AU2006201959A1 - 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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- 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
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- 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
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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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- C07D285/02—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
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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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- C07D401/02—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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- C07D405/02—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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- C07D413/02—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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- 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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Description
\O 1
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Bayer Corporation CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia 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: Field of the Invention This invention relates to the us eof a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
Background of the Invention The p21"' oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann.
Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins.
In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by coexpression of dominant negative raf kinase or dominant negative MEK, the substrate of raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. 1994, 19, 474-80; Fridman et al. J Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75).
Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21"', the instant inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal, murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating solid cancers, such as, for example, carcinomas of the lungs, pancreas, thyroid, bladder or colon, myeloid disorders myeloid leukemia) or adenomas villous colon adenoma).
The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway. The invention also provides a method for treating a raf mediated disease state in humans or mammals. Thus, the invention is directed to compounds and methods for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of formula I: 0 A-NH-C-NH-B I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below.
The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.
Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of which is a 5-6 member aromatic ring. One or more of these rings may have 1-4 carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms.
Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, isoquinoline, phthalimidinyl and combinations thereof, such as, diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenyl amine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinyithiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pyridinylnaphthyl thioether, and phthalimidylmethylphenyl.
Examples of suitable heteroaryl groups include, but are not limited to, 5-12 carbonatom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.
For example, B can be 2- or 3-uryl, 2- or 3-thienyl, 2- or 4-triazinyl, 2- or 3pyrrolyl, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 4- or 5-oxazolyl, 4or 5-isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothiazolyl, 3- or 4-pyridyl, 4-, or 6-pyrimidinyl, l,2,3-triazol-1-, or -5-yl, l,2,4-triazol-1-, or -5-yl, 1- or tetrazolyl, l, 2 ,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3. or -5-yl, l,3,4-thiadiazol-2or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 5- or 6-2H-thiopyranyl, 3- or 4-4Hthiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 6- or 7-benzofuryl, 4-, 6- or 7-benzothienyl, 6- or 7-indolyl, 4- or benzimidazolyl, 6- or 7-benzopyrazolyl, 6- or 7-benzoxazolyl, 5- 6- or 7-benzisoxazolyl, 6- or 7-benzothiazolyl, 6- or 7-benzisothiazolyl, 6- or 7-benz-1,3-oxadiazolyl, 7- or 8quinolinyl, 8- isoquinolinyl, 4- or 9-carbazolyl, 2-, 8- or 9-acridinyl, or 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl. 5-methyl-2thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl. 5-methyl-2thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.
Suitable alkyl groups and alkyl portions of groups, alkoxy, etc., throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
Suitable aryl groups include, for example, phenyl and 1- and 2-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 cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups.
Suitable halogens include F, Cl, Br, and/or I, from one to persubstitution all H atoms on the group are replaced by halogen atom), being possible, mixed substitution of halogen atom types also being possible on a given moiety.
As indicated above, these ring systems can be unsubstituted or substituted by substituents such as halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CN, -C 2 ORS, -C(O)RS, -NO 2 -NR'R",
-NR
5 C(0)OR", -NR'C(O)Rs', C,-Clo alkyl, C,-C 10 alkenyl, alkoxy, C 3 -Co cycloalkyl, C 6
-C,
4 aryl, C,-C 2 4 alkaryl, C 3 -C,3 heteroaryl, C 4
-C,
3 alkheteroaryl, substituted C,-Co alkyl, substituted C,-Co alkenyl, substituted C,-C, 0 alkoxy, substituted C 3
-C,
0 cycloalkyl, substituted C 4
-C
2 3 alkheteroaryl and -Y-Ar.
Where a substituent, X or is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of-CN, -COR', -SRS, -NO 2 -NR'C(O)Rs, -NR'C(0)OR" and halogen up to per-halo substitution.
The moieties R' and R" are preferably independently selected from H. C,-C 10 alkyl,
C,-C,
0 alkenyl, C 3
-C
10 cycloalkyl, aryl, C 3
-C
1 3 heteroaryl, alkaryl, C -C1 3 alkheteroaryl, up to per-halosubstituted
C
1 -Cl 0 alkyl, up to per-halosubstituted
C
2
-C
10 alkenyl, up to per-halosubstituted
C
3
-C
10 cycloalkyl, up to per-halosubstituted
C
6
-C
14 aryl and up to per-halosubstituted
C
3 -C,3 heteroaryl.
The bridging group Y is preferably
-N(R
5
-(CH
2 -CH(OH)-,
-(CH
2 )mO-1 -(CH 2
-(CH
2 )mN(R 5
-CHX
3 -Ca- and
-N(R
5
)(CH
2 where m and V 2 is halogen.
The moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by ZnD 1 wherein ni is 0 to 3.
Each Z substituent is preferably independently selected from the group consisting of -CN,
-C(O)NR
5
R
5
NR'
5
-NO
2 SR', NR 5
-NR
5
C(O)OR
5
-SO
2 -S0 2 NRR" alkyl, Ca alkoxy, C 3
-C,
0 cycloalkyl, C 6
-C,
4 aryl, C 3
-C,
3 heteroaryl,
C
7
-C
2 4 alkaryl, C 4 -C,2 3 alkheteroaryl, substituted C,-C, 0 alkyl, substituted C 3
-C
10 cycloalkyl, substituted alkaryl and substituted C 4
-C
23 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN,
-C(O)NR
5
-NO
2 -NR 5
C(O)R",
-PR
5 C(O)0R", C,-C 0 alkyl, C,-C 10 alkoxy, C,-C, 0 cycloalkyl, C 3
-C
1 3 heteroaryl, C 6
C
14 aryl, C 7 -C2 4 alkaryl.
The aryl and heteroaryl moieties of B of Formula I are preferably selected from the group consisting of
R
5 0
R
and which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n 0-3.
Xn -Q-4Y- Q}Z-z The aryl and heteroaryl moieties of B are more preferably of the formula: wherein Y is selected from the group consisting of-0-, -CH 2
-CH,S-,
-CHO- and -OCH,- and X' is halogen.
Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is a mono- or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4 members of the group consisting of N, O and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution.
X, Z, n and nl are as defined above and s 0 or 1.
In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution and Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, or Y-Q' is phthalimidinyl substituted or unsubstituted by halogen up to per-halo substitution. Z and X are preferably independently selected from the group consisting of -SR 6 and -NHR', wherein R' is hydrogen, C,-C, 0 ,-alkyl or C 3
-C,
0 cycloalkyl and R' is preferably selected from the group consisting of hydrogen, C 3 C,-alkyl, C,-C,-cycloalkyl and CX-C 1 -aryl, wherein R 6 and RW can be substituted by halogen or up to per-halosubstitution.
The heteroaryl moiety A of formula I is preferably selected from the group consisting of: N
I'
R
N
R R R IR
NN
N Rb R and The substituent R' is preferably selected from the group consisting of halogen,C-Ci 0 alkyl, C,-C, 10 cycloalkyl, heteroaryl, C.-C 1 3 aryl, C,-C 24 alkaryl,_up to perhalosubstituted C 1
-C
10 alkyl and up to per-halosubstituted C 3
-C
20 cycloalkyl, up to perhalosubstituted C 1
-C
13 heteroaryl, up to per-halosubstituted C 6
-C,
3 aryl and up to perhalosubstituted CX- 2 alkaryl.
The substituent R 2 is preferably selected from the group consisting of H, -CO,R 4
-C(O)NR
3 R 3 alkyl, 0 cycloalkyl, alkaryl, C 4
-C
23 alkheteroaryl, substituted C,-C 10 alkyl, substituted C 3
-C,
0 cycloalkyl, substituted C,- C, alkaryl and substituted C,-C, 3 alkheteroaryl. Where R 2 is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of -CN, C0 2 -C(O)-NR 3 R" -NO 2 and halogen up to per-halosubstitution.
R' and R" are preferably independently selected from the group consisting of H, -OR", -SR 4
-NR
4 R 4 -C02R 4 -C(O)NR4
CI-CI
0 alkyl, C 3
-C
10 cycloalkyl, aryl, C3-C,, heteroaryl, alkaryl, C 4
-C,
3 alkheteroaryl, up to per-halosubstituted
C,-C
20 alkyl, up to per-halosubstituted
C
3 -CIO cycloalkyl, up to per-halosubstituted
C
6 aryl and up to per-halosubstituted
C
3
-C
13 heteroaryl.
R' and R are preferably independently selected from the group consisting of H, C'- CIO alkyl, C,-C, 0 cycloalkyl, aryl, C 3
-C
13 heteroaryl;
C
7
-C
2 alkaryl, CX-C 3 alkheteroaryl, up to per-halosubstituted
C,-C,
0 alkyl, up to per-halosubstituted
C
3
-C,
0 cycloalkyl, up to per-halosubstituted
C,-C,
14 aryl and up to per-halosubstituted
C
3
-C
13 heteroaryl.
R' is preferably C,-C, 0 alkyl, C 3
-C,
0 cycloalkyl, up to per-halosubstituted
C
1
-C
20 alkyl and up to per-halosubstituted
C
3
-C
10 cycloalkyl.
Rb is preferably hydrogen or halogen.
R' is hydrogen, halogen, C,-C, 10 alkyl, up to per-halosubstituted
C
1
-C'
0 alkyl or combines with R' and the ring carbon atoms to which R' and RC are bound to form a or 6-membered cycloalkyl, aryl or hetaryl ring with 0-2 members selected from 0, N and S; The invention also relates to compounds of general formula I described above and includes pyrazoles, isoxazoles, thiophenes, furans and thiadiazoles. These more particularly include pyrazolyl ureas of the formula
N'
R NH-C-NH-B wherein R' RI and B are as defined above; 9 and both 5.3- and 3,5- isoxazolyl ureas of the formulae R1
NH-C-NH-B
and
N
I
NHCNHB
NH-C-NH-B
wherein R' and B are also as defined above.
Component B for these compounds is a 1-3 ring aromatic ring structure selected from the group consisting of:
R
5
N
or N which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here R and R 5 are as defined above, n 0-2 and each X I substituent is independently selected from the group of X or from the group consisting of-CN, -COR',
-C(O)NR'R
5 NO,, -NR'R 5 C,-C,o alkyl, C 2 .o-alkenyl, C,l,-alkoxy,
C
3
-C
1 0 cycloalkyl, 4 aryl and C 7 alkaryl.
The substituent X is selected from the group consisting of -NR 5 C(O)0R 5
NR
5
C(O)R
5
C
3
-C,
3 heteroaryl, C,-C 2 3 alkheteroaryl, substituted CI-C 0 o alkyl, substituted C 2 .1 0 -alkenyl, substituted C,.
1 0 -alkoxy, substituted C 3 -C1 0 cycloalkyl, substituted aryl, substituted C 7
-C
24 alkaryl, substituted C 3
-C,
3 heteroaryl, substituted C,-C 23 alkheteroaryl, and -Y-Ar, where Y and Ar are as defined ab6ve. If X is a substituted group, as indicated previously above, it is substituted by one or more substituents independently selected from the group consisting of -CN,
-C(O)NR
5
R
5
-NR
5 R" NOD, -NR 5
-NR
5 C(O)0RS 5 and halogen up to per-halo substitution, where R 5 and R" are as defined above.
The components of B are subject to the following provisos, where R' is t-butyl and R' is methyl for the pyrazolyl ureas, B is not C(O)0C 4
H
9 Where R' is 1-butyl for the 5,3-isoxazolyl ureas, B is not 0 OR 6 wherein R' is -NHC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -0-propyl, -C(O)NHi-
(CH
3 2
-OCH
2
CH(CH
3 2 or -O-CH 2 -phenyl. Where R' is t-butyl for the isoxazole ureas, B is not 0 -0/0-CH 2 and where R' is -CH 2 -t-butyl for the 3,5 -isoxazolyl ureas, B is not 0 CH 3 Preferred pyrazolyl ureas, 3,5-isoxazolyl ureas and 5,3-isoxazolyl ureas are those wherein B is of the formula Xn wherein Q, X, Z, Y, n, s and n I are as defined above.
Preferred pyrazole ureas more particularly include those wherein Q is phenyl or pyridinyl, Q' is pyridinyl, phenyl or benzothiazolyl, Y is
-SCGW-,
-OCH.- or and Z is H, -SCH 3 or -NH-C(O)-C wherein p is 1-4, n 0, s 1 and n I 0- 1. Specific examples of preferred pyrazolyl ureas are: 3-tert-Butyl-5 -pyrazolyl)-N '-(4-phenyloxyphenyl)urea; N-(3 -tert-Butyl-5 -pyrazolyl)-N -methylaminocarbonylphenyl).
oxyphenyl)urea; N-(3 -tert-Butyl-5-pyrazolyl)-N 3 4 -pyridinyl)thiophenyl)urea; N-(3-terl-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; 4 4 -pyridinyl)oxyphenyl)urea; N-(3 -tert-Butyl-5 -pyrazol yl)-N 4 4 -pyridinyl)methylphenyl)urea; I -Methyl-3 -er-butyl-5-pyrazolyl)-N -(4-phenyloxyphenyl )urea; 1 -Methyl-3 -tert-butyl-5-pyrazolyl)-N'-( 3 4 -pyridinyl)thiophenyl)urea; I -Methyl-3-tert-butyl-5-pyrazoly)..N'-(( 4 4 -pyridinyl)thiomethyl)phenyl)urea; I -Methyl-3 -tert-butyl-5-pyrazolyl)-N 4 4 -pyridinyl)thiophenyl)urea; 1 -Methyl-3 -tert-butyl-S-pyrazolyl)-N 4 4 -pyridinyl)oxyphenyl)urea; N-(l -Methyl -3 -tert-butyl-5-pyrazolyl).N 4 4 -pyridinyl)methyloxy)phenyl)urea; 1 -Methyl-3-tert-butyl-5-pyrazolyl)-N 3 2 -benzothiazolyl)oxyplienyl)urea; N-(3 -tert-butyl-5-pyrazolyl)-N '-(3-(4-pyridyl)thiophenyl) urea; '-(4-(4-pyridyl)thiophenyl) urea; -pyrazolyl)-N 4 -pyridyl)oxyphenyl) urea; -pyrazoly)-NT'-(4-(4-pyridyl)oxyphenyl) urea; 1 ty-3trtbty--przolyl)-N-(3-(4-pyridyl)thiophenyl) urea; I-methyl-3 -tert-butyl-5-pyrazolyl)-N 4 -(4-pyridyl)thiophenyl) urea; I -niethyl-3 -tert-butyl-5-pyrazolyl)-N 3 -(4-pyridyl)oxyphenyl) urea; and I-methyl-3-terr-butyl-5-pyrazolyl)-N 4 -(4-pyridyl)oxyphenyl) urea.
Preferred 3 ,5-isoxazolyl ureas more particularly include those wherein Q is phenyl or pyridinyl, Q' is phenyl, benzothiazolyl or pyridinyl, Y is or -CH 2 Z is -CH,, 12 Cl, -OCH, or -C(O)-CH3, n 0, s 1. and ni Specific examples of preferred ureas are N-(3 -Isopropyl-5-i soxazolyl)-N '-(4-(4-pyridinyl)thiophenyl )urea; -(4-(4-methoxyphenyl)oxyphenvl )urea; 2 -(4-acetylphenyl)oxy)pvridinyl)urea '-(3-(4-pyridinyl)thiophenyl)urea; N-(3 -zert-Bu tyl -5 -i sox azo lyl)-N '-(4-(4-pyridinyl)methylphen yl )urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(4-(4-pyridinyi)oxyphenyl)urea; N-(3-tert-Bu tyl-5-i sox azo lyl)-N '-(4-(4-methyl-3 -pyri dinylI)oxyphenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl).N -benzothiazolyl)oxyphenyl)urea, 1,1-Dimethylpropyl)-5-isoxazolyl)-N -(4-(4-methylphenyl )oxyphenyl)urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N 3 -(4-pyridinyl)thiophenyl)urea, N-(3 -Dimethylpropyl)-5-isoxazolyl)-N'-( 4 4 -pyridinyl)oxyphenyl)urea; 1I -Dimethylpropyt).5 -isoxazolyl)-N 4 -(4-pyridinyi)thiophenyi)urea; 1,1 -Dimethylpropyl.5-isoxazolyl)-N'-(-(2(4-methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl- I -ethylpropyi)-5-i soxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N -(3-(4-pyridinyl)thiophenyl)urea;
N-(
3 -isopropyl-5-isoxazolyl)N'.(3.(4(2methylcarbamoyl)pyidyl)oxyphenyl) urea; 4 4 -(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; '-(3-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; '-(4-(4-(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(3-tert-butyl-5-isoxazoly)-N(3-(4(2methylcarbamoyl)py-idyl)thiophenyl) urea; 1,1-dimethyiprop- 1-yl)-5-isoxazolyI)-N'-(3-(4-(2-methylcarbamoy1)yridyl)oxyphenyl) urea; 1,1 -dimethyiprop- 1 -yl)-5 -isoxazolyl)-N -methylcarbamoyl)pyridyl)oxyphenyl) urea; and 13 N-(3-tert-butyl1-5-isoxazolyl)-N 3 -chloro-4-(4-(2-methylcarbamoyl)pyrdy ri thiophenyl) urea.
Preferred S, 3 -isoxazolyl ureas more particularly include those wherein Q is is phenyl or pyridinyl, Q' is phenyl, benzothiazolyl or pyridinyl, Y is or X is CH, and Z is CPH 2PI' wherein p 1-4, -C(O)CH 3 -OH, -CN, phenyl, or -OCH 3 n 0 or 1, s 0 or 1, and n I 0 or 1. Specific examp~les of preferred 5,3-isoxazolyl ureas are: -3 -isoxazolyl)-N '-(4-(4-hydroxyphenyl )oxyphenyl)urea;
N-(
5 -tert-Butyl- 3 -isoxazolyl)N'-(4(3hydroxyphenyl)oxypheny)urea; INDN-(5-tert-Butyl-3 -isoxazolyl)-N'-( 4 4 -acetylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)w '-(3-benzoylphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl).N'-(4-phenyloxyphenyJ)urea; N-(5-tert-Butyl-3-isoxazolyl)-N 4 3 -methylaminocarbonylphenyl)thiophenyl)urea; l-3-isoxazolyl)-N '-(4-(4-(1I,2-methylenedioxy)phenyl)oxyphenyl)urea; utyl1-3-i sox azolyl)-N'-(4-(3 -pyridinyl )oxyphenyl)urea; uty!- 3-i sox azo lyl)-N 4 4 -pyidinyl)oxyphenyl)urea; N-(5-tert-Butyl1-3 -isox azolyl)>N'-( 4 -(4-pyridyl)thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-( 4 -(4-pyridinyl)methylphenyl)urea; -tert-B utyl-3-i sox azolyl)-N'-( 3 4 -pyridinyl)oxyphenyl)urea; N-(5-terz-Butyl-3-isoxazolyl)-N 3 -(4-pyridinyl)thiophenyl)urea; utyl-3 -i sox azo lyl)-N'-(3 -methy14-pyridi ny1)oxyphenyl)uea; N-(S-tert-Butyl-3-isoxazolyl)-N 3 3 -methyl-4-pyridinyl)thiophenyl)urea; N-(5-zer:-Butyl-3-isoxazolyl)-N -methyl-4-pyridinyl)thiophenyl)urea; N-(5-terz-Butyl-3-isoxazolyl)-N 3 4 -methyl-3-pyridinyl)oxyphenyl)urea; utyl -3-i sox azolyl)-N 4 3 -methyl-4-pyridinyl)oxyp henyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N 3 -(2-benzothiazolyl)oxyphenyl)urea; I-3-isoxazolyl)-N -chloro-4-(4-(2-methylcarhamoyl)pyridyl)oxyphenyl) urea; N-(5-terz-butyl-3-isoxazolyl)-N 4 4 -(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-terz-butvl-3-isoxazolyl)-N '-(3-(4-(2-methylcarbarnoyl)pyridyl)thiophenyl) urea; 1-3 -isoxazolyl)-N 2 -methyl-4-(4-(2-methylcarbanoyl)pyridyl).
oxyphenyl) urea; 14 -tert-butyl-3 -isoxazolyl)-N 4 4 2 -carbamoyl)pyridyl)oxyphenyl) urea; N-(S -:ert-butyl -3-isoxazolyl)-N -carbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3 -(4-(2-methylcarbamoyl)pyridyl).
oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-( 4 -(4-(2-methylcarbamoyl )pyridyl thiophenyl) urea; 5-tert-butyl-3-isoxazolyl)-N'-(3 -chloro- 4 -(4-(2-methylcarbamoy)pyidyl).
oxyphenyl) urea; and N-(5-tert-butyl-3-isoxazolyl)-N'-( 4 -(3-methylcarbamoyl)phenyl)oxyphenyl) urea.
Additionally included are thienyl ureas of the formulae R 0 Rb NH-C-NH-B SI ~or0 NH-C-NH-B
NH-C-NH-B
wherein R' Rb and B are as defined above. Preferred B components for the thienyl ureas of this invention have aromatic ring structures selected from the group consisting of: xln xi n x
-N
R
5
R
I I and
I
These aromatic ring structures can be substit4ted 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, -NR 5
CI-CI
0 alkyl.
The X substituents are independently selected from the group consisting of -CO,R 5
-C(O)NR
5
-NR
5 C(O)OR", -NR 5
C
2
-C,
0 cycloalkyl,
C.-C
1 4 aryl, C,-C 2 alkaryl, C 3
-C,
3 heteroaryl, CX-C 3 alkheteroaryl, and substituted C-_
C,
0 alkyl, substituted C 2 10 -alkenyl, substituted C,.
10 )-alkoxy, substituted C 3
-C,
0 cycloalkyl, substituted aryl, substituted 4 alkaryl, substituted C 3
-C,
3 heteroaryl, substituted C 4 3 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, -COR', -C(O)NR 5
-NR
5
R
5
-NO,,
-NR
5 C(O)Rs 5 -NR5C(O)0R 5 and halogen up to per-halo substitution. The moieties R3', Y and Ar are as defined above and n 0-2.
The components for B are subject to the proviso that where R' is t-butyl and R b is H for the 3-thienyl ureas, B is not of the formula 0 CH(CH 3 2 Preferred thienyl ureas include those wherein B is of the formula Xn and Q, Y, X, Z, n, s and n I are as defined above. The preferred thienyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or Z is -Cl, -CH 3 -OH or -OCH,, n 0, s 0 or 1. and n I Specific examples of preferred thienyl ureas are: -isoxazolyl)-N'-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5 -i sox azo lyl)-N 4 -(4-methoxyphenyl)oxyphenyl)urea; N-(3-tert-B utyl-5 -isoxazolyl)-N 5 2 4 -acetylphenyl)oxy)pyridinyl)urea; soxazolyl)-N -(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N 4 -(4-pyridinyl)methylphenyl)urea; 16 N-(3-ferI-Butyl..s-tsoxazolyl).N 4 4 -pyridinyl)thiophenyl)urea; 4 4 -pyridinyl)oxypheny)urea-.
-isoxazolyl)-N 4 4 -methyl-3-pyridinyl)oxyphenyl)urea; N-(3-terz-Butyl-5-isoxazolyl)-N'-(3-(2-benzothiazolyl)oxyphenyl )urea; 1,1 -Dimethylpropyl)-5-isoxazolyl).N '-(4-(4-methylphenyl)oxyphenyl )urea: 1,1 -D imethylpropyl)-5 isox azolyl)-N'-( 3 4 -pyri dinyl)thi opheny!)urea; 1, -Dimethylpropyl)-5-isoxazolyl)-N'-( 4 4 -pyridinyl)oxyphenyl)urea; 1, -Dimethylpropyl)-5-isoxazolyl-N 4 4 -pyridinyl)thiophenyl)urea; N-(3 -Dimethylpropyl-5-isoxazolyl)-N 2 -(4-methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolylyN 4 -(4-pyridinyl)oxyphenyl)urea; and 1-M ethyl- I -ethylpropyl)-5 -isoxazolyl)w -(4-pyridinyl)thiophenyl)urea.
Preferred thiophenes include: N-(5-iert-butyl-3 -thienyl)-N '-(4-(4-methoxyphenyl)oxyphenyl) urea; butyl-3-thienyl)N'(4-(4hydroxyphenyl)oxyphenyl) urea; N-(5-zert-butyl-3 -thienyl)-AT'-(4-(3-methylphenyl)oxyphenyl) urea; and N-(5-zert-butyl.3 -thienyl)-N '-(4-(4-pyridyl)thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: NI-4-B Rb NH-C-N4H-B wherein Rb, R' and B are as defined above. The thiadiazolyl and furyl ureas have preferred aromatic ring structures for B identical to those for the pyrazolyl, thienyl and isoxazolyl ureas shown above. Such ring structures can be unsubstituted or substituted by halogen, up to per-halosubstitution, and each XV substituent is independently selected from the group consisting of X or from the groupconsisting of -CN, -NO, and alkyl. The X substituents are selected from the group consisting of
-C(O)NR'R
5
-NR
5
-NR
5 C(O)0R 5
-NR'C(O)R
5 substituted
C
2 .1 0 -alkenyl, substituted
C
1 10 -alkoxy. -C -Cjo cycloalkyl, aryl, alkaryl, C 3 heteroaryl,
CI-C,
3 alkheteroaryl, and substituted
C,-C,
0 alkyl, substituted C3-CI 0 cycloalkyl, substituted aryl, substituted alkaryl, substituted heteroaryl, substituted
C,-C,
3 alkheteroaryl and -Y-Ar. Each of R" and Ar are as defined above, n 0-2, and the substituents on X where X is a substituted group are as defined for the pyrazolyl. isoxazolyl and thienyl ureas.
This invention also includes pharmaceutical compositions that include compounds described above and a physiologically acceptable carrer.
Preferred furyl ureas and thiadiazole ureas include those wherein B is of the formula Xn Q.(Y..Q1 )S,-41 and Q, X, Y, Z, n, s, and n I are as defined above. The preferred thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or n 0, s I and n I1 0. Specific examples of preferred thiadiazolyl ureas are: N-(5-IerI-Butyl-2-( 1 -thia-3,4-diazolyl))-N 3 4 -pyridinyl)thiophenyl)urea; N-(5-tert-Butyl.2.( 1 -thia-3,4-diazolyl))-N '-(4-(4-pyri dinyl)oxyphenyl)urea; N-(5-tert-butyl-2( 1 -thia-3,4-di azolyl))-N 4 2 -methylcarbamnoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-2-( 1 -thia-3 .4-diazolyl))-N'-( 4 4 2 -methylcarbamoyl)pyridyl)oxyphenyl) urea; 1 -thia-3 ,4-diazolyl))-N '-(3-chloro-4-(4.(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-lert-butyl-2-( I -thia-3 ,4-diazolyl))-N '-(2-chloro-4-(4-(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-terl-butyl-2-( 1 -thia-3,4-diazolyl))-N 3 4 -pyridyl)thiophenyl) urea; N-(5-terz-butyl-2-( I -thia-3,4-diazolyl))-N '-(2-methyl-4-(4-(2methylcarbamnoyl)pyridyl)oxyphenyl) urea; and 1,1 -dimethylprop- I 1 -thia-3,4-diazolyl))-N carbamoylphenyl)oxyphenyl) urea.
The preferred fliryl ureas more particularly include those wherein Q is phenyl, Q, is phenyl or pyridinyl, Y is or Z is -CI or -OCH 3 s =0 or 1, n 0 and n I 0-2.
The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations Li- Na' or alkaline earth cations Mg' 2 Ca' 2 or Ba'2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, NN-dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8diazabicyclo[5.4.0]undec-7-ene
(DBU).
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess Raf kinase inhibitory activity.
General Preparative Methods The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some of which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, with more detailed examples being presented in the experimental section describing the working examples.
Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984).
March. Advanced Organic Chemistry, 3" Ed.; John Wiley: New York (1985)). For 19 example. 3 -substituted-5-aminoisoxazoles are available by the reaction of hydroxylamine with an a-cyanoketone as shown in Scheme I. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an cyanoketone with hydrazine (R 2 or a monosubstituted hydrazine affords the 3substituted- or 1, 3 -disubstituted-5-aminopyrazole Pyrazoles unsubstituted at N-I
(R
2 may be acylated at N-1, for example using di-tert-butyl dicarbonate, to give pyrazole 7. Similarly, reaction of nitrile 8 with an -thioacetate ester gives the substituted-3-amino-2-thiophenecarboxylate Ishizaki et al. JP 6025221).
Decarboxylation of ester 9 may be achieved by protection of the amine, for example as the tert-butoxy (BOC) carbamate followed by saponification and treatment with acid. When BOC protection is used, decarboxylation may be accompanied by deprotection giving the substituted 3-thiopheneammonium salt 11. Alternatively, ammonium salt 11 may be directly generated through saponification of ester 9 followed by treatment with acid.
CH
3
CN
1) base 2) if 0
H
2
NOH-HCI
X base base
R'
SO
NH
2 3
R
1
N
0\ In o\ \o 0 R'iCN 2
R
1
CCN
CN
RLNHNH
2
R
NH
2
O
N
NH
2
OR
7 HS CO 2
R
ON-
R
1
S
S NH 2
CO
2 R 8
R'
t NH3+ 1) OH 2) H 9 0 0
R
1
SNHBOC
CO
2
R
1) OH 2) H Scheme I. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3" Ed.; John Wiley: New York (1985); Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAIH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a 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 Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H
2 catalyst S(eg. Ni, Pd, Pt) ArNO 2 1 ArNH 2 M(0) (eg. Fe, Sn, Ca) Scheme II Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO,, or an alternative NO, source. Nitroaryls may be further elaborated prior to reduction.
Thus, nitroaryls substituted with
HNO
3 Ar-H 0 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).
OzN ArSH 12 02N rSSH SH Br-Ar 13 R CuO base 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N.N-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an Sacid 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 Srearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea 0 may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic I0 amine.
N Het-NH 2 16
H
2 N-Ar 19
COCI
2 COC12
H
2 N-Ar O Het-NH 2 Het-NCO Het-, Ar 4 OCN-Ar 17 H H 18
N
3 DPPA
N
3
DPPA
0 0 0 0 Het- X Hetl-OH X Ar HO-Ar 21 22 23 24 S Scheme IV Selected Methods of Urea Formation (Het heterocycle) l-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed by treatment with phosgene or a phosgene equivalent. Reaction of anhydride 25 with an aryl amine can generate acid 26 which may spontaneously decarboxylate, or may be isolated. If isolated, decarboxylation of acid 26 may be induced upon heating.
R
1
RI
1) OH- S S C NH 2 2) COC 2 NH RO2C N
O
9
-H
2 N-Ar
R
S N N' Ar NI, Ar H H N N 27
HO
2 C H H 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.
The invention also includes pharmaceutical compositions including a compound of Formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or sublingually, rectally or vaginally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for.preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing 26 the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal, temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien; "Transdermal Controlled Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. W094/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated
C,-C
8 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cg-C,, fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic 27 acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -CG, fatty alcohols, saturated or unsaturated C 8 -CI, fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components.
Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
28 It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of, factors, all of which are considered routinely when administering therapeutics.
It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Attorney Docket BAYER 8 V1, filed on December 22, 1997, as Serial No.
08/996,343, converted on December 22, 1998.
The compounds are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), through the general preparative methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed, according to procedures disclosed below. The following examples are for illustrative purposes only and are not intended, nor should they be construde to limit the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg.
All temperatures are reported uncorrected in degrees Celsius Unless otherwise indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification. Thinlayer chromatography (TLC) was performed on Whatman pre-coated glass-backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the following techniques: ultraviolet illumination, exposure to iodine vapor, immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, immersion of the plate in a cerium sulfate solution followed by heating, and/or immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science" silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (8 0.00) or residual protonated solvent (CHCI 3 8 7.26; MeOH 8 3.30; DMSO 6 2.49) as standard. Carbon NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC, 8 77.0; MeOD-d 3 8 49.0; DMSO-d 6 8 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 uA. Liquidcesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (1x10 4 torr to 2.5x10 4 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan.
HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett- Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy eV).
Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. All ureas displayed NMR spectra, LRMS and either elemental analysis or HRMS consistant with assigned structures.
List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl cone concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone
I
DMF N.N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate EtOH ethanol (100%) EtO diethyl ether Et 3 N triethylamine m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoles 0
CN
Step 1. 3-Oxo-4-methylpentanenitrile: A slurry of sodium hydride (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 *C for 15 min., then a solution of acetonitrile (13.5 mL, 258 mmol) in benzene (52 mL) was added dropwise via addition funnel followed by a solution of ethyl isobutyrate (15 g, 129 mmol) in benzene (52 mL). The reaction mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water mL) via addition funnel. The organic layer was separated and set aside. EtOAc (100 mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (conc. HCI) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgSO,), and concentrated in vacuo to give the acyanoketone as a yellow oil which was used in the next step without further purification.
N I 0
NH
2 Step 2. 5-Amino-3-isopropyllsoxazole: Hydroxylamine hydrochloride (10.3 g, 148 mmol) was slowly added to an ice cold solution of NaOH (25.9 g, 645 mmol) in water (73 mL) and the resulting solution was poured into a solution of crude 3-oxo-4methylpentanenitrile while stirring. The resulting yellow solution was heated at 50 *C for 2.5 hours to produce a less dense yellow oil. The warm reaction mixture was immediately extracted with CHCI 3 (3 x 100 mL) without cooling. The combined organic layers were dried (MgSO,), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% to afford the desired isoxazole as a yellow solid (11.3 g, mp 63-65 TLC R, CHC1I.,) 0.19; 'H-NMR (DMSO-d,) d 1.12 J=7.0 Hz, 6H), 2.72 (sept, Hz, 1H), 4.80 2H), 6.44 1H); FAB-MS m/z (rel abundance) 127 67%).
A3. General Method for the Preparation of 5-Amino-l-alkyl-3-alkylpyrazoles N1 N NH 2
NC
5-Amino-3-tert-butyl-l-(2-cyanoethyl)pyrazole: A solution of 4,4-dimethyl-3oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from hexane to 70% EtOAc/30% hexane) and the resulting _material was triturated (EtO/hexane) to afford the desired product (2.5 g, TLC hexane) R 1 0.31; 'H-NMR (DMSO-d,) 8 1.13 9H), 2.82 Hz, 2H), 4.04 J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 1H).
A 4. Synthesis of 3-Amino-5-alkvlthilop hen es tSynthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids
S
NH
0 Step 1. 7-tert-Bu tyl-2H-thileno[13,2-dloxazine-2,4(l H)-d ion e: A mixture of methyl 3 -amino-5-tert-butylthiophenecarboxylate (7.5 g, 35.2 mmol) and KOH (5.92 g) in MeOH (24 mL) and water (24 mL) was stirred at 90 'C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 mL). Phosgene (20% in toluene, 70 mL) was added dropwise over a 2 h period. The resulting mixture was stirred at room temperature overnight and the resulting precipitate was triturated (acetone) to afford the desired anhydride (5.78 g, 'H- NMR (CDCI,) 8 1 .38 9H), 2.48 IH), 6.75 I FA.B-MS m/z (rel abundance) 226 100%).
0 S k N~~N N N HOOC H H Step 2. N-(5-tert-Butyl-2-ca rboxy-3-th ienyl)-N' -(4-(4-pyridinylmethyl)phenyl)urea: A solution of 7-terl-butyl-2H-thieno[3,2-d~oxazine-2,4(IH)-dione (0.176 g, 0.78 mmol) and 4-(4-pyridinylmethyl)aniline (0.144 g, 0.78 mmol) in THIF (5 mL) was heated at the reflux temp. for 25 h. After cooling to room temp., the resulting solid was triturated with Et 2 O to afford the desired urea (0.25 g, mp 187-189 TLC (50% EtOAc/50% pet. ether) Rf 0.04; 'H-NMR (DMSO-d 6 8 1.34 9H), 3.90 2H), 7.15 1=7Hz, 2H), 7.20 1=3 Hz, 2H), 7.40 J=7 Hz, 2H), 7.80 (s lH), 8.45 J=3 Hz, 2H) 9.55 IH), 9.85 1H), 12.50 (br s, IH); FAB-MS m/z (rel abundance) 410 4 S N N NII H H Step 3. N-(5-tert-Butyl-3-thlenyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea: A vial containing N-(5-tert-butyl-2-carboxy-3-thienyl)-N '-(4-(4-pyridinylmethyl)phenyl)urea (0.068 g, 0.15 mmol) was heated to 199 oC in an oil bath. After gas evolution ceased, the material was cooled and purified by preparative HPLC (C-18 column; gradient from 20% CH 3 CN/79.9% H,0/0.1% TFA to 99.9% H,0/0.1% TFA) to give the desired product (0.024 g, TLC (50% EtOAc/50% pet. ether) R 0.18; 'H- NMR (DMSO-d 6 8 1.33 9H), 4.12 2H), 6.77 1H), 6.95 1H), 7.17 J=9 Hz, 2H), 7.48 J=9 Hz, 2H), 7.69 J=7 Hz, 1H), 8.58 1H), 8.68 J=7 Hz, 2H), 8.75 1H); EI-MS m/z 365 A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-alkyl-2-thiophenecarboxylate esters
S
NH3+ CI' 5-tert-Butyl-3-thiopheneammonium Chloride: To a solution of methyl tert-butyl-2-thiophene-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp. for 2.25 h. A conc. HCI solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 mL) and a saturated NaHCO, solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCI solution (150 mL), dried (NaSO 4 and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification.
Synthesis 3 -Amino-5-alkylthiophenes from N-BOC 3-Amino-5-alkvl-2thiophenecarboxylate esters S 0 MeO 2 C H Step I. Methyl 3 -(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxlate: To a solution of methyl 3-amino-5-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 OC was added di-tert-butyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and N.N-dimethylaminopyridine (86 g, 0.70 mol, 1.00 equiv) and the resulting mixture was stirred at room temp for 7 d. The resulting dark solution was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately The resulting red solids were dissolved in CH 2
CI
2 (3 L) and sequentially washed with a 1 M H 3
PO
4 solution (2 x 750 mL), a saturated NaHCO 3 solution (800 mL) and a saturated NaCI solution (2 x 800 mL), dried (Na 2
SO
4 and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 then treated with water (500 mL) to afford the desired product as an off-white solid (163 g, 'H-NMR (CDCI 3 8 1.38 9H), 1.51 (s, 9H), 3.84 3H), 7.68 1H), 9.35 (br s, 1H); FAB-MS m/z (rel abundance) 314 S 0
HO
2 C H Step 2. 3 -(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic Acid: To a solution of methyl 3-(tert-butoxycarbonylamino)-5-tert-butyl-2thiophenecarboxylate (90.0 g, 0.287 mol) in THF (630 mL) and MeOH (630 mL) was added a solution of NaOH (42.5 g, 1.06 mL) in water (630 mL). The resulting mixture was heated at 60 °C for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0 oC. The pH was adjusted to approximately 7 with a 36 N HCI solution (approximately 1 L) while maintaining the internal temperature at approximately 0 OC. The resulting mixture was treated with EtOAc (4 The pH was adjusted to approximately 2 with a 1.0 N HCI solution (500 mL). The organic phase was washed with a saturated NaCl solution (4 x 1.5 dried (NaSO,), and concentrated to approximately 200 mL under reduced pressure. The residue was treated with hexane (1 L) to form a light pink (41.6 Resubmission of the mother liquor to the concentration-precipitation protocol afforded additional product (38.4 g, 93% total yield): 'H-NMR (CDCI 3 8 1.94 9H), 1.54 9H), 7.73 1H), 9.19 (br s, 1H); FAB-MS m/z (rel abundance) 300
S
NH
3 Cl' Step 3. 5-tert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(tertbutoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HCI solution (4.0 M in dioxane, 12.5 mL, 0.050 mol, 5.0 equiv), and the resulting mixture was heated at 80 OC for 2 h. The resulting cloudy solution was allowed to cool to room temp forming some precipitate. The slurry was diluted with EtOAc (50 mL) and cooled to -20 The resulting solids were collected and dried overnight under reduced pressure to give the desired salt as an off-white solid (1.72 g, 'H-NMR (DMSO-d,) 8 1.31 9H), 6.84 J=1.48 Hz, 1H), 7.31 J=1.47 Hz, 1H), 10.27 (brs, 3H).
General Method for the Synthesis of HOC-Protected Pyrazoles
N
NNH
2 S-Amino-3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole: To a solution of 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CH 2 CI (140 mL) was added di-:err-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp. for 13 h, then diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired carbamnate (6.26 g, mp 63-64 TLC Rf acetone/95% CH 2
CI
2
'H-NMR
(DMSO-d 6 8 1.15 9H), 1.54 9H), 5.22 6.11 2H); FAB-MS m/z A6. General Method for the Synthesis of 2-Aminothiadiazoles N
NH
2 2 -Amino-5-(1-(I-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 with a concentrated N1-IOHsolution until basic. The resulting solids were filtered to afford 2-amino-S -ethyl)propyl)thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, mp 155-158 TLC MeOH/
CHCI
3 Rf 0.14; 'H-NMR (DMSO-d,) 8 0.80 J=7.35 Hz, 6H), 1.42-1.60 (in, 2H), 1.59-1.71 2H), 2.65-2.74 1H), 7.00 (br s, 2H); HPLC ES-MS m/l 172 A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles
O
,NH2 Step 1. Isobutyric Hydrazide: A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60 °C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, which was used inb the next step withour further purification.
/-0
NJ
N
NH
2 Step 2. 2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 KHC0 3 (0.102 and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 The resulting mixture was heated at the refulx temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH,CI, mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO 4 and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 AS. General Method for the Synthesis of 2-Aminooxazoles 0
OH
Step 1. 3,3-Dimethyl-l-hydroxy-2-butanone: A neat sample of 1-bromo-3,3dimethyl-2-butanone (33.3 g) at 0 OC was treated with a IN NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (NaSO 4 and concentrated under reduced pressure to give 3 3 -dimethyl-l-hydroxy-2-butanone (19 g, 100%), which was used inb the next step withour further purification.
-K
O- NH 2 Step 2. 2 -Amino-4-isopropyl-1,3-oxazole: To a solution of 3,3-dimethyl-lhydroxy-2-butanone (4.0 g) and cyanimide (50% w/w, 2.86 g) in THF (10 mL) was added a IN NaOAc solution (8 mL), followed by tetra-n-butylammonium hydroxide (0.4 M, 3.6 mL), then a IN NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with Et,O (3 x mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CHCI2 (3 x 25 mL). The combined organic layers were dried (Na,SO 4 and concentrated under reduced pressure to afford 2-Amino-4isopropyl-1,3-oxazole (1.94 g, HPLC ES-MS m/z 141 A9. Method for the Synthesis of
N-N
N
N
NH
2 To a solution of 5-aminotetrazole (5 NaOH (2.04 g) and water (25 mL) in EtOH (115 mL) at the reflux temperature was added 2-bromopropane The resulting mixture was heated at the reflux temperature for 6 d, then cooled to room temperature, and concentrated under reduced pressure. The resulting aqueous mixture was washed with CH,CI, (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1- and 2 -isopropyl-5-aminotetrazole which was used without further purification: HPLC ES-MS m/z 128 B. General Methods for Synthesis of Substituted Anilines c BI. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene
N
H
2 Nic -N I 4-(4-Pyridinylmethyl)aniline: To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g, S32.68 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 N'H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite*. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 'H-NMR (DMSO-d 6 8 3.74 2H), 4.91 (br s, 2H), 6.48 J=8.46 Hz, 2H), 6.86 J=8.09 Hz, 2H), 7.16 J=5.88 Hz, 2H), 8.40 J=5.88 Hz, 2H); El- MS m/z 184 This material was used in urea formation reactions without further purification.
General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H20 (0.5 mL) in AcOH 5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H20 (50 mL), basified to pH 10 by adding solid K,CO, in portions (Caution: foaming). The organic layer was washed with a saturated NaCI solution, dried (MgSO), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as-a thick oil (0.135 g, TLC (30% EtOAc/70% hexanes) R 0.20.
41 la. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N 0OMe Step 1. l-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was added dropwise a solution of 4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, then a solution of 1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then cooled to room temp., quenched with HO, and concentrated in vacuo.
The residue was partitioned between EtOAc (200 mL) and H,O (200 mL) The organic layer was sequentially washed with H,O (2 x 200 mL), a saturated NaHCO, solution (200 mL), and a saturated NaCl solution (200 mL), dried (NaSO,), and concentrated in vacuo. The residue was triturated (Et,O/hexane) to afford 1methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDCI 3 8 3.83 (s, 3H), 6.93-7.04 6H), 8.18 J-9.2 Hz, 2H); EI-MS m/z 245
H
2 N OMe Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of I-methoxy-4-(4nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C g) and the resulting slurry was shaken under a H, atmosphere (50 psi) for 18 h.
The reaction mixture was filtered through a pad of Celite' with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR
(CDCI
3 8 3.54 (br s, 2H), 3.78 3H), 6.65 J=8.8 Hz, 2H), 6.79-6.92 6H); EI- MS m/z 215 3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
CF
3 0 2 NS
N
Step 1. 3-(Trlfluoromethyl)-4-(4-pyridinylthlo)nitrobenzene: A solution of 4mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with EtO (100 mL) and water (100 mL) and the aqueous layer was back-extracted with EtO (2 x 100 mL). The organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The solid residue was triturated with Et,O to afford the desired product as a tan solid (3.8 g, TLC (30% EtOAc/70% hexane) R 0.06; 'H-NMR (DMSO-d 6 8 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 J=8.7 Hz, 1H), 8.46 (dd, J=2.4, 8.7Hz, 1H), 8.54-8.56 3H).
CF
3
H
2 N
N
Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for 4 h. The mixture was diluted with Et 2 O (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 (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 TLC (50% EtOAc/50% hexane) R,0.10; 'H-NMR (DMSO-d 6 8 6.21 2H), 6.84-6.87 3H), 7.10 J=2.4 Hz, 1H), 7.39 J=8.4 Hz, 1H), 8.29 J=6.3 Hz, 2H).
13c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 43 SN S 0 2 Na
N
Step 1. 4-(2-(4-Phenvl)thiazolyl)thio-l-nitrobenzene: A solution of 2-mercapto-4phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4nitrobenzene (2.3 mL, 21.7 mmoles) followed by K,C0 3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65 IC overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCI solution (100 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated with a Et 2 O/hexane solution to afford the desired product (6.1 TLC (25% EtOAc/75% hexane) Rf 0.49; 'H-NMR (CDCI 3 7.35-7.47 (in, 3H), 7.58-7.63 (mn, 3H), 7.90 J=6.9 Hz, 2H), 8.19 J=9.0 Hz, 2H-).
S S
H
2 N
N
Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio- I -nitrobenzene was reduced in a manner analagous to that used in the preparation of 3- (tri fluoromethyl)-4-(4-pyridinylthio)ani line: TLC (25% EtOAc/75% hexane) Rf 0.18; 'H-NMR (CDCI 3 8 3.89 (br s, 2H), 6.72-6.77 (mn, 2H), 7.26-7.53 (in, 6H), 7.85-7.89 (in, 2H).
d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0
N
0 2
N'N
Step 1. 4-(6-Methyl-3-pyridinyloxy)-1-nitrobenzene: To a solution of 2-methylpyridine (5.0 g, 45.8 inmol) and 1-fluoro-4-nitrobenzene (6.5 g, 45.8 inmol) in anh DMF (50 mL) was added K 2 C0 3 (13.0 g, 91.6 inmol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined-organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na,SO 4 and concentrated in vacuo to afford the desired product (8.7 g, The this material was carried to the next step without further purification.
0
N
HN O Step 2. 4-(6-Methyl-3-pyridinyloxy)anillne: A solution of 4-(6-methyl-3pyridinyloxy)-l-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite" and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, EI-MS m/z 200 3e. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 Nc OMe Step 1. 4 3 ,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4dimethoxyphenol (1.0 g, 6.4 mmol) and 1-fluoro-4-nitrobenzene (700 uL, 6.4 mmol) in anh DMF (20 mL) was added K,CO 3 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (NaSO 4 and concentrated in vacuo to afford the desired product (0.8 g, The crude product was carried to the next step without further purification.
0 OMe
H
2 N OMe Step 2. 4-(3,4-Dimethoxyphenoxy)aniline: A solution of 4-(3,4-dimethoxyphenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to Pd/C (0.100 g) and the resulting mixture was placed under a H. atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite' and concentrated in vacuo to afford the desired product as a white solid (0.6 g, EI-MS m/z 245 3f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N' O Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added 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 were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na,S0 4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product g, 32 This material was used in the next step without further purification.
H
2
N
S Step 2. 3-(3-Pyridinyloxy)aniline: A solution of 3-(3-pyridinyloxy)-lnitrobenzene (2.0 g, 9.2 mmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resulting mixture was placed under a H 2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil (1.6 g, EI-MS m/z 186 33g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
N
Step 1. 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxy- (5.0 g, 45.8 mmol), 1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper(I) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K,CO (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 by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%).
H
2 N O" Step 2. 3-(5-Methyl-3-pyridinyloxy)-l-nltrobenzene: A solution of 3-(5-methyl-3pyridinyloxy)-l-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to Pd/C (0.100 g) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite" and concentrated in vacuo to afford the desired product as a red oil (0.9 g, CI-MS m/z 201 33h. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 0 Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4 g, 50 mmol, 1.25 equiv) and K 2 CO, (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred overnight at room temp. The resulting mixture was treated with water (600 mL) to generate a precipitate. This mixture was stirred for 1 h, and the solids were separated and sequentially washed with a 1 N NaOH solution (25 mL), water (25 mL) and pet ether (25 mL) to give the desired product (7.05 g, mp 80-82 TLC EtOAc/70% pet ether) Rf 0.79; 'H-NMR (DMSO-d 6 8 2.31 3H), 7.08 (d, J-8.46 Hz. 2H), 7.19 J=9.20 Hz, 1H), 7.24 J=8.09 Hz, 2H), 8.58 (dd, J=2.94, 8.82 Hz, 1H), 8.99 J=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 100%).
CI^ CI' CI- H 3 N
CI"
Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochloride: A solution nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 The reaction mixture was then placed under a H, atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celite®. A solution of HCI in Et 2 O was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, mp 208-210 *C (dec); TLC (50% EtOAc/50% pet ether) Rf 0.42; 'H-NMR (DMSO-d 6 8 2.25 3H), 6.98 J=8.45 Hz, 2H), 7.04 J=8.82 Hz, 1H), 7.19 J=8.09 Hz, 2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H), 8.63 J=2.57 Hz, 1H); EI-MS m/z (rel abundance) 100%).
31. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N S s Step 1. 4-(3-Thienylthio)-l-nitrobenzene: To a solution of 4-nitrothiophenol 1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper(II) oxide (0.5 g, 3.7 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1 mmol), and the resulting mixture was heated at 130 OC with stirring for 42 h and then allowed to cool to room temp. The reaction mixture was then poured into a mixture of ice and a 6N HCI solution (200 mL) and the resulting aqueous mixture was 48 extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a 1M NaOH solution (2 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (MgSO), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, GC-MS m/z 237
H
2 N S
S
Step 2. 4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B1.
B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction H N N 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7 mmol) were added. The mixture was heated to 100 OC for 18 h and at 130 °C for 48 h at which GC-MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp. and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCI solution (2 x 50 mL), dried (MgSO), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).
3k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Br OMe Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction 49 mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (N4aSO 4 and concentrated under reduced pressure to give a pale yellow, volatile oil 4 .1g, 95% yield): TLC (10% EtOAc hexane) R,0.57.
HO '-NOMe Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an nbutyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture ofa 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a IN HCI solution then extracted with Et,O (2 x 100 mL). The combined organic layers were dried (NaSO 4 and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 0 2 N N OMe Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-1-nitrobenzene: To a stirred slurry of NaH 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp. for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mnixture was heated to 95 OC overnight, then treated S 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, N N Me
H
2 N N OMe Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline: 4 -(5-(2-Methoxy)pyridyl)oxy-lnitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
H
2 N S 3-(4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K,CO, (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100mL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et,O/hexane solution to afford the desired product (4.6 g, TLC (100 ethyl acetate) R, 0.29; 'H-NMR (DMSO-d 6 6 5.41 2H), 6.64-6.74 3H), 7.01 J=4.8, 2H), 7.14 J=7.8 Hz, 1H), 8.32 J=4.8, 2H).
General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
H
2
N
4-(2-Methyl-4-pyridinyloxy)aniline: To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100 °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 (NaSO 4 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, CI-MS m/z 201 B4c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine Me
"=N
0 2 N
N
Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4nitroaniline (2.0 g, 13.2 mmol) and K,CO, (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at 90 OC 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 (NaSO,) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4nitrophenyl)-4-pyridylamine (0.42 g) Me
H
2 N- a
N
Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4pyridylamine was reduced in a manner analogous to that described in Method B 1.
General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene 0 2 N S Step 1. 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitrophenylthio)phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C until gas evolution stopped (15 min), then a solution of iodobutane (1.12 g, .690 ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 OC. The reaction was stirred at room temp. for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL). The resulting mixture was extracted with Et,O (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL), dried (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 product as a yellow solid (1.24 g, TLC (20% EtOAc/80% hexane) R,0.75; 'H- NMR (DMSO-d,) 8 0.92 J= 7.5 Hz, 3H), 1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 6.6 Hz, 2H), 7.08 J=8.7 Hz, 2H), 7.17 J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 8.09 J= 9 Hz, 2H).
H
2 N S r 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 TLC (33% EtOAc/77% hexane) R 0.38.
B6. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes
H
2 N N o
H
4-(4-tert-Butoxycarbamoylbenzyl)aniline: To a solution of 4,4'-methylenedianiline (3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of ditert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp. for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-tert-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp. for 16 h. The resulting mixture was diluted with Et,O (200 mL), sequentially washed with a 53 saturated NaHCO, solution (100 ml), water (100 mL) and a saturated NaCI solution mL), dried (MgSO4), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a white solid 2.09 g, TLC (50% EtOAc/50% hexane) R 0.45; 'H-NMR (DMSO-d 6 6 1.43 9H), 3.63 2H), 4.85 (br s, 2H), 6.44 J=8.4 Hz, 2H), 6.80 J=8.1 Hz, 2H), 7.00 J=8.4 Hz, 2H), 7.28 J=8.1 Hz. 2H), 9.18 (br s, 1H); FAB-MS m/z 298 General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction O2N4
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 OC. The resulting mixture was allowed to cool to room temp. then poured into ice water (350 mL). The aqueous mixture then made basic with a IN NaOH solution, then extracted with Et,O (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO 4 and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g. GC- MS m/z 214
"'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.
General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction
N
0 2 N N
N
Step 1. 4-(l-Imidazolylmethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K,CO 3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at rooom temp. for 18 h and then poured into water (200 mL) and the resulting aqueous solution wasextracted with EtOAc (3 x 50 mL). The combined organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x mL), dried (MgSO,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, EI-MS m/z 203
H
2 N N Step 2. 4-(1-lmidazolylmethyl)aniline: 4-(1-Imidazolylmethyl)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.
Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction
OH
2 N
N
Step 1. 4-(1-Hydroxy-l-(4-pyridyl)methyl-l-nitrobenzene: To a stirred solution of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CHC, (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 oC, and the mixture was stirred at room temp. overnight.
The reaction mixture was successively washed with a 10% NaHSO 3 solution (50 mL), a saturated K 2 CO, solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO 4 and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous NH 3 solution (30 mL).
The mixture was stirred at room temp. for 1 h, then was concentrated under reduced pressure. The residue was poured into a mixture of water (50 mL) and CHC1 2 mL). The organic layer was dried (MgSO,), concentrated under reduced pressure. and purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired product as a white solid. (0.53 g, mp 110-118 TLC (80% hexane) RfO.12; FAB-MS m/z 367 100%).
OH
H
2 N
N
Step 2. 4-(1-Hydroxy-l-(4-pyridyl)methylaniline: 4-(1-Hydroxy-l-(4-pyridyl)methyl-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
Formation of 2-(N-methylcarbamoyl)pyrldines via the Menisci reaction 0 CI' NH 2
AN
Step 1. 2-(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added cone. HSO 4 (3.55 mL) (exotherm). To this was added H 2 0 2 (17 mL, 30% wt in H20) followed by FeSO 4 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for Ih then was heated slowly over 4 h at 45 OC. When bubbling subsided,the reaction was heated at 60 OC for 16 h. The opaque brown solution was diluted with H20 (700 mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCI solution (3 x 150 mIL. The combined organics were dried (MgSO,) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc 50% hexane to 80% EtOAc hexane). The resulting yellow oil crystallized at 0 OC over 72 h to give 2-(Nmethylcarbamoyl)-4-chloropyridine in yield (0.61 g, TLC (50% hexane) R 0.50; MS; 'H NMR (CDCI 3 d 8.44 1 H, J 5.1 Hz, CHN), 8.21 (s, 56 1WH CHCCO), 7.96 (b s, I1H, NH), 7.43 (dd. I H. J 2.4, 5.4 Hz, CICHCN), 3.04 (d.
3H, J 5.1 Hz. methyl); Cl-MS m/z 171 B11. Generalmethod for the Synthesis of to-Sulfonylphenyl Anilines ZI1 I L M 0 2 N AM Step 1. 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4methylthiophenoxy)-1I-ntirobenzene (2 g, 7.66 mmol) in CHCI 2 (75 mL) at 0 IC was slowly added 'PjCPBA (57-86%. 4 and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated under reduced pressure to give 4 4 -methylsulfonylphenoxy)- 1nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsu Ifonylphenoxy)-1 -aniline: 4-(4-Methylsulfonylphenoxy)- 1nitrobenzene was reduced to the aniline in a manner anaologous to that described in Method B3d, step 2.
B12. General Method for Synthesis of w-Alkoxy-w-carboxyphenvl Anilines 0 0I OMOMe 0 2 N.'aMe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution of -(3-carboxy-4-hydroxyphenoxy)-l1-nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added K,C0 3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat the reflux tempoerature overnight, then cooled to room temperature and filtered through a pad of Celite~. The resulting solution was concentrrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography EtOAc 50% hexane) to give 4 -(3-methoxycarbonyl-4-mcthoxyphenoxy)-lnitrobenzene as a yellow powder (3 mp 115 118 'C.
0
OH
0 2 N' I e OMe Step 2. 4 -(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene (1.2 KOH (0.33 g),and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated at the reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HCI solution.
The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4 and concentrated under reduced pressure to give 4-(3-carboxy-4methoxyphenoxy)- 1 -nitrobenzene (1.04 g).
C. General Methods of Urea Formation Cla. Reaction of a Heterocyclic Amine with an Isocyanate 0 0
S)
N N H H N-(5-tert-Butyl-3-thienyl)-N'-(4-phenoxyphenyl)urea: To a solution of butyl-3-thiophene-ammonium chloride (prepared as described in Method A4b; 7.28 g, 46.9 mmol, 1.0 equiv) in anh DMF (80 mL) was added 4-phenoxyphenyl isocyanate (8.92 g, 42.21 mmol, 0.9 equiv) in one portion. The resulting solution was stirred at 50-60 °C overnight, then diluted with EtOAc (300 mL). The resulting solution was sequentially washed with HO (200 mL), a 1 N HCI solution (50 mL) and a saturated NaCI 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, which was contaminated with approximately 5% of bis(4phenoxyphenyl)urea. A portion of this material (4.67 g) was purified by flash chromatography EtOAc/27% CH 2 CI2/64% cyclohexane) to afforded the desired product as a white solid (3.17 g).
Clb. Reaction of a Heterocyclic Amine with an Isocyanate '0 N N H H N-3tr-uy--sxzll-'(-hnxpev~ra To a solution of aino- 3 -ert-butyl isoxazol e (8.93 g, 63.7 mmol, 1 eq.) in CH-.CI. (60 ml-) was added 4-phenyloxyphenyl isocyanate (15.47 g, 73.3 mmol, 1. 15 eq.) dropwise. The mixture was heated at the reflux temp. for 2 days, eventually adding additional CH 2 CI, 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, mp 182-184 0 C; TLC acetone/95% acetone) Rf 0.27; 'H-NMR (DMSO-d,) 8 1.23 9H), 6.02 1H), 6.97 (dd, J=0.2, 8.8 Hz, 2H), 6.93 J=8.8 Hz, 2H), 7.08 J=7.4 Hz, 1H), 7.34 (in, 2H), 7.45 (dd, J=2.2, 6.6 Hz, 2H) 8.80 lH), 10.04 (s, IH); FAB-MS m/z (rel abundance) 352 Cic. Reaction of a Heterocyclic Amnine with an Isocyanate N 0 0 N N N H H H
N-(
3 -tert-Butyl-5-pyrazolyl)-N-(4-(4-methylphenyl)oxyphenyl)urea: A solution of 5-amnino-3-tert-butylpyrazole (0.139 g, 1.0 inmol, 1.0 equiv) and 4-(4methylphenoxy)phenyl isocyanate (0.225 g, 1.0 minol 1.0 equiv) in toluene (10 mL) was heated at the reflux temp. overnight. The resulting mixture was cooled to room temp and quenched with MeOH (a few mL). After stirring for 30 min, the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, mp 204 TLC acetone/95% CHCl 2 Rf 0.92;'H-NMR (DMSO-d,) 8 1.22 9H), 2.24 3H), 5.92 1H), 6.83 J=8.4 Hz, 2H), 6.90 J=8.8 Hz, 2H), 7.13 J=8.4 Hz, 2H), 7.40 1=8.8 Hz, 2H), 8.85 11H), 9.20 (br s, I 11.94 (br s, I El-MS m/z 364 Cid. Reaction of a Heterocyclic Amin e with an Isocya nate S 0 N Nq CI H H C1 N-(5-tert-Butvl-3-thlenyl)-N'-(2,3-dich Iorophenyl)urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-tert-butylthiophenearnmonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2,3-dichiorophenyl isocyanate (0.32 mL, 2.02 mmol) in CH.,Cl, (10 mL) to clarify the mixture and the resulting solution was stirred at room temp. overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHCO, solution (15 mL), a IN HCl solution (15 mL) and a saturated NaCI solution (15 mL), dried (NaS0 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, mp 169-170 TLC (20% EtOAc/80% hexane) R, 0.57; 'H- NMR (DMSO-d 6 6 1.31 9H4), 6.79 1H), 7.03 IH), 7.24-7.33 (in, 8.16 (dd, 1=1.84, 7.72 Hz, 1H), 8.35 IH), 9.60 li-I); 3 C-NMR (DMSO-d 6 6 31.9 34.0, 103.4, 116.1, 119.3, 120.0, 123.4, 128.1, 131.6, 135.6, 138.1, 151.7, 155.2; FAB-MS m/z (rel abundance) 343 345 347 12%).
Cle. Reaction of a Heterocyclic Amin e with an Isocyanate N N N CI H H H razo lyl)-N'.(3,4-d ich lorop hen yl)u rea: A solution of 3-tert-butyl-N'-(tert-butoxycarbonyl)pyrazole (Method AS; 0.150 g, 0.63 minol) and 3,4-dichlorophenyl isocyanate 118 g, 0.63 mrnol) were in toluene (3.1 mL) was stirred at 55 'C for 2 d. The toluene was removed in vacuc and the solid was redissolved in a mixture of CH,C1, (3 mL) and TFA (1.5 mL). After 30 min, the solvent was removed in vacuo and the residue,was taken up in EtOAc (10 mL). The resulting mixture was sequentially washed with a saturated NaHCO 3 solution (10 mL) and a NaCI solution (5 mL), dried (NaSO,), and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 40% EtOAc/ 60% hexane to 5% hexane) to give the desired product (0.102 g, mp 182-184 OC; TLC (40% EtOAc/60% hexane) R/0.05, FAB-MS m/z 327 i. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline
N.
0 N=C=O Step 1. 3 -tert-Butyl-5-isoxazolyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CH,C1, (20 mL) at 0 oC was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-tert-butylisoxazole (0.305 g, 2.18 mmol). The resulting solution was allowed to warm to room temp. over 1 h, and then was concentrated under reduced pressure. The solid residue dried in vacuo for 0.5 h.
o s N N N IN H H Step 2. N-(3-tert-Butyl-5-isoxazolyl)-N'(4-(4-pyridinylthlo)phenyl)urea: The crude 3 -tert-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4-(4-pyridinylthio)aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 oC for 2 h then cooled to room temp. and diluted with an EtOAc/CH,CI, solution 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgSO,), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CHC1, to 4% MeOH/6% CH,CI) to afford a foam, which was triturated (Et-O/hexane) in combination with sonication to give the product as a white powder (0.18 g, TLC CHCI,) R 0.21; 'H-NMR (DMSO-d,) 5 1.23 9H), 6.06 1H), 6.95 61 J=5 Hz. 2H), 7.51 J=8 Hz, 2H), 7.62 J=8 Hz, 2H), 8.32 J=5 Hz. 2H), 9.13 1H), 10 .19 1H); FAB-MS nm/ 369 Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline N N=C=O Step 1. 5-tert-Butyl-3-isoxazolyl Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CHC1, (1 L) was added butylisoxazole (10.0 g, 71 mmol) followed by pyridine (46 mL, 569 mmol). The mixture was allowed to warm to room temp and stirred overnight (ca. 16 then mixture was concentrated in vacuo. The residue was dissolved in anh. THF (350 mL) and stirred for 10 min. The orange precipitate (pyridinium hydrochloride) was removed and the isocyanate-containing filtrate (approximately 0.2 M in THF) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) m/z 166 NN
S
H H Step 2. N-(-tert-Butyl-3-isoxazoly)-N-(4-(4-pyridinylthio)phenyurea: To a solution of 5-tert-butyl-3-isoxazolyl isocyanate (247 mL, 0.2 M in THF, 49.4 mmol) was added 4-(4-pyridinylthio)aniline (5 g, 24.72 mmol), followed by THF (50 mL) then pyridine (4.0 mL, 49 mmol) to neutralize any residual acid. The mixture was stirred overnight (ca. 18 h) at room temp. Then diluted with EtOAc (300 mL). The organic layer was washed successively with a saturated NaCI solution (100 mL), a saturated NaHCO3 solution (100 mL), and a saturated NaCI solution (100 mL), dried (MgSO4), and concentrated in vacuo. The resulting material was purified by MPLC (2 x 300 g silica gel, 30 EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 mp 178-179 OC; 'H-NMR (DMSO-d 6 8 1.28 9H), 6.51 62 1H), 6.96 J=6.25 Hz, 2H), 7.52 J=8.82 Hz. 2H), 7.62 J=8.83 Hz. 2H), 8.33 J=6.25 Hz, 2H), 9.10 1H), 9.61 IH); EI-MS n/z 368 SReaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline N N N H H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH,CI, (13 mL) at 0 °C was slowly added pyridine (0.105 mL) was added slowly over a 5 min, then 4-(4pyridinyloxy)aniline (0.250 g, 1.3 mmol) was added in one aliquot causing a transient yellow color to appear. The solution was stirred at 0 °C for 1 h, then was allowed to warm to room temp. over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-tert-butyl- N'-(terr-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 OC for 12 h forming a white precipitate. The solids were dissolved in a IN HCI solution and allowed to stir at room temp. for 1 h to form a new precipitate. The white solid was washed (50% Et,0/50% pet. ether) to afford the desired urea (0.139 g, mp >228 OC dec; TLC (10% MeOH/ CHCI,) R/0.239; 'H-NMR (DMSO-d) 5 1.24 9H), 5.97 1H), 6.88 J=6.25 Hz, 2H), 7.10 J=8.82 Hz, 2H), 7.53 J=9.2 Hz, 2H), 8.43 J=6.25 Hz, 2H), 8.92 (br s, 1H), 9.25 (br s, 1H), 12.00 (br s, 1H); EI-MS m/z rel abundance 351 24%).
a. Reaction of a Heterocyclic Amine with N,N'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline 63 N N N I H H N-(3-tert-Butyil-m nethyl-5-pyrazolyl)-N '-(4-(4-pyridinyloxy)phenyvl)u rea: To a solution of 5-amino-3-tert-butyl-l1-methylpyrazole (189 g, 1 .24 mol) in anh. CH,CI, (2.3 L) was added NNW-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The mixture was allowed to stir at ambient temperature for 5 h before adding 4-(4pyri dinyloxy)an iline. 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 The organic layer was dried (NaSO,) and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et 2 O/ll1.2%/ hexane, 2.5 L) to afford the desired urea as a white solid (230 g, mp 149-152 'H-NMR (DMSO-d 6 8 1.18 911), 3.57 (s, 3H), 6.02 1H), 6.85 J=6.0 Hz, 7.08 J=9.0 Hz, 7.52 J=9.0 Hz, 8.40 J=6.0 Hz, 2H), 8.46 lH), 8.97 1H); FAB-LSIMS m/z 366 Reaction or a Heterocyclic Amnine with NN'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline N N "N H H H -(3-(4-pyridinylth io)p hen yl)u rea: To a solution of -amino- 3 -ert-butylI-N-(Ieri-butoxycarbonyl)pyrazo Ie (0.282 g, 1.18 mmol) in CH,C1 2 (1.2 ml) was added NN'-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 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp. for I day. Then resulting solution was treated with a 10% citric acid solution (2 mL) and was allowed to stir for 4 h. The organic layer was extracted with EtOAc (3 x 15 mL), dried (MgSO,), and concentrated in vacuo. The residue was diluted with CH,CI, (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, then extracted with CH,Cl, (3 x 15 mL). The combined organic layers were dried (MgSO., and concentrated in vacuo. The residue was purified by flash chromatography MeOH/95% CH,Cl 2 The resulting brown solid was triturated with sonication (50% Et,0/50% pet. ether) to give the desired urea (0.122 g, 28%): mp >224 OC dec; TLC MeOH/ 95% CHCI 3 Rf 0.067; 'H-NMR (DMSO-d 6 6 1.23 9H), 5.98 1H), 7.04 (dm, J=13.24 Hz, 2H), 7.15-7.19 1H), 7.40-7.47 2H), 7.80-7.82 1H), 8.36 (dm, .=15.44 Hz, 2H), 8.96 (br s, 1H), 9.32 (br s, 1H), 11.97 (br s, 1H); FAB-MS m/z (rel abundance) 368 100%).
.Reaction of Substituted Aniline with N,N'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine N NN
N
H H N-(3-tert-Butyl-l-methyl-5-pyrazolyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea: To a solution of 4-(4-pyridinylmethyl)aniline (0.200 g, 1,08 mmol) in CHC1, (10 mL) was added N,N'-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for 1 h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-amino-3-tert-butyl-1methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 oC overnight. The reaction mixture was cooled to room temp and purified by column chromatography (gradient from 20% acetone/80% CH,CI, to 60% acetone/40% CH 2 CI,) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, TLC (4% MeOH/96% CH,CI 2 R/0.15; 'H-NMR (DMSO-d 6 6 1.19 9H), 3.57 3H), 3.89 2H), 6.02 1H), 7.14 J=8.4 Hz, 2H), 7.21 J=6 Hz, 2H), 7.37 J=8.4 Hz, 2H), 8.45-8.42 3H), 8.81 1H); FAB-MS m/z 364 Reaction of Substituted Aniline with NN'-Carbon,*l dlimldazole Followed by% Reaction with a Heterocyclic Amine N 0 N N N 0 S H H H N-(3-tert-Butyl-5-pyrazolyl)-N-(3-(2-benzothlazolvloxv)phenvl)urea: A solution of 3 -(2-benzothiazoly loxy)ani line (0.24 g, 1.0 mmol, 1 .0 equiv) and N.N'carbonyldilmidazole (0.162 g, 1.0 mmol, 1.0 equiv) in toluene (10 mL) was stirred at room temp for I h. 5-Amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol) was added and the resulting mixture was heated at the reflux temp. overnight. The resulting mixture was poured into water and extracted with CH,CI, (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CHCI 2 Petroleum ether was added and resulting white precipitate was resubmitted to the crystallization protocol to afford the desired product (0.015 g, mp 110- 111 TLC acetone/95% CH 2 ClI) Rf 0.05; 'H-NMR (DMSO-d 6 8 1.24 9H), 5.97 IH), 7.00-7.04 (in, 11H), 7.21-7.44 (in, 411), 7.68 k5.5 Hz, 1H), 7.92 .1=7.7 Hz, I 7.70 I1H), 8.95 I 9.34 (br s, 1IH), 11.98 (br s, I El- MIS m/z 408 Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline 0~ 0
N
S N 0N H H uty 1-3- th ienyl)-N rid in yloxy)p heny 1) urea: To an ice cold solution phosgene (1 .93M in toluene; 0.92 mL, 1 .77 mmol) in CH 2
CI
2 (5 mL) was added a solution of 4-(4-pyridinyloxy)aniline (0.30 g, 1.61 minol) and pyridine (0.255 g, 3.22 mmol) in CH,CI, (5 mL). The resulting mixture was allowed to warm to room temp. and was stirred for 1 h, then was concentrated under reduced pressure. The 66 residue was dissolved in CH,CI, (5 mL), then treated with butylthiopheneammonium chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h. then treated with 2-(dimethylamino)ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHCO 3 solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na-SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% hexane to 100% EtOAc) to give the desired product (0.38 g TLC hexane) R 0.13; 'H-NMR (CDCI 3 6 1.26 9H), 6.65 J=1.48 Hz, 1H), 6.76 (dd, J=1.47, 4.24 Hz, 2H), 6.86 J=1.47 Hz, IH), 6.91 J=8.82 Hz, 2H), 7.31 J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 J=1.47 Hz, 2H); 13C-NMR
(CDC
3 6 32.1 34.4, 106.2, 112.0 116.6, 121.3 121.5 134.9, 136.1, 149.0, 151.0 154.0, 156.9, 165.2; FAB-MS m/z (rel abundance) 368 100%).
General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine N
N
H H N-(3-terr-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 (l.OmL) was added a solution of 5-amino-4-methyl-3-tert-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL).
The reaction mixture was stirred at 70 "C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was-stirred at 40 "C for 3 h and then at RT for 17-h to produce a precipitate. The solids were washed with EtO and hexanes to give the desired urea as a beige solid (25 mg, mp 179-181 OC; 'H-NMR (DMSO-d 6 6 1.28 9H), 2.47 67 3H), 3.86 2H), 7.22 J=7.3 Hz, 1H), 7.34 2H), 7.51 J=7.3 Hz, 1H), 7.76 3H), 8.89 1H). 9.03 1H); HPLC ES-MS m/z 362 C6. General Method for Urea Formation by Curtius Rearrangement and Carbamate Trapping 0 N 3 Step 1. 5-Methyl-2-(azidocarbonyl)thiophene: To a solution of 5-Methyl-2thiophenecarboxylic acid (1.06 g, 7.5 mmol) and Et 3 N (1.25 mL, 9.0 mmol) in acetone mL) at -10 OC was slowly added ethyl chloroformate (1.07 mL, 11.2 mmol) to keep the internal temperature below 5 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 CH 2 C, (10 mL) and washed with a saturated NaCI solution (10 mL). The aqueous layer was back-extracted with CHCI 2 (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, Azidoester (100 mg, 0.6 mmol) in anhydrous toluene mL) was heated to reflux for 1 h then cooled to rt. This solution was used as a stock solution for subsequent reactions.
OCN
Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp. for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions.
0 s H H Step 3. N-(5-tert-Butyl-3-isoxazolyl)-N'-(5-methyl-2-thienyl)urea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp.
68 was added 3 -amino-5-tert-butylisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a 1 N HCI solution (2 x 25 mL) and a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was purified by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, mp 200-201 TLC (20% EtOAc/80% hexane) R,0.20; EI-MS m/z 368 C7. General Methods for Urea Formation by Curtius Rearrangement and Isocyanate Trapping
CI,
CHO
Step 1. 3-Chloro-4,4-dimethylpent-2-enal: POCI, (67.2 mL, 0.72 mol) was added to cooled (0 OC) DMF (60.6 mL, 0.78 mol) at rate to keep the internal temperature below 20 OC. The viscous slurry was heated until solids melted (approximately OC), then pinacolone (37.5 mL, 0.30 mol) was added in one portion. The reaction mixture was then to 55 °C for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCI solution (200 mL), dried (NaSO,) and concentrated under reduced pressure. The residue was filtered through a pad of silica (CHCl1) to give the desired aldehyde as an orange oil (15.5 g, TLC hexane) R0.54; 'H NMR (CDCI 3 d 1.26 9H), 6.15 J=7.0 Hz, 1H), 10.05 J=6.6 Hz, 1H).
CO2Me Step 2. Methyl 5-tert-butyl-2-thiophenecarboxylate: To a solution of 3-chloro- 4,4-dimethylpent-2-enal (1.93 g, 13.2 mmol) in anh. DMF (60 mL) was added a solution of NaS (1.23 g, 15.8 mmol) in water (10 mL). The resulting mixture was stirred at room temp. for 15 min to generate a white precipitate, then the slurry was treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids.
C" The reaction mixture was stirred at room temp. for 1.5 h, then treated with a 1 N HCI solution (200 mL) and stirred for 1 h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HCI solution (200 mL), water (2 x 200 mL) and a saturated NaCl solution (200 mL), dried (Na,SO,) and concentrated under reduced pressure. The residue was purified using 0column chromatography EtOAc/95% hexane) to afford the desired product (0.95 Sg, TLC (20% EtOAc/80% hexane) R/ 0.79; 'H NMR (CDCI 3 8 1.39 9H), O 3.85 3H), 6.84 J=3.7 Hz, 1H), 7.62 J=4.1 Hz, 1H); GC-MS m/z (rel 0 abundance) 198
CO
2
H
Step 3. 5-tert-Butyl-2-thiophenecarboxylic acid: Methyl 5-tert-butyl-2thiophenecarboxylate (0.10 g, 0.51 mmol) was added to a KOH solution (0.33 M in MeOH/10% water, 2.4 mL, 0.80 mmol) and the resulting mixture was heated at the reflux temperature for 3 h. EtOAc (5 mL) was added to the reaction mixture, then the pH was adjusted to approximately 3 using a 1 N HCI solution. The resulting organic phase was washed with water (5 mL), dried (Na 1 SOJ), and concentrated under reduced pressure (0.4 mmHg) to give the desired carboxylic acid as a yellow solid (0.067 g, TLC (20% EtOAc/79.5% hexane/0.5% AcOH) Rf 0.29; 'H NMR (CDCl,) 8 1.41 9H), 6.89 J=3.7 Hz, 1H), 7.73 J=3.7 Hz, 1H), 12.30 (br s, 1H); 'C NMR (CDC13) 6 32.1 35.2, 122.9, 129.2, 135.1, 167.5, 168.2.
~S 0 H^\ H H
CI
Step 4. N-(5-tert-Butyl-2-thienyl)-N'-(2,3-dichlorophenyl)urea: A mixture of tert-butyl-2-thiophenecarboxylic acid (0.066 g, 0.036 mmol), DPPA (0.109 g, 0.39 mmol) and Et 3 N (0.040 g, 0.39 mmol) in toluene (4 mL) was heated to 80 °C for 2 h, 2,3-dichloroaniline (0.116 g, 0.72 mmol) was added, and the reaction mixture was heated to 80 0 C for an additional 2 h. The resulting mixture was allowed to cool to room temp. and treated with EtOAc (50 mL). The organic layer was washed with a 1 N HCI solution (3 x 50 mL), a saturated NaHCO 3 solution (50 mL), and a saturated NaCI solution (50 mL), dried (Na.SO 4 and concentrated under reduced pressure.
The residue was purified by column chromatography EtOAc/95% hexane) to afford the desired urea as a purple solid (0.030 g, TLC (10% hexane) Rf0.28; 'H NMR (CDCI 3 6 1.34 9H), 6.59 (br s, 2H), 7.10-7.13 2H), 7.66 (br s, 1H), 8.13 (dd, J=2.9, 7.8 Hz, 1H); 3C NMR (CDCI 3 6 32.2 34.6, 117.4, 119.07, 119.1', 119.2, 121.5, 124.4, 127.6, 132.6, 135.2, 136.6, 153.4; HPLC ES-MS m/z (rel abundance) 343 100%), 345 347 14%).
C8. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a triphosgene solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).
The vial was capped and heat at 80 OC for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase
HPLC.
D. Misc. Methods of Urea Synthesis DI. Electrophylic Halogenation N N Br H H N-(2-Bromo-5-tert-butyl-3-thienyl)-N'-(4-methylphenyl)urea: To a slurry of tert-butyl-3-thienyl)-N'-(4-methylphenyl)urea (0.50 g, 1.7 mmol) in CHC, (20 mL) at 71 room temp was slowly added a solution of Br, (0.09 mL. 1.7 mmol) in CHCI 3 (10 mL) via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure, and the residue triturated (2 x EtzO/hexane) to give the brominated product as a tan powder (0.43 g, mp 161- 163 OC; TLC (20% EtOAc/ 80% hexane) R/0.71; 'H NMR (DMSO-d 6 6 1.29 9H), 2.22 3H), 7.07 J=8.46 Hz, 2H), 7.31 J=8.46 Hz, 2H), 7.38 1H), 8.19 (s, IH), 9.02 1H); "C NMR (DMSO-d 6 8 20.3, 31.6 34.7, 89.6, 117.5, 118.1 129.2 130.8, 136.0, 136.9, 151.8, 155.2; FAB-MS m/z (rel abundance) 367 98% 369 100%).
D2. Synthesis of o-Alkoxy Ureas 0 0 SNOAN O OH H H Step 1. N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-hydroxyphenyl)oxyphenyl)urea:
A
solution of N-(5-tert-butyl-3-thienyl)-N'-( 4 4 -methoxyphenyl)oxyphenyl)urea (1.2 g, 3 mmol) in CH,C1 2 (50 mL) was cooled to -78 OC and treated with BBr3 (1.0 M in CHCl 2 4.5 mL, 4.5 mmol, 1.5 equiv) dropwise via syringe. The resulting bright yellow mixture was warmed slowly to room temp and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), then washed with a saturated NaHCO, solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na 2 SO), and concentrated under reduced pressure. The residue was purified via flash chromatography (gradient from hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan foam (1.1 g, TLC (20% EtOAc/80% hexane) R 0.23; 'H NMR (DMSO-d 6 8 1.30 9H), 6.72-6.84 7H), 6.97 J=1.47 Hz, 1H), 7.37 (dm, J=9.19 Hz, 2H), 8.49 1H), 8.69 1H), 9.25 1H); FAB-MS m/z (rel abundance) 383 33%).
0 0 H H Step 2. N-(S-tert-Butyl-3-thienyI)-N'.(4-(4.ethoxyphenyl)oxyphenyl)urea: To a mixture of N-(5-terz-butyl-3-thienyl)-N 4 4 -hydroxyphenyl)oxyphenyl)urea (0.20 g, mmol) and Cs,C0 3 (0.18 g, 0.55 mmol, 1.1 equiv) in reagent grade ac-etone 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 powder 16 g, mp 15 5-156 IC; TLC (20% EtOAC/ 80% hexane) Rf 0.40; 'H- NMR (DMSO-d 6 6 1.30 9H), 1.30 J=6.99 Hz, 3H), 3.97 1=6.99 Hz, 211), 6.80 J=1.47 Hz, 1H), 6.86 (din, 1=8.82 Hz, 211), 6.90 4H), 6.98 1=1.47, 1H), 7.40 (din, 1=8.83 Hz, 2H), 8.54 1H), 8.73 1H); 3 C-NMR (DMSO-d 6 8 14.7, 32.0 33.9, 63.3, 102.5, 115.5 116.3, 118.4 119.7 119.8 (2C), 135.0, 136.3, 150.4, 152.1, 152.4, 154.4, 154.7; FAB-MS m/z (rel abundance) 411 D3. Synthesis of w-Carbamnoyl Ureas NN ,N I H H
H
N-(3-tert-Bu tyl-lI-methyl-5-pyrazolyl)-N-(4-(4acetaminophenyl)methylphenyl)u rea: To a solution of N-(3-teri-butyl- 1-methyl-S.
pyrazolyl)-N'-(4-(4-aminophenyl)methylphenyl)urea (0.300 g, 0.795 mmol) in CH,CI, mL) at 0 'C was added acetyl chloride (0.057 mL, 0.795 minol), followed by anhydrous EtN (0.111 mL, 0.795 mnmol). The solution was allowed to warmn to room 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 purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid 160 g, TLC (EtOAc) R, 0.33, 'H-NMR (DMSO-d 6 6 1.17 (s, 9H), 1.98 3H), 3.55 3H), 3.78 2H), 6.00 IR), 7.07 J=8.5 Hz, 2H), 7.09 J=8.5 Hz, 2H), 7.32 J=8.5 Hz, 2H), 7.44 J=8.5 Hz, 2H), 8.38 lH), 8.75 I1H), 9.82 I FAB-MS ni/z 420 General Method for the Conversion of Ester-Containing Ureas into Alcohol- Containing Ureas Nj 0 N N N I CI HO\> H H
CI
N-(N'-(2-Hydroxyethyl)-3-eert-b utyl-5-pyrazolyl)-N '-(2,3-dichlorophenyl)urea: A solution of pyrazolyl)-N-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH 0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at -65 *C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (3 mL). The resulting organic phase was washed with a saturated NaCI solution mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was crystallized (Et,O) to afford the desired product as a white solid 17 g, 64 TLC EtOAc/40% hexane) Rf 0. 16; 'H-NMR (DMSO-d 6 6 1.23 9H), 3.70 J=5.7 Hz, 2H), 4. 10 1=5.7 Hz, 2H), 6.23 I1H), 7.29-7.32 (in, 2H), 8.06-8.09 (mn, I H), 9.00 (br s, I 9.70 (br s, I FAB-MS m/z (rel abundance) 3 71 100%).
General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas
NN
HO) H H N' 0 74 Step 1. N-(N'-(Carboxymethyl)-3-terv-butvl -5-pyrazolyl)-N dichlorophenyl)u rca: A solution of N-(N',(ethoxycarbonylmethyl pyrazolyl)-N'-(2,3-dichlorophenyl)urea (prepared as described in Method A3. 0.46 g, 1.11 mmoles) and NaOH (1.2 mL, 5N in water, 6.0 mmoles) in EtOH (7 mL) was stirred at room temp. for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (4 mL). The resulting organic phase was washed with a saturated NaCi solution (25 mL), dried (MgSO,) and concentrated under reduced pressure. The residue was crystallized (Et.,O/hexane) to afford the desired product as a white solid (0.38 g, TLC (10% MeOH/90% CH2CI2) Rf 0.04; 1 H-NMR (DMSO-d 6 5 1.21 9H), 4.81 2H), 6.19 11H), 7.28-7.35 (in, 2H1), 8.09-8.12 (in, IH), 8.76 (br s, I 9.52 (br s, I1H); FAB-MS m/z (rel abundance) 3 85 100%).
MeHN .r H
)C
0 Step 2. ethylIca rb amoyl) methyl)-3-terl-bu tyl-5-py razoly dichlorophenyl)u rea: A solution of pyrazolyl)-N'-(2,3-dichlorophenyl)urea (100 mg, 0.26 minole) and NN'carbonyldiimidazole (45 mg, 0.28 mmole) in CH,Cl, (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetonef50% CHCl,) Rf 0.81). Dry methylaniine hydrochloride (28 mg, 0.41 minole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 minole). The reaction mixture was stirred at room temp. overnight, then diluted with
CHCI
2 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% CHCI, to
CH
2
CI
2 and the residue was crystallized (Et,O/hexane) to afford the desired product (47 mg, TLC (60% acetone/40% CHIC1 2 Rf 0.59; 'H-NMR (DMSO-d,) 8 1.20 9H), 2.63 J=4.5 Hz, 3H), 4.59 2H), 6.15 IH), 7.28- 7.34 (nm, 2H), 8.02-8.12 (mn, 2H), 8.79 (br s, 1H), 9.20 (br s, 1H): FAB-MS nilz (rel abundance) 398 General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas 01 0 N N N C2 H H C 2 Step 1. N-(5-tert-Butyl-3-isoxazolyl)-N '-(4-(4-carboxypbenyl)oxyphenyl)u rea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N 4 4 -ethoxyoxycarbonylphenyl)oxyphenyl)urea (0.524 g, 1.24 mmol) in a mixture of EtCH (4 mL) and THF (4 mL) was added a IM NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HCl solution (20 mL) to form a white precipitate. The solids were washed with water (50 mL) and hexane (50 mL) and then dried (approximately 0.4 mmHg) to afford the desired product (0.368 g, 75 This material was carried to the next step without further purification.
0 0 N N N H H 0 Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(N-methylearbamoy
I)-
phenyl)oxyphenyl)urea: A solution of N-(5-terz-butyl-3-isoxazolyl)-N'-(4-(4carboxyphenyl)oxyphenyl)urea (0.100 g, 0.25 mmol), methylaniine (2.0 M in THF; 0.140 mL, 0.278 mmol), I -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 I M citric acid solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined extracts were sequentially washed with water (3 x mL) and a saturated NaCI solution (2 x 10 mL), dried (NaS,S0), filtered, and concentrated in vacuc The resulting crude oil was purified by flash chromatography 76 EtOAc/40% hexane) to afford the desired product as a white solid (42 mg, EI-MS m/z 409 General Method for the Conversion of o)-Amine-Containing Ureas into Amide- Containing Ureas 0 0
N
N N N
NH
2 H H N-(5-terl-Butyl-3-isoxazolyl)-N'-(4-(4-aminophenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-tert-butoxycarbonylaminophenyl)oxyphenyl)-urea (prepared in a manner analogous to Methods B6 then C2b; 0.050 g, 0.11 mmol) in anh 1,4-dioxane (3 mL) was added a cone HCI solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp The mixture was then poured into water (10 mL) and EtOAc(10 mL) and made basic using a 1M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO,), and concentrated in vacuo to afford the desired product as a white solid (26 mg, EI-MS m/z 367 D7. General Method for the Oxidation of Pyridine-Containing Ureas O N NN
N-
H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(N-oxo4-pyridinyl)methylphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-pyridinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHCI 3 (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated KCO solution (10 mL). After 5 min, the solution was diluted with CHCI 3 (50 mL). The organic layer was washed successively with a saturated aqueous NaHSO, solution (25 mL), a saturated NaHC0 3 solution mL) and a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated in 77 vacuc. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the N-oxide (0.082 g, 79%).
General Method for the Acylation of a Hydroxy-Containing Urea 01 00 N N N H H
N-(
5 -terl-Butyl-3-isoxazolyl)-N'-(4-(4-acetoxyphenyloxy)phenyl)urea: To a INDsolution of 5-teri-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 mL, 0.544 mmol) in anh THIF (5 mL) was added acetic anhydride (0.028 mL, 0.299 mmol), and the resulting mixture was stirred at room temp. for 5 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The resulting solution was sequentially washed with a citric acid solution (10 mL), a saturated NaHCO, solution (10 mL) and a saturated NaCI solution (10 mL), dried (Na.,S0 4 and concentrated under reduced pressure to give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmlig): TLC (40% EtOAc/60% hexane) Rf 0.55; FAB-MS m/z 410 D9. Synthesis of w-Alkoxypyridines 0' 0 N ixo ,I N N N N 0 H H H Step 1. N-(5-tert-Bu tyl-3-isoxazolyl)-N'-(4-(2(1H)-pyridinon-5-y)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 133k and C3b; 1.2 g, 3.14 mmol) and trimethylsilyl iodide (0.89 mL, 6.28 mmol) in CHCI, 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 78 EtOAc) to give the desired product (0.87 g. mp 175-180 OC; TLC EtOAc/20% hexane) R/0.05; FAB-MS m/z 369 100%).
o
O
N N N N OEt H H Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(5-(2-Ethoxy)pyridyl)oxyphenl)urea: A slurry of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(2( (0.1 g, 0.27 mmol) and AgCO, (0.05 g, 0.18 mmol) in benzene (3 mL) was stirred at room temp. for 10 min. Iodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite' then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, mp 146 TLC (40% hexane) R/0.49; FAB-MS m/z 397 100%).
DIO. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide- Containing Urea N N N" H H OH
OH
N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-(1-hydroxyethyl)phenyl)oxyphenyl)urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(1acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods B1 and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH 4 (0.008 g, 0.21 mmol) in one portion. The mixture was allowed to stir for 2 h at room temp., then was concentrated in vacuo. Water (20 mL) and a 3M HC1 solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (MgSO,), and concentrated in vacuo The resulting white solid was purified by trituration (Et 2 0/hexane) to afford the desired product (0.021 g, 32 mp 80-85 'H NMR (DMSO-d,) 8 1.26 9H), 2.50 3H). 4.67 1H).
5.10 (br s, 1H), 6.45 1H), 6.90 4H), 7.29 J=9.0 Hz, 2H), 7.42 J=9.0 Hz.
2H), 8.76 1H), 9.44 1H); HPLC ES-MS 396 1. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy- Substituted Ureas 0 0 Y0^ N] 0
OP
H
N N N O N O Ph H H N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-(benzyloxycarbonylamino)phenyl)oxyphenyl)urea: To a solution of the N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(3carboxyphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods B3a, Step 2 and C2b; 1.0 g, 2.5 mmol) in anh toluene (20 mL) was added 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 OC with stirring for 3 h then allowed to cool to room temp. The resulting mixture was poured into a 10% HCI solution (50 mL) and teh resulting solution extracted with EtOAc (3 x mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCI (2 x 50 mL), dried (NaSO,), and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 mp 73-75 OC; 'H NMR (DMSO-d 6 8 1.26 9H), 5.10 2H), 6.46 1H), 6.55 J=7.0 Hz, 1H), 6.94 J=7.0 Hz, 2H), 7.70 7H), 8.78 1H), 9.46 1H), 9.81 1H); HPLC ES-MS m/z 501 IND The following compounds have been synthesized according to the General Methods listed above: Table 1. 5-Substituted-3-isoxazoll Ureas
RI
NK .R 2 N N N H H Mass mp TLC Solvent Spec. Synth.
-Entry R' R, System [Sourcel Method -Bu 148- 352 Cic 149
_JFAB_
2 E-Bu 4 C1 176- 0.16 5% 386 C2b 177 MeOH/
[FAB]
CH2CI2 3 t-Bu CI 0.50 30% 400 C2b 0 MeEtOAc! 70% [HPLC hexane ES-MSl 4 t-Bu 156- 0.50 30% 366 C2b 157 EtOAc/ (MH)+
[HPLC
hexane ES-MSl t-Bu Me 0.80 40% 492 C2b Me EtOAc/ Me Et 60% [HPLC Me Et hexane ES-MS] 6 r-Bu 190- 0.15 30% 350 C2b N 191 EtOAc/ [El] hexane 7 t-Bu 0.55 20% 352 C2b EtOAc/
[FAB]
hexane 8 t-Bu 0.25 20% 367 C2b EtOAc! [El] hexane 9 t-Bu 0 0.15 20% 363 C2b EtOAc! [El] hexane t-Bu Me 0.30 20% 381 C2b S EtOAc!
[E]
______hexane 11 t-Bu N. 0.25 30% 425 B3b. C2b EtOAc/
[HPLC
hexane ES-MS 12 t-Bu 175- 0.25 30% 409 B3a. Step 177 EtOAc/ 1. 33b [HPLC Step 2.
hexane ES-MS C2b 13 i-Bu 0.35 30% 402 B3b, C2b EtOAc/
[HPLC
hexane ES-MSJ 14 i-Bu 0.20 30% 403 B3b, C2b EtOAc!
[HPLC
hexane ES-MS1 f-Bu 0.25 30% 419 B3b, C2b EtOAc/
[HPLC
hexane ES-MS1 16 i-Bu 0.20 30% 419 B3b, C2b EtOAc!
[HPLC
hexane ES-MS 17 t-Bu 0.40 30% 352 C2b EtOAc! 0-0 70% (HPLC hexane ES.MS1 18 t-Bu c ,i 0.40 30% 365 C2b EtOAc/ [EI] hexane 19 r-Bu 0 OH 0.15 30% 367 B3a, C2b.
EtOAc/ [El] D2 Step I hexane t-Bu S Me 200- 0.20 20% 280 C6 201 EtOAc/
[FAB)
hexane 21 i-Bu 178- 368 B4a, C2b 179 [ElI 22 t-Bu H 2 N 164- 0.25 30% 351 B1, C2b 165 EtOAc!
[FAB]
hexane 23 :-Bu H 2 N 170- 0.15 30% 351 B7, BI, L G/ 172 EtOAc! C2b
[FAB]
hexane 24 i-Bu l 179- 0.20 30% 387 C2b 182 EtOAc/
[FAB]
hexane t-Bu Q O 100.55 40% 410 B3b. C2b, 0 EtOAc/ D2 Step 1, Me 60% [FAB] D8 hexane 26 i-Bu Me 176- 0.55 25% 366 B3a. C2b 182 EtOAc!
[FAB]
hexane 27 t-Bu Me 0.40 25% 366 B3a. C2b 0- ELOAc! 75% [FAB] hexane 28 t-Bu Me 150- 0.45 25% 380 B3a, C2b o Me 158 EtOAc/ 75% [FAB] hexane 29 i-Bu HO 0.30 25% 368 C2b EtOAc/
[FAB]
hexane t-Bu cI 118- 0.50 25% 420 B3a Step 0 6 C1 122 EtOAc/ 1, B3b [FAB] Step 2, hexane C2b 31 1-Bu 3 195- 0.30 25% 397 C2b 197 EtOAc/ [FAB] hexane 32 i-Bu Me 0.80 25% 366 B3a, C2b EtOAc!
[FAB]
hexane 33 i-Bu _&OOe 155- 0.55 30% 382 3a, C2b 156 EtOAc/
[FAB]
hexane 34 t-Bu 137- 0.62 25% 410 B3a, C2b, 141 EtOAc/ D2
[FAB]
hexane t-Bu 0
J\
0 164- 0.60 25% 410 B3a, C2b, 166 EtOAc! D2
[FAB]
hexane 36 i-Bu OH 78-80 0.15 25% 368 C2b EtOAc/
[FAB]
hexane 37 i-Bu 167- 374 B3i, BI, 169 C2b
FABJ
38 i-Ru a O-aH 200 0.30 5% 396 B3a Step dec MeOH/ 2, C2b
[FAB]
AcOH/ 94.5% CH2CI2
IN
39 t-Bu COH 234 0.30 5% 396 B3a Step dec MeOH 2. C2b
[FAB]
AcOH/ 94.5% CH2CI2 r-Bu H, 203- 0.35 10% 340 B8. B2b.
F -N 206 MeOH C2b
[FAB)
AcOH/ 89.5% EtOAc 41 t-Bu 0 177- 419 B8. B2b, 180 C2b
[FAB]
42 t-Bu 158- 0.25 30% 369 B4a. C2b 159 EtOAcI N 70% [FAB] I _hexane 43 t-Bu CF 3 180- 0.15 30% 437 B4a, C2b S 181 EtOAcl SNj 4 70% [FAB] hexane 44 i-Bu t 140- 0.25 20% 396 B3a, C2b, 142 EtOAc/ D2
[FAB]
hexane N-u I 68-71 0.30 50% 370 B4a, C2b Et0Ac/
[FAB]
hexane 46 t-Bu N 183- 0.30 30% 403 C2b S C1 186 EtOAc/ [Cl] hexane 47 i-Bu 98- 0.25 10% 454 C2b 101 EtOAc!
F
3 C 90% [FAB] hexane 48 t-Bu O 163- 0.25 20% 394 B1, C2b 166 EtOAc/ Me 80%
[FAB]
hexane 49 t-Bu 144- 0.25 20% 399 C2b 49Y /S 147 EtOAc/
[FAB]
hexane :-Bu 0a OMe 155- 0.25 40% 383 C2b 157 EtOAc/
[FAB]
hexane 51 i-Bu S F 162- 0.35 25% 386 C2b 164 EtOAc/
[FAB]
hexane 52 r-Bu M 149- 0.15 15% 382 C2b 150 EtOAc/
[FAB]
hexane 53 t-Bu N 77-80 0.30 30% 408 3e. C2b
S
0 L EtOAc! [EI] hexane 54 t-Bu 162- 0.17 40% 354 B3j. C2b 164 EtOAcf (MH)+
[FAB]
hexane i-Bu N- 73-76 0.20 30% 368 B2. C2b EtOAc/ [EI] _hexane 56 t-Bu MeO 73-75 0.15 25% 428 B2. G2b EtOAc/
[FAB]
OMe hexane 57 i-Bu f V 143- 0.25 30% 398 B3e. C2b 145 EtOAc/
[FAB]
hexane 58 t-Bu 148- 0.25 30% 428 B3e. C2b ~J S Oe 151 EtOAc/ OMe 70% [FAB] hexane 59 I-Bu 0- 0.30 100% 353 B4b. C3b EtOAc
[FAB
i-Bu jQ J\ 126- 0.25 30% 412 B3e, C2b 129 EtOAc/ OMe 70% [FAB] hexane 1 61 t-Bu 0 201- 0.25 10% 396 B3a. C2b, 204 EtOAc/ D2 QEt 90% [FAB] I_ hexane 62 i-Bu N 163- 0.30 40% 369 B4a, C2b 164 EtOAc/
[FAB]
hexane 63 t-Bu 162- 0.20 25% 363 C2b 163 EtOAc/ [EI] 00 hexane 64 i-Bu NIN 127- 0.22 40% 353 B3e Step 129 EtOAc/ 1, B2, [FAB] C2b hexane t-Bu 0 85-87 0.20 50% 402 B3e Step EtOAc/ [El] 1, B2, C2b hexane 66 t-Bu NIeO 108- 0.25 10 381 B3e. C2b 110 EtOAc! [ElI hexane 67 t-Bu 0 NH, 186. 0.25 30% 367 B6, C2b 189 EtOAc! D6
[FAB]
hexane 68 t-Bu 221- 0.25 60% 409 B3e, C2b.
NHMe 224 EtOAc/ (MH)i-
[FAB]
hexane 69 t-Bu 0 114- 0.25 60% 409 B3e, C2b, -NHMe 117 EtOAc/
[FAB]
hexane z-Bu 0 201- 0.25 60% 423 B3e, C2b, -NW2 203 EtOAcf DSb
[FAB]
_hexane 71 t-Bu F 148- 0.25 20% 370 B3e, C2b 151 EtOAc!
[FAB]
hexane 72 t-Bu OMe 188- 0.25 20% 382 B3e, G2b 201 EtOAc/
[FAB]
hexane 73 t-Bu 134- 0.25 20% 367 B3e. C2b Me 136 EtOAc/
[FAB]
hexane 74 t-Bu 176- 0.25 50% 403 B3e, C2b Q\ 178 EtOAc/
[FAB]
hexane N-Bu -N 132- 0.52 40% 383 B3k, C3b OMe 134 EtOAc/
[FAB]
hexane 76 t-Bu 160- 0.79 75% 381 C3a N ONe 162 EtOAc!
[FAB]
hexane 77 t-Bu 140- 0.25 50% 352 B4b, C3b 143 EtOAc/ [El] 0 CN CH2CI2 78 t-Bu 147- 0.25 50% 352 B3f, C3b 150 EtOAc! [E 0- 0\-50% N CH2CI2 79 t-Bu 166- 0.44 50% 396 C3b 0 170 EtOAc! 0 50% (FAB] 1 hexane
IN
r-Bu 1 190- 0.25 50% 367 B3g. C3b -N 193 EtOAc/ 0 /Me 50% [FAB] CH2C12__ 81 r-Bu 136- 0.25 50% 367 B4b. C3b 140 EtOAcI
[FAB]
I CH2C12 82 r-Bu Me 65-67 0.25 50% 367 B4b. C3b EtOAc/
[FAB]
CH2Cl2 83 t-Bu Me 68-72 0.25 50% 383 B4a. C3b EtOAc/ 50% [FAB) CH2C12 84 t-Bu N 146 0.49 40% 397 B3k C3b, /OEt EtOAc! D9
[FAB]
hexane 1 t-Bu Me 164- 0.25 50% 382 B4a. C3b 165 EtOAc! [EI] -OS \N CH2CI2 86 i-Bu /-NH 175- 0.25 20% 485 B3e, C3b, Ph 0 177 EtOAc! 80% [FAB) 87 i-Bu 137- 0.30 50% 366 C3a, D2 /N OH 141 EtOAc/ [El] step 1 hexane 1 88 t-Bu Ph-NH 120- 0.25 20% 471 B3e. C3b, o 122 EtOAc!
[HPLC
hexane ES-MS1 89 t-Bu Et-NH 168- 0.25 50% 423 B3e. C3b.
o 170 EtOAc!
[HPLC
I_ ___1hexane ES-MSI i-Bu OH 80-85 0.25 50% 396 BI, C2b, EtOAc/ DIO
[HPLC
hexane ES-MSJ 91 t-Bu 0 73-75 0.25 30% 501 B3e, C3b.
04 EtOAc/
DII
Ph-/ NH 70% [HPLC hexane ES-MS] 92 t-Bu Me 0.50 5% 366 Bla acetone/
[FAB]
CH2CI2 93 t-Bu CF 3 199- 0.59 5% 419 Bla J\ 200 acetone/ [FAB] 0 -0 CH2CI2 94 i-flu CF3 0.59 5% 419 Ria acetone [FAB] CH2CI2 i-Bu Me 78-82 0.25 10% 379 B3e, COb EtOAc; [El] 0-9 Mep CH2C12 96 i-Bu O H 214- 0.75 60% 463 C2b, D3 O 217 EtOAc!
F
3 C 40% [FAB) hexane 97 t-Bu 235 0.35 25% 402 B3b, C2b EtOAci (M-rH)+v _____hexane 98 t-Bu 0153- 0.25 30% 424 B3e, C2b OEt 155 EtOAc! 70% [FAB] hexane 99 i-Ru -N 100 0.62 40% 411 B3a. BI, 0 OPr-i EtOAc/ (M+H)s COb
[FAB]
hexane 100 i-flu 7 110- 0.15 100% 367 O Y2CN 115 EtOAc Table 1. 5-Substituted-3-isoxazolvl Ureas continued N N N' H H Mass mp TLC Solvent Spec. Synth.
-Entry R' 29 System rsourcei Method 101 t-Bu 0 0.50 100% 410 B 10, R4b, /NHMe EtOAc COb N [FAR] 102 i-flu 0 153- 395 COb 155 FAR1 103 i-flu 0 0.52 100% 396 RBI, B4b,
NH
2 EtOAc C2b N
[HPLC
I_ ES-MS1 104 i-Ru 00.75 100% 396 B RIO, BOb,
-NH
2 EtOAc (Mi1)+ C2b O N~ E S -M S 1 105 t-Bu 0107- 0.85 1000% 410 BIO. 134b.
-NHMe 110 EtOAc C2b O\N-
[FAB]
106 i-Bu 0132- 133d step NH1 2 135 2, C3a 107 t-Bu 0 0.58 100% C3a. D~b NHPr-n EtOAc /N o 108 i-Bu 0 0.58 100% C3a, NHPr-i EtOAc 109 i-Bu 0 137- 0.62 100% 439 133a step NHMe 140 EtOAc 1, B12, [m HPLC D5b step ES-MS1 2. C3a 110 t-Bu 0 163- 0.73 100% 425 B3a step NHMe 166 EtOAc 1, B 12, C OH [HPLC D5b step 1 2, C3a 1II t-Bu -_'-O-aSOM 180- 133b step 181 1, BiI, 133d step C2a 112 t-Bu 0 135- B3b, C2a Oa Me 139 113 t-Bu 0~~O 212- B33d step 0-a S0 215 2a, C2a 114 t-Bu MeHN 0 98- B3d step S: 100 2, C2a 115 t-Bu ,~tNJO 135-BIBb NHe138 C2a 116 t-Bu 0 Oe219- 0.78 80% 437 C3a, D~b 221 EtOAc/ step 2 N hexane [HiPLC 117 t-Bu 0 160- B3a step r 164 1, 133d NH- step 2, C3a 118 t-Bu 0 124 0.39 5% Cic, NHMe MeOH/ N EtOAc/ hexane I 119 t-flu 73-75 0.41 100% 479 B3a. C4a, NHEtOAc NH [HPLC 0 ES-MS] 120 i-Bu 0 NHc0.32 1000/0 436 Clb. 0 NH 2 e EtOAc step 1, 1- [HPLC step 2 ES-MS1 121 i-flu C -_0.23 10% 506 d3a, C4a, NHMeOH/ o 90% [HPLG 0 /HC2
E-S
122 f-Bu 0.18 10% 506 B3a, C4a, N MeOHI Et* _NH 90% [HPLC o CH2C12 ES-MS] 123 I-flu o 229- 0.37 40% 435 D5b step 231 EtOAc/ 1, B3d N.M 60[HPLC step 2, hexane ES-MSI ICOa 124 t-flu 0.21 5% 508 B3a, C4a.
\NHMeOH/ o 95% [HPLC CH2C2
ES-MS]
125 t-flu 0 167- 0.34 5% 424 COb, NHEt 170 MeOH/ 4% [HPLC EtOAc/ ES-MS) ______hexane 126 t-Bu 0 124 0.26 5% COb, CI -NHMeMeH N EtOAc/ hexane 127 I-Bu 0 125- 0.28 5% COb, D~b Me NHMe 128 MeOH/ -1 10-CN45 EtOAc/ 128 r-Bu 0.37 50% 426 COb NliMe EtOAc! me /S /50% pet [HPLC ___ether ES-MS1 129 t-Bu 0 0.10 50% 424 COb NMe 2 EtOAc/ N 50% pet [HPLC I ether ES-MSI
139 r-Bu 0.27 541 C3b
S[HPLC
ES-MS]
N
140 t-Bu 0 211- 0.27 50% 426 C3b NHMe 212 EtOAc/ N 50% pet [HPLC ether ES-MS 141 t-Bu H 2 195- B8, C2a C-N 0 198 142 t-Bu CF 3 170- C3a 171 143 t-Bu Me 141- 0.63 5% 382 B3b step 144 acetone/ 1,2, Cld
[FAB]
CH2C12 144 r-Bu F 0.57 5% 386 B3b step -0 \acetone 1,2. Cid
[FAB]
CH2C12 145 t-Bu F 145- 0.44 5% 370 B3b step 148 acetone/ 1,2. Cld
[FAB]
CH2CI2 146 t-Bu F 197- 0.50 5% 404 B3b step 202 acetone/ 1,2, Cid
[FAB]
cCH2C12 147 t-Bu F 0.60 5% 404 B3b step acetone! 1,2. Cld
[FAB]
F CH2CI2 148 t-Bu Me 126- 0.17 30% 366 B4c, C4a 129 MeOHI
[FAB]
EtOAc 149 t-Bu H 2383 C3b C S- C\N(M+H)+
[HPLC
150 t-Bu 156- 0.48 40% 395 C3a. D2 N~.tt 159 EtOAc! stepl, step hexane [HPLC 2 151 t-Bu §Q HJ'\ 157- 0.51 409 C3a, D9 159 step 1, [HPLC step2 152 t-Bu 4 130- 0.60 437 C3a, D9 132 step 1, [HPLC step2
ES.MS
153 t-Bu 7 -H 146- 0.54 40% 6*9 uO C3i DY 150 EtOAc step I, step hexane [HPLC 2
ES-MSJ
154 t-Bu 145- 0.57 40% 423 C3a, D2 -N r 148 EtOAc! stepI, step hexane [HPLC 2
ES-MSI
155 -Bu 175- 0.51 40% 457 C3a, D2 /N 178 EtOAc/ step 1, step hexane [HPLC 2-
ES-MS]
156 :-Bu O 149- 0.48 40% 407 C3a, DI N 152 EtOAc/ step 1, hexane [HPLC step 2
ES-MSI
157 t-Bu 4\Et 146- 0.36 40% 409 C3a N-OMe 147 EtOAc! hexane [HPLC
ES-MSI
158 t-Bu Me/\ 156- 0.43 40% 395 C3a xjN OMe 158 EtOAcI hexane [FAB) 159 t-Bu S 164- 0.52 5% 396 B3b step 168 acetone! 1,2, Cld Me Me 95% (HPLC I CH2C12 ES-MS 160 t-Bu 0 -0 0.36 5% 380 B3b step acetone! 1,2, Cld Me Me 95% [FAB] _H2CI2 161 t-Bu 169- 368 C3b ~,Me 171
N
162 t-Bu 168 0.11 50% C3b EtOAc/ pet ether 163 t-Bu -Sm 146 C3b 164 t-Bu 0.45 100% 369 C2b EtOAc
[FAB]
\N
165 f-Bu /0.20 100% 367 B9, C2b EtOAc
[FAB]
HO N 166 i-Bu /1 C 187- 0.46 30% 421 C3b 188 EtOAc! C I hexane [FAB] 167 t-Bu lr\ 133 0.36 409 C3a, D9 step 1, y N1 [FAB] step2 168 t-Bu OPr-i 0.39 40% 411 O~a. D9 0 -NEtOAc/ (M+H)s step I O o N60% [FAB] step2 169 t-Bu OEt 0.32 5% 3 9 7 B3k, C8 0- Nacetone/ o 95% [HPLC CH2CI2 IES-MS1 170 I-Bu OMe 0.21 5% 383 B3k, C8 -acetone!
[HPLC
___CH2CI2 ES-MS1 171 z-Bu /\0.60 100% 365 C2b EtOAc N
[FAB]
172 t-Bu 0.16 30% 369 C8 EtOAc!
[HPLC
___hexane ES-MS1 173 t-Bu 0.09 5% COb N129 MeOH/ EtOAc/ hexane 174 t-Bu cO$ M 147- B3b, C2a 149 175 t-Bu 00.30 100% 380 O~a, D~b CNEtOAc step2
(HPLC
ES-MS1 176 r-Bu 00.50 25% 353 MS N EtOAc! B
F
3 C 75% [CI] 4b, C8 hexane Table 2. 3-Substituted-5-isoxazolyl Ureas N 0 O N N' H H Mass Spec.
mp TLC Solvent (Source] Synth.
Entry R' 0 C) R, System Method 177 Me 169. 0.25 5% 324 CIb .i-e 170 acetone/
[FAB)
CH2CI2 178 i-Pr 0. 153- 0.54 50% 338 Cib 156 EtOAc/ pet [FAB] 179 i-Pr 166- 0.54 50% 352 Clb 170 EtOAci pet [FAB] ether 180 i-Pr 112. 0.29 5% 355 A2.
117 MeOH/ B4a, [FAB] C3a CH2C12 181 i-Pr 0 0.08 50% 395 C8 )-NHMc EtOAc/
[HPLC
hexane ES-MSI 182 i-Pr 0 N 169- 0.20 50% 396 C3b 170 EtOAc/ N 50% pet [HPLC ether ES-MSI 183 i-Pr 0 -N 0.10 50 353 C8 EtOAc/
[HPLC
hexane ES-MS 184 i-Pr I 0.09 50 389 CS EtOAc/
[HPLC
hexane ES-MSj 185 i-Pr Me 0.23 30% 352 C8 EtOAc/
[HPLC
hexane ES-MS 186 i-Pr 0q~ N~ 9 t~l 1 194- 0.29 50% 396 C3b NHMe 195 EtOAc/ 0 N 50% pet [HPLC ether ES-MS 187 0.03 50% 401 CS Et0Ac/
[FAB)
hexane 188 351 C8 NY
[HPLC
ES-MS1 189 4> 175- 0.43 50% 364 Clb Me 0178 EtOAc/ pet [FAB) ether 190 t-Bu 0.21 5% 369 B4a, MeOH/ C2a
[FAB]
CH2CI2 191 t-Bu J 0.52 50% 426 B5, C4a EtOAc!
[FAB)
hexane 192 I-Bu 182- 352 Clb 184
FABJ
193 t-Bu -a 165 0.34 60% 366 Clb dec EtOAc pet [FAB) ether 194 t-Bu 210 0.05 5% 353 C3a dec acetone
[FAB]
CH2CI2 195 t-Bu a OMc 174- 0.25 5% 382 C3a 175 acetone:
[FAB)
CH2CI2 196 r-Bu /90-92 0.16 5% 409 C2a Nacetone/
[FAB]
s_ CH2CI2 197 i-Bu N 221 0.14 5% 409 C2a dec acetone/
[FAB)
CH2CI2 198 i-Bu N 196- 0.17 5% 368 A2, 0 O Me 198 MeOH/ B3h, N 95% [FAB] C3a CH2C2 199 i-Bu I 1 204- 0.27 50% 383 A2, 19 /206 EtOAc/ B3a, pet [FAB] C3a ether 200 t-Bu H 2 179. 351 A2, C3a C C N 180 I FFABJ 201 i-Bu sI-&Q 0.33 50% 414 A2, 201 BEtOAc/ [El] B4a, pet C3a ether 202 t-Bu S 0 188- 0.49 50% 399 A2, Se 189 EtOAc,' B4a, pet [HPLC C3a ether ES-MS1 203 i-Bu ~179. 0.14 5% 395 A2, 7 10180 MeOH/ B4a, [FAB) C3a CH2C02 204 i-Bu NI 197- 0.08 10% 353 A2, 199 acetone! B3h, N 90% [FAB] C3a CH2CI2 205 t-Bu Ci 136- 0.33 50% 421 A2, 0_ C 139 EtOAc/ B3h, 50% pet [FAB] C3a N_ ether 206 t-Bu 213 0.05 5% 369 C3a dec acetone/ N 95% [FAB] 1 CH2CI2 I I 207 i-Bu Me0.60 5% 274 C2a MeOH/
[FAB)
____CH2CI2 208 i-Bu F 118- 0.19 5% 387 A2, /F 121 MeOHI B4a.
[FAB] O~a CH2CI2 209 t-Bu 0 217- 0.18 5% A2, COb NHMc 219 MeOH/ CHC13 210 t-Bu 00.48 50% 394 C8 -0 -/MeEtOAc! Me50%
[HPLC
_____hexane ES-MS1 211 i-Bu \0j 0.17 30% 364 C8 -C -0EtOAcI
[HPLC
___hexane ES-MSI 212 :-Bu 0 0.79 70% 421 B3a \~0/(EtOAc/ step 1, NH 30% [HPLC B3d 0 hexane ES-MS] step 2, _C~a 213 t-Bu o 0.50 50% 407 B3a IEtOAc/ step I, Q 50% [HPLC B3d o hexane ES.MS] step 2, C3a 214 t-Bu 0 182- 0.25 5% 424 COb, NHEt 185 MeOH/ N\ 45% (HPLC EtOAc/ ES-MS) _____hexane 215 t-Bu 0 198- 0.20 5% 444 COb, NHMe 200 MeOHf \N 45% [HPLC EtOAc/ ES-MS] hexane 216 t-Bu 0 0.24 50% 426 COb NHMe EtOAc/ -Q -50% pet [HPLC NH~ 1 ether ES.MS1 217 t-Bu 0 215- 426 COb 218 I-Bu 0 NHe188- 0.22 50% 410 COb 0-N 50% pet [HPLC ther ES-MS1 219 i-BuI C-O--a 214- 1 l0.35 5% acetone/ CH2C12 1 1 A2. C2b 220 i-Bu y o-K 180 C3b 221 i-Bu 1 160- 0.58 50% 336 C3b 162 EtOAc/ [CI] pet ether 222 I-Bu S 0.18 50% C3b N EtOAc/ pet ether 223 t-Bu 163- 0.21 5% 453 C3b 165 MeOH/
[HPLC
CH2C12 ES-MSI 224 t-Bu 208- 0.17 5% 353 C3b 212 MeOH/
[FAB]
CH2C12 225 I-Bu 0 109- 0.17 5% 369 C3b 112 MeOH/
[FAB]
CH2CI2 226 I-Bu OCF, 155- 0.57 10% 453 C3b -a 156 MeOH/ CH2CI2 [FAB 227 i-Bu N-0 231- 0.54 10% 534 C3b NH 234 MeOH/ y o- 0 CH2C12 [FAB]
-&/NH
228 t-Bu 179- 0.24 5% A2. C3b -N 180 MeOH/ O\/Me CHC13 229 -Bu 0.30 5% 370 A2, Ob 229 t- /MeOH/
[FAB]
CHC13 230 t-Bu 0 Me 178- 0.20 5% A2. C3b au M 180 MeOH/
N
CHC13 231 t-Bu 186- 0.20 5% A2. C3b 187 MeOH/ Me CHC13 232 t-Bu 149- 0.28 5% A2. C3b 152 MeOH/ s CHC13 210- 0.06 10% 421 C3b 213 MeH/ [FA.Bi 234 I-Bu OMe 132- 0.43 5% A2. C3b 133 M e QH/ CHC13 235 -Bu /71-73 0.27 5% A2. C3b MeOHI O~U, CHC13 236 t-Bu Cl 176- 0.44 10% 437 C3b /y 177 MeOH/ CH2CI2
[FAB]
237 t-Bu H, 0.09 50 351 C8 C EtOAc/ N 50%
[HPLC
hexane ES-MS] 238 f-Bu N 0.16 50% 403 C8 EtOAc/
[HPLC
hexane ES-MSI 239 I-Bu 0 0.15 50 381 C8 EtOAc! Me 50% [HPLC hexane ES-MSI 240 -Bu 215- 0.19 100% 370 C3b 216 EtOAc
[HPLC
ES-MS]
241 i-Bu u 0.42 rz- MeOH/ CH2CI2 242 t-Bu 0.74 100% 366 B4b, C8 0 /EtOAc Me
[HPLC
ES-MS1 243 t-Bu 0.12 30% 421 C8 EtOAc/
F
3 C 70% [HPLC hexane ES-MS 245 t-Bu 0.68 100% 368 B4b, C8 EtOAc HO
[HPLC
ES-MSI
246 t-Bu -142- 0.13 5% A2,C3b N 144 MeI Um EtQAc/ hexane 247 t-Bu 0 205- 0.31 50% 410 C3b NHMe 207 EtOAc/ 0 N750% pet [HPLC O Nether ES-MSI 248 Me-L -et~ 5 [I 24 Me o154- 0.50 50% 365 Clb 155 EtOAc/ [El] Et 50% pet ether 249 Me ke -Oa 160- 0.37 5% 380 clb E xjO\\jM 162 acetone.;
[FAB)
____CH2CI2 250 Me ci ci 196- 0.58 5% 342 Clb -A-Me 199 acetone! Et 95%
[FAB]
CH2CI2 251 Me M a Oe137. 0.25 5% 396 A2Z M Oe 138 acetone! B3a.
Et 95% [FAB] Ca CH2CI2 /5 Me 0.18 5% 364 A2, C3a Et N- N\JN MeOH/
[EI]
Et CHC13 253 Me/\ 215- 383 A2, Me221 B4a, S-CN dec (FAB] C3a 254 Me C\ 187- 0.42 10% 383 A2, S- 188 MeOH/ B4a, Et CHC13 [FAB] C3a 255 Me 90-92 0.19 30% 366 A2, C3a -A-Me EtOAC/ [El] Et 70% pet /5 Me N 199- 0.33 70% 423 A2, kMe200 EtOAc/ B3e, Et 30% pet [FAB) C3a 258 Me 0 117- 0.14 5% A2,COb -k-Me NHMe 119 MeOH/ Et CHC13____ 259 Me 0 0.37 75% 409 C8 -Me u ~o EtOAc! Et Me25%
[HPLC
ES-MS1 260 Me 0 194- 0.25 50% 424 COb -4--Me NHMe 195 EtOAc! Et 50% pet [HPLC 0o ether ES-MS1 261 Me 0 216- 0.20 50% 424 COb Me NHMe 217 EtOAc! Et .<FO ~e 50% pet [HPLC ether ES-MSj 262 Me 6-501 5%A2, COb Me M6-6 018 5 Et -N eH s CHC13 263 Me 8-901 5%A2,COb -k-Me Me 86890.6 Et CHC13 264 Me 145- 0.32 5% A2. COb Et 146 -MeOH/ CHC13 265 Me 0.23 5% 381 A-2, C3b -k-e X M MeOHI
[FAB]
___CHC13 266 Me OMe 0.20 5% 396 A2. COb et acetone!
[FAB]
CH2CI2 267 Me 0.38 50 366 C 8 Et \EtO c0 050%
[HPLC
hexane ES-MS] 268 M e 0.14 50 36-7 C8 0 EtOAci
[HPLC
269__ hexane E S-M SI 269 Me 0.21 50 383 C8 COXMe EtOAc! Et N50%
[HPLC
_____hexane
ES-MSJ
270 Me H 2 -0.10 50 365 C8 CL0 -,EtOAc/ (M+H)i Et N 50%
[HPLC
hexane ES-MS1 271 Me H2 -0.14 50 365 C8 jjC \/EtOAcI Et N 50%
[HPLC
hexane ES-MS] 272 Me 0.35 50% 382 C8 E -QO 3 j EtOAc! HO 50% [HPLC hexane IES-MS1 273 Me 0.48 50% 382 C8 0 -Me EtOAcl EtOH 50% [HPLC hcxane ES-MS] 274 M 0.20 100% 367 B4b, C8 cEtOAc (M +H)4- 0-C\N[HPLC 275 Me
NE-S
\Me 0 o- 0.56 100% 435 B4b, C8 Et EtOAc
F
3 C
[HPLC
276 Me
E-S
-k-Me 0 0.57 75% 383 C 8 EtOAc/ (M+H)i-
[HPLC
____hexane ES-MS] 277 M 0.40 100% B3f, C8 Et o-~j)EtOAc 278 Me -Q---63-65 410 A2.C3a Et 279 Me-G 84 0.16 5% 381 A2. C3a -Et -MeOHf Et 95%
[FAB]
CHC13 280 N 189- 0.16 5% 397 A2, 192 MeOH/ B4a, [HPLC C3a CHC13 ES-MS 281 Me 189- 0.17 5% 397 A2, Et 191 MeOH/ B4a, S-CN 95% [FAB] C3a CHC13 282 Me 123- 414 A2. C3a -k-Et 0 125 Et- FAB_ 283 Me H2 -j 175- 0.16 5% 379 A2, C3a Et C L N 177 MeOH/ Et 95%
[FAB]
CHC13 284 Met 0 135- 0.33 5% A2. C3b Et 137 MeOH/ CHC13 285 Me 67 0.41 5% -t McA2. COb kEt MeOH/ CHC13 286 155- 0.38 5000 377 Clb 156 EtOAc/ [EI] pet ether 287 0.18 5% 379 A2, C3b MeOH/
[FAB]
CHC13 I I I Table 3. N'-Substituted-3-tert-butyl-5-pyrazoly Ureas N/ 0 2
R
2 N N N' 3 H H 291 Me 50 EtOAci h.P.~ 365
[HPLC
T:
292 H -N 366 S 366 C8 -0 M C(M +H [FAB] 293 H 0.53 50% 398 C8 EtOAc/
[HPLC
hexane ES-MS 294 H I I F369 C8
[HPLC
ES-MSJ
295 H 0 0.27 50% 351 CIc EtOAc/
[FAB]
hexane 296 H CI Cl 0.59 50% 327 Clc EtOAc!
[FAB]
hexane 297 H r-\H 2 0.30 60% 350 C4a C N acetone/
[FAB]
CH2C12 2 9 8 HQ 0.07 5% 368 B4a, MeOH/ C4a S-EN 95% [FAB] CHC13 299 H 0.18 5% 367 B4a, S C\N MeOH/ [EIj C4a CHC13 300 H 0 160- 408 A5, B6, HO CF N 161 C3b -NHe (FAB] isolated at TFA salt 301 H 0 C 228- 0.24 10% 351 C3a 232 MeOH/ [El] dec CHC13 302 H I 0 204 0.06 5% 364 C3b acetone/ [EI] CH2CI2 110- 0.05 5% 408 C3b 111acetone! (I 1 CH2CI2 304 Me H2 0.10 20% 380 C4a F\0CL\acetone/
(FAB]
CH2C02 103 305 Me 0 99- 0.19 100% 452 B3a -NHMe 101 EtOAc step 1, OMe (HPLC B12, ES-MS] DSb step 2, C3a 306 M e H,H, ,.0.48 30% 378 Bi. COa FJC C I N acetone!
[FAB]
CH2CI2 307 Me Me 135- 0.03 30% 408 C3a N OMe 137 EtOAc/
[HPLC
hexane ES-MS1 308 Me 0.35 70% 382 B4a, acetone/ G4a
[FAB]
CH2CI2 309 Me 0.46 70% 382 B4a, acetone/ C4a S- 30% [FAB] CH2CI2 310 Me CF3 0.32 70% 450 B3b, N acetone/ C4a 30% [FAB] CH2C02 311 Me S 0.09 50% 381 C4a EtOAc/
[FAB]
hexane 312 Me S OH 0.61 100% 397 B3c, EtOAc C4a
[FAB]
313 Me On 0.25 50% 453 135, C4a EtOAc!
[FAB]
hexane 314 Me I ~H2p=. 0.65 100% 462 B6, C4a NH EtOAc
[FAB]
i-Bu 315 Me I ~-H2p 0.67 100% 478 B6, C4a ~JC~JNH EtOAc _O [FAB] t-BuO 316 Me L 0.50 100% 378 G4a C NH2 EtOAc
[FABI
317 Me H 0.33 100% 420 C4a, D3 C NH EtOAc La =0[FAB] Me 318 Me H 0.60 10% 478 C4a, D3 N H water/ 0 90%
(FAB]
H
2 C CH3CN 319 Me H2 0.55 100% 434 C4a. D3 C 1JNH EtOAc
[FAB]
Et 320 Me 0.52 100% 380 C4a O-j NH 2 EtOAc
[ABI
321 Me C 0.25 60% 366 C4a acetone/
[FAB]
CH2CI2 322 Me -F -N 0.52 100% 452 C4a. D3 EtOAc EtO
[FAB]
323 Me H2 0.34 60% 396 C4a S CLCN acetone!
[FAB]
CH2C12 324 Me H 0.36 60% 396 C4a C \Nacetone
[FAB]
CH2CI2 325 Me 147- 365 CIc 149
[ABJ
326 Me HL, 161- 0.15 4% 364 C2b fC N 162 MeQH/ 96% [FAB] CH2C12 327 Me 228 379 C2b dec I I IFABI 328 Me 0.30 5% 422 C2b MeOH/ 1 95% [FAB] CH2C12 329 Me 0.46 100% 464 B3c.
I [FAB] 330 M e 0.52 100% 506 B3c, sJL) EtOAc G4a
CF
3
[FAB]
331 Me 0.75 100% 421 B3c, EtOAc C4a
[FAB]
332 Me 0 0.50 100% 465 B3c, S- -SCF 3 EtOAc C4a I FABJ 333 Me /0.50 100% 349 C4a EtOAc
[FAB]
334 Me 0.60 100% 4-1 B2. C4a 0 -OEtOAc
[FAB]
335 Me ~O+NH 0.52 100% 466 C4a. D3 EtOAc [FAB) 336 Me j\0.42 100% 439 B5, C4a ~~f\~fOP~lEtOAc FABI 337 -CH,-CF, 433 C3a O~j,
FABJ
338 -(CH,)ICN /\0.37 50% 404 A3, Cib EtOAc/
[HPLC
hexane IES-MS1 339 0 Me-NH 159- 508 A5, B6, 0 161 C2b t'B 0O4V [FAB] Table 4. 5-Substituted-2-thiadiazohl,. lreas s-S 0 H H Mass Spec, mp TLC Solvent [Source) Synth.
Enr R' (OC) R, Sstem Method 340 t-Bu a O~ 0.37 5% 399 E13a, C3a O~eMeOH/
[FAB]
CH2CI2 341 t-Bu 0.26 5% 370 O~a MeOH/
[FAB]
CH2CI2_ 342 t-Bu /\386 B4a, O~a
S-C\N[FAB]
343 t-Bu me~\ 0.30 5% 383 Clb jr-- acetone!
[FAB)
CH2CI2 344 i-Bu \1 0.60 10% 412 COb Me MeOH/ N CH2CI2 [FABI 345 t-Bu 0 245- 0.23 100% 456 B3a step J NHMe 250 EtOAc 1, B 12, 0 OM e [HLC D5b step ES-MS 1 2, C3a 346 r-Bu 0 0.10 50% COb NHMe EtOAc/ 0 50% pei ether 347 t-Bu 0 0.13 50% 441 COb NWe 2 EtOAc/ -70 CN 50% pe, [HPLC ____ether ES-MS1 348 t-Bu 0 0.14 5% 441 COb, NHEt MeOH/ N~ 45% [HPLC NEtOAc!
ES-MS]
hexane 349 t-Bu 0 0.23 5% 461 COb, Cl NHMe MeOR! 0 N45% [HPLC EtOAc/ ES-MS] hexane 350 t-Bu 0 0.09 5% 461 COb, CI 2 NHMe MeOH/ 0 'N 4% [HPLC EtOAc/ ES-MS] hexane t-Bu 0 Me NHMe 5% MeOI-U EtOAc/ 44'
[HPLC
ES-MSI
hexanc 352 t-Bu 0 159- 0.10 50% 427 COb NHMc 160 EtOAC/ N 50% pel [HPLC -ether ES-MS1 353 i-flu cI 0.47 10% 438 COb MeOH! -0 0/ Cl CH2C12 [FAB] C N 354 i-Bu 0.31 10% 371 COb 0/O\ MeOH/ ___CH2CI2 [FAR. 355 t-Bu CI 0.51 10% 400 COb \l MeOH/ O ClCH2CI2
[FAB]
356 I-flu \1 -0.43 10% 385 COb C /Me N N MeOH/ N__N CH2CI2 rFAj 357 i-Bu ~o -&~sme 0.70 10% 416 C b NMeOHI C112C2 rFABI 358 i-Bu 0.11 50 O/438 C8 X, EtOAc/
F
3 C 50% [[[LC ____hexane ES-MS1 359 i-flu 0.06 5% 432 COb ~rSji-~eMeOHI
[FAB]
CH2CI2_ 360 i-flu 0.20 50% 385 C8 -QEtOAc/ HO 50% [HPLC hexane ES-MS1 361 i-flu 107- 0.05 30% 412 C3a -N-/OMe 110 EtOAc/ 70% [HPLC hexane ES-MSI 362 i-flu /\0.16 100% 370 C8 EtOAc O-CN __C 363 Me 0 0.12 100% -k-Me NHEt EtOAc Et-2- 364 Me 0 183- B3d step MeNH, 185 2, C3a Et 365 Me 1yM0.19 6% 413 A6,C3b /t O-a o m MeOH! 94% [FAB] CHCI3 366 Me8 248- 0.34 6% A6. COb 366
N
Et 249 MeOH/ 94% ___CHC13 367 Me /\0.20 400 A6. COb Et S N[FAB] 368 Et o182- 0.33 5% A6.COb -0 \/Cl 183 MeOH/ Et kn I CHC13 369 Et 180- 0.19 5% A6,COb Et Sx N .181 MeOH/ CHC13 370 Et a -a m 168- 0.24 5% A6, COb Et 169 MeOHI Et CHC13 371 Et 168- 0.17 6% A6. COb Et O N 171 MeOH/ 94% CHC13 372 Et N 156- 0.19 6% A6, COb Et 158 MeOH/ 94% ___CHC13 Table 5.S-Substltuted-3-thienN-1 Ureas 0 St. NAN R 2 H H mp TLC Solvent Mass Synth.
Entry R' 0 C R, System Spec. Method 373 i-Bu O144- 0.68 5% A4b.
145 acetone! Cia CH2C2 374 t-Bu Me 0.52 30% 381 \Et2O/ pet [HPLC ether ES-MS 375 t-Bu0- e 0.26 30% 397 need Et2O/ recipie pet [HPLC ether ES-MS 376 t-Bu N 0.28 50% 368 need Et2O/ recipie pet [HPLC ether ES-M 377 r-Bu O -Me 57 381 A4a
[FAB]
378 t-Bu H2C 0.15 50% 365 A4a C N EtOAc/ [EI] pet ether 379 t-Bu 0 OH 0.44 50% 383 A4a EtOAc/ pet [FAB] ether 380 t-Bu S-N 384 A4a
(FAB]
381 t-Bu 176- 0.45 20% 425 D2 177 EtOAc/
[FAB]
I hexane I I Table 5. Additional Ureas Mass Spec.
mp TLC Solvent [Source] Synth.
Entry R2 (OC) R, System M ethod 382 161- 0.71 20% 367 DI Me 163 EtOAc/ 080% 369 S- N A hexane Br H H
AB_
110 383 145- 0.57 5% A2.
CI 0 147 MeOH; C3b N N 0 NN(aN-. CHC13 384 132- 0.33 5% 339 A9.
N 0acetone. (M+H Cd 1 H95% [HPLC ES- N N NCH2012
MS]
H H 385 0.60 50% 462 C8 0' EtOAc! 0 N050% [HPLC ES- N. HA hexane MSJ N N MSF H H H 386 0.28 5% 339 A7.
acetone! Cld N 1 95% [FAB] C-I NN N CH2C12
H
387 340 B3b 00 o step N- N ,IIN [FAB] 1,2, N H H Cld 388 174-5 424 B4b, C 0 00 NN -1 [HPLC ES- N
MS]
H H 0 NHEz 389 0 H 198- C3b, 0 0 0 200 0 HNHPr-i 390 169- 0.23 100% 24b. CS 0 0 170 EtOAc H H 0 NHMe 391 167- 0.12 100% B4b, C8 f o 171 EtOAc N 'N1-11N N
N
-H H 392 0.08 50% 400 C8 EtOAc/ [HPLC ES- N-N N -a N hexane MS) H H BIOLOGICAL EXAMPLES In Vitro raf Kinase Assay: In an in vitro kinase assay, raf is incubated with MEK in 20 mM Tris-HC1, pH 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution ]iL) is mixed with water (5 |iL) or with compounds diluted with distilled water from mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 VL [y-"P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCI, pH 120 mM NaCI, 1.6 mM DTT, 16 mM MgCI,. The reaction mixtures are incubated at 32 usually for 22 min. Incorporation of "P into protein is assayed by harvesting the reaction onto phosphocellulose mats, washing away free counts with a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation counting. For high throughput screening, 10 p.M ATP and 0.4 piM 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 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 5 so of between 1 nM and 10 p.M.
Cellular Assay: For in vitro growth assay, human tumor cell lines, including but not limited to HCT116 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage independent growth in soft agar. Human tumor cell lines were obtained from ATCC (Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% CO, incubator. Compounds are titrated in media in dilution series and added to 96 well cell cultures. Cells are allowed to grow 5 days typically with a feeding of fresh compound containing media on day three. Proliferation is monitored by measuring metabolic activity with standard XTT colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader at OD 490/560, or by measuring 'H-thymidine incorporation into DNA following an 8 h culture with 1 .Cu 'H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 'H-thymidine incorporation by liquid scintillant counting.
For anchorage independent cell growth, cells are plated at 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 compound at 3-4 day intervals. Colony formation is monitored and total cell mass, average colony size and number of colonies are quantitated using image capture technology and image analysis software (Image Pro Plus, media Cybernetics).
These assays establish that the compounds of Formula I are active to inhibit raf kinase activity and to inhibit oncogenic cell growth.
In Vivo Assay: An in vivo assay of the inhibitory effect of the compounds on tumors solid cancers) mediated by raf kinase can be performed as follows: CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1 x 106 cells with human colon adenocarcinoma cell line. The mice are dosed i.v. or p.o.
at 10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is between 50-100 mg. Animals are dosed for 14 consecutive days once a day; tumor size was monitored with calipers twice a week.
The inhibitory effect of the compounds on raf kinase and therefore on tumors solid cancers) mediated by raf kinase can further be demonstrated in vivo according to the technique of Monia et al. (Nat. Med. 1996, 2, 668-75).
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.
Claims (31)
1. A compound of the formula R 1 N I0 N I R2 NH-C-NH-B wherein R 2 is selected from the group consisting of H, -C(O)R 4 -C0 2 R 4 -C(O)NR 3 R, CI-Co alkyl, C 3 -Clo cycloalkyl, substituted Ci-Clo alkyl, substituted C 3 -CIO cycloalkyl, where if R 2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of-CN, -C0 2 R 4 -C(O)-NR 3 -NO 2 -OR 4 -SR 4 and halogen up to per-halosubstitution, wherein R 3 and R 3 are independently selected from the group consisting of H, Ci-Clo alkyl, C 3 -CIO cycloalkyl, up to per-halosubstituted CI-Clo alkyl, and up to per- halosubstituted C 3 -CIO cycloalkyl, and wherein R 4 and R 4 are independently selected from the group consisting of H, Ci-Clo alkyl, C 3 -C 10 cycloalkyl, up to per-halosubstituted Ci-Clo alkyl and up to per- halosubstituted C 3 -C 10 cycloalkyl, 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 -C 6 cycloalkyl, B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl; substituted by pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X'n and wherein n 0-2; each X' is independently selected from the group of -CN, -C0 2 R 5 C(O)R 5 -C(O)NRR 5 -OR S -NO 2 -NRsR 5 C,-Clo alkyl, C2-io-alkenyl, Cl-io-alkoxy, 115 C 3 -CI 0 cycloalkyl, -NR 5 C(O)0R 5 NR 5 substituted CI-CI 0 alkyl, substituted C 2 .io-alkenyl, substituted CI-io-alkoxy, substituted C 3 -CIO cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO 2 R -C(O)R 5 -C(O)NR 5 -SR 5 -NR 5 R" NO 2 -NR 5 C(O)R" -NR 5 C(O)0R and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, C 1 -CI 0 alkyl, C 2 10 alkenyl, C 3 -CI 0 cycloalkyl, C 6 -CI 4 aryl, C 3 -C 1 3 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -Cio alkyl; up to per-hal osubstituted C 2 -1 0 alkenyl and up to per-halosubstituted C 3 -CI 0 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 0O-, -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 )mnS-, -(CH 2 5 -O(CH 2 -CHXa, _CXa 2 -S-(CH 2 and -N(R 5 )(CH 2 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, subject to the proviso that where Y is -(CH 2 or Ar is not phenyl wherein Ar is unsubstituted or substituted by halogen up to per-halo and optionally substituted by wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)R 5 =0, -C(O)NR 5 R 5 -NO 2 SR 5 NR 5 R 5 -NR 5 C(O)0R 5 -NR 5 S0 2 R 5 -S0 2 R 5 R 5 CI-Ci 0 alkyl, C 1 -CI 0 alkoxy, C 3 -CI 0 cycloalkyl, substituted C 1 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)NR 5 R 5 -NO 2 -NR 5 R 5 NR 5 C(O)R 5 -NR 5 C(O)0R 5 CI-CIO alkyl, C 1 -C 10 alkoxyl, and C 3 -CIO cycloalkyl.
2. A compound of claim 1, wherein B is I I 116 xln -Q YZQ' Zn 1 wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, -CXa 2 -CXaH-, -CH 2 and -OCH 2 Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; N 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, subject to the proviso that where Y is -CH 2 or Q' is not phenyl, X' is C 1 -C 4 alkyl or halosubstituted CI-C 4 alkyl up to per halo, Z, n and nl 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 is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, and X' is as defined in claim 2, and Z is selected from the group consisting of -R 6 -OR 6 and -NHR 7 wherein R 6 is hydrogen, Cl-Clo-alkyl or C 3 -Clo-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -C 6 -cycloalkyl wherein R6 and R7 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 is pyridinyl, phenyl or benzothiazolyl optionally substituted by halogen up to per-halosubstitution, Y is -CH 2 -SCH 2 -CH 2 -OCH 2 or -CH 2 X' is C'-C 4 alkyl or halosubstituted C'-C 4 alkyl up to per halo, and Z is -SCH 3 or -NH-C(O)-CPH 2 p+ 1 wherein p is 1-4, n 0 or1I and nl 0-1 A compound of the formula t-B u N 0 N NH-C-NH-B wherein R 2 is as defined in claim 1 and B 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, substituted by one or more substituents independently selected from the group consisting of halogen, up to per- halosubstitution, and X~, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R 5 -NO 2 SR', -NR 5 R 5 NR 5 C(O)0R", -NR 5 C,-C 10 alkyl, C 2 -Cl 0 alkenyl, C 1 -C 10 alkoxy, C 3 -CI 0 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo- substituted C 1 -Cl 0 alkyl, up to per halo-substituted C 2 -CI 0 alkenyl, up to per halo- substituted C 1 -Clo alkoxy, up to per halo-substituted C 3 -CIO cycloalkyl, and -Y-Ar; wherein R 5 and R 5 are independently selected from H, C 1 -Cl 0 alkyl, C 2 -CI 0 alkenyl, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted C 1 -Clo alkyl, up to per-halosubstituted C 2 -C 10 alkenyl, up to per- halosubstituted C 3 -CI 0 cycloalkyl, and up to per-halosubstituted phenyl, pyridinyl, naphthyl, isoquinolinyl and quinolinyl wherein Y is -N(R 5 -(CH 2 -(CH 2 )m0-, -NR 5 C(O)NR' -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 ),rnN(R 5 0O(CH 2 -CHXa, _CXa. S(CH 2 and -N(R 5 )(CH 2 )mn-, m 1-3, and Va is halogen; and Ar is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, 118 N pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, Ct indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by halogen up to per-halosubstitution and optionally substituted by wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R 5 NR', trn N0 2 -OR 5 SR, -NR 5 R 5 -NR 5 C(O)0R 5 -C(O)R 5 -NR 5 -S0 2 R 5 S0 2 NR 5 R 5 CI-Cl 0 alkyl, C 1 -CI 0 alkoxyl, C 3 -CI 0 cycloalkyl, up to per halo- substituted C 1 -Cl 0 alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl, subject to the proviso that where R' is methyl 13 is not C(O)0C 4 H 9
6. A compound as in claim I selected from the group consisting of: N-(3-tert-Butyl-5-pyrazolyl)-N '-(4-phenyloxyphenyl)urea; methy lam inocarbonylphenyl)oxyphenyl)urea; '-(3-(4-pyridinyl)thiophenyl)urea; '-(4-(4-pyridinyl)thiophenyl)urea; N-(3-teri-Butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urca; '-(4-(4-pyridinyl)methylphenyl)urea; 1 -Methyl-3 -teri-butyl-5-pyrazolyl)-N '-(4-phenyloxyphenyl)urea; I -MethyI-3-t'eri-butyI-5-pyrazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; 1 -Methyl-3-teri-butyl-5-pyrazolyl)-N pyridinyl)thiomethyl)phenyl)urea; 1 -Methyl-3 -ert-butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; 1 -Methyl-3 -teri-butyl-5-pyrazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; I -Methyl-3 -tert-butyl-5-pyrazolyl)-N pyridinyl)methyloxy)phenyl)urea; I -Methyl-3-teri-butyl-5-pyrazolyl)-N benzothiazolyl)oxyphenyl)urea; -(4-pyridyl)thiophenyl) urea; '-(4-(4-pyridyl)thiophenyl) urea; I 119 N-(3 -trt-butyl-5-pyrazolyl)-N '-(3-(4-pyridyl)oxyphenyl) urea; N-(3 -tert-butyl-5 -pyrazolyl)-N '-(4-(4-pyridyl)oxyphenyl) urea; I -methyl-3-Iert-butyl-5-pyrazolyl)-N -(4-pyridyl)thiophenyl) urea; I -methyl-3-tert-butyl-5-pyrazolyl)-N '-(4-(4-pyridyl)thiophenyl) urea; 1-methyl-3-tert-butyl-5-pyrazolyl)-N -(4-pyridyl)oxyphenyl) urea; 1 -methyl-3-iert-butyl-5-pyrazolyl)-N '-(4-(4-pyridyl)oxyphenyl) urea; and pharmaceuticalliy acceptable salts thereof.
7. A compound of the formula 0_ 0 N wherein R1 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 -CI 0 cycloalkyl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl which is substituted by X, optionally substituted by halogen, up to per- halosubstitution, and optionally substituted by X' 11 wherein n 0-2; each X1 is independently selected from the group of X or from the group consisting of -CN, -C0 2 -C(O)NR 5 R 5 NO 2 -NR 5 CI-C 10 alkyl, C 2 -10-alkenyl, C,.to-alkoxy, C 3 -CI 0 cycloalkyl, and C 6 -CI 4 and X is selected from the group consisting of -SR 5 -NR C(O)0R, NR C(O)R, C 3 -C 1 3 heteroaryl, substituted C 1 -Cl 0 alkyl, substituted C 2 .io)-alkenyl, substituted Cj_ 10 -alkoxy, substituted C 3 -CIO cycloalkyl, substituted C 6 -C 1 4 aryl, substituted C 3 -C 1 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)NR 5 -OR 5 -SR 5 -NR 5 R" NO,, -NR 5 C(O)R" -NR 5 C(O)0R and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, C 1 -Clo alkyl, C 2 10 alkenyl, C 3 -C 10 cycloalkyl, C 6 -CI 4 aryl, C 3 -C 1 3 heteroaryl, C-y-C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per-halosubstituted C 1 -Clo alkyl, up to per-halosubstituted C 2 10 alkenyl, and up to per-halosubstituted C 3 -CI 0 cycloalkyl, wherein Y is N(R 5 -(CH 2 -(CH 2 )mnO-, -NR 5 C(O)NR 5 R 5 -NR 5 C(O)NPR 5 -(CH 2 -(CH 2 5 0O(CH 2 -CHXa' _CX. S(CH2)mn and -N(R 5 )(CH 2 mn 1-3, and Xa is halogen; and Ar is wherein B 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, subject to the proviso that where Y is -(CH 2 or Ar is not phenyl, wherein Ar is unsubstituted or substituted by halogen up to per-halo and optionally substituted by wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R -C(O)R -C(O)NR R -C(0)R NO 2 -OR 5 SR', NR 5 -NR 5 C(O)0R 5 -NR 5 C(0)R 5 -S0 2 -SO 2 R 5 C 1 CIO alkyl, C 1 -CI 0 alkoxy, C 3 -CI 0 cycloalkyl, substituted CI-CI 0 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 C(0)NR 5 R 5 -OR 5 -NO 2 -NR 5 R 5 -NR 5 C(0)R 5 -NR 5 C(O)0R" C-I alkyl, C 1 -CIO alkoxyl, and C 3 -C 10 cycloalkyl, subject to the proviso that where R, is t- butyl, B is not O 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 121 -O-CH 2
8. A compound of claim 7, wherein B is Xn -Q Y-QZn 1 S wherein Y is selected from the group consisting of -CH 2 -SCH 2 CH 2 -CXa 2 -CXH-, -CH 2 0- and -OCH 2 Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; 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 Q 1 is not phenyl, X' is C 1 -C 4 alkyl or halosubstituted C 1 -C 4 alkyl up to per halo, and Z, n and nl are as defined in claim 7.
9. A compound of claim 8, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X' is as defined in claim 8 and Z is selected from the group consisting of -OR and -NHR 7 wherein R 6 is hydrogen, CI-Clo-alkyl or C 3 -Clo-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. A compound of claim 8, 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 or -CH 2 XI is as defined in claim 8, Z is-NH-C(O)-CPH 2 p+ 1 wherein p is 1-4, -CH 3 -OH, -OCH 3 -0C 2 H 5 -CN or -C(O)CH 3 n 0 or 1, and n 1 0 or 1.
11. A compound as in claim 7 selected from the group consisting of: N-(5-tert-Butyl-3 -isoxazolyl).N '-(4-(4-hydroxyphenyl)oxyphenyl)urea; N-(5-teri-Butyl-3-isoxazolyl)-N -hydroxyphenyl)oxyphenyl)urea; N-(5-terz-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-phenyloxyphcnyl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N -methylaminocarbonyiphenyl)- thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N 1,2-methylenedioxy)phenyl)- oxyphenyl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N '-(4-(3-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3 -isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; -tert- Butyl -3 isoxazolyl)-N '-(4-(4-pyridylI)thi ophenyl)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-fert-Butyl-3 -isoxazolyl)-N -methyl-4-pyridinyl)oxyphenyl)urea; -tert- Butyl -3 -isoxazo lyl)-N -methyl -4-pyrid inylI)th iophenylI)urea; N-(5-teri-Butyl-3-isoxazolyl)-N -methyl-4-pyridinyl)thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N -(4-methyl-3-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N -methyl-4-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N -(2-benzothiazolyl)oxyphienyl)urea; 123 -ter-butyl -3 isoxazolyl)-N -chio ro-4- -methylIcarbamoyl)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-ter-butyl-3-isoxazolyl)-N '-(4-(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; N-(5-iert-butyl-3 -isoxazolyl)-N '-(3-(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; N-(5-teri'-butyl-3-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)- thiophenyl) urea; N-(5-tert-butyl-3 -isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl)urea; N-(5-tert-butyl-3-isoxazolyl)-N '-(4-(3-methylcarbamoyl)phenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof.
12. A compound of the formula t-Bu 0 0 N NH-C;-NH-B3 wherein B is 5-methyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinol inyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and X 1 IND 124 wherein n is 0-3 and each X is independently selected from the group Ct consisting of -CN, -C0 2 -C(O)NR 5 -NO 2 SR', -NR 5 R 5 NR 5 C(O)0R 5 -NR 5 C 1 -CI 0 alkyl, C 2 -C 1 0 alkenyl, CI-CI 0 alkoxy, C 3 -CI 0 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl, up to per halo- substituted C 1 -CI 0 alkyl, up to per halo-substituted C 2 -CI 0 alkenyl, up to per halo- In substituted CI-C 1 0 alkoxy and, up to per halo-substituted C 3 -CIO cycloalkyl, wherein R 5 and R 5 are independently selected from H, C 1 -C 1 0 alkyl, C 2 -C 1 0 alkenyl, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted C 1 -CI 0 alkyl, up to per-halosubstituted C 2 -C 10 alkenyl, and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 )mO-, -NR 5 C(O)NR 5 -NR 5 -C(O)NR 5 {(CH 2 -(CH 2 11 N(R 5 0O(CH 2 -CHXa, _CXa 2 -S-(CH 2 and -N(R 5 )(CH 2 m 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 wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -CN, 0O, -C0 2 -C(O)NR R. NR -NO 2 SR 5 NR 5 R 5 -NR 5 C(O)0R", -NR 5 C(O)R 5 -S0 2 R 5 S0 2 NR 5 C 1 -C 10 alkyl, C 1 -C 1 0 alkoxyl, C 3 -CI 0 cycloalkyl, up to per halo-substituted C 1 -C 10 alkyl and up to per halo-substituted C 3 -CIO cycloalkyl; subject to the proviso that B is not -a0 -aR 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 125 -O-CH 2
13. A compound of the formula R' N I 1 0 SOI I NH-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 -C 6 cycloalkyl, and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl or naphthyl, which is substituted by X, optionally substituted by halogen, up to per-halosubstitution, and optionally substituted by X'n, wherein n 0-2; each X' is independently selected from the group of X or from the group consisting of -CN, -CO 2 Rs, -C(O)R 5 -C(O)NR'R 5 -ORS, NO 2 -NR'R, C 1 -Co alkyl, C2-10o-alkenyl, Cl.- 1 o-alkoxy, C 3 -Clo cycloalkyl, C 6 -C 1 4 aryl and C 7 -C 2 4 alkaryl, and X is selected from the group consisting of -SR 5 -NR 5 C(0)OR", NR 5 C(O)R 5 C 3 -C 1 3 heteroaryl, substituted CI-Clo alkyl, substituted C2-10o-alkenyl, substituted Cl.lo- alkoxy, substituted C 3 -CIO cycloalkyl, substituted C 6 -C 1 4 aryl, substituted C 3 -C 1 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 -C(O)NR'R 5 -ORS, -NR'R" NO 2 -NR 5 C(O)R 5 -NRSC(0)OR" and halogen up to per-halosubstitution; wherein R 5 and R5' are independently selected from I-I, CI-Clo alkyl, C 2 10 alkenyl, C 3 -CIO cycloalkyl, C 6 -C 1 4 aryl, C 3 -C 13 heteroaryl, C 7 -C 2 4 alkaryl, C 4 -C 2 3 126 alkheteroaryl, up to per-hal osubstituted C 1 -Clo alkyl, up to per-halosubstituted C 2 10 alkenyl, and up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is N(R -(CH 2 -(CH 2 )mnO-, -NR 5 C(O)NR 5 -NR 5 C(O)NR 5 -(CH 2 -(CH 2 )mN(R 5 -O(CH 2 -CHX', -CXa 2 -S-(CH 2 and -N(R 5 )(CH 2 m 1-3, and XV 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, subject to the proviso that where Y is -(CH 2 or Ar is not phenyl, wherein Ar which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 0O, -C(O)NR 5 R 5 NO 2 SR', NR 5 -NR 5 C(O)0R", -NR 5 C(O)R 5 -S0 2 -SO 2 R 5 R 5 C 1 CIO alkyl, C 1 -CI 0 alkoxy, C 3 -CI 0 cycloalkyl, substituted C 1 -CI 0 alkyl and substituted C 3 -CI 0 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 C(O)NR 5 -NO 2 -NR 5 R" -NR 5 C(O)R 5 and -NR 5 C(O)0R", C,- C 10 alkyl, C I-C 10 alkoxyl, and C 3 -C 1 0 cycloalkyl, and where R1 is -CH 2 -t-butyl, B is not CH H 3
14. A compound of claim 13, wherein B is 127 xn -Q Y-Q Zn 1 wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, -CXa 2 -CXaH-, -CH 2 0- and -OCH 2 IN Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; 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 Q' is not phenyl, Z, n and nl are as defined in claim 13 and X' is C 1 -C 4 alkyl or halosubstituted CI-C 4 alkyl up to per halo. A compound of claim 14, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X' is as defined in claim 14 and Z is selected from the group consisting of -OR 6 and -NHR 7 wherein R 6 is hydrogen, Ci-Clo-alkyl or C 3 -Clo-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -C 6 -cycloalkyl, wherein R6 and R 7 can be substituted by halogen or up to per-halosubstitution.
16. A compound of the formula t-B u 0 I I II 0 NH-C-NH-B __wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, ID 5 pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 R 5 C(O)NR 5 -C(O)R 5 -NO 2 -OR 5 SR', -NR 5 -NR 5 C(O)0R 5 -NR 5 C(O)R 5 C,_ CIO alkyl, C 2 -CIO alkenyl, CI-CIO alkoxy, C 3 -C 10 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted C 1 -CI 0 alkyl, up to per halo-substituted C 2 -CI 0 alkenyl, up to per halo-substituted C 1 -CI 0 alkoxy, up to per halo-substituted C 3 -CIO cycloalkyl, and -Y-Ar; wherein R 5 and R 5 are independently selected from H, C 1 -CI 0 alkyl, C 2 -CI 0 alkenyl, C 3 -C 10 cycloalkyl, up to per-halosubstituted CI-C 10 alkyl, up to per- halosubstituted C 2 -C 10 alkenyl and up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 -NR 5 C(O)NR 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 )rnN(R 5 0(CH1 2 -CHXa, CXa 2 S-(CH 2 and -N(R 5 )(CH 2 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 wherein n] is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)NR 5 NR', -NO 2 -OR 5 SR', -NR 5 R 5 NR 5 C(O)0R", -NR 5 -S0 2 SONR 5 R 5 C 1 -CIO alkyl, CI-CIa alkoxyl, C 3 -CI 0 cycloalkyl, up to per halo-substituted CI-CI 0 alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl.
17. A compound of claim 14, wherein Q is phenyl or pyridinyl optionally substituted by halogen up to per-halo substitution, Q1 is phenyl, benzothiazolyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Y is or -CH 2 X' is as defined in claim 14, n 0 or 1, Z is -CH 3 0C 2 H 5 or -OCH 3 and ni 0Oor 1. 1 8. A compound as in claim 13 selected from the group consisting of: -isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert- Butyl- 5- isoxazolyl)-N '-(4-(4-methox yphenylI)oxyphenylI)urea; -isoxazolyl)-N '-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea; N-(3-tert-Butyl-5 -isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl)urea; '-(4-(4-pyridinyl)methylphenyl)urea; '-(4-(4-pyridinyl)thiophenyl)urea; '-(4-(4-pyridinyl)oxyphenyl)urea; '-(4-(4-methyl-3-pyridinyl)oxyphenyl)urea; N-(3-tert-Butyl-5-isoxazolyl)-N '-(3-(2-benzothiazolyl)oxyphenyl)urea; 1 -Dimethylpropyl)-5-isoxazolyl)-N'-(4-(4- methylphenyl)oxyphenyl)urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N -(4-pyridinyl)thiophenyl)urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; 1,1 -Dimethylpropyl-5-isoxazolyl)-N methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N pyridinyl)oxyphenyl)urea; I-Methyl- I -ethylpropyl)-5-isoxazolyl)-N pyridinyl)thiophenyl)urea; '-(3-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; '-(4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; 130 N-(3 -tert-butyl-5 -isoxazolyl)-N -(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; '-(4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(3 -tert-butyl-5-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)- thiophenyl) urea; 1-dimethylprop- 1-yl)-5-isoxazolyl)-N -(4-(2-methylcarbamoyl)- pyridyl)oxyphenyl) urea; 1,1 -dimethyiprop- 1 -yl)-5-isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)- pyridyl)oxyphenyl) urea; N-(3 -tert-butyl-5-isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- thiophenyl) urea; and pharmaceutically acceptable salts thereof.
19. A compound of the formula S 0 0 Rb NH-C-NH-B wherein R1 is selected from the group consisting Of C3-C 6 alkyl, C 3 -C 6 cycloalkyl, up to per-halosubstituted C 3 -C 6 alkyl and up to per-halosubstituted C 3 -C 6 cycloalkyl, R b is hydrogen or halogen and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl substituted by phenyl, pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by and wherein n 0-2; each X 1 is independently selected from the group consisting of CN, -NR 5 R 5 C 1 -Cl 0 alkyl; -C0 2 -C(O)NR 5 -NO 2 NR 5 C(O)0R 5 -NR 5 C 3 -CIO cycloalkyl, substituted C 1 -Cl 0 alkyl, substituted C 2 -10-alkenyl, substituted C 1 -alkoxy, and substituted C 3 -CIO cycloalkyl, 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)NR'R 5 -SR 5 -NR'R 5 -NO 2 -NR 5 C(O)R 5 -NR 5 C(0)OR 5 and halogen up to per-halo substitution; wherein R 5 and R 5 are independently selected from H, C 1 -Clo alkyl, C 2 10 alkenyl, C 3 -Co 0 cycloalkyl, up to per-halosubstituted CI-C 0 lo alkyl, up to per- halosubstituted C2-10o-alkenyl and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -(CH 2 -(CH 2 -NR 5 C(O)NR 5 R -C(O)NR -(CH 2 -(CH 2 -O(CH 2 -CHXa, -CXa2-, -S- (CH 2 1 11 and -N(R 5 )(CH 2 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, which is unsubstituted or substituted by halogen up to per- halosubstitution and optionally substituted by ZnI, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C0 2 R 5 NR 5 -NO 2 -OR 5 SRS, -NR'Rs, -NRSC(0)OR 5 S, -NRSC(O)Rs, -S0 2 R 5 -S0 2 RR 5 CI-CIO alkyl, C 1 -Clo alkoxy, C 3 -CIO cycloalkyl, substituted CI-C 0 lo alkyl, and substituted C 3 -CIO cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, -C0 2 R 5 C(O)NR 5 R 5 -OR 5 -SRS, -NO 2 NRR', NRC()R' -NR C()OR 5 CI-C 1 o alkyl, CI-C 0 lo alkoxyl, and C 3 -CIO cycloalkyl, subject to the proviso that where R' is t-butyl and Rb is H, B is not of the formula 0 CH(CH 3 2 A compound of claim 19, wherein B is Xl n -Q Y-QL Zn 1 wherein Y is selected from the group consisting of-O-, -Cl-I 2 -SCH 2 -CH 2 S-, -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; 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, optionally substituted by halogen up to per-halosubstitution, X' 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 19.
21. A compound of claim 20, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo, X' is as defined in claim 20 and Z is selected from the group consisting of -R 6 -OR 6 and -NHR 7 wherein R 6 is hydrogen, Cl-Clo-alkyl or C 3 -Clo-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -C 6 -cycloalkyl wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution.
22. A compound of the formula t-B u T 0 NHr-C-NH-B wherein B 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, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 R 5 C(O)NR 5 -C(O)R 5 -NO 2 SR', -NR 5 R 5 -NR 5 C(O)0R", -NR 5 C 1 CIO alkyl, C 2 -CIO alkenyl, C 1 -C 10 alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted C 1 -CI 0 alkyl, up to per halo-substituted C 2 -CI 0 alkenyl, up to per halo-substituted CI-CI 0 alkoxy, up to per halo-substituted C 3 -CIO cycloalkyl, and -Y-Ar; wherein R 5 and R 5 are independently selected from H, C 1 -CI 0 alkyl, C 2 -CI 0 alkenyl, C 3 -CI 0 cycloalkyl, up to per-halosubstituted C 1 -CI 0 alkyl, up to per- halosubstituted C 2 -CIO alkenyl and up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R CH 2 CH(OH)-, -(CH 2 )m0-, -NR 5 C(O)NR 5 NR 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 5 0O(CH 2 -CHXa, -CXa 2 -S-CH 2 and -N(R 5 )(CH 2 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 ZnI, wherein n I is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)NR R NR', -NO 2 -OR 5 SR -NR R,- IND 134 0NR C(O)0R -NR 5 C(O)R 5 -S0 2 R, SONR 5 C 1 1 akl CI- 1 alkoxyl, C 3 -CIO cycloalkyl, up to per halo-substituted C 1 -C 10 alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl, subject to the proviso that B is not of the formula 0O CH(CH 3 2 IND 23. A compound of claim 20, wherein (Ni Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q1 is phenyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, and Y is or Z is -Cl, -CH- 3 -OH or -OCH 3 X 1 is as defined in claim n 0 or I and ni 0-2.
24. A compound as in claim 19 selected from the group consisting of: N-(5-ter/-Butyl-3-thienyl)-N '-(4-(3-methylphenyl)oxyphenyl)urea; N-(5-teri'-Butyl-3-thienyl)-N '-(4-(4-hydroxyphenyl)oxyphenyl)urea;, -teri- Butyl-3 -th ienyl)-N -(4-methoxyphenylI)oxyphenyl)urea; N-(5-t'ert-Butyl-3-thienyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; and pharmaceutically acceptable salts thereof. A compound of the formula N ilS 0 N1 -NH-C,-NH1-B wherein R a is 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 -C 6 cycloalkyl; and B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl; ct substituted by phenyl, pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X'n wherein n 0-2, each X1 is independently selected from the group consisting of -CN, -NO 2 ,-OR 5 and C 1 -CI 0 alkyl,-SR', -C0 2 R 5 -C(O)NR 5 R 5 -NR 5 R 5 -NR 5 C(O)0R", -NR 5 C(O)R 5 -C 3 -CI 0 cycloalkyl, substituted C 1 -CI 0 alkyl, substituted C 2 1 o-alkenyl, substituted CI- 1 o-alkoxy, and substituted C 3 -CIO cycloalkyl, c-i wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 CI 10 C(O)R 5 -C(O)NR 5 R 5 -SR 5 -NR 5 R 5 -NO 2 -NR 5 C(O)R 5 -NR 5 C(O)0R" and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, C 1 -C~o alkyl, C 2 -lo-alkenyl, C 3 CIO cycloalkyl, up to per-halosubstituted CI-C 10 alkyl, up to per-halosubstituted C 2 10 alkenyl, and up to per-halosubstituted C 3 -CI 0 cycloalkyl, wherein Y is -N(R 5 -(CH 2 CH(OH)-, -(CH 2 )mO-, -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 CH 2 -(CH 2 )mN(R 5 0(C H 2 -CHXa, -CXa 2 -S-(CH 2 and -N(R 5 )(CH 2 m 1-3, and Xa is halogen; and Ar is a 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, which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by ZnI, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)R 5 0O, -C(O)NR 5 R 5 -C(O)R 5 NO 2 SR', NR 5 R 5 -NR 5 C(O)0R", -NR 5 C(O)R 5 -S0 2 -S0 2 R'R 5 C 1 -C 1 0 alkyl, C 1 -CI 0 alkoxy, C 3 -CIO cycloalkyl, substituted C 1 -CI 0 alkyl, 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, -C0 2 R C(O)NR 5 -NO 2 -NR 5 -NR 5 C(O)R" and -NR 5 C(O)0R", C,- CIO alkyl, C,-CI 0 alkoxyl, and C 3 -CIO cycloalkyl,
26. A compound as in claim 25, wherein B is Xn -Q Y Q' Z, wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, -CXa 2 -CXaH-, -CH 2 -OCH 2 Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; 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, X' is C 1 -C 4 alkyl or halosubstituted CI-C 4 alkyl up to per-halo, Z, n and nl are as defined in claim 25, and s is 0 or 1.
27. A compound as in claim 26, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q' is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X' is as defined in claim 26 and Z is selected from the group consisting of -R 6 -OR 6 and -NHR 7 wherein R 6 is hydrogen, Cl-Clo-alkyl or C 3 -Clo-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, C 3 -C 6 -cycloalkyl and wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution.
28. A compound as in claim 26, 137 wherein Q is phenyl optionally substituted by halogen up to per- halosubstitution, Q 1 is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Y is or X is as defined in claim 26, n= 0 or 1 and nl 0.
29. A compound as in claim 25, of the formula CF \O 3 N S O c~I_ N NH-C-NH-B wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl substituted by phenyl, pyridinyl or -Y-Ar, optionally substituted by halogen, up to per halo, and wherein each cyclic structure of B is optionally substituted by X', wherein n 0-2; each X 1 is independently selected from the group consisting of -CN, -OR 5 -NR'R 5 CI-Clo alkyl, -C0 2 R, -C(O)NR'RS, -C(O)RS, -NO 2 -SR, NR'C(0)OR 5 -NRSC(O)RS, C 3 -CIO cycloalkyl, and substituted CI-Clo alkyl, substituted C2-10o-alkenyl, substituted CI-lo-alkoxy, and substituted C 3 -CIO cycloalkyl, wherein R 5 and R 5 are independently selected from H, CI-Clo alkyl, C2- 10 alkenyl, C 3 -Clo cycloalkyl, up to per-halosubstituted CI-Clo alkyl, up to per- halosubstituted C 2 o10-alkenyl; up to per-halosubstituted C 3 -Clo cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 )m0-, -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NRS 5 -(CH 2 -(CH 2 5 -O(CH 2 -CHXa, -CXa 2 -S-(CH 2 and -N(RS)(CH 2 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, which is unsubstituted or substituted by halogen up to per- halosubstitution and optionally substituted by Z,, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C0 2 R 5 -C(O)RS, -C(O)NR R NR -NO 2 -OR, 138 SR', -NR 5 R 5 -NR 5 C(O)0R 5 -NR 5 -S0 2 -S0 2 CI-Cl 0 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, substituted C 1 -C 10 alkyl, substituted C 3 -CIO cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R 5 =0, -NO 2 -NR 5 -NR 5 C(O)R 5 -NR 5 C(O)0R", C 1 -CI 0 alkyl, C 1 -C 1 0 alkoxyl, and C 3 -CI 0 cycloalkyl. A compound as in claim 25 selected from the group consisting of: N-(5-tert-Butyl-2-( I -thia-3 ,4-diazolyl))-N '-(3-(4-pyridinyl)thiophenyl)urea; N-(5-tert-Butyl-2-( 1 -thia-3 ,4-diazolyl))-N '-(4-(4-pyridinyl)oxyphenyl)urea; -tert-butyl I -thia-3 ,4-diazolyl))-N methylcarbamoyl)pyridyl)-oxyphenyl)urea; N-(5-tert-butyl-2-(1. -thia-3,4-diazolyl))-N'-(4-(4-(2- methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5-tert-butyl-2-( I -thia-3,4-diazolyl))-N '-(3-chloro-4-(4-(2- methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5-i'ert-butyl-2-( 1 -thia-3,4-diazolyl))-N '-(2-chloro-4-(4-(2- methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5-tert-butyl-2-( 1-thia-3 ,4-diazolyl))-N -(4-pyridyl)thiophenyl) urea; N-(5-tert-butyl-2-( I -thia-3 ,4-diazolyl))-N '-(2-methyl-4-(4-(2- methylcarbamoyl)pyridyl)oxyphenyl) urea; 1,1 -dimethylprop- I 1 -thia-3,4-diazolyl))-N carbamoylphenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof.
31. A compound of one of the formulae 0or 0 NH-C-NH-B NH-C-NH-B wherein R' is selected from the group consisting of halogen, C 3 -CI 0 alkyl, C 1 13 -heteroaryl, C 6 14 -aryl, C 7 24 -alkaryl, C 3 -CI 0 cycloalkyl, up to per-halosubstituted CI- CIO alkyl, up to per-halosubstituted C 3 -CIO cycloalkyl, up to per-halo substituted C 1 13 heteroaryl, up to per-hal osubstituted C 6 14 -aryl and up to per-halosubstituted C 7 24 alkaryl; B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl substituted by phenyl, pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X', wherein n 0-2; each X 1 is independently selected from the group consisting of -CN, -NR 5 C 1 -Clo alkyl, -C(O)R 5 -NO 2 -NR 5 C(O)0R", C 3 -CI 0 cycloalkyl, substituted CI-Clo alkyl, substituted C 2 -1o-alkenyl, substituted C 1 10 alkoxy, and substituted C 3 -C 10 cycloalkyl, wherein if X' is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO 2 -C(O)NR 5 R 5 -OR 5 -S -NR 5 R" -NO 2 -NR 5 C(O)R" -NR 5 C(O)0R and halogen up to per-halo substitution; wherein R 5 and R 5 are independently selected from H, C 1 -CI 0 alkyl, C 2 10 alkenyl, C 3 -CI 0 cycloalkyl, up to per-halosubstituted C 1 -CI 0 alkyl, up to per- halosubstituted C 2 10 -alkenyl, and up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 0O, NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 5 0O(CH 2 CHXa, CXa 2 -S-(CH 2 and -N(R 5 )(CH 2 m 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 which is unsubstituted or substituted by halogen up to per- halosubstitution and optionally substituted by Z, wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 0O, -C(O)NR 5 NR', -NO 2 SR,- NR 5 -NR 5 C(O)0R 5 -NR 5 -SO 2 R 5 -S0 2 C 1 -Clo alkyl, C 1 -Cl 0 alkoxy, C 3 -CI 0 cycloalkyl, substituted C 1 -C 10 alkyl, substituted C 3 -CIO cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)NR 5 R 5 =0, -OR 5 -SR 5 -NO 2 -NR 5 R 5 -NR 5 C(O)R 5 -NR 5 C(O)0R 5 CI-Clo alkyl, CI-Cl 0 alkoxyl and C 3 -CI 0 cycloalkyl.
32. A compound of one of the formulae t-Bu NHi-C-NH-B t-Bu 0 NH-C-NH-B wherein B is as defined in claim 3 1.
33. A compound of claim 31, wherein B is wherein Y is selected from the group consisting of -CH 2 -SCH 2 -CH 2 S-, _CXa 2 -CXaH-, -CH 2 O- and -OCH 2 Xa is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; 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 substituted by halogen up to per-halosubstitution, X' is C 1 -C 4 alkyl or halosubstituted CI-C 4 alkyl up to per halo, Z, n and nl are as defined in claim 31 or n is 0-3, nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO 2 R 5 -C(O)NRR 5 NR 5 -NO 2 -OR 5 SR 5 -NRR 5 -NRSC(O)OR 5 -C(O)R 5 -NRSC(O)R', S0 2 R 5 SO 2 NRR 5 Ci-Clo alkyl, Ci-Cio alkoxyl, C 3 -CIO cycloalkyl, up to per halo- substituted CI-Clo alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl.
34. A compound of claim 33, wherein Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- halosubstitution, Q is selected from the group consisting of phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, optionally substituted by halogen, up to per-halo, X' is as defined in claim 33 and Z is selected from the group consisting of-R 6 -OR 6 and -NHR 7 wherein R 6 is hydrogen, Ci-Clo-alkyl or C3-Clo-cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -C 6 -cycloalkyl wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution. A compound of claim 33, wherein Q is phenyl optionally substituted by halogen up to per- halosubstitution, Q' is phenyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, and Y is or X' is as defined in claim 33, n 0 or 1, Z is -Cl, -CH 3 -OH or OCH 3 and nl 0-2.
36. A compound of the formula R1I RbNHCN- 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 -C 6 cycloalkyl and wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl substituted by phenyl, pyridinyl or -Y-Ar, wherein the cyclic structures of B are optionally substituted by halogen, up to per halo, and optionally substituted by X' wherein n 0-3 and each X1 is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R -NO 2 -OR 5 SR 5 NR R,- NR 5 C(O)0R", -NR 5 C(O)R 5 CI-Clo alkyl, C 21 o-alkenyl, C 1 1 o-alkoxy, C 3 -CIO cycloalkyl, substituted C 1 -Clo alkyl, substituted C 2 10 -alkenyl, substituted C 1 10 alkoxy, and substituted C 3 -CIO cycloalkyl, wherein if X1 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)R 5 -C(O)NR 5 R 5 -OR 5 -SR 5 -NR 5 R 5 -NO 2 -NR 5 C(O)R 5 -NR 5 C(O)0R and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, CI-Clo alkyl, C 2 10 alkenyl, C 3 -CIO cycloalkyl, up to per-halosubstituted C 1 -Cl 0 alkyl, up to per- halosubstituted C 2 10 -alkenyl and up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 )mO-, -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 )mN(R 5 0O(CH 2 -CHXa, .CXa 2 -S(CH 2 and -N(R 5 )(CH 2 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, which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Z, 1 wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN, -CO 2 -C(O)NRSRS, -NO 2 -OR 5 SR', NR'R -S0 2 -SO 2 R 5 CI-Clo alkyl, C 3 -CIO In cycloalkyl, substituted C 1 -Clo alkyl, substituted C 3 -CIO cycloalkyl, wherein if Z is a substituted group, it is substituted by one or more substituents independently selected C from the group consisting of -CN, -C0 2 R 5 -C(O)NR 5 R 5 -OR 5 -NO 2 \O NR 5 R 5 -NR 5 C(O)R" -NR 5 C(O)OR 5 CI-Clo alkyl, CI-Cl 0 alkoxyl, and C 3 -CIO S 10 cycloalkyl.
37. A compound of claim 36, wherein B is 1 xn 15 -Q Y-Q1 Zn1 wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, -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; 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, X' is CI-C 4 alkyl or halosubstituted C 1 -C 4 alkyl up to per halo, and Z, n and nl are as defined in claim 36.
38. A compound of claim 37, 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, X' is as defined in claim 37 and Z is selected from the group consisting of -OR 6 and -NHR 7 wherein R 6 is hydrogen, Cl-Clo-alkyl or C 3 -Co 10 -cycloalkyl and R 7 is selected from the group consisting of hydrogen, C 3 -Clo-alkyl, and C 3 -C 6 -cycloalkyl wherein R 6 and R 7 can be substituted by halogen or up to per-halosubstitution.
39. A compound of the formula t-Bu O o NH-C-NH-B wherein B 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, substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 R 5 C(O)NR'R 5 -NO 2 -OR 5 SR 5 -NR 5 -NR 5 C()OR 5 -NR'C(O)R C 1 Cio alkyl, C 2 -C 1 0 alkenyl, CI-CIo alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted CI-Clo alkyl, up to per halo-substituted C 2 -Clo alkenyl, up to per halo-substituted C 1 -Clo alkoxy, up to per halo-substituted C 3 -Clo cycloalkyl, and -Y-Ar; wherein R 5 and R 5 are independently selected from H, Ci-Clo alkyl, C 2 -C 10 alkenyl, C 3 -Co 10 cycloalkyl, up to per-halosubstituted C 1 -Clo alkyl, up to per- halosubstituted C 2 -C10 oalkenyl and up to per-halosubstituted C 3 -Clo cycloalkyl, wherein Y is -(CH 2 -(CH 2 )m0-, -NRSC(O)NRS NRS-, -NRSC(O)-, -C(O)NRS-, -(CH 2 -(CH 2 -O(CH 2 -CHXa, -CXa 2 -S-(CH 2 and -N(R')(CH 2 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 Zn, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 NRS, -NO 2 -OR 5 SRS, -NRSR, NR 5 C(0)OR", -S0 2 R 5 SO 2 NR 5 R 5 CI-Clo alkyl, C 1 -Clo alkoxyl, C 3 -CIo cycloalkyl, up to per halo-substituted C 1 -Clo alkyl, and up to per halo-substituted C 3 -Co 10 cycloalkyl. A compound as in claim 37, wherein Q is phenyl optionally substituted by halogen up to per- halosubstitution, Q' is phenyl or pyridinyl optionally substituted by halogen up to per- halosubstitution, and Y is or X' is as defined in claim 37, Z is -Cl or -OCH 3 n 0, s 0 andnl =0-2.
41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 and a physiologically acceptable carrier. DATED this eleventh day of May 2006 BAYER CORPORATION By their Patent Attorneys CULLEN CO.
Priority Applications (2)
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|---|---|---|---|
| AU2006201959A AU2006201959B2 (en) | 1997-12-22 | 2006-05-11 | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
| AU2008252068A AU2008252068B2 (en) | 1997-12-22 | 2008-12-04 | Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas |
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| US08996343 | 1997-12-22 | ||
| AU2003204708A AU2003204708B2 (en) | 1997-12-22 | 2003-06-13 | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
| AU2006201959A AU2006201959B2 (en) | 1997-12-22 | 2006-05-11 | Inhibition of Raf Kinase using Substituted Heterocyclic Ureas |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008000252A1 (en) * | 2006-06-27 | 2008-01-03 | Schebo Biotech Ag | New urea derivatives and the application thereof |
| WO2012087630A1 (en) * | 2010-12-20 | 2012-06-28 | E.I. Du Pont De Nemours And Company | Pyridine and pyrimidine compounds for controlling invertebrate |
| WO2013113776A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113716A1 (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 |
| WO2013113715A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
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| EP4219489A3 (en) | 2018-05-30 | 2023-11-15 | Washington University | Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3754887A (en) * | 1969-05-05 | 1973-08-28 | Du Pont | Ureidopyrazoles defoliants |
| JPS5031039A (en) * | 1973-07-27 | 1975-03-27 | ||
| FR2639636B1 (en) * | 1988-11-30 | 1994-03-04 | Novapharme | NOVEL HETEROCYCLIC COMPOUNDS WITH ANTICONVULSIVE ACTIVITY, PREPARATION METHOD AND THERAPEUTIC COMPOSITIONS CONTAINING THEM |
| EP0630373A1 (en) * | 1992-03-12 | 1994-12-28 | Smithkline Beecham Plc | Indole derivatives as 5ht1c antagonists |
| WO1994014801A1 (en) * | 1992-12-29 | 1994-07-07 | Smithkline Beecham Plc | Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists |
| GB9723789D0 (en) * | 1997-11-12 | 1998-01-07 | Zeneca Ltd | Chemical compounds |
| CA2315720A1 (en) * | 1997-12-22 | 1999-07-01 | Bayer Corporation | Inhibition of p38 kinase activity using substituted heterocyclic ureas |
| RU2265597C2 (en) * | 1997-12-22 | 2005-12-10 | Байер Копэрейшн | Aryl- and heteroaryl-substituted heterocyclic derivatives of urea, method for inhibition of raf kinase activity and pharmaceutical composition |
-
2006
- 2006-05-11 AU AU2006201959A patent/AU2006201959B2/en not_active Ceased
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| WO2008000252A1 (en) * | 2006-06-27 | 2008-01-03 | Schebo Biotech Ag | New urea derivatives and the application thereof |
| WO2012087630A1 (en) * | 2010-12-20 | 2012-06-28 | E.I. Du Pont De Nemours And Company | Pyridine and pyrimidine compounds for controlling invertebrate |
| WO2013113791A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
| WO2013113863A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
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| WO2013113787A1 (en) | 2012-02-03 | 2013-08-08 | Basf Se | Fungicidal pyrimidine compounds |
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| AU2006201959B2 (en) | 2008-09-04 |
| AU2008252068B2 (en) | 2011-02-03 |
| AU2008252068A1 (en) | 2009-01-08 |
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