% 423 A2. -- Me O-- C'\ 200 EtOAc/ (M+H)+ B3e, 30% pet [FAB) C3a ether 258 Me 0 117. 0.14 5% A2. C3b H- Me NHMe 119 MeOH/ Et
-
95% CHC13 259 Me 0 0.37 75% 409 C8 MeOEtOAc/ (M+H)+ Ft \25% [HPLC hexane ES-MS] 260 Me 0 194- 0.25 50% 424 C3b -Me NHMe 195 EtOAc/ (M+H)+ Et O N 50% pet (HPLC 0-__ _ _ ether ES-MS] 261 Me 0 216- 0.20 50% 424 C3b -. k-Me NHMe 217 EtOAc/ (M+H)+ Et O- N 50% pet [HPLC I , I ether ES-MSJ 262 Me 62-65 0.18 5% A2, Cb --- Me MeOH/ EtS 95% -\' CHCl3 263 Me /\86-89 0.16 5% - A2, COb -..4-me _ Me MeOH/ Et S C N 95% CHC13 100 264 .\ 145- 0.32 5% A2. C3b -- Me 0 146 MeOH.' Et 95% CHC13 265 Me 0 -Me 0.23 5% 381 A2. C3b E NM MeOH. (M+H) Et - N 95% [FAB] CHC13 266 Me OMe 0.20 5% 396 A2. C3b Et O acetonei (M+H) 95% (FAB) CH2CI2 267/ \ 0.38 50 % 366 C8 Et EtOAci (M+H)+ O 50% [HPLC hexane ES-MS1 268 Me 0 0.14 50 % 367 C8 Et N EtOAc' (M+H) 50% [HPLC hexane ES-MS1 269 Me S ) 0.21 50 % 383 C8 Et N EtOAc/ (M+H)+ Et N50% [HPLC hexane ES-MS] 270 Mc HI 0.10 s O65 C8 / ~ - 0.10 50% 3[HPLC 271 e H EtOAc; (M+H)+ Et
-
N 50% [HPLC hexane ES-MSI 271 Me O 0.14 50 % 365 C8 E -c EtOAc/ (M+H)+ H N 50% [HPLC hexane ES-MS1 272 Me O'14o \ 0.35 50% 382 C8 Et -- EtOAc.' (M+H) HO 50% [HPLC hexane ES-MS] 273 Me 0.48 50% 382 CS -E - - _ EtOAc' (M+H) OH 50% [HPLC hexane ES-MS 274 Me 0.20 100% 367 B4b, C8 MEt NEtOAc (M+H)+ 0_ - %N [HPLC 275xMee-ES-MS1 277 Me N 0.56 100% 435 B4b. C8 m e 0 j EtOAc (M+H)+ Et C [HPLC 27 M -______ ES-MSJ ___ -Me -Ns- 1 O EtOAc! (M+H)+ EtN25% [HPLC ____________________hexanie ES-MS] ____ 277 Me 0.40 100% B3f. C8 OEtOAc _ _
NC
27S M e 01636- - -410 A2.COa -- Ert -- \J--O-&~-OMe (~ [FABJ 279 Me 84 0.16 5%38A.Ca . Er-> , M eOl-l (M +H ) Ft95% [FAB] CHC13 _____ _ _ _ 280 Me 189- 0.16 5% 397 A2. - t192 MeOHi (M+H)- B4a. Er 95% [HPLC C3a __________________CHC13 ES-MS1 ___ 281 Me /\189- 0.17 5% 397 A2. -- Et 191 MeOH/ (M+H)-i- B4a, S-C\ 9% [FAB] O~a ___ __ __ __ ___ __ __ __CHC13 __ _ _ _ _ _ _ 282 Me 123- 414 A2,COa Et ___ _ FABJ ___ 283 E MeH 175- 0.16 5% 379 A2. C3a Et177 MeOH/ (M+H)s Et 95% [FAB) ______ _______ _______ _____CHC13 _ _ __ _ _ _ 28 M ,' 135- 0.33 5% A2. COb -- Ert, 137 MeOH! Et 95% ______ _____ ____________CH-C13 _ _ _ __ _ _ _ 285 Me /- Et 0/ M 67 0.41 5% A2,COb -k-Er / 0 ~/ MeMeOH/ Er 95% ___________ _____ ____ CHC13 _ _ _ _ _ _ _ 286 0155- 0.38 50% 377 (M+s) Cib 156 EtOAc/ [El] 50% per ether 287 ,0 0.18 5% 379 A2. COb MeOH/ (M+I-)+ 95% [FAB] Table 3. N'-Substituted-3-tert-butvl-5-pyrazolyl Ureas N 0 2 N N N' H H _ __ _ Mass Spec. mp TLC Solvent [Source] Synth. Ex. R____ R2________ (00) R, Svstem Method 289 H 00750% 393 C 289 -Y2--o .- 4 ~ 0X7 EtOAc/ (M+H)+ C 50% [HPLC ___________________hexane ES-MS1 I____ 290 H 0181- 381 COb 183 (M+H)+ - - ________ FABI _ _ _ 102 291 H Me 0.30 50 % 365 CS EtOAc
(M--H)-
50% [HPLC hexane ES-MS) 292 H N 366 C8 O Me
(M+H)
[FABI 293 H - 0.53 50% 398 CS N OMe EtOAc/ (M+H)+ 50% [HPLC hexane ES-MS1 294 H 369 C8 F (M+H)+ [HPLC ES-MS) 295 H 0.27 50% 351 CIc - O \ / EtOAc/ (M+H)+ 50% [FAB] hexane 296 H C1 C1 0.59 50% 327 CIc / \ EtOAc/ (M+H)+ 50% [FAB] hexane 297 H H 0.30 60% 350 C4a CL \ N acetone/ (M-+H)+ 40% [FAB] CH2C12 298 H / \ 0.07 5% 368 B4a, MeOH/ (M+H)+ C4a S N 95% [FAB] CHC13 299 H \S 0.18 5% 367 (M+) B4a, MeOH/ [El] C4a 95% CHC13 300 H 0 160- 408 A5. B6, HO CF 0 161 (M+H)+ C3b NHMc [FAB) isolated Oat TFA ____________salt 301 H \ O N 228- 0.24 10% 351 (M+) C3a 232 MeOH/ [El] ,dec CHC13 302 H / M 204 0.06 5% 364 (M+) C3b acetone/ [El] 95% CH2Cl2 303 H 110- 0.05 5% 408 C3b N1 acetone/ (M+H+) O0 |-~l- 95% S CH2C12 304 Me H 2 - 0.10 20% 380 C4a 0O-C \N acetone/ (M+H)+ 80% [FAB) CH2C12 i 103 305 Me 0 99- 0.19 100% 452 B3a -NHMc 101 EtOAc (M+H)- step I. / OMe [HPLC B12. ES-MS] D5b step 2. C3a 306 Me H 2 H , 0.48 30% 378 BI, C3a C C-N acetone' (M+H)+ 70% [FAB] CH2CI2 307 Me Me 135- 0.03 30% 408 C3a _N OMe 137 EtOAc; (M+H)+ 70% [HPLC hexane ES-MS1 308 Me S N 0.35 70% 382 B4a, - Nacetone/ (M+H)- C4a 30% [FAB] CH2C12 309 Me / \ 0.46 70% 382 B4a, acetone, (M+H)+ C4a S N 30% [FAB] CH2Cl2 310 Me CF 3 0.32 70% 450 B3b, S N acetone/ (M+H)+ C4a 30% [FAB] CH2CI2 311 Me 0.09 50% 381 C4a EtOAc! (M+H)+ 50% [FAB] hexane 312 Me S OH 0.61 100% 397 B3c, EtOAc (M+H)+ C4a IFABI 313 Me / \S-& OBu-n 0.25 50% 453 35, C4a - EtOAci (M+H)+ 50% [FAB] hexane 314 Me H - 0.65 100% 462 B6. C4a NH EtOAc (M-H)+ i-Bu [_(FAB] 315 Me H 2 0.67 100% 478 B6, C4a \j CL\/NH EtOAc (M+H)+ 0 t-BuO [FAB] 316 Me H 0.50 100% 378 C4a F C NH 2 EtOAc (M+H)+ [FAB] 317 Me H2 - 0.33 100% 420 C4a, D3 C \ N NH EtOAc (M+H)+ MeO [FAB] 318 Me HI 0.60 10% 478 C4a. D3 C NH water/ (M+H)+ 0 90% [FAB]
HO
2 C CH3CN 104 319 Me - H, /-- 0.55 100% 434 C4a. D3 C N O EtOAc (M-H) Et [FAB] 320 Me NH 0.52 100% 380 C4a - EtOAc (M+H) [FABI 321 Me - C N 0.25 60% 366 C4a acetone' (M+H)+ 40% (FAB] CH2CI2 322 Me OG NH 0.52 100% 452 C4a, D3 }=0 EtOAc (M+H)+t EtO [FAB] 323 Me - H, -, 0.34 60% 396 C4a S-C -N acetone/ (M+H)+ 40% [FAB] CH2C12 324 Me H2 0.36 60% 396 C4a C-S N acetone/ (M+H)+ 40% [FAB] CH2Cl2 325 Me 0 147- 365 CIc 149 (+) [FAB] 326 Me H 161- 0.15 4% 364 C2b \ CLC N 162 MeOH/ (M+H)+ 96% [FAB] CH2Cl2 327 Me O Me 228 379 C2b dec (+) [FABI 328 Me 0.30 5% 422 C2b N MeOH/ (M+H)+ O - 95% (FAB] S_0 CH2CI2 329 Me 0.46 100% 464 B3c. N EtOAc (M+H)-- C4a S [FAB] 330 Me N 0.52 100% 506 B3c, - 0EtOAc (M+H)+ C4a
CF
3 [FAB] 331 Me 0.75 100% 421 B3c, EtOAc (M+H)- C4a [FAB] | 332 Me - 0.50 100% 465 B3c. EtOAc (M+H)+ C4a I____ FABI 333 Me 0.50 100% 349 C4a EtOAc (M+H)+
[FAB]
B20C5 33 Me 0.52 100% 4-162 C-4aD EtOAc IM-Hh ______ ______________ ___ ____ _____ FAB] 33 e0.42 1000% 469 BC4aD EtOAc (M\.-Hh+ ____ ___ ____ ____ ____ ____ _ _____ ____ ___ (FABI _ _ _ _ 337 -CH.-CF, 433, C3a _____f [FABI 338 -(CH4.:CN -- FV - 0.37 50% 404 A3, Clb EtOAc/ (\-'+H)+' 50% [HPLC ____ _____ hexane ES-MS 1 .____ 339 0 Me-NH 159- 508 A5, B6, 0 161 (\M+H)+ C2b t-B6 0 /
[FAB]
106 Table 4.5-Substituted-2-thiadiazolvi Ureas R' >-S O N j,- R 2 N N N.R H H Mass Spec mp TLC Solvent I[Source] Synth. Entry R' R- (*C) R, Svstem Method 340 i-Bu O OMe 0.3 5% 399 B3a. C3a MeOH, (M+H)+ 95% [FAB] CH2CI2 341 t-Bu /\0.26 5% 370 C3a -0 eacN MeOH (M+H)+ 95% [FAB] CH2CI2 342 t-Bu 386 B4a, C3a - 0(M+H)+ S HCN [FAB) 343 t-Bu 0 Me 0.30 5% 383 Clb acetone; (M+H)+ 95% [FAB] CH2Cl2 344 t-Bu O0M 0.60 10*0/ 42+) Cb =N MeCH2Cl2 [FAB) 345 t-Bu 0 245- 0.23 100% 456 B33a step NHMe 250 EtOAc (M+H)+ 1, B 12, 0 OMe [HPLC D5b step 1_ _ ES-MS1 2. C3a 346 t-Bu 0 0.10 50% C3b /\-NHMe EtOAc/ 50/o pet 0 Nether 347 t-Bu 0 0.13 50% 441 C3b NMe, EtOAct (M+H)+ O N 50% pei [HPLC ether ES-MS _ 348 t-Bu 0 0.14 5% 441 C3b, NHEt MeOH/ (M+H)+ D5b 0 N 45% [HPLC EtOAc/ ES-MS] 50% hexane 349 t-Bu O 0.23 5% 461 C3b, CI NHMe MeOH/ (M+H)+ D5b / N 45% [HPLC EtOAc/ ES-MS] 50% hexane 350 t-Bu 0 0.09 5% 461 C3b. CI NHMe MeOH/ (M+H)+ D5b O N 45% [HPLC EtOAci ES-MS] 50% hexane 107 351 t-Bu 0 0.13 5% 441 C3b. Me 'NHMc MeOH: (M+H - D5b O N 45% [HPLC EtOAc' ES-MS] 50% hexane 352 t-Bu 0 159- 0.10 50% 427 C3b NHMc 160 EtOAc/ (M+H)+ / N - 50% pei [HPLC = N ether ES-MS1 353 I-Bu Cl 0.47 10% 438 C3b / \10 clMeOH! (M+Hh S Cl CH2C [FAB 354 t-Bu - 0.31 10% 371 C3b O MeOH/ (M+H)+ \-14 N CH2CI2 [FAB _ 355 t-Bu Cl 0.51 10% 400 C3b 356 B O - 0 M eOH/ (M +H)-C CH2C12 [FAB] 356 t-Bu 0.43 10% 385 C3b N O N MeOH/ (M+H) ___ N___ CH2C12 [FAB I 357 z-Bu 0 J' \ 0.70 10% 416 COb 0 S eMeOH.' (M+H)+ N__, CH2Cl2 [FAB] 358 t-Bu 0.11 50 % 438 C8 O N EtOAc/ (M+H)+
F
3 C 50% [HPLC hexane ES-MS1 359 t-Bu /\ 0.06 5% 432 C3b / SMe MeOH/ (M+H)+ 95% [FAB] CH2Cl2 360 i-Bu - 0.20 50% 385 C8 \ / EtOAc/ (M+H)+ HO 50% [HPLC hexane ES-MS) 361 t-Bu OMe 107- 0.05 30% 412 C3a - N jr Me 110 EtOAc/ (M+H) 70% [HPLC hexane ES-MS] 362 t-Bu 0.16 100% 370 CS EtOAc (M+H)+ 0-(N [HPLC ES-MS 363 Me 0 0.12 100% C4a, D5b -k-Me NHEt EtOAc Et O 364 Me 0 183- B3d step -- \ Me
NH
2 185 2, C3a Et / 365 M e O OMe 0.19 6% 413 A6, C3b -~ e -~jO O~eMeOH/ (M+H)+ Et 94% [FAB] CHC13 108 366 Me ~- ~ ' 248- 0.34 6% A6. C3b -k-Me -N 249 MeOH: Et 94% CHCl3 367 Me 7\ 0.20 400 A6. C3b -M e
(M+H)
S-K N [FAB) 368 Et 182- 0.33 5% A6. C3b 0..(/ Cl 183 MeOH/ Et 95% CHC13 369 Et / (:N 180- 0.19 5% A6. C3b ... S \N 181 McOH/ Et 95% CHC13 370 Et \ - M 168- 0.24 5% A6, C3b -.- \ e 169 MeOH/ Et 95% CHC13 371 Et _ -O N 168- 0.17 6% A6. C3b 171 MeOH! Et 94% CHC13 372 Et \ - 156- 0.19 6% A6. C3b S\N 158 MeOH/ Et 94% CHC13 I 109 Table 5.5-Substituted-3-thienvl Ureas Ri - 0 S N N'R2 H H mp TLC Solvent Mass Synth. Entrv R' R: ( 0 C) R. System Spec. Method 373 i-Bu / 144- 0.68 5% A4b. 145 acetone/ Cla 95% CH2C2 374 t-Bu Me 0.52 30% 381 / \OEt20/ (M+H)+ 70% pet [HPLC ether ES-MS] 375 i-Bu O Ole 0.26 30% 397 need Et20/ (M+H)+ recipie 70% pet [HPLC ether ES-MS1 376 t-Bu -N 0.28 50% 368 need -- O\/ Et2O/ (M+H)+ recipe 50% pet [HPLC ether ES-MS1__ 377 z-Bu 57 381 A4a \.j-Me [FAB) 378 i-Bu H 0.15 50% 365 (M+: A4a C N EtOAc/ [El] 50% pet ether 379 t-Bu O -OH 0.44 50% 383 A4a & / HEtOAc/ (M+H)+ 50% pet [FAB] ether 380 I-Bu & S N 384 A4a (M-H)a - _[FABI 381 t-Bu 176- 0.45 20% 425 D2 177 EtOAc/ (M+H)+ 80% [FAB] hexane 5 Table 5. Additional Ureas Mass Spec. mp TLC Solvent [Source] Synth. En R2 (C) R, Sstem Method 382 161- 0.71 20% 367 - DI Me 163 EtOAc/ (M+H)+, S80% 369 N N hexane (M+3) Br H H [ _FABI 110 383 145- 0.57 5% A2. C O 147 MeOH C3b H HCHC3 384 132- 0.33 5% 339 A9. N-N 0 O 135 acetone (M+H)- Cid 1t 95% [HPLC ES N N H CH2CI2 MS] __ H H 385 0.60 50% 462 C8 0 EtOAc (M+H) O N 0 50% [HPLC ES N.N SCF 3 hexane MS] H H H 386 0.28 5% 339 A7. O O O acetone.' (M+H)+ Cld 95% [FAB] N N N CH2CI2 H H 387 340 B3b 0 OON (M+H)- step NAN0 N 'N [FAB] 1,2, N N Cid H H 388 174-5 424 B4b, C8 O O Of 0 (M+H)+ N N, N [HPLC ES N N MS] H H 0 NHEt 389 198- C3b, O O~ 200 D5b NN N N H H 0 NHPr-i 390 169- 0.23 100% B4b. C8 O~ O O 170 EtOAc N. ANN N H H 0 NHMe 391 167- 0.12 100% B4b, C8 0 O 171 EtOAc N N N 'N H H 392 0.08 50% 400 C8 0 EtOAc/ (M+H)+ N A N 50% [HPLC ES N N N N hexane MS] H H 111 393 0.55 90% 443 B10, EtOAc, (M+H)- B4b. S 0 10% [FAB] C2b N N N hexane NN Nj r I-N H H 0 NHMe 394 OEt 230 377 C5 0 N N " dec (M+H)+ 0 [HPLC ES N NNJO MS] H 395 0.48 50% 383 C8 S 0 N EtOAc/ (M+H)+ N-S N 50% (FAB] H H Me hexane 396 417 C8
(M+H)
SOr O rN [HPLC ES N"N N MS] H H 397 155- 0.44 5% 380 Clb 157 acetone/ (M+H)+ 0 95% [FAB) 0 N N CH2C12 H H 5 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 pL) is mixed with water (5 pL) or with compounds diluted with distilled water from 10 10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 piL [y- 3 P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCI, pH 7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCI,. 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 15 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 .iM ATP and 0.4 pM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laemmli sample buffer. Samples are boiled 3 min and the proteins resolved by 112 electrophoresis on 7.5% Laemmli gels. Gels are fixed. dried and exposed to an imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging Analyzer System. All compounds exemplified displayed IC 0 s of between I nM and 10 tM. 5 Cellular Assav: For in vitro growth assay, human tumor cell lines, including but not limited to HCTI 16 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage 10 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 15 10' cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 *C in a 5% CO, incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT colorimetric assay (Boehringer 20 Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring 'H-thymidine incorporation into DNA following an 8 h culture with I 4Cu 'H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 3 H-thymidine incorporation by liquid scintillant counting. 25 For anchorage independent cell growth, cells are plated at 1 x 10' to 3 x 10' in 0.4% Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing only 0.64% agar in RPMI complete media in 24-well tissue culture plates. Complete media plus dilution series of compounds are added to wells and incubated at 37 "C in a 5% CO, incubator for 10-14 days with repeated feedings of fresh media containing 30 compound at 3-4 day intervals. Colony formation is monitored and total cell mass, average colony size and number of colonies are quantitated using image capture technology and image analysis software (Image Pro Plus, media Cybernetics).
113 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: 5 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 I x 106 cells with human colon adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o. 10 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., 15 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 20 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 25 various usages and conditions. Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.
Claims (8)
1. A compound of the formula R1 I__ 0 N II N H-C-NH-B wherein R' is selected from the group consisting of C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl, up to per-halosubstituted C 3 -C 6 alkyl and up to per-halosubstituted C 3 -CIO cycloalkyl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl which is substituted by -Y-Ar and optionally substituted by X, halogen, up to per-halosubstitution, and optionally substituted by X', wherein n = 0-2; each X1 is independently selected from the group of X or from the group consisting of -CN, -C0 2 R 5 , -C(O)R', -C(O)NR 5 R 5 , -OR', -NO 2 , -NR 5 R 5 , CI-Cio alkyl, C 2 - 1 o-alkenyl, C.o 10 alkoxy, C 3 -CIO cycloalkyl, and C 6 -Ci 4 and X is selected from the group consisting of -SR 5 , -NR 5 C(O)OR", NR 5 C(O)R 5 , C 3 -CI 3 heteroaryl, substituted CI-C 1 o alkyl, substituted C 2 - 1 o-alkenyl, substituted Ci- 1 o-alkoxy, substituted C 3 -CIO cycloalkyl, substituted C 6 -CI 4 aryl, substituted C 3 -CI 3 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, -C0 2 R 5 , -C(O)R', -C(O)NR 5 R", -OR', -SR', -NR 5 R", NO 2 , -NR 5 C(O)R 5 , -NR 5 C(O)OR" and halogen up to per-halosubstitution; wherein R 5 and R 5 ' are independently selected from H, CI-CIO alkyl, C 2 -io-alkenyl, C 3 CIO cycloalkyl, C 6 -C 1 4 aryl, C 3 -C 13 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per halosubstituted CI-Cio alkyl, up to per-halosubstituted C 2 - 10 -alkenyl, and up to per halosubstituted C 3 -CIO cycloalkyl, wherein Y is -0-, -S-, -N(R 5 )-, -(CH 2 )-m, -C(O)-, -CH(OH)-, -(CH 2 )m0-, -NR 5 C(O)NR 5 R -, -NR 5 C(O)-, -C(O)NR 5 -, -(CH 2 )mS-, -(CH 2 )mN(R 5)-, -O(CH 2 )m-, -CHXa, -CXa2-, -S-(CH 2 )m- and -N(R 5 )(CH 2 )m-, m = 1-3, and Xa is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, 115 benzothiazolyl or benzisothiazolyl, subject to the proviso that where Y is -(CH 2 )-m or -C(O)-, Ar is not phenyl, wherein Ar is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Zi, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 5 , -C(O)R', =0, -C(O)NRR 5 , -C(O)R', -NO 2 , -OR', -SR', -NR 5 R 5 -NR 5 C(0)OR", -NR 5 C(O)R", -S0 2 R', -S0 2 R'R", C 1 -C 10 alkyl, Ci-CI 0 alkoxy, C 3 -Cio cycloalkyl, substituted Ci-Cio alkyl, and substituted C 3 -C 10 cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO 2 R', -C(O)NR 5 R 5 , =0, -OR 5 , -SR5, -NO 2 , -NR 5 R 5 , -NR 5 C(O)R 5 , -NR 5 C(O)ORs, CI-Clo alkyl, CI-CI 0 alkoxyl, and C 3 -CIO cycloalkyl, subject to the proviso that where R' is t-butyl, B is not 0 R 6 wherein R 6 is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -O-n-propyl, -C(O)NH-(CH 3 ) 2 , -OCH 2 CH(CH 3 ) 2 , or -0-CH 2 - /
2. A compound of claim 1, wherein B is Xn -Q (Y-Q±Ze 1 wherein Y is selected from the group consisting of -O-, -S-, -CH 2 -, -SCH 2 -, -CH 2 S-, -CH(OH)-, -C(O)-, -CXa 2 , -CXaH-, -CH 2 0- and -OCH 2 -, Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per halosubstitution; 116 Q' is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, unsubstituted or unsubstituted by halogen up to per-halosubstitution, subject to the proviso that where Y is -CH 2 -or -C(O)-, Q' is not phenyl, X1 is CI-C 4 alkyl or halosubstituted CI-C 4 alkyl up to per halo, and Z, n and nI are as defined in claim 1.
3. A compound of claim 2, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per halosubstitution, Q 1 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 2 and Z is selected from the group consisting of -R 6 , -OR 6 and -NHR 7 , wherein R6 is hydrogen, C 1 -Cio-alkyl or C 3 -Cio-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Cio-alkyl, and C 3 -C 6 -cycloalkyl wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution.
4. A compound of claim 2, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Q 1 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -0-, -S-, -C(O)- or -CH 2 -, X, is as defined in claim 2, Z is-NH-C(O)-CpH 2 p+I, wherein p is 1-4, -CH 3 , -OH, -OCH 3 , -OC 2 H 5 , -CN or -C(O)CH 3 , n = 0 or 1, and nl = 0 or 1.
5. A compound as in claim I 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)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methylaminocarbonylphenyl)-thiophenyl)urea; 117 N-(5 -tert-Butyl-3 -isoxazolyl)-N '-(4-(4-( 1,2-methylenedioxy)phenyl)-oxyphenyl)urea; N-(5 -iert-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-iert-butyl-3 -isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl)urea; N-(5 -tert-butyl-3 -isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl) oxyphenyl)urea; N-(5 -tert-butyl-3 -i soxazolyl)-N '-(4-(3 -methylcarbamoyl)phenyl)oxyphenyl)urea; and pharmaceutically acceptable salts thereof.
6. A compound of the formula 118 t-Bu 0 O N NH-C-NH-B wherein B is 5-methyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by -Y-Ar and optionally substituted by halogen up to per halosubstitution, and Xr, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 R', -C(O)NR 5 R", -C(O)R', -NO 2 , -OR', -SRs, -NR 5 R', -NR 5 C(O)ORs, -NR 5 C(O)R", CI-C 1 o alkyl, C 2 -Cio alkenyl, CI-C 1 o alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl, up to per halo-substituted Ci-Cio alkyl, up to per halo substituted C 2 -C 10 alkenyl, up to per halo-substituted CI-C 10 alkoxy and, up to per halo substituted C 3 -CIO cycloalkyl, wherein R 5 and R 5 are independently selected from H, CI-C o alkyl, C 2 -Cio alkenyl, C 3 Cio cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted CI-Cio alkyl, up to per-halosubstituted C 2 -CI0 alkenyl, and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is - 0-, -S-, -N(R 5 )-, -(CH 2 )-m, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -NR 5 C(O)NR' NR"-, -NR 5 C(O)-, -C(O)NR 5 -, -(CH 2 )mS-, -(CH 2 )mN(R)-, -O(CH 2 )m-, -CHXa, -CXa2-, -S-(CH 2 )m- and -N(R 5 )(CH 2 )m-, m = 1-3, and Xa is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zai, wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, =O, -C0 2 R 5 , -C(O)NR 5 R", -C(O)-NR', -NO 2 , -OR 5 , -SR 5 , -NR 5 R 5 , -NR 5 C(O)OR 5 , -C(O)R', -NR 5 C(O)R", -S0 2 R 5 , SO 2 NR 5 R 5 , CI-Cio alkyl, CI-Clo alkoxyl, C 3 -CIO cycloalkyl, up 119 to per halo-substituted CI-CIO alkyl and up to per halo-substituted C 3 -CIO cycloalkyl; subject to the proviso that B is not 0 R 6 wherein R 6 is -NHC(0)-O-t-butyl, -0-n-pentyl, -0-n-butyl, -O-n-propyl, -C(O)NH-(CH 3 ) 2 , -OCH 2 CH(CH 3 ) 2 , or -0-CH 2
7. A compound of the formula R 0 0 N I NH-C-NH-B as defined in claim 1 and substantially as hereinbefore described with reference to one or more of the accompanying examples.
8. A compound of the formula t-Bu 0O N II NH-C-N H-B as defined in claim 6 and substantially as hereinbefore described with reference to one or more of the accompanying examples. Dated: 4 January 2011
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| DE102006029795A1 (en) * | 2006-06-27 | 2008-01-03 | Schebo Biotech Ag | New urea derivatives and their uses |
| WO2012087630A1 (en) * | 2010-12-20 | 2012-06-28 | E.I. Du Pont De Nemours And Company | Pyridine and pyrimidine compounds for controlling invertebrate |
| US9055750B2 (en) | 2012-02-03 | 2015-06-16 | Basf Se | Fungicidal pyrimidine compounds |
| BR112014018812A8 (en) | 2012-02-03 | 2017-07-11 | Basf Se | COMPOUNDS, PROCESS FOR PREPARING COMPOUNDS I, AGROCHEMICAL COMPOSITION, METHOD TO COMBAT HARMFUL PHYTOPAGENIC FUNGI, USE OF COMPOUNDS OF FORMULA I AND SEED |
| WO2013113716A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113773A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113788A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113720A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113776A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013135672A1 (en) | 2012-03-13 | 2013-09-19 | Basf Se | Fungicidal pyrimidine compounds |
| US9732063B2 (en) | 2012-11-16 | 2017-08-15 | Respivert Limited | Kinase inhibitors |
| CA2957785C (en) | 2014-08-11 | 2023-01-03 | Angion Biomedica Corporation | Cytochrome p450 inhibitors and uses thereof |
| CN107531631B (en) | 2014-12-31 | 2021-09-03 | 安吉昂生物医药公司 | Methods and agents for treating diseases |
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| DE2436179A1 (en) * | 1973-07-27 | 1975-02-06 | Shionogi & Co | ISOXAZOLE DERIVATIVES AND HERBICIDAL AGENTS |
| EP0371876A1 (en) * | 1988-11-30 | 1990-06-06 | Novapharme | Isoxazoles and isoxazolines with an anticonvulsive activity, and pharmaceutical compositions containing them |
| AU1042099A (en) * | 1997-11-12 | 1999-05-31 | Astrazeneca Ab | Chemical compounds |
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| US3754887A (en) * | 1969-05-05 | 1973-08-28 | Du Pont | Ureidopyrazoles defoliants |
| JPH07504429A (en) * | 1992-03-12 | 1995-05-18 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Indole derivatives as 5HT↓1c antagonists |
| WO1994014801A1 (en) * | 1992-12-29 | 1994-07-07 | Smithkline Beecham Plc | Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists |
| DE69834842T2 (en) * | 1997-12-22 | 2007-05-10 | Bayer Pharmaceuticals Corp., West Haven | INHIBITION OF RAF-KINASE USING ARYL AND HETEROARYL SUBSTITUTED HETEROCYCLIC UREA |
| ES2154253T3 (en) * | 1997-12-22 | 2012-01-27 | Bayer Healthcare Llc | INHIBITION OF THE ACTIVITY OF P38 CINASA USING REPLACED HETEROCYCLIC UREAS. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2436179A1 (en) * | 1973-07-27 | 1975-02-06 | Shionogi & Co | ISOXAZOLE DERIVATIVES AND HERBICIDAL AGENTS |
| EP0371876A1 (en) * | 1988-11-30 | 1990-06-06 | Novapharme | Isoxazoles and isoxazolines with an anticonvulsive activity, and pharmaceutical compositions containing them |
| AU1042099A (en) * | 1997-11-12 | 1999-05-31 | Astrazeneca Ab | Chemical compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US11407771B2 (en) | 2018-05-30 | 2022-08-09 | Washington University | Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof |
| US12006337B2 (en) | 2018-05-30 | 2024-06-11 | Washington University | Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof |
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