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AU2008252068A1 - Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas - Google Patents

Inhibition of Raf Kinase Using Substituted Heterocyclic Ureas Download PDF

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Publication number
AU2008252068A1
AU2008252068A1 AU2008252068A AU2008252068A AU2008252068A1 AU 2008252068 A1 AU2008252068 A1 AU 2008252068A1 AU 2008252068 A AU2008252068 A AU 2008252068A AU 2008252068 A AU2008252068 A AU 2008252068A AU 2008252068 A1 AU2008252068 A1 AU 2008252068A1
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substituted
per
alkyl
pyridinyl
halogen
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AU2008252068B2 (en
Inventor
Jacques Dumas
Holia Hatoum-Mokdad
Jeffrey Johnson
Uday Khire
Wendy Lee
Timothy Bruno Lowinger
Holger Paulsen
Aniko Redman
Bernd Riedl
William J. Scott
Roger A. Smith
Jill E. Wood
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Bayer Healthcare LLC
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Bayer Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

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: la 00 O O 00 O 5 INHIBITION OF RAF KINASE USING SUBSTITUTED HETEROCYCLIC UREAS
OO
SField of the Invention This invention relates to the us eof a group of aryl ureas in treating raf mediated 00 10 diseases. and pharmaceutical compositions for use in such therapy.
0 C 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).
00 2 0 0 Summary of the Invention 0 The present invention provides compounds which are inhibitors of the enzyme raf Q 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 00 cancerous cell growth mediated by raf kinase. In particular, the compounds are useful
\O
I in the treatment of human or animal, murine cancer, since the progression of t these cancers is dependent upon the ras protein signal transduction cascade and 00 10 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
II
A-NH-C-NH-B I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below.
The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.
00 3 Suitable aryl and heteroarvi 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.
00 Examples of suitable aromatic ring structures include phenyl. pyridinyl, naphthyl, IND pyrimidinyl, benzothiazolyl, quinoline. isoquinoline, phthalimidinyl and combinations thereof, such as, diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenylamine (phenylaminophenyl), phenylpyridinyl ether 00 (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazoly] thioether (benzothiazolylthiophenyl), phenylpyi-imidinyl ether, phenyiquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pynidinylnaphthyl thioether, and phthalimidylmethylphenyl.
Examples of suitable heteroaryl groups include, but are not limited to, 5-12 carbonatom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.
For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 2- or 3pyrrolyl, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 4- or 5-oxazolyl, 4or 5-isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothiazolyl, 3- or 4-pyridyl, 4-, or 6-pyrimidinyl, 1,2,3-triazol-1-, or -5-yl, 1,2,4-triazol-1-, or -5-yl, I- or tetrazolyl, 1,2,3-oxadiazol-4- or -5-yI, 1,2,4-oxadiazol-3- or -5-yI, 1,3,4-thiadiazol-2or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3or -5-yl, I ,2,3-thiadiazol-4- or -5-yl, 5- or 6-2H-thiopyranyl, 3- or 4-4Hthiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 6- or 7-benzofuiryl, 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-bcnzisothiazolyl, 6- or 7-benz-I,3-oxadiazolyl, 7- or 8quinolinyl, 8- isoquinolinyl, 4- or 9-carbazolyl, 2-, 8- or 9-acridinyl, or 7- or 8-quinazolinyl, or additionally 004 optionally susiue hnl 2 r3tini .3.4-th'd'Ai, substituted~~~ phny, r -tieyl 3 -pyrryl. 3-pyrazoiyi.
cK1 2-thiazolyl or 5-thiazolyl, etc. For example. B can be 4 -methyl-phenN 5-methyl-2.
thienyl,~ 4mehl- tin,1-methyl-3-pyrryl. I-methyl-3-pyrazoly 1. 5-mnethyl-2thiazolyl or 5-methyl1,24thiadiazoI2-yi Suitable alkyl groups and alkyl portions of groups, alkoxy, etc.. throughout 00 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,
"Q
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 1, from one to persubstitution all H atoms on the group are replaced by halogen atom), bei ng possible, mixed substitution of halogen atom types also being possible on a given moiety.
As indicated above, these ring systems can be unsubstituted or substituted by substituents such as halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include -CN, -COR',
-C(O)NR
5
-NR
5
R
5 -NR'C(O)0R 5
-NR
5
C,-C
10 alkyl,
C,-C,
0 alkenyl, alkoxy,
C
3
-CI
0 cycloalkyl, C,,-CII arYl,
C
7
-C
2 alkaryl, heteroaryl,
C
4 3 alkheteroaryl, substituted
C
1
-C
10 alkyl, substituted
C.-C,
0 alkenyl, substituted alkoxy, substituted
C
3 cycloalkyl, substituted
C,-C,
3 lhtray n -YA.
'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,
-C(O)NR
5
-NR
5
R
5
-NO
2
-NR
5
C(O)R
5
-NR
5 C(O)OR" and halogen up to per-halo substitution.
005 The moieties R5 and are preferably independently selected from H. alkyl.
N=K alkenyl,
C,-C
0 cycloalkyl,
C,-C,
4 aryl, C,-C 3 heteroaryl,
C.-C.
4 alkaryl, alkheteroaryl, up to per-halosubstituted
C
1
-C
10 alkyl, up to per-halosubstituted alkenyl, up to per-halosubst Ituted C 3
-C,
10 cycloalkyl, up to per-halosubstituted
C,-C,
4 aryl and up to per-halosubstituted
C
3
-C,
3 heteroaryl.
00 The bridging group Y is preferably
-N(R
5
-CH(OH)-,
-(CH,)mN(R 5
-O(CH
2 -CXa and in where m and XV is halogen.
00 The moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by wherein n I is 0 to 3.
Each Z substituent is preferably independently selected from the group consisting of -CN.
-C(O)NR
5
R
5 NR', -NO 2 SR', WW'R, -NR'C(O)0R'*
-NR
5 C(0)R5',
-SO,NR
5
C,-C,
10 alkyl, alkoxy,
C
3
-C
10 cycloalkyl, aryl, heteroaryl,
C,-C
24 alkaryl, alkheteroaryl, substituted alkyl, substituted
C
3
-C
0 1 cycloalkyl, substituted alkaryl and substituted
C,-C,
3 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN,
-CO,R
5
-C(O)NR
5 R -NO, -NR 5 -NR3C(0)R 5
-NR
5 C(O)0R",
C
1
-C,
0 alkyl, C,-C, 0 alkoxy, C 3
-C,
0 cycloalkyl,
C
3
-C,
3 heteroaryl,
C,-
C, aryl, C.
7 alkaryl.
The aryl and heteroaryl moieties of B of Formula I are preferably selected from the group consisting of
R
5
R
and 00 \o 0 0 which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n 0-3.
Xn -0 Y- a, Z, The aryl and heteroaryl moieties of B are more preferably of the formula: wherein Y is selected from the group consisting of-O-, -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 n 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 00 7 of and -NHR-, wherein R' is hydrogen, C 1 -C,(,-alkvl or C,-C 0 o- 0 cvcloalkyl and R" is preferably selected from the group consisting of hydrogen, C,- C(,-alkvl, C,-C,-cycloalkyl and C,-C,,-aryl, wherein R' and R_ can be substituted by halogen or up to per-halosubstitution.
00 The heteroaryl moiety A of formula I is preferably selected from the group consisting of: R1 R1 Ra 00 l N: k I S
S
II
N 00 N NNNNS 11 -a-I N aS RR RR The substituent R' is preferably selected from the group consisting of halogenC,-C, 0 alkyl, C,-C, 0 cycloalkyl, heteroaryl, aryl, alkaryl,_up to perhalosubstituted C,-C 10 alkyl and up to per-halosubstituted
C
3 cycloalkyl, up to perhalosubstituted C 1
-C
1 3 heteroaryl, up to per-halosubstituted aryl and up to perhalosubstituted
C,-C
24 alkaryl.
The substituent R 2 is preferably selected from the group consisting of H. -C(O)R 4
-C(O)NR
3
R
3
C,-C,
0 alkyl, C 3
-CI
0 cycloalkyl, alkaryl, C.
4
-C,
3 alkheteroaryl, substituted alkyl, substituted C,-C 0 cycloalkyl, substituted C,-
C,
4 alkaryl and substituted CX-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, -C(O)-NR 3 R V -NO 2 and halogen up to per-halosubstitution.
00 8 R' and R' are preferably independently selected from the group consisting of H. -OR',
-NR
4
R
4 -C(O)NR R 4
C,-C
10 alkyl, 0 cycloalkyl, aryl, heteroaryl, alkaryl, C,-C, 3 alkheteroaryl, up t o per-halosubstituted 0 alkyl, up to per-halosubstituted
C,-C,
0 cycloalkyl, up to per-halosubstituted
C,-
00 aryl and up to per-halosubstituted heteroaryl.
R" and R are preferably independently selected from the group consisting of H, C,-
C,
0 alkyl, C,-C, 0 cycloalkyl, aryl, C 3 heteroaryl; alkaryl, C 4 -C,,3 1 0a k e e or0 p t e a l s b t t t d C 1 l y u p t e a o u s i u e 3
C
cylalkhtryl, up to per-halosubstituted C-C ayln up to per-halosubstituted
C,-C
13 heteroaryl.
R
3 is preferably C,-C 0 alkyl, C,-C 10 cycloalkyl, up to per-halosubstituted alkyl and up to per-halosubstituted
C
3 cycloalkyl.
Rb is preferably hydrogen or halogen.
R' is hydrogen, halogen, C,-C 10 alkyl, up to per-halosubstituted
C,-C
10 alkyl or combines with R' and the ring carbon atoms to which R' and R' 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 pyrazolyll ureas of the formula I 1 0 R 2 NH-C-NH-B wherein R' W 1 and B are as defined above; 9 and both 5.3- and 3.5- isoxazolyl ureas of the formulae
R
1 0 O N
II
NH-C-NH-B
R'
N
I 0
SNH-CNH-B
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
Rs
'O
R
or which is substituted or unsubstituted by halogen, up to per-halosubstitution. Here Rs and R 5 are as defined above, n 0-2 and each X' substituent is independently selected from the group of X or from the group consisting of-CN, -CO,R 5 -C(O)NR'R NO,, -NR'R 5 alkyl, C,.,o-alkenyl, C,,,-alkoxy, 00 0 0 cycloalkyl, aryl and alkaryl.
The substituent X is selected from the group consisting of -NR 5 C(O)0R', NR'C(O)R C 3
-C
13 heteroaryl, C 4 -C,2 3 alkheteroaryl, substituted alkyl, substituted C,.
1 0 -alkenyl, substituted C,.
1 -alkoxy, substituted C,-C, 0 cycloalkyl, 00 substituted aryl, substituted alkaryl. substituted C 3
-C
13 heteroaryl, substituted alkheteroaryl, and -Y-Ar, where Y and Ar are as defined above. If In X is a substituted group, as indicated previously above, it is substituted by one or 00 more substituents independently selected from the group consisting of -CN, C(O)R5, -C(O)NRR5*, -NR 5
R
5 NO,, -NR5C(O)R 5
-NR
5 C(O)0R 5 and halogen up to per-halosubstitution, where R3 and R" are as defined above.
The components of B are subject to the following provisos, where R' is t-butyl and R 2 is methyl for the pyrazolyl ureas, B is not /C(O)00 4
H
9 Where R' is 1-butyl for the 5,3-isoxazolyl ureas, B is not 0-R 6 wherein R' is -NIIC(O)-O-t-butyl, -O-n-pentyl, -O-n-butyl, -0-propyl,
-OCH,CH(CH
3 2 or -O-CH, -phenyl. Where R' is t-butyl for the isoxazole ureas, B is not 0-0 /0-CH 2 -0 and where R' is -CH, -t-butyl for the 3,5 -isoxazolyl ureas, B is not
CH
3 Preferred pyrazolyl ureas, 3,5-isoxazolyl ureas and 5,3-isoxazolyl ureas are those wherein B is of the formula xn 00 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 pyndinyl, Q' is pyndinyl, phenyl or benzothiazoiyl, Y is
-SCH,-,
-CHO-. -OCR,- or -CH and Z is H, -SCH~, or -NH-C(O)-C H, wherein p is 1-4.
oo n 0, s =I and nlI 0- 1. Specific examples of preferred pyrazolyl ureas are: 3-Iert-Butyl-5-pyrazolyl).N 4 -phenvloxyphenyl)urea; 3 3 -methylaminocarbonylphenyl)- 00 oxyphenyl)urea; 100( e I B t l 5 py a o y 3 y id n l t i p ey0r a ~N-(3-ier-i-Butyl-5-pyrazolyl)-N'-(3-( 4 -pyridinyl)thiophenyl)urea; -(4-(4-pyridinyl )tophenyl)urea; 3 -ler-t-Butyl-5-pyrazolyl)-N 4 4 -pyridinyl)methylphenyl)urea; I -Methyl-3 -zerl-butyl-5-pyrazolvl)-N'-( 4 -phenyloxyphenvl)urea; I -Methyl-3-tert-butyl-5.pyrazolyl)-N 3 4 -pyridinyl)thiophenyl)urea; -M ethyl -3-tert-butvl-5-pyrazo lyvIN -((4-(4-pyridi nyl )thiomethyl)phenyl )urea; N-(1I -M ethyl -3 -i'ert-butyl- 5-pvrazolyl)-N 4 4 -pyri dinyl)thiophenyl)urea; N-(l -Methyl 3-ert-butyl- 5-pyrazo Iyl-N 4 4 -pyri di nyl)oxyph enyl )urea; 1 -M ethyl -3 -tert-butyl- 5-pyrazolIyI)-N 4 4 -pyri dinyl)m ethyl oxy)phen y I)urea;* 1 -Methyl -3 -tert-butyl -5-pyrazolIyI)-N 3 2 -benzothi azol yl)oxypheny I)urea; N-(3-!erl-butyl-5-pyrazolyl)-N'-(3-(4-pyridyl)thiophenyl) urea; 3-tert-butyl-5-pyrazolyl)-N 4 -(4-pyridyl)thiophenyl) urea; '-(3-(4-pyridyl )oxyphenyl) urea;
N-(
3 -ter-butyl-5-pyzolyl)-N(4(4pyidyl)oxyphenyi) urea; I-methyl-3-lert-butyl-5-pyrazolyl).N 3 4 -pyridyl)thiophenyl) urea; I-methyl-3-lert-butyl.5-pyrazolyl).N 4 4 -pyridyl)thiophenyl) urea; N-(1I -methyl-3-lert-butyl-5-pyrazolyl)-N 3 4 -pyridyl)oxyphenyl) urea; and I-methyl-3-ter-t-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 Z is -CH,, 00 12 Cl. -OCH, or -C(O)-CH 3 n s 1. and n] 0- 1. Specific examples of preferred ureas are: 4 4 -pyridinyl)thiophenyl)urea, '-(4-(4-methoxyphenyl )oxyphenvl )urea; N-(3-tert-Butyl-S-isoxazolyl)-N'-(5-( 2 4 -acetylphenyl)oxy)pyridinyl)urea; 00 N-(3-tert-Butyl-5-isoxazolyl)-N'-(3-(4-pynidinyl)thiophenyl )urea, 00N-(3-tirt-Butyl-5-isoxazolyl '-(4-(4-pyridinyl )methylphenvl )urea; N-(3 -tert- Butyl -5 isox azo ly)N'-(4-(4-pyridi nyl)thiophenyl )urea; 4 4 -pyridinyl)oxyphenyl)urea; 00 10 N-(3-zert-Butyl-5-i soxazoil)-N 4 4 -methyl- 3 -pyridinyl)oxyphenyl)urea; '-(3-(2-benzothiazolyl)oxyphenvl )urea;, 1,1 -D imethy lpropyl)-5 -i sox azoIyi I)-N ethylIph envl hox yphenylI)urea; 1,1 -Dimethylpropyl)-5-isoxazoli)-N'-( 3 4 -pyridinyl)t hiophenyl)urea; I, I -Dimethylpropyl)-5 isox azolIyl)-N'-( 4 4 -pyr d in yl)ox yph enyl) urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N 4 4 -pyridinyl)thiophenyl)urea; 1, -Dimethylpropyl-5-isoxazolyl)-N'-(5-( 2 4 -methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N 4 -(4-pyridinyl )oxyphenyl)urea; -Methyl- I -ethylpropyl)-5-isoxazolyl)4v '-(3-(4-pyridinyl )thiophenyl)urea; 3 4 -(2-methylcarbamoyl)pyridyl)oxyphenyl) urea;
N-(
3 -isopropyJ-5isoxazoy)N'(4(4-(2methylcarbamoyl)pyrdyl)oxyphenyl) urea; 3 -(4-(2-methylcarbamoyl pyridyl)oxyphenyl) urea; N-(3-tert-butyl-5 isox azo ly 4 4 -(2-methylcarb amoylI)pynidylI)oxyphenyl) urea; 3 4 -(2-methylcarbamoyl)pynidyl)thiophenyl) urea; 1,1-dimethylprop- 1 -yi)-5-isoxazolyl)-N 3 4 -(2-methylcarbamoyl)yridyl)oxyphenyl) urea; 1,1 -dimethylprop- I -yl)-5-isoxazolyl)-N 4 4 2 -methylcarbarnoyl)pyridyl)oxyphenyl) urea; and 00 13 N-(3-tert-butv'1-5- isxzl)--( -clr--4(-ehlabmy~viy) CK1 Ihiophenyl) urea.
Preferred 5,3-isoxazolyl ureas more paricularly include those wherein Q is is phenyl or pyndinyl, Q' is phenyl, ben~zothiazolyl or pyridinyl, Y is or X is CH3 and Z is CPP, wherein p 1-4, -C(O)CH 3
-CH
3 -OH, -OC,H, 00 CN, phenyl. or -OCH 3 n =O0or 1, s =Q0or 1, and n I 0 or 1. Specific examples of preferred 5.3-isoxazolvl ureas are: tr~ N-(5-tert-Butvl-3-i soxazolyl)-N 4 4 -hydroxyphenyl)oxyphenyl)urea; 00 10 N-(5-tert-Butyl-3-i soxazolyl)-N -hydroxyphenyl )oxyphenyl)urea; N-(5-ieri-Butyl-3-isoxazolyl)-N '-(4-(4-acetylphenyl )oxyphenyl)urea; N-(5-iert-Butvl-3 -isoxazolyl)-N '-(3-benzoylphenyl)urea; -tert- But 1- 3 -i sox azo lyl)-N 4 -pheny Iox ypheny1) urea; N-(5-zer-t-Butvl-3-i soxazolyl)-N 4 3 -methylaminocarbonylphenyl thiophenvl)urea; N-(5-ieri-Butvl-3)-i soxazolyl)-N 2 -methylenedioxy)phenyl)oxyphenyl )urea; -tert-ButylI- 3-1sox azo Iyl)-N -pyri din yl )ox yphenylI)urea; -Iert-B utyI- 3 1sox azo IylI)-N '-(4-(4-pyri di nyl )oxyphenyl)urea; N-(5-teri-Butyl-3-isoxazolyl)-N'-( 4 4 -pyridyl)thiophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N 4 4 -pyridinyl)methylphenyl )urea; -teri-B ut I- 3 -1 sox azolIyl)-N -(4-pyri din yl )ox yphenylI)urea; N-(5-reri.Butyl-3-isoxazolyl)-N '-(3-(4-pyridinyl)thiophenyl )urea; -iert-B uty 1- 3 -1soxazolIyl)-N 3 3 -meth yl -4-pyri d inyl)oxyp hen yl)urea; N-(5-ieri-Butyl-3-isoxazolyl)-N 3 3 -methyl-4-pyridinyl)thiophenyl)urea; N-(5-terr-Butyl-3 -isoxazolyl)-N 4 3 -methyl-4-pyridinyl)thiophenyl)urea; 5-iert-Butyl-3-isoxazolyl)-N 3 4 -methyl-3-pyridinyl)oxyphenyl)urea; N-(5-ierz-Butyl-3-isoxazolyl)-N 4 3 -methyl-4-pyridinyl)oxyphenyl)urea; N-(5-terzi-Butyl-3-isoxazolyl)-N '-(3-(2-benzothiazolyl )oxyphenyl )urea; N-(5-Iert-butyl-3-isoxazolyl)-N 3 -chloro-4-(4-(2-methylcarbanoyl)py-idyl)oxyphenyl) urea; N-(5-terr-butyl-3-isoxazolyl)-N 4 -(4-(2-methvlcarbamoyl)pynidyl)oxyphenyl) urea; -3-i soxazolyl)-N -(3-(4-(2-methylcarbamoyl)pyridyl)thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N 2 -methyl-4-(4-(2-methylcarbanioyl)pyridyi)oxyphenyl) urea; 00 1 N-(5-tert-butyl.3-isoxazolyl)-N 4 -(4-(2-carbamoyl)pyridyI oyhnl ra N-(5-tert-butyl3 i sox aolyi)-N 3 4 2 -carbamoyl)pyidyl)oxypjhenyI) urea; U N-(S-Ier-butyl-3-soxazolyl)-N'-( 3 4 2 -merhylcarbamoyl)pyrjdyl)oxyphenyl) urea; N(-erbutl3isoxazolyIN(-(4 4(,etycamll rdy thiophenyl) urea; 00 N-(5-ert-butyl-3isoxazolyl)-N 3 -chloro-4-(4-(2-methylcarbamoyl)pyidyl IND oxyphenyl) urea; and N-(5-terIt-butyl3isoxazolyl)-N 4 3 -methylcarbamoyl)phenyl )oxyphenyl) urea.
00 Additionally included are thienyl ureas of the formulae S N 0 Rb
NH-C-NH-B
0 orS 0 1,nt-IMB
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: x1n Xln
X
00
R
~and
I
00 1 These aromatic ring structures can be substituted or unsubstituted by halogen. up to per-halosubstitution. The X' substituents are independently selected from the g-roup consisting of X or from the group consisting of -CN, -OR3. -NR5R3, alkyl.
The X substituents are independently selected from the group consisting of -COR 5 00
C(O)NR
5
-C(O)R
5 -NR3C(O)OR3, -NRC(O)R", cycloalkyl, IND aryl, C 7 alkaryl. heteroaryl,
C
4
-C.
3 alkheteroaryl, and substituted
C,-
N
C,
0 alkyl, substituted C,.,-alkenyl, substituted C. ,-alkoxy, substituted
C
3
-CIC
N cycloalkyl, substituted aryl, substituted
C
7 alkaryl, substituted 00 heteroarvl, substituted alkheteroaryl, and -Y-Ar. Where X is a substituted CK1 group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -C(O)R3,
-C(O)NR
5 -ORW,
-NR
5
R
5
-NO,,
-N R 5
-NR'C(O)OR
5 and halogen up to per-halo substitution. The moieties
R
5 Y and Ar are as defined above and n 0-2.
The components for B are subject to the proviso thatk where R' is t-butyl and R' is H for the 3-thienyl ureas, B is not of the formula 0O CH(0H 3 2 Preferred thienyl ureas include those wherein B is of the formula )s-Zni.
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 pyi-idinyl, Y is or Z is -Cl, -CH 3 -OH or -OCH, n s =0 or 1. and n I 0-2. Specific examples of preferred thienyl ureas are: -4(-yiiy~tlpey~ra N-(3-zert-Butyl-5-isoxazolyl)-N'-(4 -(4-methoxyphenyl )oxyphenyl)urea; N-(3-zert-Butyl-5-isoxazolyl)-N'-(5-(2 -(4-acetylphenyl)oxy)pyridinyl)urea; 3 -(4-pyridinyl)thiophenyl)urea; N-(3-tert-Butyl -5-i soxazolyl 4 -(4-pyridinyl )methylphenyl )urea; 00 16 N-(3 -terr- Buty1- 5 -1soxazo ly l)-N -(4-(4-pyrI dinyl)thiopheny I)urea; o N-(3 -tert-B uty 1-5 -isox azo lyl)-N'-(4-(4-pynd inyl)oxyphenyl)urea: '-(4-(4-methyl-3-pyridinyl)oxvphenyl)urea; N-(3 -rert-Butyl-5-isoxazolyl)-N '-(3-(2-benzothiazolyi)oxyphenvl )urea; 3-(1,1 -Dimethylpropyl)-5-isoxazolyl)-N -(4-(4-methylphenyi oxyphenyl )urea: 00 1,1 -Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl)thiophenyl)urea; N-(3 -Dimethy lpropyl)- 5 -isox azolIyl)-N '-(4-(4-pyri d inyl)ox yph envl )urea; 1,1 -Dimethylpropyl)-5-isoxazolyl)-N -(4-(4-pyridinyl)thiophenyl )urea:! 10 1,1 -Dim ethy lpropylI- 5-i soxazo Iyl)-N -(2-(4-methox yph enyl)- 00 oxy)pyndinyl)urea; -Methyl- I -ethy lpropyl)- 5 -1sox azo Iy -(4-(4-pyri dinyl)oxyphenyl)urea; and -Methyl- I -ethyipropyl)-5-isoxazolyl)-N -(3-(4-pyridinyl)thiOphenyl)urea.
Preferred thiophenes include: 5-ierri-butyl-3-thienyl)-N -(4-(4-methoxyphenyl)oxyphenyl) urea; N-(5-ierrt-butyl-3-thienyl)-N '-(4-(4-hydroxyphenyl)oxyphenyl) urea; N-(5-ierz-butyl-3-thienyl)-N -(4-(3-methylphenyl)oxyphenyl) urea; and 5-zerrt-butyl-3-thienyl)-N '-(4-(4-pyridvl)thiophenyl) urea; and Also included are the thiadiazolyl and furyl ureas of the formulae: Nils 0 0 1 -104 1B NH-C -NH-B wherein R' and B are as defined above. The thiadiazolyl and furyl ureas have preferred aromatic ring structures for B identical to those for the pyrazoiyi, thienyl and isoxazolyl ureas shown above. Such ring structures can be unsubstituted or substituted by halogen, up to per-halosubstitution, and each X' substituent is independently selected from the group consisting of X or from the groupconsisting of -CN, -NO, -OR' and C,-C 10 alkyl. The X substituents are selected from the group consisting of -C(O)NR 5
R
5
-NR'R
5
-NR
5 C(O)0R", 00 17 substituted C,,-alkenyl. substituted C.
0 -alkoxy. cycloalkyl.
aryl, 1 alkaryl. heteroaryl, alkheteroarvl. and substituted alkyl, substituted C,-C, 0 cycloalkyl, substituted aryl. substituted alkaryl, substituted heteroaryl, substituted alkheteroarvl and -Y-Ar. Each of R3, R" and Ar are as defined above, n 0-2, and the substituents on X where X is a substituted 00 ~~~~group are as defined for the pyrazolyl.ioxzlladhinlues This invention also includes pharmaceutical compositions that include compounds 00 described above and a physiologically acceptable carrier.
c-K1 Preferred fury! ureas and thiadiazole ureas include those wherein B is of the formula Xn and Q, X, Y, 7, n, s, and nI are as defined above. The prefer-red thiadaizolyl ureas more particularly include those wherein Q is phenyl, Q' is phenyl or pyridinyl, Y is or n s I and n I1 0. Specific examples of prefer-red thiadiazolyl ureas are: N-(5-tert-Butyl-2-( I -thia-3,4-diazolyl))-N 3 4 -pyridinyl)thiophenyl)urea; N-(5-iert-Butyl-2-( I -thia-3,4-diazolyl))-N 4 4 -pyridinyl)oxyphenyl )urea; N-(5-ieri-butyl-2-( I -thia-3 ,4-diazolyl))-N 4 -(2-methylcarbamoyl)pyridyl oxyphenyl) urea; N-(5-ieri-butyl-2-( I -thia-3 .4-diazolyl))-N 4 4 -(2-methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-iert-butyl-2-( I -thia-3,4-diazolyl))-N '-(3-chloro-4-(4-(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-2-( 1 -thia-3 ,4-diazolyl))-N -(2-chloro-4-(4.(2methylcarbamoyl)pyridyl)oxyphenyl) urea; N-(5-iert-butyl-2-( I-thia-3 ,4-diazolyl))-N 3 -(4-pyridyl)thiophenyl) urea; N-(5-Iert-butyl-2-( I -thia-3 ,4-diazolyl))-N '-(2-methyl-4-(4-(2methylcarbamoyl)pyridyl)oxyphenyl) urea; and 1,1 -dimethylprop- I 1 -thia-3,4-diazolyl))-N carbamnoylphenyl)oxyphenyl) urea.
The preferred fuiryl ureas more particularly include those wherein Q is phenyl, Q is phenyl or pyridinyl, Y is or Z is -CI or -OCH,, s =0 or 1, n 0 and n I 0-2.
00 0 18
O
0 The present invention is also directed to pharmaceutically acceptable salts of formula S1. 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 00 acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, Soxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts OO include acid salts of inorganic bases, such as salts containing alkaline cations Li' 8 10 Na- or alkaline earth cations Mg' Ca- 2 or Ba- 2 the ammonium cation, as Swell as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N.N-diethylamine, N.N-dicyclohexylamine, pyridine, N.N-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 Rafkinase 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, 3rd Ed.; John Wiley: New York (1985)). For 00 O 19 0 example. 3-substituted-5-aminoisoxazoles are available by the reaction of U hydroxylamine with an a-cyanoketone as shown in Scheme I. Cyanoketone 2, in Sturn. is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide. or an acid anhydride. Reaction of an cyanoketone with hydrazine (R2=H) or a monosubstituted hydrazine affords the 3- 00 substituted- or 1,3-disubstituted-5-aminopyrazole Pyrazoles unsubstituted at N-I O may be acylated at N-1, for example using di-tert-butyl dicarbonate. to give t' pyrazole 7. Similarly, reaction of nitrile 8 with an -thioacetate ester gives the 00 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
00 00 1) base 0 R1,'
CN
2
R'
CI
CN
8
R'
NH
3 11
R
2
NHNH
2 4
H
2
NOH-HCI
,-base i
R'
N/
0 NH 2 3
R
1
N
N NH 2 O R2
A
RO X 6
NH
2
R
R'
NI
N NH 2
OR
7 HS CO 2
R
1) OH 2) H', 9 0 0
R'
1) OH-
S
2) H
NHBOC
CO2R Scheme I. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3" Ed.; John Wiley: New York (1985); Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H, or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH, (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a 00 0 21 0 zero valent metal. such as Fe. Sn or Ca. often in acidic media. Many methods exist O for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 d Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H
2 catalyst 0 0 (eg. Ni. Pd, Pt)
O
1 ArNO 2 ArNH 2 In 1 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 1 Ar-H o ArNO 2 potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme
III).
0 2 N O2N "ArSH R base 12 O 2
N
S-Ar OV SH Br-Ar 13 CuO base 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroarvls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine The heteroaryl isocyanate may be 00 22 synthesized from a heteroaryl amine by treatment with phosgene or a phosgene C" equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) d carbonate (tnphosgene), or N.N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus. reaction of acid derivative 21 with an azide source, followed by rearrangement affords the isocyanate.
OO
\0 The corresponding carboxylic acid (22) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic 00 0 10 amine.
Het-NH 2 16
H
2 N-Ar 19 I COCI 1 2 COCI2
H
2 N-Ar O Het-NH 2 Het-NCO Het-. Ar OCN-Ar 17 H H 18 N3 DPPA N3
DPPA
0 0 0 0 Het X Het 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.
00
O
R'
S
NH
2 ROzC 1) OH' 2) COCI 2
R
1
S
S25 NH
H
2 N-Ar
R
1 0 S N N Ar
HO
2 C H H 26
R'
S N Ar H H 27
A
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 00 24 order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable U 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, steanc acid or talc. The 0 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 0 10 glyceryl monostearate or glyceryl distearate may be employed. These compounds CN 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 Sby 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 O above. Additional excipients, for example, sweetening, flavoring and coloring agents.
may also be present.
(N
o The compounds may also be in the form of non-aqueous liquid formulations, oily O 10 suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral 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 00 26 O 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 O known to those skilled in the art (see, for example: Chien; "Transdermal Controlled 0 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 C, combined with additional additives known to those skilled in the an, such as matrix materials and bactenocides. 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 1 may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated
C
8 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 Sacids with a total of up to 24 carbons such as diisopropyl adipate. diisobutvl 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 IN from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 fatty alcohols, saturated or unsaturated 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.
00 0 28 SIt will be appreciated by those skilled in the anrt that the particular method of O administration will depend on a variety of factors, all of which are considered Sroutinely when administering therapeutics.
It will also be understood, however, that the specific dose level for any given patient 00 will depend upon a variety of factors, including, the activity of the specific compound I, 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 bc further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Attorney Docket BAYER 8 VI, filed on December 22, 1997, as Serial No.
08/996,343, converted on December 22, 1998.
The compounds are producible from known compounds (or from starting materials which, in 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.
00 S29
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 00 IN introduced into reaction vessels through rubber septa. Unless otherwise stated, the CK1 term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator rC at approximately 15 mmHg.
00 C 10 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 gm plates. Visualization of plates was effected by one or more of the following techniques: ultraviolet illumination, exposure to iodine vapor, immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, immersion of the plate in a cerium sulfate solution followed by heating, and/or immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science' silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either MeSi (5 0.00) or residual protonated solvent (CHCIl 5 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCI, 6 77.0: MeOD-d,; 49.0; DMSO-d, 8 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass 00 spectra or as fast atom bombardment 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 p.A. Liquid- 00 cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom \0 Sbombardment were obtained using a Kratos Concept I-H spectrometer. Chemical tt) ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine 00 (5989A) with methane as the reagent gas (1x10 I torr to 2.5x10 4 torr). The direct 0 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-I 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(1H)-pyrimidinone
DMF
DMSO
DPPA
EtOAc EtOH Et,O Et 3
N
m-CPBA MeOH pet. ether
THF
TFA
Tf 31 N.N-dimethylformamide dimethylsulfoxide diphenylphosphoryl azide ethyl acetate ethanol (100%) diethyl ether triethylamine 3-chloroperoxybenzoic acid methanol petroleum ether (boiling range 30-60 OC) tetrahydrofuran trifluoroacetic acid 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.
00 32
N
0
NH
2 Step 2. 5-AmiDO-3-isopropylisoxazole: Hydroxylamine hydrochloride (10.3 g, 148 0 0 mmol) was slowly added to an ice cold solution of NaOH (25.9 g, 645 mmol) in water (73 mL) and the resulting solution was poured into a solution of crude 3-oxo-4- Vt methylpentanenitrile while stirring. The resulting yellow solution was heated at 50 *C 0O for 2.5 hours to produce a less dense yellow oil. The warm reaction mixture was Simmediately 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% CH,CI,) to afford the desired isoxazole as a yellow solid (11.3 g, mp 63-65 TLC R, CH,C1_) 0.19; 'H-NMR (DMSO-d 6 d 1.12 J=7.0 Hz, 6H), 2.72 (sept, Hz, 1H), 4.80 2H), 6.44 1H); FAB-MS m/z (rel abundance) 127 67%).
A3. General Method for the Preparation of 5-Amino-l-alkyl-3-alkylpyrazoles
NH
2 N NH,
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 EtOAc/70% hexane) Rf 0.31; 'H-NMR (DMSO-d,) 6 1.13 9H), 2.82 J=6.9 Hz, 2H), 4.04 J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 1H).
00 33 OA 4. Synthesis of AMa. Synthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids 00
S
NH
00 50 0 Step 1. 7-tert-Butyl-2H-tbienoj3,2-djoxazine-2,4(1 1)-dione:. A mixture of methyl 3 -am Ino 5-teri-butylthi ophenecarbox ylate (7.5 g, 35.2 mmol) and KOH (5.92 g) in MeGH ('24 mL) and water (24 niL) was stirred at 90 'C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 niL). Phosgene (20% in toluene, 70 niL) 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-
N
T
MR (CDCI 3 6 1.38 9H), 2.48 IH), 6.75 I FAB-MS ni/z (rel abundance) 226 100%).
0 S N N N' HOOC H H Step 2. N-(5-rerr-Butyl-2-carboxy-3-thienyl)-N' -(4-(4-pyridinylmethylI)pbenyl)urea: A solution of 7-iert-butyl-2H-thieno[3 ,2-d]oxazine-2,4( 1H)-dione (0.176 g, 0.78 mrnol) and 4-(4-pyridinylmethyl)aniline (0.144 g, 0.78 rnmol) in THF (5 mL) was heated at the reflux. temp. for 25 h. After cooling to room temp., the resulting solid was triturated with Et.,O to afford the desired urea (0.25 g, nip 187-189 OC; TLC (50% EtOAcI5O% pet. ether) Rf 0.04; 'H-NMR (DMSO-d 6 8 1.34 9H), 3.90 2H), 7.15 J=7Hz, 2H), 7.20 1=3 Hz, 2H), 7.40 1=7 Hz, 2H), 7.80 (s IH), 8.45 1=3 Hz, 2H) 9.55 IH), 9.85 IH), 12.50 (Ibr s, IR); FAB-MS m/z (rel abundance) 410 000 N N H H Step 3. N-(5-ter,-Bu tvl- 3 -thienvI).N (4(4-p)ridilylmethN.l)phenvI)urea: A vial 00 containing N-(5-tert-butyI-2carboxy-3.thienyl)-N'-( 4 -(4-pyridinylmethyl)phenyl)- IND urea (0.068 g, 0.15 mmol) was heated to 199 'C in an oil bath. After gas evolution ceased, the material was cooled and purified by preparative HPLC (C-IS column; 00 gradient from 20% CHCN/79.9%/ H-,0/0.1I% TFA to 99.9% H,0/0- I TFA) to give the desired product (0.024 g, TLC (50% EtOAc/50% pet. ether) Rf 0.18; 1- NMR (DMSO-d,) 5 1.33 4.12 2H), 6.77 I 6.95 I1H), 7.17 J=9 Hz, 2H), 7.48 .1=9 Hz, 2H), 7.69 J=7 Hz, I 8.58 I 8.68 J=7 Hz, 2H), 8.75 I1H); El-MS m/z 365 A4b. Synthesis 3 -Amino-5-alkylthiopbenes from 3 -Amino-5-alkyl.2-hiophenecarboxylate esters
S
NH
3 C1- 5-ter:-Butvl-3-thiopheneammonium Chloride: To a solution of methyl 3 terrt-butyl-2-thiophene-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp. for 2.25 h. A conc. HCI solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for I h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 rnL) and a saturated NaI-C0 3 solution (150 mL) was added to dissolve. The organic layer was washed with water (150 ml-) and a saturated NaCI solution (150 mL), dried (NaSO., and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification.
00 AMc. Synthesis 3-Amino-5-alkvlthiophenes from N-BQC 3-Amino-5-alk% th iopb en eca rboxy late esters 0 00N k INDMeO 2 C H Step 1. Methyl 3-(rert-Butoxycarbonylamino)-5-terf-butylI-2-tbiophenecarboxi-- 00 5 late: To a solution of methyl 3-amino-5-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 'C was added di-zert-butyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and k.N-dimethylaminopyri dine (86 g, 0.70 mol, 1.00 equiv) and the resulting mixture was stirred at room temp for 7 d. The resulting dark solution was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately 20 The resulting red solids were dissolved in CH,CI, (3 L) and sequentially washed with a I M H 3 P0 4 solution (2 x 750 mL), a saturated NaHCO 3 solution (800 mnL) and a saturated NaCI solution (2 x 800 mL), dried (Na SO,) and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 0 C, then treated with water (500 rnL) to* afford the desired product as an off-white solid (163 g, 'H-NMR (CDCI 3 5 1.38 9H), 1.51 (s.
3.84 3H), 7.68 1H), 9.35 (br s, 1H); FA.B-MS ?n/z (rel abundance) 314 S0 H0 2 C H Step 2. 3-Qtert-Bu toxyca rbonylamin o)-5-terr-b utyl1-2-th iop hen eca rb oxylic Acid: To a solution of methyl 3-(tert-butoxycarbonylanino)-5-ter-butyl-2thi ophenecarboxy late (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 TC for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0 The pH was adjusted to approximately 7 with a 00 00 36 N HCI solution (approximately I L) while maintainin2 the internal temperature at Sapproximately 0 oC. The resulting mixture was treated with EtOAc (4 The pH Swas adjusted to approximately 2 with a 1.0 N HCI solution (500 mL). The organic phase was washed with a saturated NaCI solution (4 x 1.5 dried (NaSO,), and concentrated to approximately 200 mL under reduced pressure. The residue was Streated with hexane (1 L) to form a light pink (41.6 Resubmission of the mother 11 liquor to the concentration-precipitation protocol afforded additional product (38.4 g, S93% total yield): 'H-NMR (CDCI 3 5 1.94 9H), 1.54 9H), 7.73 1H), 9.19 (br oo s, 1H); FAB-MS m/z (rel abundance) 300 00
S
NH3- Cr Step 3. 5-ert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(tertbutoxycarbonylamino)-5-ter-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 6 8 1.31 9H), 6.84 J=1.48 Hz, 1H), 7.31 (d,J=1.47 Hz, 1H), 10.27 (br s, 3H).
00 37 General Method for the Synthesis of BOC-Protected Pyrazoles
NI
N0 NH2 000 S-Amino-3-ler:-butvl-N'-(terf-butoxycarbonyl)pyrazole: To a solution of 00 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CHC1, (140 mL) was added di-tert-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp. for 13 h, thcn diluted with EtOAc (500 mL). The organic layer was washed with water (2 x 300 mL), dried (MgSO,) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired carbamnate (6.26 g. mp 63-64 TLC Rf acetone/95% CH 2
'H-NMR
(DMSO-d,) 8 1.15 1.54 9H), 5.22 1H), 6.11 2H); FAB-MS m/z A6. General Method for the Synthesis of 2-Aminothiadiazoles
'S
H
2-Amino-5-(1 -eth yl)p ropylI)th iad iazin e: To concentrated sulfuric acid (9.1 rnL) was slowly added 2-ethylbutyric acid (10.0 g, 86 mmnol, 1.2 equiv). To this mixture was slowly added thiosemicarbazide (6.56 g, 72 mmcl, I equiv). The reaction mixture was heated at 85 *C for 7 h, then cooled to room temperature. and treated with a concentrated NHOHsolution until basic. The resulting solids were filtered to afford 2 -amino-5-(I-(1-ethyl)propyl)thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, mp 155-158 0 C; TLC MeOHI CHCl 3 Rf 0.14; 'H-NMR (DMSO-d 6 8 0.80 J=7.35 Hz, 6H), 1.42-1.60 (in. 2H-), 00 O 38 O 1.59-1.71 2H), 2.65-2.74 1H), 7.00 (br s, 2H); HPLC ES-MS mn.- 172 O
C(
i A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles 00 00 N.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 00 Sthen stirred at 60 oC 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.
-to N
NH
2 Step 2. 2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 KHCO, (0.102 and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 The resulting mixture was heated at the refulx temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH,CI, mL). The organic layer was washed with water (2 x 10 mL), dried (MgSO,) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 A8. General Method for the Synthesis of 2-Aminooxazoles 0
OH
Step 1. 3,3-Dimethyl-l-hydroxy-2-butanone: A neat sample of 1-bromo-3,3dimethyl-2-butanone (33.3 g) at 0 °C was treated with a IN NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (Na SO,) and concentrated under reduced pressure to 00 8 39 give 3.3-dimethyl-l-hydroxy-2-butanone (19 g. 100%), which was used inb the next step withour further purification.
N
O
NH
2 00 \0 Step 2. 2-Amino-4-isopropyl-1,3-oxazole: To a solution of 3,3-dimethyl-l- C, 5 hydroxy-2-butanone (4.0 g) and cyanimide (50% w/w, 2.86 g) in THF (10 mL) was Cg added a IN NaOAc solution (8 mL), followed by tetra-n-butylammonium hydroxide
OO
00 S(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 EtO (3 x mL). The combined organic layers were treated with a IN NaOH solution tuntil basic, then extracted with CH,CI, (3 x 25 mL). The combined organic layers were dried (Na,SO) and concentrated under reduced pressure to afford 2-Amino-4isopropyl-l,3-oxazole (1.94 g, HPLC ES-MS m/z 141 A9. Method for the Synthesis of
N-
N
I
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 CHCI1 (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 00 O o B. General Methods for Synthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of Sa Nitroarene 00 5 H 2 N N
\O
0 4-(4-Pyridinylmethyl)aniline: To a solution of 4 4 -nitrobenzyl)pyridine (7.0 g, 32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry 00 was shaken under a H, atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and S'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 6 3.74 2H), 4.91 (br s, 2H). 6.48 J=8.46 Hz, 2H), 6.86 J=8.09 Hz, 2H). 7.16 J=5.88 Hz, 2H), 8.40 J=5.88 Hz, 2H); El- MS 184 This material was used in urea formation reactions without further purification.
B2. General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-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 KCO, 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.
00 0 41 O B3a. General Method for Substituted Aniline Formation via Nitroarene Formation U Through Nucleophilic Aromatic Substitution. Followed by Reduction 0 2 N OMe Step 1. 1-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH
OO
00 5 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was added dropwise a solution of 4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, Sthen a solution of 1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was 00 Sadded dropwise to form a dark green solution. The reaction was heated at 95 °C Sovernight, then cooled to room temp., quenched with H,O, 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 NaCI solution (200 mL), dried (NaSO,), and concentrated in vacuo. The residue was triturated (EtO/hexane) to afford 1methoxy- 4 -(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDCI 3 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 D O OMe Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of l-methoxy-4-(4nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g) and the resulting slurry was shaken under a H: atmosphere (50 psi) for 18 h.
The reaction mixture was filtered through a pad of Celite' with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR
(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 B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
CF
3 0 2 N.
N
00 42 Step 1. 3 -(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4- C1 mercaptopyridine (2.8 g, 24 mmoles), 2 -fluoro-5-nitrobenzotrifluoride (5 g, 23.5 d 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 Et,O (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et,O (2 x 100 mL). The organic layers were 00 washed with a saturated NaCI solution (100 mL), dried (MgSO,), and concentrated C under reduced pressure. The solid residue was triturated with Et,O to afford the Sdesired product as a tan solid (3.8 g, TLC (30% EtOAc/70% hexane) R, 0.06; 00 'H-NMR (DMSO-d 6 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 J=8.7 Hz, 1H), 8.46 (dd, N J=2.4, 8.7Hz, 1H), 8.54-8.56 3H).
CF
3
H
2N
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,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 NaCI solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 TLC (50% EtOAc/50% hexane) R 0.10; 'H-NMR (DMSO-d) 6.21 2H), 6.84-6.87 3H), 7.10 (d,J=2.4 Hz, 1H), 7.39 J=8.4 Hz, 1H), 8.29 J=6.3 Hz, 2H).
B3c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 00 43 NS S 0 2
N
Step 1. 4 2 4 -Phenyvl)thiazolyl)thio-l-nitrobenzene: A solution of 2-mercapto-4- 00 phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mnL) was treated with I-fluoro-4- IND nitrobenzene (2.3 mL, 21.7 mmoles) followed by KCO 3 (3.18 g, 23 mmol). and the mixture was heated at approximately 65 'C overnight. The reaction mixture was then 00 diluted with EtOAc (100 mL), sequentially washed with water (100 ml-) and a saturated NaCI solution (100 mL), dried (MgSO 4 and concentrated under reduced CK1 pressure. The solid residue was triturated with a Et,Olhexane solution to afford the desired product (6.1 TLC (25% EtOAc/75% hexane) Rf 0.49; 'H-NMR (CDCI 3 6 7.35-7.47 (in, 3H), 7.58-7.63 (in, 3H), 7.90 J=6.9 Hz, 2H), 8.19 J=9.0 Hz, 2H).
11
H
2
N
Step 2. 4 2 -(4-Pbenyl)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-pyndinylthio)aniuine: TLC (25% EtOAc/75% hexane) R. 0.18; 'H-NMR (CDCI,) 6 3.89 (br s. 2H), 6.72-6.77 (in, 2H), 7.26-7.53 (in, 6H), 7.85-7.89 (in, 2H).
133d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0
N
0 2
NZ(
Step 1. 4 6 -Methvl-3-pyridiuyloxy)-l-nitrobenzene: To a solution of 2-methylpyridine (5.0 g, 45.8 mmol) and I -fluoro-4-nitrobenzene (6.5 g, 45.8 rnmol) in anh DMF (50 mL) was added K2 C0 3 (13.0 g, 91.6 niol) in one portion. The mixture was heated at the reflux temp. with stirring for 1 8 h and then allowed to cool 00 44 to room temp. The resulting mixture was poured into water (200 mLj and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with Swater (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na,SO,, and Sconcentrated in vacuo to afford the desired product (8.7 g, The this material was carried to the next step without further purification.
00 0 H 2 N I V) Step 2. 4 6 -Methvl-3-.pridinyloxy)aniline: A solution of 4 -(6-methyl-3- 00 pyridinyloxy)-l-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to O 10% 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 a and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, El-MS ml: 200 B3e. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 N O Me Step 1. 4 3 ,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4dimethoxyphenol (1.0 g, 6.4 mmol) and I-fluoro-4-nitrobenzene (700 PL, 6.4 mmol) in anh DMF (20 mL) was added KCO 3 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (NaSO.), and concentrated in vacuo to afford the desired product (0.8 g, The crude product was carried to the next step without further purification.
f~ 0 -OMe HN' O OMe Step 2. 4 3 4 -Dimethoxyphenoxy)aniline: A solution of 4 3 ,4-dimethoxy.
phenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 00 0 O 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 245 00 B3f. General Method for Substituted Aniline Formation via Nitroarene Formation N Through Nucleophilic Aromatic Substitution, Followed by Reduction 00 0 2 N O SStep 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), 1-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper(I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K.CO 3 (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (NaSO,), 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 ,O Step 2. 3 -(3-Pyridinyloxy)aniline: A solution of 3-(3-pyridinyloxy)-1nitrobenzene (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, 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 B3g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 00 46 S0 2 N O SStep 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(l) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K,CO, 0 5 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp. with O stirring for 18 h and then allowed to cool to room temp. The mixture was then poured ninto water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics 0 were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x S100 mL), dried 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%).
HzN O N Step 2. 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3pyridinyloxy)-l-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to Pd/C (0.100 g) and the resulting mixture was placed under a H, atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite' and concentrated in vacuo to afford the desired product as a red oil (0.9 g, Cl-MS 201 2B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction O N ON 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,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) 00 47
O
and pet ether (25 mL) to give the desired product (7.05 g, mp 80-82 TLC (30% EtOAc/70% pet ether) R, 0.79; 'H-NMR (DMSO-d) 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%).
00. 1'
IND-
0CI H 3 N NH CI ri 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,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,) 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%).
B3i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 0 2 NI 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 00 48 O extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a IM 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 237
SS
00
SH
2
N
lt Step 2. 4-(3-Thienylthio)aniline: 4 -(3-Thienylthio)-l-nitrobenzene was reduced to 00 the aniline in a manner analogous to that described in Method BI.
0 B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
H
2 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 oC 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%).
B3k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Br- YN OMe
-N
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 00 49 O mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na,SO,) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc hexane) Rf 0.57.
HOf -OMe 00 5
N
N Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2- C methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n- 00 butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the Sresulting mixture was allowed to stir at -78 oC for 45 min. Trimethyl borate (7.06
C
10 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture 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,) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 0 2 N O N OMe Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene: To a stirred slurry of NaH 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp. for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mnixture was heated to 95 °C ovemight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgSO,) and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g,
H
2 N, N OMe 00 Step 4. 4 -(5-(2-Methoxy)pyridyl)oxyaniline: 4 -(5-(2-Methoxy)pvrdyl)oxy- nitrobenzene was reduced to the aniline in a manner analogous to that described in SMethod B3d, Step2.
B4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic 00 Substitution using a Halopyridine
\O
H
2 N S N 00 3-(4-Pvridinvlthio)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 KCO, (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (100mL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et,O/hexane solution to afford the desired product (4.6 g, TLC (100 ethyl acetate) Rf 0.29; 'H-NMR (DMSO-d 6 5 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).
2B4b. 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 stimng for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaSO,), and concentrated in vacuo.
00 o 51 O The resulting oil was purified by flash chromatography (50 EtOAc/50% hexane) to Safford the desired product as a yellow oil (0.7 g. CI-MS m/z 201
C)
B4c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine Me 00 02NN 00 0 Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4- C nitroaniline (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 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried (Na.SO,) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4nitrophenyl)-4-pyridylamine (0.42 g) Me
H
2 N- 1N Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4pyridylamine was reduced in a manner analogous to that described in Method B1.
General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene S O 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 52 00 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 C. The reaction was stirred at room temp. for 18 h at which time TLC indicated the presence of Sunreacted phenol, and additional iodobutane (56 mg, 0.035 mL. 0.303 mmol. 0.05 Sequiv) 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 EtO (2 x 500 mL). The combibed organics were OO washed with water (2 x 400 mL). dried (MgSO), and concentrated under reduced Spressure 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 00 10 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 J= 6.6 Hz, 2H), 7.08 J=8.7 Hz. 2H), 7.17 J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz. 2H), 8.09 J= 9 Hz, 2H).
H
2 N S0O 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 0
H
4 4 -ter-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 EtO (200 mL), sequentially washed with a 00 53 O saturated NaHCO. solution (100 ml), water (100 mL) and a saturated NaCl solution o (50 mL), dried (MgSO 4 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 00 (DMSO-d 6 8 1.43 9H), 3.63 2H), 4.85 (br s, 2H), 6.44 J=8.4 Hz, 2H), 0 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, t 1H); FAB-MS ml: 298 00
S
1 B7. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction 0 2 N N Step 1. 3-(4-Nitrobenzyl)pyridine: A solution of 3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 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,), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, GC- MS m/z 214
H
2
N
Step 2. 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method B1.
B8. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzvl Halides Followed by Reduction 00 00 54 O r^ 0 2 N N
N
Step I. 4 -(I-Imidazolylmethyl)-1-nitrobenzene: To a solution of imidazole (0.5 g 7.3 mmol) and 4 -nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added KCO 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 Swasextracted 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 0 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 NI
N
Step 2. 4-(I-Imidazolylmethyl)aniline: 4-(I-Imidazolylmethyl)-.-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.
1B9. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzvl Compounds Followed by Reduction
OH
O,N
0 2 N
'N
Step 1. 4 -(l-Hydroxy-l-(4-pyridyl)methyl--nitrobenzee: To a stirred solution of 3 4 -nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH,CI, (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, solution (50 mL), a saturated K,CO3 solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO 4 and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous NH, solution (30 mL).
The mixture was stirred at room temp. for I h, then was concentrated under reduced pressure. The residue was poured into a mixture of water (50 mL) and CH,C, 00 0 O mL). The organic layer was dried (MgSO,). concentrated under reduced pressure, and o purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired Sproduct as a white solid. (0.53 g, mp 110-118 TLC (80% hexane) R 0.12; FAB-MS n: 367 100%).
00
OH
CN
N
n
H
2
N
OO Step 2. 4-(1-Hydroxy-l-(4-pyridyl)methylaniline: 4-(l-Hydroxy-l-(4-pyridyl)- 0methyl-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d. Step2.
BI0. Formation of 2 -(A-methylcarbamoyl)pyridines via the Menisci reaction 0 CI
-NH
2 Step 1. 2 -(N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc. HSO, (3.55 mL) (exotherm). To this was added H,O, (17 mL, 30% wt in H20) followed by FeSO, 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for Ih then was heated slowly over 4 h at 45 OC. When bubbling subsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was diluted with H20 (700 mL) fol.lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCI solution (3 x 150 mlL. The combined organics were dried (MgSO,) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc 50% hexane to 80% EtOAc hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(Nmethylcarbamoyl)-4-chloropyridine in yield (0.61 g, TLC (50% hexane) R,0.50; MS; 'H NMR (CDCI 3 d 8.44 1 H, J 5.1 Hz, CHN), 8.21 (s, 00 56 I H, CHCCO). 7.96 (b s, IH,.NH), 7.43 (dd. I1H .1 2.4. 5.4 Hz. CICH-CN). 3.04 (d.
CN 3H. J 5.1 Hz. methyl); Cl-MS iml: 17] B1i. Generalmeth od for th e Sy~n thesis of o)-Su lfonylpheny'I AniHines -~0 Me 00 0 2 Ncas: Step 1. 4 4 -NMethylsulfon-*'lphenoxy)..1nitrobenzene: To a solution of 4-(4methylthiophenoxy)- I-ntirobenzene (2 g, 7.66 mmol) in CH,CI, (75 mL) at 0 'C was 00 ~slowlyv added nzCPBA (57-86%. 4 and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a I N NaGH solution mnL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure to give 4 -(4-methylsulfonyiphenoxy)-lnitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsulfonylpbenoxy)-l -aniline: 4 -(4-Methylsulfonylphenoxy)- 1nitrobenzene was reduced to the aniline in a manner anaologous, to that described in Method 133d, step 2.
B12. General Method for Synthesis of o)-Alkoxv-w-carbox-sphenyl Anilines 0 01(: MOMe 0 2 N Oe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)1 -nitrobenzene: To a solution of 3 -carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous to that described in Method B3a. step 1, 12 mmol) in acetone (50 mL) was added K,C0 3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaat the reflux tempoerature overnight, then cooled to room temperature and filtered through a pad of Celite". The resulting solution was concentirrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography EtOAc 50% hexane) to give 4 -(3-methoxycarbonyl-4-methoxyphenoxy)initrobenzene as a yellow powder (3 mp 115 118 *C.
00 57 00 N OH O o 0 2 N "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 0 water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then N 5 heated at the reflux temperature for 4 h. The resulting mixture was cooled to room N temperature and concentrated under reduced pressure. The residue was dissolved in CN water (50 mL), and the aqueous mixture was made acidic with a IN HCI solution.
00 SThe resulting mixture was extracted with EtOAc (50 mL). The organic layer was CN1 dried (MgSO,) and concentrated under reduced pressure to give 4-(3-carboxy-4methoxyphenoxy)- -nitrobenzene (1.04 g).
C. General Methods of Urea Formation Cla. Reaction of a Heterocyclic Amine with an Isocvanate N N O H H N-(5-tert-Butyl-3-thienyl)-N'-(4-phenoxyphenyl)urea: To a solution of butyl-3-thiophene-ammonium chloride (prepared as described in Method A4b; 7.28 g, 46.9 mmol, 1.0 equiv) in anh DMF (80 mL) was added 4-phenoxyphenyl isocyanate (8.92 g, 42.21 mmol, 0.9 equiv) in one portion. The resulting solution was stirred at 50-60 °C overnight, then diluted with EtOAc (300 mL). The resulting solution was sequentially washed with H,O (200 mL), a 1 N HCI solution (50 mL) and a saturated NaCI solution (50 mL), dried (NaSO,), 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% CHCl1/64% cyclohexane) to afforded the desired product as a white solid (3.17 g).
Clb. Reaction of a Heterocyclic Amine with an Isocvanate 00 58 '0 N NC H H N-3tr-uN--sxzli)N-4peope~~ra To a solution of 00 amino-3-tei--butylisoxazole (8.93 g, 63.7 mmol. I eq.) in CHCI, (60 mL) was added 1-10 4-phenyioxyphenyl isocyanate (15.47 g, 73.3 mmol, 1. 15 eq.) dropwise. The mixture N-K 5 was heated at the reflux temp. for 2 days, eventually adding additional CH,CI, NK rnL). The resulting mixture was poured into water (500 mL) and extracted with Et,O 00 (3 x 200 mL). The organic layer was dried (MgSO,) then concentrated under reduced c-K1 pressure. The residue was recrystallized (EtOAc) to give the desired product (15.7 g, mp 182-184 TLC acetone/95% acetone) R, 0.27; 'H-NMR (DMSO-db) 6 1.23 9H), 6.02 I1H), 6.97 (dd, J=0.2. 8.8 Hz, 2H), 6.93 J=8.8 Hz, 2H), 7.08 J=7.4 Hz, 1 7.34 (in, 2H), 7.45 (dd, J=2.2, 6.6 Hz. 2H) 8.80 I 10.04 (s, 1 FAB-MS rn/: (rel abundance) 352 CIc. Reaction of a Heterocyclic Amine with an Isocyanate NI 0 0 N N N H H H
N-(
3 -ter:.Butvl-5-pyrazolyl)-N'.(4.(4.methylphen ,l)oxyphenvI)urca: A solution of 5-amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4-(4methylphenoxy)phenyl isocyanate (0.225 g, 1.0 mmol 1.0 equiv) in toluene (10 mnL) 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 (0.12 1 g, mp 204 TLC acetone/95% CHCl 2 Rf 0.92; 'H-NMR (DMSO-d,) 5 1.22 9H), 2.24 3H), 5.92 111), 6.83 J=8.4 Hz, 2H), 6.90 J=8.8 Hz, 2H), 7.13 J=8.4 Hz, 2H), 7.40 J=8.8 Hz, 2H), 8.85 I 9.20 (br s, I1H), 11.94 (br s, I1H); El-MS m/z 364 00 59 U Cid. Reaction of a Heterocvclic Amin e with an Isocyanate 0 1 0 N Nk N 00 H H4c tyl,-3-tb ienyl)-N'-(2,3-d ichioropbenyl)u rea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-tey-t-butylthiopheneammonium chloride (Method A4c; 0.30 g, 1.56 mmol) and 2.3-dichlorophenyl isocyanate (0.32 mL. 2.02 mmol) in CI-LCI. (10 rnL) to clarify the mixture and the resulting solution was stirred at room temp. overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHCO, solution (15 mL), a IN HC1 solution (15 mL) and a saturated NaCl solution (15 mL), dried (Na.S,S0), 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) Rf 0.57; 'H- NMR (DMSO-d 6 5 1.31 9H), 6.79 lH), 7.03 IH), 7.24-7.33 (in, 2H), 8.16 (dd, 1=1.84, 7.72 Hz, IH), 8.35 IH), 9.60 LH); 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; FAR-MS nilz (rel abundance) 343 345 347 12%).
Cle. Reaction of a Heterocvclic Amine with an Isocyanate N N N C1 H H H
N-(
3 -tert-Butyl-5-pyrazolyl)-N'-(3,4-dichlorophenyl)urea: A solution of 3-zep-i-butyl-N'-(ier-t-butoxycarbonyl)pyrazole (Method A5; 0.150 g, 0.63 mrnol) and 3,4-dichiorophenyl isocyanate 118 g, 0.63 mmol) were in toluene (3.1 mL) was stirred at 55 'C for 2 d. The toluene was removed in vacuo and the solid was 00 redissolved in a mixture of CH,CI, (3 mL) and TFA (1.5 mL). After 30 min. the 0 solvent was removed in vacuo and the residue was taken up in EtOAc (10 mL). The Q resulting mixture was sequentially washed with a saturated NaHCO, solution (10 mL) Sand a NaCI solution (5 mL). dried and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 40% EtOAc/ 60% hexane to 00 55%EtOAc/ 5% hexane) to give the desired product (0.102 g, mp 182-184 OC; O TLC (40% EtOAc/60% hexane) R/0.05, FAB-MS 327 00 C2a. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline N 0O 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,CI1 (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.
S
NIN
0 N N N H H Step 2. N-( 3 -tert-Butyl-5-isoxazolyl)-N'-(4-(4pyridinylthio)phenyl)urea: The crude 3 -rert-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4 -(4-pyridinylthio)aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 °C for 2 h then cooled to room temp. and diluted with an EtOAc/CH,CI, solution 125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgSO), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CH,CI, 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 CH,CI,) R/ 0.21; 'H-NMR (DMSO-d,) 8 1.23 9H), 6.06 1H), 6.95 00 61 J=5 Hz. 2H), 7.51 J=8 Hz. 2H), 7.62 1=8 Hz. 2H). 8.32 J=5 Hiz. 2H), 9.13 I 10 19 I FAB-MS nil: 369 Reaction of a Heterocyclic Amine with Phosgene to Form an lsocy'anate Followed Reaction with Substituted Aniline 00 N0C 00 Step 1. 5-tert-Butyl-3-isoxazolylI Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CH,Cl, (I 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 THE) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) nil: 166 0
S
N N N H H Step 2. N-(5-rer,-Butyl-3-isoxazolyl)-N'-(4-(4-pyridinylth io)phenvl)u rea: To a solution of 5-tei-t-butyl-3-isoxazolyl isocyanate (247 inL, 0.2 M in THE, 49.4 mmol) was added 4-(4-pyridinylthio)ani line (5 g, 24.72 inmol), followed by THE (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), dri ed (MgSO4). and concentrated in vacuo. The resulting material was purified by MPLC (2 x 300 silica gel, 30 EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 mp 178-179 'H-NMR (DMSO-d,) 8 1.28 9H), 6.51 00 62 6.96 k6.25 Hz. 7.52 J=8.82 Hz. 2H), 7.62 J=8.83 Hz. 2H).
8.33 J=6.25 Hz. 9. 10 I 9.61 I EI-MS 368 C2c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline 00 N N N CIH H H 00 N-(3-terr-ButvII-5-pyrazolylI)-N'-(4-(4-pyridinvloxy)phenyl)u rea: 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)ani line (0.250 g, 1.3 mmol) was added in one aliquot causing a transient yellow color to appear. The solution was stirred at 0 *C for I h, then was allowed to warm to room temp. over I h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5 -amino- 3 -ert-butyl N'-Qtert-butoxycarbonyl)pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 'C for 12 h forming a white precipitate. The solids were dissolved in a IN HCI solution and allowed to stir at room temp. for I h to form a new precipitate. The white solid was washed (50% Et.,O/50% pet. ether) to afford the desired urea (0.139 a, mp >228 'C dec; TLC (10% MeOH/
CHCI
3 Rf 0.239; '1--NMR (DMSO-d 6 5 1.24 9H), 5.97 6.88 1=6.25 Hz, 2H), 7.10 J=8.82 Hz, 2H), 7.53 J=9.2 Hz, 2H), 8.43 1=6.25 Hz, 2H1), 8.92 (br s, 1H), 9.25 (br s, lH), 12.00 (br s, 1H); EI-MS Yn/z rel abundance 351 24%).
C3a. Reaction of a Heterocyclic Amine with NN'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline 00 63 0 O'0 N N N I H H 00 N-(3-ieri-Buty'l-lI-methvl-5-pyrazolvl)-N'-(4-(4-pyrid inyloxy')pen-. l)u rea: To a 00D solution of S-amino-3-tert-butyl- I-methylpyrazole (189 g, 1.24 mol) in anh. CH.CI.
(2.3 L) was added N.N'-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The c-i mixture was allowed to stir at ambient temperature for 5 h before adding 4-(4- 00 pyridinylox y)ani line. The reaction mixture was heated to 36 'C for 16 h. The c-KI 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 (Na,S0 4 and concentrated in vacua. The residue was purified by crystallization (44.4% EtOAc/44.4%/ Et.,O/1 1 hexane, 2.5 L) to afford the desired urea as a white solid (230 g, mp 149-152 'H-NMR (DMSO-d,) 8 1.18 9H), 3.57 (s, 3H), 6.02 1H), 6.85 J=6.0 Hz, 2H), 7.08 J=9.0 Hz, 7.52 1=9.0 Hz, 211), 8.40 1=6.0 Hz, 2H), 8.46 1H), 8.97 FA.B-LSIMS ml: 366 O~b. Reaction of a Heterocyclic Amine with NN'-Carbon)yldiimidazole Followed by Reaction with a Substituted Aniline 0 N N N H H H N-(3-tert-B utyl-5-py razoly l)-N rid in yltbio) ph en yl)urea: To a solution of -amnino- 3 -ert-butyl -N'-Qtert-butoxycarbon yl)pyrazolIe (0.282 g, 1 .18 mmol) in CHC], (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)ani line (0.239 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp. for 1 day. Then resulting solution was treated with a 10% citric acid solution (2 mL) and was allowed to stir for 4 h. The 00 64 organic layer was extracted with EtOAc (3 x 15 mL), dried (MgSO,), and oconcentrated in vacuo. The residue was diluted with CHCl. (5 mL) and trifluoroacetic acid (2 mL) and the resulting solution was allowed to stir for 4 h. The trfuoocti ecto ixture was made basic with a saturated NaHCO 3 solution then extracted with CR, (3 x 15 mL). The combined organic layers were dried 00(MgSQ, and concentrated ini vacuo. The residue was purified by flash 1-10chromatography MeOH/95% CI~1). The resulting brown solid was triturated with sonication (50% Et.,0150% pet. ether) to give the desired urea (0.122 g, 28%): 00 mp >224 'C dec; TLC MeOH/ 95% CHCI,) Rf 0.067; 'H-NMR (DMSO-d) 1.23 9H), 5.98 1H), 7.04 (din, 1=13.24 Hz, 2H), 7.15-7.19 (mn. IH), 7.40-7.47 (in, 7.80-7.82 (in, IH), 8.36 (din, J=15.44 Hz, 2H), 8.96 (br s, IH), 9.32 (br s, IRH), 11.97 (br s, I1H); FAB-MS in/z (rel abundance) 368 100%).
C4a. Reaction of Substituted Aniline with NN-Carbonvldjimidazole Followed by Reaction with a Heterocyclic Amine 0 N N NC:: I H H N-(3-teri-ButvlI-1I-methyl-5-pyrazolyl)-N'.(4-(4-pyridinvlmethvl)pb envl)u rea: To a solution of 4 -(4-pyr-idinylmethyl)aniline (0.200 g, 1.08 mmol) in CH,CI, (10 mL) was added NN -carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for I h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-aniino-3-tert-butyl-lmethylpyrazole (0.165 g, 1.08 minol) and stirred at 40-45 TC 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% and the resulting solids were crystallized (Et2O) to afford the desired urea (0.227 g, TLC (4% MeOHI96% CHCI,) Rf 0. 15; 'H-NMR (DMSO-d 6 5 1. 19 911), 3.5 7 3 3.8 9 2H), 6.02 I 7.14 J=8.4 Hz, 2H), 7.21 1=6 Hz, 2H), 7.3 7 1=8.4 Hz, 2H), 8.45-8.42 (mn, 3H), 8.81 I FAB-MS ni/z 364 00 S C4b. Reaction of Substituted Aniline with N,N'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine 00 N N N SH H H N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(2-benzothiazolyloxy)phenyl)urea: A solution 00 5 of 3-(2-benzothiazolyloxy)aniline (0.24 g, 1.0 mmol, 1.0 equiv) and N.N'carbonyldiimidazole (0.162 g, 1.0 mmol, 1.0 equiv) in toluene (10 mL) was stirred at room temp for 1 h. 5-Amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol) was added and the resulting mixture was heated at the reflux temp. overnight. The resulting mixture was poured into water and extracted with CH,C1, (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CH,CI,. 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,C1,) Rf0.05; 'H-NMR (DMSO-d,) 8 1.24 9H), 5.97 1H), 7.00-7.04 1H), 7.21-7.44 4H), 7.68 J=5.5 Hz, 1H), 7.92 (d,J=7.7 Hz, 1H), 7.70 1H), 8.95 1H), 9.34 (br s, 1H), 11.98 (br s, 1H); EI- MS nm/ 408 C4c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline
N
N N H H N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinyloxy)phenyl)urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CHCI, (5 mL) was added a solution of 4-(4-pyridinyloxy)aniline (0.30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH,C1 2 (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 00 66 residue was dissolved in CH,CI1 (5 mL), then treated with Obutylthiopheneammonium 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 stirrin at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL).
00 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 lt residue was purified by column chromatography (gradient from 30% 00 hexane to 100% EtOAc) to give the desired product (0.38 g TLC EtOAc/50% hexane) R. 0.13; 'H-NMR (CDC13) 6 1.26 9H), 6.65 J=1.48 Hz, 1H), 6.76 (dd, J=1.47, 4.24 Hz, 2H), 6.86 J=1.47 Hz, 1H), 6.91 J=8.82 Hz, 2H). 7.31 J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 J=1.47 Hz. 2H); "'C-NMR (CDC1 3 5 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%).
CS. General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine 0 N N H H N-(3-tert-Butyl-4-methyl-5-isoxazolyl)-N'-(2-fluorenyl)urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (1.OmL) was added a solution of 5-amino-4-methyl-3-tert-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL).
The reaction mixture was stirred at 70 °C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was-stirred at 40 °C for 3 h and then at RT for 17h 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 'H-NMR (DMSO-d,) 6 1.28 9H), 2.47 00 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
(U
C6. General Method for Urea Formation by Curtius Rearrangement and Carbamate Trapping 00 ,D 0 D
N
00 Step 1. 5-Methyl-2-(azidocarbonyl)thiophene: To a solution of 5-Methyl-2thiophenecarboxylic acid (1.06 g, 7.5 mmol) and EtN (1.25 mL, 9.0 mmol) in acetone mL) at -10 °C was slowly added ethyl chloroformate (1.07 mL, 11.2 mmol) to keep the internal temperature below 5 OC. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the reaction mixture was stirred for 2 h at 0 °C.
The resulting mixture was diluted with CH,CI, (10 mL) and washed with a saturated NaCI solution (10 mL). The aqueous layer was back-extracted with CH,C1, (10 mL), and the combined organic layers were dried (MgSO,) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc/ 90% hexanes) to give the azidoester (0.94 g, Azidoester (100 mg, 0.6 mmol) in anhydrous toluene mL) was heated to reflux for 1 h then cooled to rt. This solution was used as a stock solution for subsequent reactions.
OCN S Step 2. 5-Methyl-2-thiophene Isocyanate: 5-Methyl-2-(azidocarbonyl)thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp. for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions.
H H Step 3. N-(5-tert-Butyl-3-isoxazolyl)-N'-(5-methyl-2-thienyl)urea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp.
00 68 C was added 3 -amino-5-tert-butylisoxazole (0.092 g. 0.658 mmol) and the resulting U mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) Sand 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 O0 (0.156 g. mp 200-201 oC; TLC (20% EtOAc/80% hexane) R,0.20; El-MS ml: O 368 00 C7. General Methods for Urea Formation by Curtius Rearrangement and Isocvanate Trapping Cl
CHO
Step 1. 3-Chloro-4,4-dimethylpent-2-enal:
POCI
3 (67.2 mL, 0.72 mol) was added to cooled (0 DMF (60.6 mL, 0.78 mol) at rate to keep the internal temperature below 20 The viscous slurry was heated until solids melted (approximately then pinacolone (37.5 mL, 0.30 mol) was added in one portion. The reaction mixture was then to 55 oC for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCI solution (200 mL), dried (NaSO,) and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH,CI,) to give the desired aldehyde as an orange oil (15.5 g, TLC hexane) R,0.54; 'H NMR (CDCI,) d 1.26 9H), 6.15 J=7.0 Hz, 1H), 10.05 J=6.6 Hz, 1H).
/S
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 Na,S (1.23 g, 15.8 mmol) in water (10 mL). The resulting mixture was stirred at room temp. for 15 min to generate a white precipitate, then the slurry was 00 69 O treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids.
SThe reaction mixture was stirred at room temp. for 1.5 h, then treated with a 1 N HCI solution (200 mL) and stirred for I h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HCI solution (200 mL), water (2 x 200 mL) and a saturated NaCI solution (200 mL), dried 00 (Na,SO,) and concentrated under reduced pressure. The residue was purified using 0 column chromatography EtOAc/95% hexane) to afford the desired product (0.95 in g, TLC (20% EtOAc/80% hexane) R 0.79; 'H NMR (CDCI 3 5 1.39 9H), 00 3.85 3H), 6.84 J=3.7 Hz, 1H), 7.62 J=4.1 Hz, 1H); GC-MS m/z (rel abundance) 198 C0 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 and concentrated under reduced pressure (0.4 mmHg) to give the desired carboxylic acid as a yellow solid (0.067 g, TLC (20% EtOAc/79.5% hexane/0.5% AcOH) Rf 0.29; 'H NMR (CDCI,) 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 (CDC1,) 5 32.1 35.2, 122.9, 129.2, 135.1, 167.5, 168.2.
s 0 N N Cl H H 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 oC 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 00 0 C room temp. and treated with EtOAc (50 mL). The organic layer was washed with a 1 o N HCI solution (3 x 50 mL), a saturated NaHCO, solution (50 mL). and a saturated SNaCI solution (50 mL), dned (NaSO), 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% 00 hexane) Rf0.28; 'H NMR (CDC1,) 5 1.34 9H), 6.59 (br s. 2H), 7.10-7.13 2H), O 7.66 (br s, 1H), 8.13 (dd, J=2.9, 7.8 Hz, 1H); "C NMR (CDCI') 6 32.2 34.6, 117.4. 119.07, 119.15, 119.2, 121.5, 124.4, 127.6, 132.6, 135.2, 136.6, 153.4; HPLC 00 ES-MS m/i (rel abundance) 343 100%), 345 347 O 10 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 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane. mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h. cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase
HPLC.
D. Misc. Methods of Urea Synthesis Dl. Electrophylic Halogenation NS N Br H
H
N-(
2 -Bromo-5-ert-butyl-3-thienyl)-N'-(4-methylphenyl)urea: To a slurry of teri-butyl-3-thienyl)-N'-(4-methylphenyl)urea (0.50 g, 1.7 mmol) in CHCI, (20 mL) at 00 0 71 O room temp was slowly added a solution of Br, (0.09 mL. 1.7 mmol) in CHC, (10 mL) 0 via addition funnel causing the reaction mixture to become homogeneous. Stirring was continued 20 min after which TLC analysis indicated complete reaction. The reaction was concentrated under reduced pressure. and the residue triturated (2 x Et,O/hexane) to give the brominated product as a tan powder (0.43 g, mp 161- 00 163 oC; TLC (20% EtOAc/ 80% hexane) R0.71; 'H NMR (DMSO-d 6 6 1.29 9H), IN 2.22 3H), 7.07 J=8.46 Hz, 2H), 7.31 J=8.46 Hz, 2H), 7.38 1H), 8.19 (s, N 1H), 9.02 1H); "C NMR (DMSO-d,) 6 20.3, 31.6 34.7, 89.6, 117.5, 118.1 00 129.2 130.8. 136.0, 136.9, 151.8, 155.2; FAB-MS m/z (rel abundance) 367 98% 369 100%).
D2. Synthesis of o-Alkoxy Ureas S. 0 0 NON 0 H 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 (50 mL) was cooled to -78 OC and treated with BBr 3 (1.0 M in CHCIl, 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 3 solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na 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,) 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%).
00 72 N N J H H Step 2. A (-etBt,--he.I-'(-4ehxhnioNpe~~ra To a mixture of N-(5-terri-butyl-3-thienyl)-N 4 4 -hydroxyphenyl)oxyphenyl)urea (0.20 g, 00 ~0.5 mmol) and Cs,C0 3 18 g, 0.55 mmol, 1. 1 equiv) in reagent grade acetone mL) was added ethyl iodide (0.08 mL, 1.0 mmol, 2 equiv) via syringe, and the In resulting slurry was heated at the reflux temp. for 17 h. The reaction was cooled, 00 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% 1-1,/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, mp 155-156 TLC (20% EtOAC! 80%/ hexane) Rf 0.40; 'H- NMVR (DMSO-d 6 8 1.30 9H), 1.30 J=6.99 Hz, 3.97 1=6.99 Hz. 2H-), 6.80 1= 1.47 Hz, I1H), 6.86 (din, 1=8.82 Hz, 2H), 6.90 6.98 1= 1.47, 1IH), 7.40 (din, 1=8.83 Hz, 2H), 8.54 1H), 8.73 13C-NMR (DMSO-d,) 8 14.7, 32.0 (3C, 33.9, 63.3, 102.5, 115.5 116.3, 118.4 119.7 119.8 (2Q), 135.0, 136.3, 150.4, 152.1, 152.4, 154.4, 154.7; FAB-MS m/z (rel abundance) 411 D3. Synthesis of o)-Carbamoyl Ureas N 0
N~
N N ca H H H N-(3-rer:-But'l1-1-methyl-5-pyrazolyl)-N'..(4-(4 acetaminophenvl)methylpbenyl)urea: To a solution of N-(3-tert-butyl- 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 111 m.L, 0. 795 rimol). The solution was allowed to warm to room temp over 4 h, then was diluted with EtOAc (200 mL). The organic layer was sequentially washed with a IM HCI solution (125 mL) then water (100 mL), dried (MgSO 4 and concentrated under reduced pressure. The resulting residue was 00 73 purified by filtration throu2h a pad of silica (EtOAc) to give the desired product as a O white solid (0.160 iP_ TLC (EtOAc) R. 0.33, 'H-NMR (DMSO-d,) 8 1.17 (s.
9H), 1.98 3H), 3.55 3H). 3.78 2H), 6.00 IH). 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 1H), 9.82 11-i); FAB-MS i! 420 00 D4. General Method for the Conversion of Ester-Containing Ureas into Alcohol- Containing Ureas 00
NI
HO) H H C N-0 4-2- Hvd roxyethyl)-3-tert-bu tyl-5-pyrazolyll)-N '-(2,3-dich lorop hen yl)u rea: A solution of 2 2 ,.3-dichlorophenylarino)carbonyloxyethyl)3..eri-butyl-5 pyrazolyl)-N-(2,3-dichlorophenyl)urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH 0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at -65 'C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HCI solution (3 mL). The resulting organic phase was washed with a saturated NaCI solution mL), dried (MgSO.) 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-NM R (DMSO-d 6 6 1.23 9H), 3.70 J=5.7 Hz, 2H), 4.10 J=5.7 Hz, 2H), 6.23 lH), 7.29-7.32 (in, 2H), 8.06-8.09 (mn, IH), 9.00 (br s, IH), 9.70 (brs, 1H); FAB-MS ni/z (rel abundance) 371 100%).
D~a. General Method for the Conversion of Ester-Containing Ureas into Amnide-Containing Ureas N/ 0 HOrN N N'q CI _0~j H H C 0 00 7 Step 1. xyehl)3tr-u t'l.S-pyrazojI)..N dichloropheny.l)urea: A solution of N-(N'-(ethoxvcarbon),methyl Upyrazolyl)N(23dichlorohl)ue (prepared as described in Method A3. 0.46 g 1.1! 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 mi xture was diluted with EtOAc (25 mL) and acidified with a 2N HG] 00 solution (4 mL). The resulting organic phase was washed w Ith a saturated NaCl solution (25 mL), dried (MgSO,) and concentrated under reduced pressure. The In residue was crystallized (EtO/hexane) to afford the desired product as a white solid 00 10 (0.38 g, TLC (10% MeOH/90% CI-12C1 2 RtO04; H-NMR (DMSO-d,) 8 1.21 9H), 4.81 2H), 6.19 7.28-7.35 (in, 8.09-8.12 (in, 8.76 (br s, I 9.52 (br s. I FAB-MS i/z (rel abundance) 3 85 100%).
N
N N N 0I MeHN )rI H H
C
0 Step 2. eth lca rbam o1) met hy I)3erb ty1 5 p aoyI dichlorophenvl)urea: A solution of pyrazoly)N-(23dichlorophenyl)urea (100 mg, 0.26 mmole) and
N.N'-
carbonyiliimidazole (45 mg, 0.28 mmole) in CHCI, (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% R. 0.81). Dry methylamine hydrochloride (28 mg.
0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The reaction mixture was stirred at room temp. overnight, then diluted with CH,CI,, 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% CH.,CI, to acetone/60% and the residue was crystallized (EtO/hexane) to afford the desired product (47 mg, TLC (60% acetone/40% CI-LCl,) Rf 0.59; 1-l-NMR (DMSO-d,) 8 1.20 9H), 2.63 J=4.5 Hz, 3H), 4.59 6.15 IH), 7.28- 00 7.34 (mn. 2H), 8.02-8.12 (in. 2H), 8.79 (br s, IH)K 9.20 (br s, I FAB-N4Si!:(e U abundance) 398 General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas 00 IND. 00 N N N C2 c-I H H
C
2 00 Step I. N-(5-feri.Butyl.3isoxazoly)..AV..(4-a (4carbtloxyphenvl)url) To a solution of N(-ertbutyl3isoxa olyI)N(4(44eth oxyrovcalphy)oxyphenvl)urea (0.524 g, 1.24 mmol) in a mixture of EtOH- (4 mL) and THF (4 mL) was added a I M NaGH 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 3MA HCI solution (20 mL) to form a white precipitate. The solids were washed with water (50 rnL) 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 0- NI N NN NHMe H H I)_ 0 Step 2. N-5tr-utl3ioaoy)N-(-4(-mthlcrba y) pbenyl)oxyphenyl)urea: A solution of N-(5-1erz-butyl-3.isoxazolyl)-N carboxyphenyl)oxyphenyj)urea 100 g, 0.25 mmol), methylamine (2.0 M in TI-F; 0.140 mL, 0.278 mmol), Il-ethyl- 3 3 -dimeth yl aminopropyl)carbodi imide hydrochloride (76 mg, 0.39 mmol), and N-methylmorpholine (0.030 mL, 0.27 mniol) in a mixture of THF (3 mL) and DMF (3mL) was allowed to stir overnight at room temp. then was poured into a IM citric acid solution (20 mnL) and extracted with EtOAc (3 x 15 mL). The combined extracts were sequentially washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (Na.,S0 4 filtered, and concentrated in vacuo The resulting crude oil was purified by flash chromatography 00 76 EtOAc/40% hexane) to afford the desired product as a wvhite solid (42 m2.
El-MS nii: 409 D6. General Method for the Conversion of oi-Amine-Containing Ureas into Amide- Containing Ureas 00 0.
ciN N N
H
H HNH 00 A 5tert-Butvi-3-isoxazoyl)-N(4(4amiOophenl)oxy phenyl)urea:Toasltn of N4(5 -er-butyl-3-1isox azo lyl)-N'-( 4 4 -tert-b utox ycarbonylIam inoph en yl)ox y phenyl)-urea (prepared in a manner analogous to Methods B6 then C2b; 0.050 g, 0. 11 mmol) in anh 1,4-dioxane (3 mL) was added a conc HCI solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp The mixture was then poured into water (10 mL) and EtOAc( 10 mL) and made basic using a 1 M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NaS,SO, and concentrated in vacuc to afford the desired product as a white solid (26 mg, El-MS m/z 367 D7. General Method for the Oxidation of Pyridine-Containing Ureas N N N. 0 H H N-5tr-uy--sxzli-'(-(-x4prdnimtypey~ra To a solution of N-(5-Ierri-butyI-3-isoxazolyl)-N 4 4 -pynidinyl)methylphenyl)urea (0.100 g, 0.29 mmol) in CHC 3 (10 m.L) was added rn-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated K.C0 3 solution (10 mL). After 5 min, the solution was diluted with CHC1 3 (50 mL). The organic layer was washed successively with a saturated aqueous NaHSO, solution (25 mL), a saturated NaHCO 3 solution mL) and a saturated NaCI solution (25 mL), dried (MgSO 4 and concentrated in 00 77 vacuo. The residual solid was purified by MPLC (15% MeOH/85%,, EtOAc) to give o the N-oxide (0.082 g, 79%).
D8. General Miethod for the Acy'lation of a H-ydroxy-Containing Urea 00 0* o 0 0 N N N H H C1N-(5-ier:-Butvl-3-isoxa zolyl)-N'-(4-(4-acetoxyphenvioxy)pbenyl)urea: To a 00 solution of N-(5 -tert-butyl- 3-1isox azol yl) N 4 4 -hydroxyphenylIox y)ph en y 1)urea ri(0.100 g,0.272 mmol), N, N-dim ethyl ami nopyridi ne (0.003 g, 0.027 rnmol) and Et 3
N
(0.075 rnl-, 0.544 mmol) in anh THF (5 mL) was added acetic anhydnde (0.028 mL, 0.299 mmol), and the resultingy mixture was stirred at room temp for 5 hi. 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 3 solution (10 mL) and a saturated NaCI solution (10 mL), dried (Na 1 SOJ, 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 mm.Hg): TLC (40% EtOAc/60% hexane) Rf 0.55. FA.B-MS in/z 410 D9. Synthesis of (o-Alkoxypyridines 01- 0 N N N NO0 H H H Step 1. N-(5-terr-Bur t-y-3-iso xazolvl)-N'-(4-(2(I H)-pyridi non -5-y I)oxyph enyl)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 BAk and C3b; 1.2 g, 3.14 mmol) and trimethylsilyl iodide (0.89 mL, 6.28 mmol) in CH.,CI, (30 mL) was allowed to stir overnight at room temp., then was to 40 TC 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 00 78 EtOAc) to gPIve the desired product (0.87 g. mp 175-180 OC;, TLC o (80% EtOAc/20%/ hexane) R.,0.05; FAB-MS nil: 369 100%).
0 I 0 N NNNN N QEt H H 0 A slurry of N-(5-tiri-butvl-3-isoxazolyl)-N 1 g, 0.27 mmol) and Ag,C0 3 (0.05 g, 0. 18 mmol) in bcnzenc (3 rL) was stirred at 00 room temp. for 10 min. lodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celite' then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAcI75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, mp 146 TLC (40% hexane) RfO0.49; FAB-MS inl: 397 100%).
D1O. Reduction of an Aldehyde- or Ketone-Containing Urea to a Hydroxide- Containing Urea 0 0 N N N
O
H H
OH
N-(5-fer:-Butyl-3-isoxazoly)-N'-(4-(4-(1 -hydroxvethylI)phenvl)oxypbenyl)urea: To a solution of N-(5-zerzi-butyl-3-isoxazolyl)-N-(4-(4.(I acetylphenyl)oxyphenyl)urea (prepared in a manner analogous to that described in Methods B I and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH, (0.008 g, 0.21 mmol) in one portion. The mixture was allowed to stir for 2 h at room temp., then was concentrated in vacuo. Water (20 mL) and a 3M HCI solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (MgSOj), and concentrated in vacuo The resulting white solid was purified by trituration (Et 2 Q/hexane) to afford the desired product (0.021 g, 00 79 32 mp 80-85 0 Q- 'H NMR (DMSO-d,) 6 1.26 9H), 2.50 3H). 4.67 (in. I H), U. 5. 10 (br s. I 6.45 I 6.90 (in, 4H). 7.29 J=9.0 Hz. 2H), 7.42 J=9.0 Hz.
2H), 8.76 I 9.44 I HPLC ES-MS nil/: 396 DI1. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of CarboxNv- 00 Substituted Ureas
H
0 0 N 0 -Ph 00 ~N N N0 H H Bu tyl1-3-iso xazolylI)-N en zyloxyca rb o nylami no)p henylI)ox3yphenyl)urea: To a solution of the N-(5 -tert-butyl -3-1isox azolyl)-N'-(4-(3carboxyphenvl)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 minol) was added and the mixture was heated at 80 0 C with stirring for 3 h then allowed to cool to room temp. The resulting mixture was poured into a 1 0% 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 (NaSOj, and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 mp 73-75 'H NMR (DMSO-dl,) 6 1.26 5.10 2H), 6.46 1H), 6.55 J=7.0 Hz, 1H), 6.94 J=7.0 Hz, 2H), 7.70 (in, 7H), 8.78 IH), 9.46 IH), 9.81 lH); HPLC ES-MS nz/z 501 The followin-2 compounds have been synthesized according to the General Methods listed above: Table 1.
5-Substituted-3-isoxazolvl Ureas R2 N N N H H Mass mp TLC Solvent Spec. Synth.
En__v R1 (OC) R, System [Sourcel Method I-Bu 148- 352 CIC 149
(M+H)
[FABI
2 t-Bu 0 Cl 176- 0.16 5% 386 C2b 177 MeOH/
[FAB)
CH2CI2 3 t-Bu Cl 0.50 30% 400 C2b 0 Me EtOAc/ Me70%
[HPLC
hexane ES-MS 4 t-Bu 7Q 156- 0.50 30% 366 C2b 157 EtOAc/
[HPLC
hexane ES-MSl t-Bu Me 0.80 40% 492 C2b Me EtOAc! Me Et 60% [HPLC Me Et hexane ES-MS] 6 t-Bu H 190- 0.15 30% 350 C2b C- N 191 EtOAc! [ElI hexane 7 I-Bu 0.55 20% 352 C2b EtOAc/
[FAB)
hexane 8 i-Bu 0.25 20% 367 C2b EtOAc! [Ell hexane 9 I-Bu 0 0.15 20% 363 C2b Ph EtQAc/ [EI] hexane t-Bu Me 0.30 20% 381 C2b S EtOAc/
[EI]
11 i-Bu N 0.25 30 425 B3b. C2b EIOAc/
[HPLC
hexane ES-MS1 12 i-Bu 175- 0.25 30% 409 B3a. Step 177 EtOAcI I. B3b o 70% [HPLC Step 2.
S ~hexane ES-MSJ C2b 13 t-Bu /0.35 30% 402 B3b. C2b EtOAc!
(HPLC
hexane ES-MS 14 i-Bu 0.20 30% 403 B3b. C2b 0 EtOAc!
[HPLC
hexane ES-MS1 S i-u0.25 30% 419 B3b. C2b N EtOAc/
[HPLC
hexane ES-MS 16 i-Ru 0.20 30% 419 B3b. C2b /N EtOAc/ 70% [HPLC hexane ES-MS1 17 t-Bu 0.40 30% 352 C2b EtOAc/
[HPLC
hexane ES-MSI 18 r-Bu 0.40 30% 365 C2b EtQAc/ [El] hexane I 19 i-Bu 0.15 30% 367 3a. C2b.
EtOAc/ [El] D2 Step 1 hexane i-Bu S Me 200. 0.20 20% 280 C6 201 EtOAc!
[FAB
hexane 21 i-Bu j 178- 368 B4a, C2b 179 [El] 22 :-Bu H 2 N 164- 0.25 30% 351 B1. C2b 165 EtOAc/
[FAB
hexane I I 23 r-Bu H2,=N 170- 0.15 30% 351 B7, B1, JC-j 172 EtOAc/ C2b
[FAB
hexane 24 -Bu _&179- 0.20 30% 387 C2b 182 EtOAc/
[FAB]
hexane I-Bu 26 r-Bu 27 i-Bu 28 I-5lu 29 i-Bu t-Bu 31 r-Bu 32 i-Bu 33 i-Bu 34 I-Bu Me Me Me Me 00-&Me 176- 182 150- 158 0.55 40% EtOAci 60% hexane 0.55 25% EtOAc; hexane 0.40 25% EtOAci hexane 0.45 25% EtOAc! hexane 0.30 25% EtOAc! hexane 0.50 25% EtOAc/ hexane 0.30 25% EtOAc!
HO
CI
Me -c0-0 122 195- 197I 410
[FAB]
366
[FAB)
366
(MH)-
[FAB)
380
[FAB]
368
[FAB]
420
[FAB]
397
[FAB]
366
(FAB]
382
[FAB)
410
(M+H)
[FAB]
410
[FAB]
368
[FAB)
374
[FABI
396
[FAB]
B3b. C2b.
D2 Step 1, D8 B3a, C2b B3a. C2b B3a. C2b C2b B3a Step 1. B3b Step 2, C2b C2b B3a. C2b B3a, C2b B3a, C2b, D2 B3a C2b.
D2 CEb B3i, B 1, C2b B3a Step 2. C2b 155- 156 0 80 0.55 0.62 0.60 OPT-11 137- 1141 i-Bu 36 i-9lu 37 i-Bu 38 r-Bu 4F \0 Or-i
OH
-O-o-O ~I~s c: 164- 166 hexane 25% EtOAc/ hexane 30% EtOAc/ hexane 25% EtOAc/ hexane 25% EtOAc/ hexane 25% EtOAc/ 75% hexane 5% MeOHI AcOH/ 94.5% CH2C2 78-80 1 5: 167- 169 200 dec 0.30 I 00
U
39 t-Bu COH 234 0.30 5% 396 B~a Step dec MOH (M-Hh 2.C~b 0.5% [FAB] AcOH' 94.59/o CH2Cl2 t-Bu H2 203- 0.35 10 340 BS. B2b.
C 206 MeOH C2b
[FAB]
AcOH/ 89.5/ EtOAc 41 i-Bu 0 177- 419 B8. B2b.
/JF C H,)N180 C2b
CF-NAB
42 j-Bu 158- 0.25 30% 369 B4a. C2b 159 EtOAc/ S 70% [FAB] I _hexane 43 i-Bu CF 3 180- 0.15 30% 437 B4a. C2b 181 EtOAc;
[FAB]
hexane 44 :-Bu 0 E 140- 0.25 20% 396 B3a, C2b, 142 EtOAc/ D2
[FAB)
hexane I-Bu N- 68-71 0.30 50% 370 B4a. C2b EtOAc/
(M+H)
N 50%
[FAB
hexane 46 i-Bu N 183- 0.30 30% 403 C2b 186 EtOAc/
[CI]
hexane 47 t-Bu 6 98- 0.25 10% 454 C2b 101 EtOAc
F
3 C 90% IFAB] hexane 48 t-Bu O 163- 0.25 20% 394 B1, C2b 166 EtOAc/
[FAB]
hexane 49 i-Bu 144- 0.25 20% 399 C2b 147 EtOAc/
[FAB]
hexane r-Bu O-a. .Me 155- 0.25 40% 383 C2b 157 EtOAc.
[FAB]
hexane 51 t-Bu F 162- 0.35 25% 386 C2b 164 EtOAc/
[FAB]
hexane I 52 i-Bu S M 149- 0.15 15% 382 C2b 150 EtOAc!
[FAB)
hexane 53 I-Bu 77-80 0.30 30% 40S B3e. C2b -EtOAc! [El) hexane 54 i-Bu OCN 162- 0.17 40% 354 B3j C2b 164 EtOAc! N 60%
[FAB)
hexane i-Bu N- 73-76 0.20 30% 368 B2. C2b 07/ EtOAc/ [EI] hexane 56 i-Bu MeO 73-75 0.15 25% 428 B2. C2b EtOAc/
[FAB]
OMe hexane 57 i-Bu S 1 143- 0.25 30% 398 B3e. C2b 145 EtOAc!
[FAB]
I hexane 58 i-Bu 148- 0.25 30% 428 B3e. C2b \J 3 ~e 151 EtOAc/ OMe 70% (FAB] hexane 59 t-Bu C 0 0.30 100% 353 B4b. C3b N EtOAc (MH)+ I_ fFAB i-Bu 0 126- 0.25 30% 412 B3e. C2b x ~e 129 EtOAc/ OMe 70% [FAB] hexane 61 r-Bu 0Qj' 201- 0.25 10% 396 B3a. C2b.
204 EtQAc/ D2 OEt 90% [FAB] hexane 62 z-Bu NN 163- 0.30 40% 369 B4a. C2b 164 EtOAc!
[FAB]
hexane 63 t-Bu 162. 0.20 25% 363 C2b 163 EtOAcI [Eli 0~ hexane 64 i-Bu 6 N 127. 0.22 40% 353 B3e Step 129 EtOAc! 1, B2.
[FAB] C2b hexane r-Bu 85-87 0.20 50% 402 B3c Step EtOAc/ [EI] 1. B2.
C2b hexane F 6-6 ~I 0- N leO -0-0I 108.
110 186- 189 0.25 0.25 67 1 t-Bu
I
N
NHMc 0.25 69 t-Bu 0 114- 0.25 NHMe 117 10% EtOAc 90% hexane 30% EtOAc.' hexane 60% EtOAc' hexane 60% EtOAcI 40% hexane 60% EtOAci hexane 20% EtOAc! I- -~n 381 (NI-)
IEIJ
367
[FAB)
409 (M+H
[FAB)
409
[FAB]
423
[FAB]
370
[FAB)
0 LNMe, 00F 201.
203 148- 151 0.25 0.25 71 1 t-Bu u OMe 188- 0.25 20% 382 201 EtOAc!
[FAB
hexane 7 N-fl 134- 0.25 20% 367 /M 136 EtOAc! (M-sH).
[FAB]
hexane 74 -Bu 176- 0.25 50% 403 178 EtOAc/
[FAB)
hexane f-Bu -N 132- 0.52 40% 383 OMe 134 EtOAc.'
[FAB)
hexane 76 i-Bu H 160- 0.79 75% 381 N~-0 -Me 162 EtOAc!
[FAB]
hexane 77 t-Bu 140- 0.25 50% 352 143 EtOAc! [El] CH2CI2 78 i-Bu 147- 0.25 50% 352 150 EtOAc [Ell 0- CH2CI2 79 i-Bu 166- 0.44 50% 396 170 EtOAc! 0 50% [FAB] hexane B3e. C2b 136, C2b, D6 f3e. C2b.
DSb B3e. C2b, f3e, C2b, DSb B3e. C2b B3c, C2b f3e. C2b f3e C2b B3k. C3b C3a B4b C3b B3fO C3b r-Bu 86 0 Me .2: 50% EtOAci 50% 367
[FAB]
367
[FAB)
B3g. C3b 234b. C3b r I 81 i-Bu 82 I -Bu /1 Me
OCN
50% EtOAc/ 50% CH2CI2 Me -&0-CN 1 65-67 10.25T CH2CI2 50% EtOAc/ 50% rrzlrlll 367
[FAB]
1 B4b. Cb 83 t-Bu Me 68-72 0.25 50% 383 B4a. C3b EtOAc/
[FAB]
CH2C12 84 Nu ,Q 146 0.49 40% 397 B3k C3b, O ~Et EtOAc/ D9
[FAB]
hexane r-Bu Me 164- 0.25 50% 382 B4a. C3b N 165 EtOAc! [EI] 50% CH2CI2 86 I-Bu P-NH 175- 0.25 20% 485 B3e. C3b.
Ph 0 177 EtOAc/
[FAB)
87 i-Bu hexane 87 r-Bu 7O H 137- 0.30 50% 366 C3a. D2 141 EtOAc! [El] step I hexane 88 r-Bu Ph-N- 120- 0.25 20% 471 B3e. C3b.
122 EtOAc/
[HPLC
I hexane ES-MS 89 t-Bu Et-NH 168- 0.25 50% 423 B3e. C3b.
170 EtOAc/
[HPLC
hexane ES-MS t-Bu jH OH 80-85 0.25 50% 396 BI, C2b, EtOAc/
DIO
[HPLC
hexane ES-MS 91 t-Bu 0 73-75 0.25 30% 501 B3e. C3b.
04 EtOAc/ DII P- NE70%
[HPLC
hexane ES.MS] 92 r-Bu Me 0.50 5% 366 Bla acetone/
[FAB]
CH2C12 93 t-Bu
CF
3 199- 0.59 5% 419 Bla 200 acetone! [FAB] 95% 00 00 00 94 f-BU CF, 0.5 9 5%419 (s)Bla 00acetone
[FAB]
CH2CI2 i-Ru Me 78-82 0.25 10% 379 B3e. C3b EtOAc [El] CH2C12 96 i-Ru N 214. 0.75 60% 463 C2b. D3 =217 EtOAci FIC 40% [FAB] 97 i-Bu 235 0.35 2% 402 Bb ~hexane 98 t-RU 0 153- 0.25 30% 424 B3e, C2b \'-0Et 155 EtOAc/ O 70% [FAB) 99 I-RUN 100 0.62 40% 411 B3a, BL.
0 OriEtOAc: COb
[FAB]
hexane 100 i-Ru OH110- 0.15 100% 367 0 -2 115 EtOAc rFABI Table 1. 5-Substituted-3-isoxazolyl Ureas continued N N N H H Mass mp TLC Solvent Spec. Synth.
Entry R' R2(C R, Sstem [Sourcel Method 101 t-Bu 0 0.50 100% 410 RIO, B4b, NHeEtOAc C2b N
[FAB)
102 i-Ru OU 153- 395 COb 0_ 155 Me- [FAB] 103 i-Ru 0 0.52 100% 396 RIO, B4b,
NH
2 EtOAc C2b N [HPLC I
ES-MS]
104 i-Ru 00.75 100% 396 RIO, B4b, H ~EtOAc C2b 0\N
[HPLC
ES-MSJ 105 I-1u 0 107- 0.85 100 410 BIO. B4b.
'Q NHMe 110 EtOAc C2b 0 *N [FAB] 106 r-B 015 I2 16 B132- B3d step 107 i-Bu 0BY-o 135 0.58 100% C3a. D~ NHPr-n EtOAc 108 i-Bu 0NHi 0.58 100% C3a. DSb EtOAc 109 t-Bu 0 137- 0.62 100% 439 B3a step -NHMc 140 EtOAc 1, B12.
OMe [HPLC D~b step ES-MS 2. C3a 110 t-Bu 0 163- 0.73 100% 425 B3a step NHMc 166 EtOAc 1, B 12, 0 OH [HPLC Db step ES-MSI 2. C3a III t-Bu 13- Q>O, .o 180- B3b step 181 1, BI1.
B3d step 2. C2a 112 t-Bu 0 135- B3b, C2a me 139 113 i-Ru 0 212- B3d step NHe 215 2a. C2a 114 z-Bu MeHN .0 98- B3d step S 0 100 2, C2a 115 i-Bu 0 135- BIO. B4b, \NH Me 138 C2a 116 i-Bu 0 O 219- 0.78 80% 437 C3a, Ho 221 EtOAc/ step 2 hexane
[HPLC
-a LES-MS1 117 i-Bu s 160- B3a step 0- ro 164 1. 133d step 2.
C3a 118 i-Bu 0 124 0.39 5% CicDb MeOH/ ~N EtOAc/ CI hexane 00 00 119 i-Bu 73-75 0.41 100% 479 B3a. C4a.
EtOAC D~b NH
[HPLC
0
ES-MS]
0 120 i-Bu 0 0.32 100% 436 Clb. 0, NHMc EtOAC step I, N HPLC step 2
ES-MS]
121 t-Bu 0.23 10% 506 B3a. C4a.
C -NHMeOHI
[HPLC
CH2CI2 ES-MS] 122 i-Bu 0.18 10% 506 B3a. C4a, N MeOH/ D~b Et* N 90% [HPLC oCH2C12
ES-MS]
123 i-flu _0 2- 0.740% 435 D5b step 231 EtOAc! 1, B3d N. Me 60% (HPLC step 2, 0o__ hexane ES-MS1 O~a 124 i-flu 0.21 5% 508 B3a, C4a, -\-HMeOH/
[HPLC
CH2CI2 ES-MS] 125 t-flu 0 167- 0.34 5% 424 NHEt 170 MeOH/ (Mi-H)4 N 45%/ [HPLC EtOAc! ES-MS] I hexane 126 I-flu c 0 NHc124 0.26 5% COb. Ci NH~eMeOHI 0 N EtQAc/ 127 t-Bu 0 125- 0.28 5% COb. Me NHMe 128 MeOH/ N EtOAc/ ~~~hexane 128 i-flu 0 0.37 50% 426 COb -NHMe EtOAc/ (M+H)i- Me S /50% pet [HPLC ether ES-MS1 129 I-Bu 0 0.1 0 50% 424 COb NMe 2 EtOAc! \\ON 50% pet [HPLC I ether ES-MSI 00
-NH
0.18 70% EtOAC hexane 472 f HPLC
ES-NIS]
D~b step2 131 1-13U 0 02582 fCOb Me 0.2(M+H
[HPLC
ES-MS]
0 132 t-Bu F 0.57 558 COb 0 [HPLC 0 0 13 t-Bu 00.21 598 COb 0
[HPLC
ON
ES-MS]
0 134 r-Bu F& H0.86 489 COb
[HPLC
0 ES-MS] 135 I-Bu 0.64 514 COb
HN---,[HPLC
\-NHES-NIS]
136 r-Bu MeO 0.29 453 COb N0 0 [HPLC
ES-MS)
137 I-Bu N 0.70 502 COb MeO NH 0 [HPLC
ES-MS]
138 t-Bu0.056
O
0 05056 0
[HPLC
(.J
0
\/ES-MS]
91 139C 0.27 541 C C N
[HPLC
Q)
ES-MS]
0 140 t-Bu 0 211- 0.27 50% 426 C3b NHMe 212 EtOAc/ N 50% pet [HPLC ether ES-MS 141 i-Bu 2C-NO 195- BS, C2a I -a C-N 0 198 142 i-Bu CF 3 170- C3a 171 143 i-Bu Me 141- 0.63 5% 382 B3b step S 144 acetone! 1.2. Cld 95% [FAB] _____CH2CI2 144 i-Bu F 0.57 5% 386 B3b step -0 /acetone! 1.2. Cid
[FAB)
I CH2C12 145 t-Bu F 145- 0.44 5% 370 B3b step 148 acetone! 1.2. Cld
[FAB]
CH2C12 16 u F 197- 0.50 5% 404 B3b step _0~J 202 acetone! 1,2, Cid
[FAB]
CI CH2C12 147 t-Bu F 0.60 5% 404 B3b step /acetone! 1.2. Cld 95% [FAB] F CH2C12 148 r-Bu ~Me 126- 0.17 30% 366 B4c. C4a C N 129 MeOH!
[FAB]
EtOAc 149 I-uH 383 C3b C-
[HPLC
ES-MS1 150 i-Bu 156- 0.48 40% 395 C3a. D2 159 EtOAc! step 1. step hexane [HPLC 2
ES-MSI
151 :-Bu 157- 0.51 409 C3a. D9 ~N -O P -n 159 (M+H)4 step I, (HPLC stcp2 ES-MS I 152 :-Bu 130- 0.60 437 C3a, D9 132 step 1, [HPLC step2 ES-MS 153 t-Bu H 146- 0.54 4 0%0,16 a %j C3a. D2 N j OPr-i 150 ErOAc! step I. step hexane [HPLC 2 ES-MS 154 H t-B 145- 0.57 40% 423 C3a, D2 148 EtOAc. step 1. step hexane [HPLC 2 ES-MS 1 155 i-Bu H 175- 0.51 40% 457 C3a. D2 178 EtOAc; stepl. step hexane [HPLC 2 6
ES-MS]
156 t-Bu 149- 0.48 40% 407 C3a. DI 0 152 EtOAc! step i, hexane [HPLC step 2
ES-MSJ
157 z-Bu 146- 0.36 40% 409 C3a N- OMe 147 EtOAc! hexane [HPLC ES-MS1 158 I-Bu 156- 0.43 40% 395 C3a 158 EtOAc/ hexane [AB) 159 t-Bu 164- 0.5-2 5% 396 B3b step r 168 acetone/ 1,2, Cld Me Me 95% [HPLC CH2C12 ES-MSJ 160 t-Bu 0.36 5% 380 B3b step acetone! 1,2. Cld Me Me 95% [FAB] CHC2 161 I-Bu \1 169- 368 C3b S171
[FAB]
162 I-Bu \1 0 168 0.11 50% C3b EtOAc/ pet ether 163 I-Bu S- *SMe 146 C3b N-u
+H
164 i-Ru \0.45 100% 369 C2b EtOAc
[FAB]
165 i-Bu 0.20 100% 367 B9, C2b EtOAc N I I IIFAB] H_\N HO FAN 166 I-Bu y\ -0l 187- 0.46 30% 421 C3b 188 EtOAc! CI hexane [FAB] 167 i-Bu 133 0.36 409 C3a, D9 step 1, N [FAB] step2 00
U
00 00 93 168 i-Bu OPr-i 0.39 40 411 C3a. D9 EtOAc! step I iO-~~N 60% [FAB) step2 hexane 169 i-Bu OEt 0.32 5% 397 B3k. C8 0 acetone!
[HPLC
CH2CI2 ES-MSI 170 i-Bu OMe 0.21 5% 383 B3k, C8 0 acetonei 95% [HPLC CH2C12 ES-MS1 171 t-Bu /0.60 100% 365 C2b EtOAc \N [FAB]
X__
172 i-flu S 0.16 30% 369 C8 N EtOAcf
[HPLC
hexane ES-MS I 173 r-Bu 125- 0.09 5% Cb N 129 NMeOH/ EtOAc/ hexane 174 i-Bu j 7 e 147- B3b C2a 149 175 i-Bu H 0 0.30 100% 380 C3a. N1-xj EtOAc step2
(HPLC
ES-MS 176 t-Bu O 0.50 25% 353 MS N EtOAc! B
F
3 C 75% [CI] 4b, C8 hexane Table 2. 3-Substituted-5-isoxazolvl Ureas R1 O N'NR2 H H Mass Spec.
mp TLC Solvent [Source] ynth.
Entry R' R2 R, System Method 177 Me 0 -a Me 169- 0.25 5% 324 Cib 170 acetone/
[FAB]
CHC12 178 i-Pr J 153- 0.54 50% 338 Clb 156 EtOAc! pet [FAB] ether 179 i-Pr 180 i-Pr 181 ITP 182 i-Pr 183 i-Pr 184 i-Pr 185 i-Pr 186 i-Pr 0 0 -NHMe i-N S/Me 0\ &O-CJ?&Me 166- 0.54 170 112- 0.29 117 0.08 169- 0.20 170 0.10 0.09 0.23 F9 4 0 2-9 195 0.03 50%p 3 52 C"b EtOAc' Pet
[FAB)]
ether 5% 355 A2.
MeOH/ B4a, [FAB] C3a CH2CI2 50% 395 C8
[HPLC
hexane
-ES-S
50% 396 COb EtOAc! petHlPLC ehern
ES-S
30% 352 C8 EtOAc! (M+H)s
[HPLC
hexane ES- MS 39 C8 EtOAc! pe [HPLC ehean
ES-
30% 401 C8 EtOAc! 50%
(FAB]
hexane
E
EtO~c/ et[HPLC 34 C8b EtOAc! pe (FAB) hean MeOH/ Ca 50% 34B Ca EtOAc/
[FAB]
hexane 7 188 189 4> Me F7 78 19 i-Bu 191 t-Bu 0.21 192 184 352
FAB
Clb 193 r-Bu Me 165 0.34 60 366 Clb dec EtOAc pet (FAB] ether 194 i-Bu 210 0.05 5% 353 C3a dec acetonei
[FAB]
I_ CH2CI2 195 t-Bu _a a 174- 0.25 5% 382 C3a 175 acetone
[FAB]
CH2CI2 196 t-Bu 90-92 0.16 5% 409 C2a Nacetone/ (M-sH)+
[FAB)
CH202 197 t-Bu 221 0.14 5% 409 C2a s- dec acetone! 95% [FAB] CH2CI2 198 t-Bu -N 196- 0.17 5% 368 A2.
me 198 MeOH,' B3h.
[FAB] C3a CHC2 199 t-Bu jOMe 204- 0.27 50% 383 A2, 206 EtOAc/ (MiH)+ B3a, pet [FAB] C3a ether 200 r-Bu H2179. 351 A2, C3a C_ 180 fABJ 201 r-Bu sme 0.33 500/u 414 A2.
N SeEtOAc [El] B4a.
pet C3a ether 202 t-Bu 0 sme 188- 0.49 50% 399 A2, N j- 189 EtOAc. B4a, 50% pet [HPLC C3a ether ES-MS 203 t-Bu 0 179. 0.14 5% 395 A2, \u 180 MeOH/ B4a, -C Me N 95% [FAB] C3a CH2CI2 204 t-Bu N 197- 0.08 10% 353 A2.
199 acetone: B3h, [FAB] C3a CH2CI2 205 f.Bu CI 136- 0.33 50% 421 A2, 0 139 EtOAc: B3h, pet [FAB] C3a N ether 206 t-Bu /\213 0.05 5% 369 C3a dec acetone! (M4H)+
[FAB
CH2CI2 I 207 i-flu Me0.60 5% 274 C2a V/MeMeOH/
(M+H)
(FAB)
208 i-flu F 118- 0.19 5% 387 A2.
121 MeOH/ B4a.
[FAB] C3a ____CH2CI2 209 I-Bu 0 217- 0.18 5% A2.COb NHMe 219 MeOH/ CHCl3 210 i-Bu j0j' 0 0.48 50% 394 C8 EtOAc/ e50%
[HPLC
hexane ES.MS] 211 i-flu 0-O, 0.17 30% 364 C8 EtOAc/
[HPLC
hexane ES.MS] 212 i-Bu -0.79 70% 421 B3a ~~O\/(EtOAc/ step 1 NH 30% [HPLC B3d 0 hexane ES-MS] step 2, 213 r-Bu 00.50 50% 407 B3a /IEtOAc/ stepI [HPLC B3d 0 hexane ES-MS] step 2, O~a 214 i-flu 0 182- 0.25 5% 424 COb, NHEI 185 MeOH/ 0- N 45% [HPLC \=1EtOAc/
ES-MS]
hexane 215 i-flu 0 198- 0.20 5% 444 COb, -2NHMe 200 MeOH/ -N 4~5% [HPLC EtQAc/ ES-MS] ______hexane 216 t-Bu 0 0.24 50% 426 C3b -NH-Me EtOAc/ S N50% pet [HPLC ether
ES-MSI
217 i-Bu 0 215- 426 COb 2NHMe 217 N [HPLC 218 i-Bu 0188- 0.22 50% 410 COb ~-NHMe 200 EtOAc! 0 C\N50% pet [HPLC ES-MS1 219 i-B u 214- 0.35 5% C~b 215 acetone/ CH2CI2 220 i-Bu 0 Q e 180 Ob 221 -13u 160- 0.58 50% 336 C3b 162 EtOAc! [CI] pet ether 222 t-Bu 0.18 50% COb 'N EtOAc/ pet ether 223 t-Bu 0 ~?O-3.SCF3 163- 0.21 5% 453 COb -a 165 MeOH
[HPLC
CH2CI2 ES-MS 224 i-Bu \vJ' 208- 0.17 5% 353 C3b 212 MeOH/
[FAB)
CH2CI2 225 i-Bu 109- 0.17 5% 369 C3b 112 MeOH/
[FAB]
CH2C12 226 i-Bu 155- 0.57 10% 453 C3b -N'3 156 MeOH I CH2C02 [FABI 1 227 t-Bu N-0 231- 0.54 10% 534 C3b NH 234 MeQH/ O N CH2CI2 [FAB] 228 t-Bu 179- 0.24 5% A2. C3b -N 180 MeOH/ 0 M e 95% CHC13 229 t-Bu 0.30 5% 370 A2, C3b MeOH/
[FAB]
CHC13 230 i-Bu I 178. 0.20 5% A2. C3b 180 MeOH/ CHC13 231 I-Bu 1S6- 0.20 5% A2. Cb 187 MeOH/ Me CHC13 232 t-Bu 149- 0.28 5% A2. C3b N 152 MeOH/ s CHC13 233 :-Bu 210- 0.06 10% 421 Cb 213 MeH/ CH2CI2 [FABJ 00
U
OMe MeOH/ rut-vi A2. C3b A2. C3b t I-i 0 71-73 5% MeOH; CHC13 236 I-Bu Cl 176- 0.44 10% 437 C3b 177 MeOH/ -O CH2C12 [FAB] 237 r-Bu H, 0.09 50 351 C8 C EtOAc!
[HPLC
hexane ES-MS 238 t-Bu 016 50% 403 C8 EtOAc!
[HPLC
hexane ES-MSj 239 i-Bu 0 0.15 50 381 C8 EtOAc/ (M+H) Me 50% [HPLC hexane ES-MS 240 t-Bu 215- 0.19 100% 370 C3b 216 EtOAc
[HPLC
ES-MS 241 i-Bu 0.42 N=N QeMeH/ CH2CI2 242 t-Bu 0 0.74 100% 366 B4b, C8 EtOAc Me
[HPLC
ES-MS1 243 t-Bu o 0.12 30% 421 C8 EtOAc!
F
3 C 70% [HPLC hexare ES-MS 245 I-Bu 0 0.68 100% 368 B4b, C8 EtOAc HO
[HPLC
ES-MS1 246 t-Bu 142- 0.13 5% A2, C3b 144 MeOHI CXNI EtOAc/ hexane 247 t-Bu 0 205- 0.31 50% 410 C3b INHMe 207 EtOAc!
(M+H)
0 50% pet [HPLC ES-MS 248 Me 154- 0.50 50% 365 Clb M 155 EtOAc! [El] Et 50% pet I ether 249 Me' 160. 0.37 5% 380 CIb M e162 acetone
[FAB)
CH2C02 250 Me C I C 196- 0.58 5/ 342 Clb -Me k199 acetone Et 95% [FAB] I I_ CH2CI2 251 M eO M e 137- 0.25 5% 396 A2.
-kMe O138 acetone! B3a.
Et 95% [FAB] C3a CH202 252 Me H 0.18 5% 364 A2. C3a M e s NN~I MeOH/
[EI]
Et kCHC13 MeOH [El] M 3 me 215- 383 A2.
221 B4a.
s N dec [FAB) C3a 254 Me S_-N 187. 0.42 10% 383 A2, Me 188 MeOH/ B4a, Et CHC13 [FAB] C3a 255 Me OC- \M 90-92 0.19 30% 366 A2. C3a FtMm EtOAc/ [El] pet ether 257 Me 199- 0.33 70% 423 A2.
-k-Me cI\ 200 EtOAc/ (MH) B3e, Et 30% pet [FAB) C3a ether 258 Me 0 117. 0.14 5% A2. C3b NH Me 119 MeOH/ Et 095% CHCI3 259 Me 0 0.37 75% 409 C8 Me EtOAc! Et \25%
[HPLC
_hexane
ES-MS
260 Me 194- 0.25 50 424 C3b -k-Me y NHMe 195 EtOAc! Ft0 N 50% pet [HPLC ether ES-MS 261 Me 0 216- 0.20 50% 424 C3b Me NHMe 217 EtOAc! (MH)+ Et e\N 50% pet [HPLC I_ ether ES-MSJ 262 Me 62-65 0.18 5% A2, Ob Me MeOH/ Et N _CHC13 263 Me 86-89 0.16 5% A2. C3b Mee Me MeOH/ Ft 1 CHC13 26-4 M4e 145- 0.32 5% A2. COb -ME~ 146 MeOH.' Et CHC13 26 M -/-e0.23 5% 381 A2. C3b -Me MeOH. Et N
[FAB]
CHC13 26 M eM 0.20 5% 396 A2. COb Et -KJO-j acetonei (M+H)h
(FAB)
___CH2CI2 /6 Me\-M 0.38 50 366 C8 EtEtOAci: (M+H)f E0 50% (HPLC _____hexane
ES-MSI
268 Me Meo0.14 50 367 C8 0EtOAc,
[HPLC
hexane ES-MS1 269 Me0.21 50 383 C8 NEtOAc/
[HPLC
ES-MS] /7 Me HI 0.10 s0o 365 C8 Me/ EtOAC; Et N 50%
[HPLC
hexane ES-MSI 271 Me N- H 0.14 50 365 C8 -KAj-c \/EtOAc/ Et N 50%
[HPLC
ES-MS1 272 M e 1,4o 0.35 50% 382 C8 Et Q\1EtOAc.' (M+H)i HO 50% [HPLC
ES-MSI
273 Me 0.48 50% 382 CS8 Me 0 EtOAc' OH 50% [HPLC hexane ES-MS1 274 M e 0.20 100% 367 B4b, C8 Me EtOAc O- CN
[HPLC
275 Me ES-MS) 275 Me =N 0.56 100% 435 B4b. C8 -e 0 EtOAc Et FC[HPLC 27 M ES-MS1 27 M 1 .5 7% 383 C8 -Me -Ns- 1 O EtOAc!
[HPLC
ES-MS] 277 Me 0.40 100%0 B3f. C8 14 e EtOAc 27S M e 63-65 -410 A2. C3a Er t OMe Et (M-H)
[FABJ
279 Me 84 0. 16 5% 381 A2. C3a Er N Et MeOHi.
[FAB]
CHCI3 280 Me 189- 0.16 5% 397 A2.
E 192 MeOHi B4a.
Er 95% [HPLC C3a CHC13 ES-MS 281 Me 189- 0.17 5% 397 A2.
-E 191 MeOH/ (M+H)i B4a, S- C\f 95% [FAB] C3a CHC13 282 Me 123- 414 A2.C3a Et 125 Et
FB
Er FFAB 283 Me H, 175- 0.16 5% 379 A2. C3a Et 177 MeOH/ Et 95%
[FAB)
CHCl 2841 Me 0CE ~"7c 3 eH 135- 0.33 5% A2. C3b Ert, 137 MeOH! Et CHC13 285 Me 67 0.41 5% A2,C3b cEt 0 MeI -k-Er/ 0 MeMeOH/ Et CHC13 286 155- 0.38 50% 377 Clb 156 EtOAc/ [El] per ether 287 ,0 0.18 5% 379 A2. C3b MeOH/
[FAB]
CHC13 I I_ I Table 3. N'-Substituted-3-tert-butl-5pvrazoly Ureas Mass Spec.
mp TLC Solvent [Source] ynth.
Ex. R' R2 (OC) R, System ethod 289 H 0 0.07 50% 393 C8 EtOAc/
[HPLC
hexane ES-MS 290 H 181- 381 Cb 183 I I_ [FABi Me 50 EtOAc hexan 365
[HPLC
FCMc~t 292 H N 366 C8 O-N\ I-M
[FABI
293 H 0.53 50% 398 CS N- EtOAc/
[HPLC
hexane ES-MS
H(M+H)+
[HPLC
_ES-MS
295 H 0.27 50% 351 CIC EtOAc!
[FAB]
hexane 296 CI CI 0.59 50% 327 CIc EtOAc/
[FAB]
hexane 297 H 0.30 60% 350 C4a C acetone/ (M-4H)-c
[FAB]
CH2CI2 298 H 0.07 5% 368 B4a, MeOH/ C4a 95% [FAB] CHC13 299 H /7 0.18 5% 367 B4a.
MeOH/ [El] C4a CHCI3 300 H 0 160- 408 AS. B6, HOACF 0 161 C3b HOC3 NHMc [FAB) isolated at TFA salt 301 H 228- 0.24 10% 351 C3a 232 MeOH/ [El] dec CHC13 302 H 0 e 204 0.06 5% 364 C3b acetone! [El] CH2C12 110- 0.05 5% 408 C3b N1II acetone! (M-sH+) o-i/ II 195% so CH2CI2 304 Me H 2 0.10 20% 380 C4a C CNacetone!
[FAB)
CHC12 305 Me 0 99- 0.19 1 00% 452 B3a -NHWc 101 ElOAc step I S0 l\/\~ome [HPLC B12.
N-.ES-MS] step 2.
ICOa 306 1M e HH, ,.0.48 30% 378 BI. Cha C CINacetone,
[FAB)
CH2CI2 307 Me 135- 0.03 30% 408 C3a _xN Me 137 EtOAc; (M-sH)+
[HPLC
hexane ES-MS1 308 Me S-CN0.35 70% 382 B4a, acetone! C4a
[FAB]
309 Me /\0.46 70% 382 B4a, acetone, C4a
[FAB]
310 Me CF 3 0.32 70% 450 B3b, _Nacetone! C4a
[FAB]
CH2CI2 311 Me 0.09 50% 381 C4a EtOAc!
[FAB]
hexane 312 Me O 0.61 100% 397 B3c, EtOAc C4a I_ FABI 313 Me O~u-0 0.25 50% 453 135, C4a \,~\~flEtOAci
[FAR]
hexane 314 Me ~-H 2 0.65 100% 462 B6. C4a NHEtOAc
(MH)+
i-Bu /_(FAB) 315 Me 2 0.67 100% 478 B36, C4a jNH EtOAc 0-u
[FAB]
316 M e H0.50 100% 378 C4a JC-L NH 2 EtOAc 00% [FAB] 317 Me H0.33 10% 420 C4a, D3 M [FAB] 318 M e H0.60 10% 478 C4a. D3 NHwater/ 1090%
[FAB]
2 C CH3CN 319 Me T- H 0.5 100% 434 C4a. D, C NH EtOAc Et
[FAB]
320 Me NH, 0.52 100% 380 C4a EtOAc (M+H) [FABI I 321 Me 0 0.25 60% 366 C4a acetone' (M+H)r
(FAB)
CH2CI2 322 Me -NH 0.52 100% 452 C4a, D3 =O EtOAc (M+H)-t EtO [FAB] 323 Me H, 0.34 60% 396 C4a S-Cacetone/
[FAB]
CH2CI2 324 Me 0.36 60% 396 C4a C-S acetone!
[FAB]
CH2CI2 325 Me 147- 365 CIc 149
[FAB]
326 Me H 161- 0.15 4% 364 C2b C N-<LC 162 MeOH/ 96% [FAB] CH2CI2 327 Me 0 Me 228 379 C2b dec
[FABI
328 Me ~0.30 5% 422 C2b NMeOH/ 01 95% (FAB) CH2CI2 329 Me 0.46 100% 464 B3c.
N EtOAc C4a Ip
[FAB]
330 Me N-0 0.52 100% 506 B3c, EtOAc C4a
CF
3 [FAB] 331 Me 0.75 100% 421 B3c, EtOAc C4a [FAB 332 Me -F 0.50 100% 465 B3c.
EtOAc C4a
FAB
333 Me 0.50 100% 349 C4a EtOAc
[FAB]
334 0~0 0.60 100%/ EtOAc 4 -1I B2. C4a L H'J 335 Me 0 NH0.52 1000, 466 C4a. D3 oElOAc (M-Hh
[FAB]
336 Me Orn0.42 100% 4 39 B5. C4a EtOAc (FABI 1 337 -CH.-CF, 433, C3a FABI 338 -(CH.CN F- 0.37 50% 404 A3, Clb EtOAc/
[HPLC
hexane ES-MS1 339 0 Me-NH 159- 508 A5, B6, 0 161 C2b t-B6 0
[FAB]
106 Table 4. 5-Substituted-2-thiadiazoiN I Ureas N j, 2 N ,N
N*
H H T Mass Spcc mp TLC Solvent I sourcej Iynth.
Entrv R' R: 0 C) R, jSvsten, I _i Method 342 i-Bu O< 396 B33a. C3a MH
[FAB]
343 I-BU- 0.30 5% 373 C~b 0 acN etone
[FAB]
C H 2CI2_ 344 t-13u /8 13060 10a41 C3 Me MeOH!(M+H)+ H2N [FAB) 345 I-Bu 0 245 0.30 50% 456 CB~ase NH~e 250etone; 1,B.
346 r-Bu 0 0.10 10%1 1 COb Me-NH/ EtOHc! 0N N ete 347 t-Bu 0 N e 24- 0.13 10% 441 13ase 2 N 25 EtOAcI 1 B-2 N 50% pe HPLC Dbse et er ES-M SI 1 _2 348 t-Bu 0 0.14 50% 44Cb, \-HeEtOAc!
S-S
b 501%pe 349 t-Bu 0 02 41 Cb C N~e EtOH/! D- ~0 50% pl[HPLC ether/ ES-MS] 350 t-Bu 0 0.09 5% 461 OCb, CI NH~E MeOH/ D~b 0 eN45% [HPLC EtOAc/ ES-MS] hexane 351 0 Me -NHMc 5% MeOR;, EtOAc' hexane 441 (M+H-1-
[HPLC
ES-MS]
352 t-Bu 0 159- 0.10 50% 427 COb NHMc 160 EtOAc/ ~o -50% pel [HPLC Nether ES-MS] 353 I-Bu C 1 0.47 10%/ 438 COb MeOH! (M+Hh- 0~ CI CH2CL2 [FAB) 354 t-Bu 0.31 10% 371 COb COMeOH/ CH2CI2 [FABI 355 t-Bu Cl 0.51 10% 400 COb 0 IMeOH/ N CH2CI2 [FAB] 356 t-Bu Me 0.43 10% 385 COb NMeOH/ CH2CI2 [FAB~ 357 z-Bu 0 j' V 0.70 10% 416 COb 0 S eMeOH.' CH2CI2 [FAB] 358 t-Bu ~0.11 50 438 C8 N EtOAc/
F
3 C 50% [HPLC ____hexane ES-MSJ 359 t-Bu 0.06 5% 432 COb S ~j'--S~eMeOH/
[FAB]
CH2CI2 360 i-Bu -0.20 50% 385 C8 ~0 ~EtOAc! HO 50% [HPLC hexane ES-MS1 361 t-Bu 4 ~e\107. 0.05 30% 412 C3a N Oe 110 EtOAc/
[HPLC
_____hexane ES-MSI 362 i-Bu 0.16 100% 370 CS EtOAc 0-C\N[HPLC ES-MSJ 363 Me 0 0.12 100% C4a. k- Me NHEt EtOAc Et 364 Me 0 183- B3d step ,MeNH, 185 2. C3a Et 365 Me \M F\-a Oe0.19 6% 413 A6,COb e -~jO 0MeMeOH/ Et94%
[FAD]
366 e 28- 034 0/6A6. C3b -Me 0O N Et249 NleOH:' Et 94%k 37Me 770.20 CC3 400 A6. COb 367 -M e (M-'Hh, S- N
[FAB)
368 Et 182- 0.33 A6. COb 0 c C 183 MeOH/ Et CHC13 369 /Et 180- 0.19 5% A6. COb S \N 181 McOHl Et CHC13_ 370 /t \1 OaoMe 168- 0.24 5% A6, COb Et ~j 169 MeOHI Et 371 Et 168- 0.17 6% A6. COb 171 MeOH! Et 94% CHC13 1 372 Et S' N\ 156- 0.19 6% A6. COb -,158 MeOH/ Et 94% CHC13 Table 5.5-Substituted-3-thjnenl Ureas 0 H H mp TLC Solvent Mass Svnth.
Entry R' R: R. System Spec. Method 373 i-Bu 144- 068 5% A4b.
145 acetone/ Cia CH2CI2 374 t-Bu Me 0.52 30% 381 EtO/ pet [HPLC ether ES-MS 375 i-Bu 0 Oe 0.26 30% 397 need recipie pet [HPLC ether ES-MS 376 r-Bu N 0.28 50% 368 need Et2O/ (MaH)- recipie pet [HPLC ether ES-MSi__ 377 z-Bu 57 381 A4a fFABJ 378 i-Bu H 0.15 50% 365 (Ma- A4a C C/ N. EtOAcI [El] pet ether 379 i-Bu 0 O 0.44 50% 383 A4a EtOAc! (MaH)+ pet [FAB] ether 380 I-Bu S-C\ 384 A4a (M-H)a-
[FABI
381 t-Bu 176- 0.45 20% 425 D2 177 EtOAc!
[FAB]
hexane Table 5. Additional Ureas 00 110 -,83 145. 0.57 50,6 A2.
Cl 0 147 MeOH C3b oNo A.u ON N CHC3 H H 384 132- 0.33 50 339 A9.
NN0135 acetone Cid N I A095% [HPLC ES- N N N r CH2CI2
MS]
H H 00 38 0.60 50% 462 C8 ID0N EtOAc (MH)- 0 50% [HPLC EScI N N N
S
N. N H H N SCF 3 hexane MS] ~nH H H 00 386 0.28 5% 339 A7.
acetone.' Cld 0N i, k 95% [FAB] N N CH2CI2 387 340 B3b 0 0 I I(M+H)f step N [FAB] 1,2.
N N Cid H
H
388 174-5 424 B4b, C8 [HPLC
ES-
NN N
MS]
H H
S
0 MNHt 319 198- C3b, 200 D~b .N N ANta-' 0 HNHPr-i 390 169- 0.23 100% B4b. C8 Nr N KI' N170 EtOAc N N N 'C f
IO~
H H 0 NMe 391 167- 0.12 100% B4bC8 00171 EtOAc N N N H H 392 0.08 50% 400 C8 0 ll EtOAc! (M+H) 50% [HPLC ES- N/l NN-r N hexane MS] H H 00 cI393 0.55 90% 443 B EtOAc, B4b.
00- 10% [FAB] C2b hexane N N NO0- IH H 0 NHMe 394 QEt 230 377 00 0dec N\)k~jLQ[HPLC
ES-
N N NO MS] 3951 0.48 50% 383 C8 c-iV EtOAc! 00 '7S 0 N0 FB N N- Me hexane
HH
ci396 417 C8 (M-sH)- Qp\-Iro[HPLC
ES-
N "I'N A N(YO'MS] 397 155- 0.44 5% 380 Clb 157 acetone! (M+H)s 0 -CH2C12
HH
BIOLOGICAL EXAMPLES In Vitro raf Kinase Assay: In an in vitro kinase assay, raf is incubated with MEK in 20 mnM Tris-HCI, pH- 8.2 containing 2 mM 2-mercaptoethanol and 100 mM NaCI. This protein solution g.L) is mixed with water (5 or with compounds diluted with distilled water from 10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction is initiated by adding 25 j.±L [y- 33 P]ATP (1000-3000 dpmlpmol) in 80 mM Tris-H-CI, pH 120 mM NaCI, 1.6 m.M DTT, 16 mM MgCI,. The reaction mixtures are incubated at 32 usually for 22 min. Incorporation of 3 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 iM ATP and 0.4 JAM MEK are used. In some experiments, the kinase reaction is stopped by adding an equal amount of Laernmli sample buffer. Samples are boiled 3 min and the proteins resolved by 00 112 electrophorcsis on 7.5% Laemmli gels. Gels are fixed, dried and exposed to an (K imaging plate (Fuji). Phosphorylation is analyzed using a Fujix Bio-Imaging U Analyzer System.
All compounds exemplified displayed IC 0 s of between 1 nM and 10 uM.
Cellular Assay:
OO
\0 For in vitro growth assay, human tumor cell lines, including but not limited to SHCTII6 and DLD-1, containing mutated K-ras genes are used in standard proliferation assays for anchorage dependent growth on plastic or anchorage 00 independent growth in soft agar. Human tumor cell lines were obtained from ATCC CI (Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine serum and 200 mM glutamine. Cell culture media and additives are obtained from Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences, Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X 10' cells are seeded into 96-well tissue culture plates and allowed to attach overnight at 37 °C in a 5% 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 I Cu 'H-thymidine, harvesting the cells onto glass fiber mats using a cell harvester and measuring 3 H-thymidine incorporation by liquid scintillant counting.
For anchorage independent cell growth, cells are plated at 1 x 10' 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).
00 113
O
O
1 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: 0 5 An in vivo assay of the inhibitory effect of the compounds on tumors solid NO cancers) mediated by raf kinase can be performed as follows: SCDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at I x 10 6 00 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 (23)

  1. 2. A compound of claim 1, wherein B is Xn Y Q+ n wherein Y is selected from the group consisting of -CH 2 -SCH 2 -CH 2 CH(OH)-, -CXa 2 -CXaH., -CH 2 O- and -OCH 2 Xa is halogen, 00 Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- o 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, 00 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, X' is CI-C 4 alkyl or halosubstituted C 1 -C 4 alkyl up to per 00 halo, and Z, n and n 1 are as defined in claim 1.
  2. 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, 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, 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 can be substituted by halogen or up to per-halosubstitution.
  3. 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 or -CH 2 X' is as defined in claim 2, Z is-NH-C(O)-CH 2 p+ 1 wherein p is 1-4, -CH 3 -OH, -OCH 3 -OC 2 H 5 -CN or -C(O)CH 3 n 0 or 1, and nl 0 or 1. A compound as in claim 1 selected from the group consisting of: N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-hydroxyphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-acetylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-benzoylphenyl)urea; 00 N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-phenyloxyphenyl)urea; o N-(5-tert-Butyl-3-isoxazolyl)-N -methylaminocarbonylphenyl)-thiophenyl)urea; N-(5-iter-Butyl-3-isoxazolyl)-N 1,2-methylenedioxy)phenyl)-oxyphenyl)urea; -er-Butyl-3-isoxazolyl)-N '-(4-(3-pyridinyl)oxyphenyl)urea; -tert-Butyl-3-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; 00 N-(5-tert-Butyl-3-isoxazolyl)-N '-(4-(4-pyridyl)thiophenyl)urea; IND-etBtl3ioazll- -4(-yiinlmtypey~ra -tert-Butyl-3-isoxazolyl)-N '-(3-(4-pyridinyl)oxtyphenyl)urea; 00 N-(5-tert-Butyl-3-isoxazolyl)-N'-(3-(4-pyridinyl)hiophenyl)urea; 00N-(5-tert-Butyl-3-isoxazolyl)-N '-(3-(3-hl4-pyridinyl)xyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N '-(3-(3-methyl-4-pyridinyl)thiophenyl)urea; -tert-Butyl-3-isoxazolyl)-N '-(4-(3-methyl-4-pyridinyl)thiophenyl)urea; -tert-Butyl-3-isoxazolyl)-N -(4-methyl-3 -pyridinyl)oxyophenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N -methyl-4-pyridinyl)oxyphenyl)urea; N-(5-tert-Butyl-3-isoxazolyl)-N '-(3-(2-benzth-riazoyl)oxyphenyl)urea; N-(5-tert-butyl-3-isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl)urea; -tert-butyl-3 -isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea; N-(5-tert-butyl-3 -isoxazolyl)-N '-(2-methyl-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl)urea; N-(5-tert-butyl-3 -isoxazolyl)-N '-(4-(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; N-(5-tert-butyl-3 -isoxazolyl)-N -(4-(2-carbamoyl)pyridyl)oxyphenyl) urea; -tert-butyl-3-isoxazolyl '-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(5 -tert-butyl-3-isoxazolyl '-(4-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea; -tert-butyl-3-isoxazolyl)-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl)urea; N-(5-tert-butyl-3-isoxazolyl)-N -methylcarbamoyl)phenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof.
  4. 6. A compound of the formnula 00 t-Bu U0 NH-C-NH-B 00 wherein B is 5-methyl-2-thienyl or selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, 00 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 -NO 2 SR', -NR 5 R 5 -NR 5 C(O)0R 5 -NR 5 C(O)R 5 C 1 -CI 0 alkyl, C 2 -CIO alkenyl, CI-C 1 0 alkoxy, C 3 -CI 0 cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl, up to per halo-substituted C 1 -C 10 alkyl, up to per halo- substi tuted C 2 CIO alkenyl, up to per halo-substituted CI-C 10 alkoxy and, up to per halo- substituted C 3 -C 10 cycloalkyl, wherein R 5 and R 5 are independently selected from H, C I-C 10 alkyl, C 2 -C 10 alkenyl, C 3 CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per-halosubstituted C 1 -C 10 alkyl, up to per-halosubstituted C 2 -Cj 0 alkenyl, and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 )m0-, -NR 5 C(O)NR 5 -NR 5 -C(O)NR 5 -(CH 2 )mnS-, -(CH 2 )mnN(R 5 0O(CH 2 -CHXa, _CXa 2 -S(CH 2 )mn 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 Z,, wherein n I 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', -NO 2 -OR 5 SR', -NR 5 R 5 -NR 5 C(O)0R 5 -NR 5 -S0 2 SO 2 NR 5 R 5 C 1 -Clo alkyl, C 1 -CIO alkoxyl, C 3 -CI 0 cycloalkyl, 00 up to per halo-substituted C 1 -C 10 alkyl and up to per halo-substituted C 3 -C 1 0 cycloalkyl; subject o to the proviso that B is not 00 0 R 6 6 wherein R is -NHC(0)-O-t-butyl, -O-n-pentyl, -0-n-butyl, -O-n-propyl, N- -C(0)NH-(CH 3 2 -OCH 2 CH(CH 3 2 or 00 -0-CH 2 -0
  5. 7. A compound of the formnula NH-C-rN-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 1 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 NO 2 -NR 5 C 1 -CI0 alkyl, C 2 -10-alkenyl, CI_ 10 alkoxy, C 3 -CI 0 cycloalkyl, C 6 -CI 4 aryl and C 7 -C 24 alkaryl, and X is selected from the group consisting of -SR, -NR 5 C(O)0R 5 NR 5 C 3 -C 1 3 heteroaryl, substituted C 1 -CI 0 alkyl, substituted C 2 -10-alkenyl, substituted C 11 0 o-alkoxy, substituted C 3 -C 10 cycloalkyl, substituted C 6 -C 1 4 aryl, substituted C 3 -C 1 3 heteroaryl, and -Y-Ar, 00 and wherein if X is a substituted group, it is substituted by one or more substituents o independently selected from the group consisting of -CN, -COR', -C(O)NR R -NR NO 2 -NR 5 C(O)R 5 -NR 5 C(O)0R 5 and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, C 1 -CIO alkyl, C 2 1 0-alkenyl, C 3 00 CIO cycloalkyl, C 6 -C 1 4 aryl, C 3 -CI 3 heteroaryl, C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl, up to per- halosubstituted CI-CI 0 alkyl, up to per-halosubstituted C 2 10 -alkenyl, and up to per- I~n halosubstituted C 3 -CIO cycloalkyl, wherein Y is -(CH 2 -CH(OH)-, 00 -(CH 2 )rnO-, -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 )mN(R 5 -O(CH 2 p-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, fury], 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 nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 -NO 2 -OR 5 SR', NR 5 -NR 5 C(O)0R", -NR 5 -S0 2 -SO 2 R 5 R 5 C 1 -CI 0 alkyl, C 1 -CIO alkoxy, C 3 -C 10 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 -C(O)NR 5 R 5 -NO 2 -NR 5 R 5 -NR 5 C(O)R and -NR 5 C(O)0R 5 C,-Clo alkyl, C 1 -C 10 alkoxyl, and C 3 -CIO cycloalkyl, and where R1 is -CH 2 -t-butyl, B is not 0 CH 3
  6. 8. A compound of claim 7, wherein B is 00 Xn O -Q Zn 00 IN wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, 00 -CXa 2 -CXaH-, -CH 2 0- and -OCH 2 O 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 7 and X 1 is CI-C 4 alkyl or halosubstituted Cj-C 4 alkyl up to per halo.
  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 -R 6 -OR 6 and -NHR 7 wherein R6 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 R 6 and R 7 can be substituted by halogen or up to per-halosubstitution. 00 A compound of the formula t-Bu 0 I I I 0 NH1 -C-NH1 -B 00 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, 00 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 -C(O)NR 5 R 5 -NO 2 SR', -NR 5 R 5 NR 5 C(O)0R", -NR 5 C 1 -CI 0 alkyl, C 2 -CIO alkenyl, C 1 -Clo alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted C 1 -C 10 alkyl, up to per hal o- substituted C 2 -Clo alkenyl, up to per halo-substituted C 1 -C 10 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 I-C 10 alkyl, C 2 -C 1oalkenyl, C 3 CIO cycloalkyl, 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(OH)-, -(CH 2 )mO-, -NR 5 C(O)NR' NR" -NR 5 -C(O)NR 5 -(CH 2 )mnS-, -(CH 2 )mnN(R -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, 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", NR', -NO 2 SR', -NR 5 -NR 5 C(O)0R 5 -NR 5 C(O)R 5 -S0 2 R', SO 2 NR 5 C 1 -C 10 alkyl, C 1 -CIO alkoxyl, C 3 -CIO cycloalkyl, up to per halo-substituted C 1 -CI 0 alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl. 00
  8. 11. A compound of claim 8, wherein Q is phenyl or pyridinyl optionally substituted o by halogen up to per-halosubstitution, Q 1 is phenyl, benzothiazolyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, Y is or -CH 2 X, is as defined in claim 8,n =O0or 1, Zis -CH 3 OC 2 H- 5 or -OCH 3 andnlI =O0or 1. 00 12. A compound as in claim 7 selected from the group consisting of: N-(3 -Isopropyl-5-isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(4-(4-methoxyphenyl)oxyphenyl)urea; 00 N-(3 -tert-Butyl-5-isoxazolyl)-N '-(5-(2-(4-acetylphenyl)oxy)pyridinyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N -(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(4-(4-pyridinyl)methylphenyl)urea; '-(4-(4-pyridinyl)thiophenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; N-(3 -tert-Butyl -5-i soxazol yl)-N '-(4-(4-methyl-3 -pyridinyl)oxyphenyl)urea; N-(3 -tert-Butyl-5-isoxazolyl)-N '-(3-(2-benzothiazolyl)oxyphenyl)urea; N-(3 -(1,1I -Dimethylpropyl)-5-isoxazolyl)-N '-(4-(4-methylphenyl)oxyphenyl)urea; 1, -Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl)thiophenyl)urea; N-(3 -(1,1I -Dimethylpropyl)-5-isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; 1, -Dimethylpropyl)-5-isoxazolyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; 1, -Dimethylpropyl-5-isoxazolyl)-N methoxyphenyl)oxy)pyridinyl)urea; 1-Methyl- 1 -ethylpropyl)-5 -isoxazolyl)-N '-(4-(4-pyridinyl)oxyphenyl)urea; 1-Methyl- I -ethylpropyl)-5-isoxazolyl)-N -(4-pyridinyl)thiophenyl)urea; N-(3 -i sopropyl-5-isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)-oxypbenyl) urea; N-(3 -isopropyl-5-isoxazolyl)-N '-(4-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(3 -tert-butyl-5 -isoxazolyl)-N '-(4-(4-(2-metbylcarbamoyl)pyridyl)-oxyphenyl) urea; N-(3 -tert-butyl-5 -isoxazolyl)-N '-(3-(4-(2-methylcarbamoyl)pyridyl)-thiophenyl) urea; 1, -dimethylprop- 1 -yl)-5-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)- pyridyl)oxyphenyl) urea; 1, -dimethylprop- 1 -yl)-5-isoxazolyl)-N'-(4-(4-(2-methylcarbamoyl)- pyridyl)oxyphenyl) urea; N-(3 -tert-butyl-5 -isoxazolyl)-N -chloro-4-(4-(2-methylcarbamoyl)pyridyl)- thiophenyl) urea; and pharmaceutically acceptable salts thereof. 00
  9. 13. A compound of the formula S 0 Rb NH-C-NH-B 00 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 -C 6 cycloalkyl, 00 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 X In and wherein n 0-2; each X 1 is independently selected from the group consisting of CN, OR', -NR 5 C 1 -Clo alkyl; -C0 2 R 5 -C(O)NR 5 R 5 -C(O)R 5 -NO 2 -SR 5 -NR 5 C(O)0R", NR 5 C 3 -CI 0 cycloalkyl, substituted C 1 -C 10 alkyl, substituted C 2 1 o-alkenyl, substituted C 1 10 -alkoxy, and substituted C 3 -CI 0 cycloalkyl, wherein if X 1 is a substituted group, it is substituted by one or more substituents pindependently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 OR', -SR 5 -NR 5 R 5 -NO 2 -NR 5 C(O)R 5 -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 -CIO alkyl, C 2 1 0-alkenyl, C 3 CIO cycloalkyl, up to per-halosubstituted C 1 -CIO alkyl, up to per-halosubstituted C 2 -io-alkenyl and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -N(R 5 -(CH 2 -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 (CH 2 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-halosubstitution and optionally substituted by Z, 1 00 wherein n I is 0 to 3 and each Z is independently selected from the group consisting of- o CN, -CO 2 -C(O)NR 5 R 5 NR', -NO 2 SR', -NR 5 NR C(O)OR", -NR C(O)R 5 -S0 2 -S0 2 C 1 -Clo alkyl, C 1 -CI0 alkoxy, C 3 -CIO cycloalkyl, substituted C 1 -CI 0 alkyl, and substituted C 3 -CIO cycloalkyl, wherein if Z is a substituted group, it is substituted by the one or more substituents 00 independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R 5 SR', -NO 2 -NR 5 -NR 5 C(O)R" -NR 5 C(O)0R", CI-Clo alkyl, C 1 -CIo alkoxyl, and C 3 -CIO in cycloalkyl, 00 subject to the proviso that where R1 is t-butyl and Rb is H, B is not of the formula 0 CH(CH 3 2
  10. 14. A compound of claim 13, wherein B is xl1 wherein Y is selected from the group consisting of -CH 2 -SCH 2 -CH 2 S-, -CVa 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 1 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, XI is C 1 -C 4 alkyl or halosubstituted C 1 -C 4 alkyl up to per halo, and Z, n and n I are as defined in claim 13. 00 o 15. 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, 00 quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo, tn X' is as defined in claim 14 and oo00 Z is selected from the group consisting of -R 6 -OR 6 and -NHR 7 wherein R 6 is O hydrogen, C,-Clo-alkyl or C 3 -Clo-cycloalkyl and R 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.
  11. 16. A compound of the formula t-Bu S_ 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 Xn, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 RS, -C(O)NRR 5 -C(O)RS, -NO 2 -ORS, SRS, -NR'RS, NR'C(0)OR", -NR'C(O)RS, C 1 -Co 10 alkyl, C 2 -C 1 0 alkenyl, C 1 -CIo alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted C 1 -Clo alkyl, up to per halo-substituted C 2 -C 10 alkenyl, up to per halo-substituted CI-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, CI-C 1 lo alkyl, C 2 -C 10 alkenyl, C 3 Clo cycloalkyl, up to per-halosubstituted Ci-Clo alkyl, up to per-halosubstituted C 2 -C 10 alkenyl and up to per-halosubstituted C 3 -Clo cycloalkyl, 00 wherein Y is 0, CH(OH)-, -(CH 2 )m0-, -NR 5 C(O)NR 5 NR 5 -NR 5 -C(O)NR 5 -(CH 2 -(CH 2 )mnN(R 5 -O(CH 2 -CHX', -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, 00 IND isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, C1 benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, optionally substituted by C1 halogen up to per-halosubstitution and optionally substituted by Z,I 1 wherein nI is 0 to 3 and 00 each Z is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 R", NR', -NO 2 SR', -NR 5 -NR 5 C(O)0R", -NR 5 -SO 2 R', SO 2 NR 5 C,-Clo alkyl, C 1 -C 1 0 alkoxyl, C 3 -CIO cycloalkyl, up to per halo-substituted C 1 -C 10 alkyl, and up to per halo-substituted C 3 -CI 0 cycloalkyl, subject to the proviso that B is not of the formnula 0 CH(CH 3 2
  12. 17. A compound of claim 14, 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, and Y is or Z is -Cl, -CH 3 -OH or -OCH 3 X1 is as defined in claim 14, n 0 or 1 and nl 0-2.
  13. 18. A compound as in claim 13 selected from the group consisting of: -tert-Butyl-3-thienyl)-N '-(4-(3-methylphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-thienyl)-N '-(4-(4-hydroxyphenyl)oxyphenyl)urea; -tert-Butyl-3-thienyl)-N '-(4-(4-methoxyphenyl)oxyphenyl)urea; N-(5-tert-Butyl-3-thienyl)-N '-(4-(4-pyridinyl)thiophenyl)urea; and pharmaceutically acceptable salts thereof. 00
  14. 19. A compound of the formula N S N NH-C-NH-B 00 N ~wherein R a is C 3 -C 6 alkyl, C 3 -C 6 cycloalkyl, up to per-halosubstituted C 3 -G 6 alkyl and up to 00 per-halosubstituted C 3 -C 6 cycloalkyl; 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 X 1 n wherein n 0-2, each X' is independently selected from the group consisting of -CN, NO 2 and CI-C 10 alkyl,-SR', -C0 2 -C(O)NR 5 -NR 5 R 5 -NR 5 C(O)0R 5 NR 5 C(O)R 5 -C 3 -C 10 cycloalkyl, substituted C 1 -C 10 alkyl, substituted C 2 10 -alkenyl, substituted C 1 1 o-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 -C(O)NR 5 R 5 OR', -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 -Clo alkyl, C 21 o-alkenyl, C 3 -CI 0 cycloalkyl, up to per-halosubstituted C 1 -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 2 -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 XV 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 Zn 1 wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 5 -C(O)R 5 C(O)NR 5 R 5 -C(O)R 5 -NO 2 -OR, SR, NR 5 R 5 -NR 5 C(O)0R 5 -NR 5 C(O)R 5 -S0 2 00 S0 2 R'R, C 1 -Clo alkyl, CI-Clo alkoxy, C 3 -Co 0 cycloalkyl, substituted Ci-Clo alkyl, substituted o 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 -C(O)NR'R', -ORS, -NO 2 -NR 5 R, -NR 5 C(O)R and -NR'C(0)ORs, Ci-Clo alkyl, CI-Clo alkoxyl, and C 3 -Clo cycloalkyl, 00 A compound as in claim 19, wherein B is 00 O ln -Q Y-QI Zn1 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 CI-C 4 alkyl or halosubstituted CI-C 4 alkyl up to per-halo, Z, n and nl are as defined in claim 19, and s is 0 or 1.
  15. 21. A compound as in 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, optionally substituted by halogen, up to per-halo, X' is as defined in claim 20 and Z is selected from the group consisting of -R6, -OR6 and -NHR wherein R6 is hydrogen, Ci-Clo-alkyl or C 3 -Clo-cycloalkyl and R 7 is selected from the group consisting of 00 hydrogen, C 3 -C 1 0 -alkyl, C 3 -C 6 -cycloalkyl and wherein R 6 and R 7 can be substituted by halogen N or up to per-halosubstitution.
  16. 22. A compound as in claim wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, 00 Q 1 is phenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, IND ~Y is or X 1X is asdefined in claim 20, n =O0orlI andnlI 0. 00 p23. A compound as in claim 19, of the formnula CF 3 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 wherein n 0-2; each X1 is independently selected from the group consisting of -CN, OR', -NR 5 R 5 CI-C 10 alkyl, -CO 2 R 5 -C(O)NR 5 -NO 2 -NR 5 C(O)0R 5 NR 5 C(O)R 5 C 3 -CI 0 cycloalkyl, and substituted C 1 -C 10 alkyl, substituted C 2 10 -alkenyl, substituted CI 1 -alkoxy, and substituted C 3 -CIO cycloalkyl, wherein R 5 and R 5 are independently selected from H, CI-CIO alkyl, C 2 1 0-alkenyl, C 3 CIO cycloalkyl, up to per-halosubstituted CI-C 10 alkyl, up to per-halosubstituted C 2 10 -alkenyl; up to per-halosubstituted C 3 -C 10 cycloalkyl, wherein Y is (CH 2 -(CH 2 -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 )mnN(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-halosubstitution and optionally substituted by ZnI, 00 wherein n I is 0 to 3 and each Z is independently selected from the group consisting of- o CN, -C0 2 -C(O)NR 5 R 5 NR', -NO 2 SR', -NR 5 R 5 NR C(O)0R", -NR 5 -S0 2 -S0 2 R'R 5 C 1 -C 1 0 alkyl, CI-Clo alkoxy, C 3 -CI 0 cycloalkyl, substituted C 1 -Clo 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 00 consisting of -CN, -C0 2 -C(O)NR 5 -NO 2 -NR 5 -NR 5 C(O)R 5, NR C(O)OR", C 1 -Cl 0 alkyl, C 1 -Cl 0 alkoxyl, and C 3 -CIO cycloalkyl. 00 24. A compound as in claim 19 selected from the group consisting of: N-(5-tert-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-pyridinyl)oxyphenyl)urea; -tert-butyl-2-( 1 -thia-3 ,4-diazolyl))-N -(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl)urea; -tert-butyl-2-( I -thia-3 ,4-diazolyl))-N '-(4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-2-( 1 -thia-3 ,4-diazolyl))-N '-(3-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-2-( 1 -thia-3,4-diazolyl))-N'-(2-chloro-4-(4-(2-methylcarbamoyl)pyridyl)- oxyphenyl) urea; -tert-butyl-2-( 1-thia-3 ,4-diazolyl))-N '-(3-(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-dimethyiprop- 1-thia-3 ,4-diazolyl))-N carbamoylphenyl)oxyphenyl) urea; and pharmaceutically acceptable salts thereof. A compound of one of the formulae 00 R R 0 or 0 S 11 11 NH-C-NH-B NH-C-NH-B 00 1-10 wherein R1 is selected from the group consisting of halogen, C 3 -C 10 alkyl, C 1 13 N heteroaryl, C 6 14 -aryl, C 7 24 -alkaryl, C 3 -Cl 0 cycloalkyl, up to per-halosubstituted CI-C 10 alkyl, 00 up to per-halosubstituted C 3 -CIO cycloalkyl, up to per-halosubstituted C 1 13 -heteroaryl, up to per-halosubstituted 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 1 n wherein n 0-2; each X 1 is independently selected from the group consisting of -CN, NR 5 R 5 C 1 -Clo alkyl, -C(O)R 5 -NO 2 -NR 5 C(O)0R 5 ',C 3 -CI 0 cycloalkyl, substituted CI-C 10 alkyl, substituted C 2 1 o-alkenyl, substituted C 1 io-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, -C0 2 -C(O)NR 5 R 5 OR', -NR 5 R" -NO 2 _NR 5 C(O)R" -NR 5 C(O)0R 5 and halogen up to per-halo substitution; wherein R 5 and R 5 are independently selected from H, CI-Clo alkyl, C 2 1 o-alkenyl, C 3 Cl 0 cycloalkyl, up to per-halosubstituted Ci-C 10 alkyl, up to per-halosubstituted C 2 .io0-alkenyl, and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 -NR 5 C(O)NR 5 R 5 -NR 5 -C(O)NR 5 -(CH 2 (CH 2 )mnN(R 5 0O(CH 2 )mn, -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, fuiryl, 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 Zn I, wherein nlI is 0 to 3 and each Z is independently selected from the group consisting of CN, -C0 2 -C(O)NR 5 NR', -NO 2 SR', NR 5 00 NR 5 C(O)0R", -NR 5 -SO 2 -S0 2 C 1 -Clo alkyl, CI-Cl 0 alkoxy, C 3 -CI 0 o cycloalkyl, substituted CI-Clo 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 -SR, -NO 2 -NR 5 R" -NR 5 C(O)R" NR 5 C(O)0R 5 C 1 -C 10 alkyl, C 1 -Cl 0 alkoxyl and C 3 -CIO cycloalkyl. 00
  17. 26. A compound of one of the formulae 00t-Bu t-Bu 0K or S I I I I NHr--C-NH-B NH-C-NH-B wherein B is as defined in claim
  18. 27. A compound of claim 25, wherein B is xl1 113 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 Va is halogen, Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- halosubstitution; Q1 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, 00 O X' is Ci-C 4 alkyl or halosubstituted Ci-C 4 alkyl up to per halo, O Z, n and nl are as defined in claim 25 or n is 0-3, nl is 0 to 3 and each Z is Sindependently selected from the group consisting of -CN, -C0 2 R s -C(O)NRSR S SNR 5 -NO 2 SR 5 -NRR 5 -NRsC(O)OR 5 -C(O)R 5 -NR'C(O)R 5 -S0 2 R 5 SO 2 NRR 5 CI-Clo alkyl, CI-Clo alkoxyl, C 3 -Clo cycloalkyl, up to per halo-substituted Ci-Clo alkyl, and up 00 to per halo-substituted C 3 -Clo cycloalkyl. (N t) 28. A compound of claim 27, wherein 00 Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per- Shalosubstitution, 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 27 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 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.
  19. 29. A compound of claim 27, 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 -0- or X' is as defined in claim 27, n 0 or 1, Z is -Cl, -CH 3 -OH or OCH 3 and nl 0-2. A compound of the formula R 1 °0 0 Rb 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 00 wherein B is phenyl, pyridinyl, indolinyl, isoquinolinyl, quinolinyl, or naphthyl o 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 -NO 2 SR', NR 5 R 5 -NR 5 C(O)0R", 00 NR 5 C(O)R 5 C 1 -C 10 alkyl, C 2 .io-alkenyl, C 1 i-alkoxy, C 3 -CI 0 cycloalkcyl, substituted C 1 -CIO alkyl, substituted C 2 1 o-alkenyl, substituted C 1 j-alkoxy, and substituted C 3 -CIO cycloalkyl, wherein if X' is a substituted group, it is substituted by one or more substituents 00 independently selected from the group consisting of -CN, -C0 2 R', 0 -C(O)NR 5 R 5 -SR, -NR 5 R 5 -NO 2 -NR 5 C(O)R" -NR 5 C(O)0R 5 and halogen up to per-halosubstitution; wherein R 5 and R 5 are independently selected from H, CI-Clo alkyl, C 2 -lo-alkenyl, C 3 CIO cycloalkyl, up to per-halosubstituted C 1 -CIO alkyl, up to per-halosubstituted C 2 -io-alkenyl and up to per-halosubstituted C 3 -CIO cycloalkyl, wherein Y is -N(R 5 -(CH 2 -(CH 2 )m0-, -NR 5 C(O)NR 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 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, 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 -C(O)R 5 -C(O)NR 5 R 5 -C(O)R 5 -NO 2 -OR 5 SR', NR 5 R 5 NR 5 C(O)0R", -NR 5 C(O)R 5 -S0 2 R 5 -SO 2 R 5 CI-C 10 alkyl, C 3 -CIO cycloalkyl, substituted CI-C 10 alkyl, 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 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 Cj-CI 0 alkyl, C 1 CIO alkoxyl, and C 3 -CIO cycloalkyl.
  20. 31. A compound of claim 30, wherein B is 00 N n -Z wherein Y is selected from the group consisting of-O-, -CH 2 -SCH 2 -CH 2 S-, 00 -CXa 2 -CXaH-, -CH 2 0- and -OCH 2 O Xa is halogen, V¢ Q is phenyl or pyridinyl substituted or unsubstituted by halogen, up to per- 00 halosubstitution; 0 Q 1 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 CI-C 4 alkyl up to per halo, and Z, n and nl are as defined in claim
  21. 32. A compound of claim 31, 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 31 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 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. 33. A compound of the formula 00 t-Bu 0 0 NH-C-NH-B 00 wherein B is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, naphthyl, quinolinyl, isoquinolinyl, phthalimidinyl, fuiryl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzofuryl, benzothienyl, indolyl, benzopyrazolyl, 00 benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl, substituted by one or more substituents independently selected from the group consisting of halogen, up to per- halosubstitution, and Xl, wherein n is 0-3 and each X is independently selected from the group consisting of -CN, -C0 2 -C(O)NR 5 -NO 2 SR', -NR 5 NR 5 C(O)0R", -NR 5 C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -CI 0 alkoxy, C 3 -CIO cycloalkyl, phenyl, pyridinyl, naphthyl, isoquinolinyl, quinolinyl up to per halo-substituted CI-CIO alkyl, up to per halo-substituted C 2 -C 10 alkenyl, up to per halo-substituted C 1 -C 10 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 -CIoalkenyl, C 3 CIO cycloalkyl, up to per-halosubstituted C 1 -CI 0 alkyl, up to per-halosubstituted C 2 -CI 0 alkenyl and up to per-halosubstituted C 3 -CI 0 cycloalkyl, wherein Y is -(CH 2 -(CH 2 )m0-, -NR 5 C(O)NR' -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 )(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, optionally substituted by halogen up to per-halosubstitution and optionally substituted by Zn, 1 wherein nl 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', -NO 2 SR', -NR 5 R 5 -NR 5 C(O)0R", -C(O)R 5 -NR 5 C(O)R 5 -S0 2 R', SO 2 NR 5 R 5 CI-Clo alkyl, CI-CIO alkoxyl, C 3 -CI 0 cycloalkyl, up to per halo-substituted CI-C 10 alkyl, and up to per halo-substituted C 3 -CIO cycloalkyl. 138 00
  23. 34. A compound as in claim 31, o wherein Q is phenyl optionally substituted by halogen up to per-halosubstitution, Q' is Sphenyl or pyridinyl optionally substituted by halogen up to per-halosubstitution, and Y is -0- Sor X' is as defined in claim 31, Z is -Cl or -OCH 3 n 0, s and nl 0-2. 00 Date: 4 December 2008 0N 00oO
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WO2019232275A1 (en) * 2018-05-30 2019-12-05 Washington University Mitogen-activated protein kinase inhibitors, methods of making, and methods of use thereof

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