AU2501600A - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Download PDF

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Publication number
AU2501600A
AU2501600A AU25016/00A AU2501600A AU2501600A AU 2501600 A AU2501600 A AU 2501600A AU 25016/00 A AU25016/00 A AU 25016/00A AU 2501600 A AU2501600 A AU 2501600A AU 2501600 A AU2501600 A AU 2501600A
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AU
Australia
Prior art keywords
substituted
phenyl
acid
heteroatoms selected
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU25016/00A
Inventor
Jacques Dumas
Uday Khire
Timothy B. Lowinger
Mary-Katherine Monahan
Reina Natero
Joel Renick
Bernd dr. Riedl
William J. Scott
Robert N. Sibley
Roger A. Smith
Jill E. Wood
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Bayer Corp
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Bayer Corp
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27381740&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AU2501600(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer Corp filed Critical Bayer Corp
Priority claimed from PCT/US2000/000648 external-priority patent/WO2000042012A1/en
Publication of AU2501600A publication Critical patent/AU2501600A/en
Priority to AU2004200722A priority Critical patent/AU2004200722B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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Description

WO 00/42012 PCT/USOO/00648 5 co-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors 10 Cross-Reference to Related Applications This is a continuation-in-part of Serial No. 09/257,266 filed February 25, 1999 and a continuation-in-part of Serial No. 60/115,877 filed January 13, 1999. Field of the Invention 15 This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy. Background of the Invention The p2las oncogene is a major contributor to the development and progression of human 20 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 25 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 30 Biol. 1994. 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of WO 00/42012 PCT/USOO/00648 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. 5 Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996, 2, 668-75). Summary of the Invention 10 The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p 21 "", the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal 15 solid cancers, e.g., murine cancer, since the progression of these cancers is dependent upon the ras protein signal transduction cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by inhibiting raf kinase. Accordingly, the compounds of the invention are useful in treating cancers, including solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., 20 myeloid leukemia) or adenomas (e.g., villous colon adenoma). The present invention therefore provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the raf kinase pathway. The invention also provides a method for treating a raf mediated disease state in humans or 25 mammals. Thus, the invention is directed to compounds which inhibit the enzyme raf kinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutically acceptable salt thereof. A-D-B (I) 30 In formula I, D is -NH-C(O)-NH-, 2 WO 00/42012 PCT/US0O/00648 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L' )q where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 5 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting 10 of -SO 2 Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally 15 containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, 20 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon 25 atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or 3 WO 00/42012 PCTUSOO/00648 b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, 5 S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a CI-C 5 divalent alkylene group or a substituted C C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1
-C
5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up 10 to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; 15 wherein each W is independently selected from the group consisting of -CN, -C0 2
R
7 , -C(O)NRR', -C(O)-R', -NO 2 , -OR', -SR', -NR 7 R', -NR 7 C(0)OR', -NR 7
C(O)R
7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2
R
7 , -C(O)R 7 , -C(O)NR 7
R
7 , -OR 7 , -SR 7 , 20 NR 7
R
7 , -NO 2 , -NR 7
C(O)R
7 , -NR 7
C(O)OR
7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )m-, (CH 2 )mS-,
-(CH
2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa 2 -, -S-(CH 2 )m- and -N(R 7
)(CH
2 )m-, where m= 1-3, 25 and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z,, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO 2 R', -C(O)R', -C(O)NR R 30 NO2, -OR-, - SR7 -NR'R 7 , -NR 7
C(O)OR
7 , -NR 7
C(O)R
7 , and a carbon based moiety of up to 4 WO 00/42012 PCT/USOO/00648 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R', COR', -C(O)NR 7
R
7 , -OR', -SR 7 , -NO 2 , -NR 7
R
7 , -NR 7
C(O)R
7 , and -NR 7
C(O)OR
7 , with R' as defined above. 5 In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 10 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5 yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4 oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4 15 thiadiazol-2- or -5-yl, 1,3,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5 or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7 20 benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8 or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, I 25 methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2 yl. Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc. Suitable aryl groups which do not contain heteroatoms include, for example. pheni and i- and 2-naphthyl. 5 WO 00/42012 PCT/USOO/00648 The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C 4 cycloalkyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein also includes saturated heterocyclic groups. Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety. The invention also relates to compounds per se, of formula I. 10 The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, 15 benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2 naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+ Na* or K), 20 alkaline earth cations (e.g., Mg+2 , Ca+ 2 or Ba+ 2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, NN-dicyclohexylamine, lysine, pyridine, NN-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) 25 and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). A number of the compounds of Formula I possess asymmetric carbons and can therefor 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 3o encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity. 6 WO 00/42012 PCT/USOO/00648 General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing 5 these compounds, with more detailed examples being provided in the Experimental section which follows. Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic 10 Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne. 15 Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)).
H
2 / catalyst (eg. Ni, Pd, Pt) ArNO 2 [H~] o ArNH 2 M(0) 20 (eg. Fe, Sn, Ca) Scheme I 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 7 WO 00/42012 PCT/USOO/00648 Ar-H HN0 3 ArNO 2 potential leaving groups (e.g. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II). 0 2 N (2 F ArSH R base 1 0 2 N S-Ar 0 2 N R D SH Br-Ar 2 CuO / base 5 3 Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids 10 (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5). 0 2 N ArB(OR') 2 0 2 N ''X A r R Pd(0) R A 4 5 Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride 15 source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with CHCIF, in the 8 WO 00/42012 PCT/USOO/00648 presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO 3 -acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).
SO
2 C1
CISO
3 H R3 -+-R 7 6 K n(Hg)
SO
2 F SH R 8 --- R 10 (Me 2
N)
3 S Me 3 SiF 2 CHCF2 Me 3 SiCF 3 base
SO
2
CF
3
SCHF
2 R 9 - S101 O]2
SO
2
CHF
2 R 12 5 Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or 0 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 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be 9 WO 00/42012 PCT/USOO/00648 subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. Ar'-NH 2 13 COC12
H
2 N-Ar 2 O Ar-NCO 3K ArsN N'Ar 2 14 H H 15 N3 DPPA 0 0 Ar X Ar OH 16 17 Scheme IV Selected Methods of Non-Symmetrical Urea Formation 5 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, and a physiologically acceptable carrier. 10 The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or. more compounds may be present in association with one or more non toxic pharmaceutically acceptable carriers and if desired other active ingredients. 15 Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable 20 preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate. sodium 10 WO 00/42012 PCT/US0O/00648 carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby 5 provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form. Formulations for oral use may also be presented as hard gelatin capsules wherein the active 10 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 15 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 20 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 25 or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Dispersible powders and granules suitable for preparation of an aqueous suspension by the So 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 I1 WO 00/42012 PCT/USOO/00648 and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily 5 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 10 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 15 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. 20 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. 25 The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. 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 12 WO 00/42012 PCT/US0O/00648 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 topical dosage regime will preferably be from 0.1 5 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight. It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering 10 therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound 15 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, 20 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 enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Serial No. 60/115,877, 25 filed January 13, 1999 and non-provisional application Serial No. 09/257,266 filed February 25, 1999. The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), e.g., through the general preparative 30 methods shown below. The activity of a given compound to inhibit raf kinase can be routinely assayed. e.g.. according to procedures disclosed below. The following examples 13 WO 00/42012 PCT/USOO/00648 are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way. EXAMPLES 5 All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at 10 approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 - 1.0 mmHg. All temperatures are -reported uncorrected in degrees Celsius (*C). Unless otherwise indicated, all parts and percentages are by weight. 15 Commercial grade reagents and solvents were used without further purification. N cyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3 (trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5 20 (trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4 isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3 (trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4
-(
3 -carbamoylphenoxy)-l-nitrobenzene 25 (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert butylphenyl isocyanate (0. Rohr et al. DE 2,436,108) and 2-methoxy-5 (trifluoromethyl)phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described. 30 Thin-layer chromatography (TLC) was performed using Whatmant pre-coated glass-backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) 14 WO 00/42012 PCT/USOO/00648 immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2
,
4 -dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 5 230-400 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. 10 Proton ('H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual protonated solvent (CHCl 3 8 7.26; MeOH 8 3.30; DMSO 6 2.49) as standard. Carbon ( 13 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDCl 3 6 77.0; MeOD-d 3 ; 8 49.0; DMSO-d 6 6 39.5) as standard. Low resolution 15 mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 *C. Electron impact ionization was performed with 20 electron energy of 70 eV and a trap current of 300 pA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (lx10^4 torr to 2.5x 104 torr). The direct insertion desorption chemical ionization (DCI) probe 25 (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10amps 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 30 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-\S) 15 WO 00/42012 PCT/USOO/00648 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ. 5 All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures. List of Abbreviations and Acronyms: 10 AcOH acetic acid anh anhydrous atm atmosphere(s) BOC tert-butoxycarbonyl CDI 1,1'-carbonyl diimidazole 15 conc concentrated d day(s) dec decomposition DMAC NN-dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 20 DMF NN-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate 25 EtOH ethanol (100%) Et 2 Q diethyl ether Et 3 N triethylamine h hour(s) HOBT 1 -hydroxybenzotriazole 30 n-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 'C) 16 WO 00/42012 PCT/USOO/00648 temp. temperature THF tetrahydrofuran TFA trifluoroAcOH Tf trifluoromethanesulfonyl 5 A. General Methods for Synthesis of Substituted Anilines Al. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3-methoxynaphthalene.
CO
2 Me 10 OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2
CO
3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. 15 overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 ), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): 'H NMR (DMSO-d 6 ) 6 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, I H), 7.53 20 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, IH), 8.21 (s, IH). C0 2 H OMe Step 2. 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). 25 The mixture was heated at the reflux temp. for 3 h, cooled to room temp.. and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 \ I0I 17 WO 00/42012 PCT/USOO/00648 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 'H-NMR (DMSO-d 6 ) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 5 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H). 0 N0 OMeN Step 3. 2 -(N-(Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a 10 solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 'C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed to 80 *C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a 15 saturated NaCl solution, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N (carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d 6 ) 5 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, IH), 8.76 (s, 1H).
NH
2 20 OMe Step 4. 2 -Amino-3-methoxynaphthalene A slurry of 2 -(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H 2 atm (balloon) at room temp. overnight. The resulting mixture was filtered through Celiteg and concentrated under 25 reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 18 WO 00/42012 PCT/USOO/00648 85%): 'H-NMR (DMSO-d 6 ) 6 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); El-MS m/z 173 (M*). A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine 5 Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4 (2-N-Methylcarbamyl-4-pyridyloxy)aniline 0 C1 NHMe Step la. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci reaction 10 Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc.
H
2
SO
4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 0 2 (30% wt in H 2 0, 17 mL) followed by FeSO 4 -7H 2 0 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 'C. 15 When bubbling had subsided, the reaction was heated at 60 'C for 16 h. The resulting opaque brown solution was diluted with H 2 0 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were combined, dried (MgSO 4 ) and filtered through a pad of silica gel with the aid of EtOAc. The 20 resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 'C over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; 'H NMR (CDCl 3 ) 8 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, IH), 8.21 (s, IH), 8.44 (d, J=5.1 Hz, I H); CI-MS m/z 171 ((M+H)*). 25 0 CI *N CI CN HCI Step lb. Synthesis of 4-chloropyridine-2-carbonvl chloride HCI salt via picolinic acid 19 WO 00/42012 PCT/USO0/00648 Anhydrous DMF (6.0 mL) was slowly added to SOC1 2 (180 mL) between 400 and 50 OC. The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 'C (vigorous S02 evolution) for 16 h to generate a yellow solid precipitate. The resulting 5 mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCl salt as a yellow-orange solid (92.0 g, 89%). 0 CI "N OMe 10 N HCI Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt Anh DMF (10.0 mL) was slowly added to SOCl 2 (300 mL) at 40-48 *C. The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 'C (vigorous SO 2 evolution) for 16 h to 15 generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2 carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside. 20 The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 'C. The contents were stirred at room temp. for 45 min., cooled to 5 'C and treated with Et 2 0 (200 mL) dropwise. The resulting solids were filtered, washed with Et 2 O (200 mL) and dried under reduced pressure at 35 *C to provide methyl 4-chloropyridine-2 25 carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 'C; 'H-NMR (DMSO-d 6 ) S 3.88 (s, 3H); 7.82 (dd, J=5.5, 2.2 Hz, IH); 8.08 (d, J=2.2 Hz, IH); 8.68 (d, J=5.5 Hz, I H); 10.68 (br s, IH); HPLC ES-MS nz 172 ((M+H)*). 20 WO 00/42012 PCT/US0O/00648 0 Cl - NHMe Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4 chloropyridine-2-carboxylate A suspension of methyl 4 -chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in 5 MeOH (75 mL) at 0 'C was treated with a 2.0 M methylamine solution in THF (1 L) at'a rate which kept the internal temp. below 5 *C. The resulting mixture was stored at 3 *C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2 10 pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 *C; 'H-NMR (DMSO d 6 ) 5 2.81 (s, 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 (d, J=2.2, 1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)*). 0 C NHMe Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4 15 chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 *C. The resulting mixture was stored at 3 *C for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate 20 was washed with a saturated NaCl solution (2 x 100 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure to provide 4 -chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 'C. 0 -~ 0 ~ NHMe
H
2 N ON~ Step 4. Synthesis of 4 -(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline 25 A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at 21 WO 00/42012 PCT/USOO/00648 room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2 pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 C0 3 (6.50 g, 47.0 mmol) and then heated at 80 'C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with 5 EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 *C for 3 h to afford 4 -(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline as a light-brown solid 17.9 g, 84%): 'H-NMR (DMSO-d,) 5 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5, 2.5 Hz, 10 1H), 7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)*). A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4 Aminophenoxy)isoindoline-1,3-dione 15 0 HO NH HOO 0 Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated 20 at 120 *C for 45 min., then the clear, bright yellow mixture was heated at 160 0 C for 2 h. The resulting mixture was maintained at 160 'C and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 'C and slowly acidified to pH 5 using a IN HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5 25 hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): 'H NMR (DMSO-d 6 ) 8 7.00-7.03 (in, 2H), 7.56 (d, J=9.3Hz, 1H). 22 WO 00/42012 PCT/USOO/00648 0 0 2 N O O NH 0 Step 2. Synthesis of 5-(4-nitrophenoxy)isoindoline-1,3-dione To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 *C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright 5 yellow-green mixture was allowed to return to room temp. and was stirred for I h, then 1 fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 'C overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 5-(4 10 nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H NMR (DMSO-d 6 ) 5 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H)*, 100%). 0
H
2 Nc O 0 NH 0 Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-1,3-dione 15 A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to give 5-(4 20 aminophenoxy)isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) Rf 0.27; 'H NMR (DMSO-d 6 ) 8 5.14 (br s, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, IH), 7.75 (d, J=8.4 Hz, IH), 11.02 (s, IH); HPLC ES-MS m/z 255 ((M+H)*, 100%). 25 A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert Butyl-2-(2,5-dimethylpyrrolyl)aniline 23 WO 00/42012 PCTIUSOO/00648
NO
2 N Step 1. Synthesis of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (0.1mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The 5 reaction mixture was heated at 120 'C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH 2 Cl 2 (10 mL) and sequentially washed with a IN HCl solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCl solution (15mL), dried ( MgSO 4 ) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO 2 ; gradient from 6% 10 EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5 dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67; 'H NMR (CDCl 3 ) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS m/z 273 ((M+H)*, 50%).
NH
2 N 15 Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H 2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite*. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 20 99%): TLC (10% EtOAc/90% hexane) Rf 0.43; 'H NMR (CDCl 3 ) 6 1.28 (s, 9H), 1.87-1.91 (m. 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, I H). 24 WO 00/42012 PCT/USOO/00648 A5. General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4-(2-(N Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCl Salt 0 I -~ j NHMe
H
2 N HCe a Me HCI Me 5 A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 'C for 8 h. The mixture was cooled to room temp. and diluted with 10 water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgSO4) and concentrated under reduced pressure. The residual black oil was treated with Et 2 0 (50 mL) and sonicated. The solution was then treated with HCl (1 M in Et 2 0; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by 15 filtration from solution and stored under anaerobic conditions at 0 *C prior to use: 'H NMR (DMSO-d 6 ) 8 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, J=5.5, 2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1.H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H). 20 A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N Protection, Nucleophilic Aromatric Substitution and Deprotection. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline O OH
F
3 C N H CI Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol 25 Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2 chloro-4-nitrophenol (10.0g, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from solution and the 25 WO 00/42012 PCTIUS00/00648 remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO, solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated 5 from solution (determined-was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The 1H NMR (DMSO-d 6 ) indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol. The crude material 10 was taken on to the next step without further purification. 0 0" NHMe
F
3 C NNH1 H q C1 Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in 15 dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2 pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 *C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into 20 cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222 trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol). 0 0 NHMe 25
H
2 N CINHN Step 3. Synthesis of 4-(2-(N-Methylcarbamovl)-4-pyridyloxy)-2-chloroaniline 26 WO 00/42012 PCT/USOO/00648 A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222 trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) 5 and the solvent was concentrated to yield 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2 chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR (DMSO-d 6 ) 6 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5, 2.6 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.07 (dd, J=5.5, 2.6, Hz, IH), 7.27 (d, J=2.6 Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.75 (q, J=4.8, 1H). 10 A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline
CF
3 CI
NH
2 OMe A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 15 mmol) in a 6M HCl solution (24 mL) was heated at the reflux temp. for I h. The resulting solution was allowed to cool to room temp. during which time it solidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaOH and a saturated NaHCO 3 solution until the solution was basic. The organic layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined 20 organics were dried (MgSO 4 ) and concentrated under reduced pressure to yield 4 chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 1H NMR (DMSO-d 6 ) 6 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H). A8. General Method for Synthesis of o-Alkoxy-o-carboxyphenyl Anilines. 25 Synthesis of 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)an line. 0 j 0 OMe 0 2 N OMe Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: 27 WO 00/42012 PCTIUSOO/00648 To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared from 2,5 dihydroxybenzoic acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K 2
CO
3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and 5 filtered through a pad of Celite*. The resulting solution was concentrated under reduced pressure, absorbed onto SiO 2 , and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 115-118 *C. 0 O 1 OH 0 2 N OMe 10 Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene: A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous 15 mixture was made acidic with a iN HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was-dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g). 0 O- OMNHMe 2 Nc OMe Step 3. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene: 20 To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in
CH
2 C1 2 (12 mL) was added SOCl 2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH 2 Cl 2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 25 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a IN NaOH solution, then extracted with CH 2 Cl 2 (25 mL). 28 WO 00/42012 PCT/USOO/00648 The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure to give 4-(3 (N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%). 0 O j NHMe
H
2 N OMe Step 4. 4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)aniline: 5 A slurry of 4 -(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under I atm of H 2 (balloon) for 2.5 d, then was filtered through a pad of Celite*. The resulting solution was concentrated under reduced pressure to afford 4
-(
3 -(N-methylcarbamoly)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et 3 N/99.9% EtOAc) Rf 0.36. 10 A9. General Method for Preparation of o-Alkylphthalimide-containing Anilines. Synthesis of 5 -(4-Aminophenoxy)-2-methylisoindoline-1,3-dione 0 O2N ON-Me 0 2 Nl I 0 Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione: 15 A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to *C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline 20 1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf 0.61. 0 H2N N-Me
H
2 N 29 WO 00/42012 PCT/USOO/00648 Step 2. Synthesis of 5
-(
4 -Aminophenoxy)-2-methylisoindoline-1,3-dione: A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H 2 (balloon) overnight. The resulting mixture was filtered through a pad of Celite* and concentrated under reduced pressure. The resulting 5 yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of SiO 2 (60% EtOAc/40% hexane) to afford 5-( 4 -aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf 0.27. Al0. General Method for Synthesis of o-Carbamoylaryl Anilines Through 10 Reaction of o-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4
-(
2
-(N-(
2 -morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline 0 CI N N O Step 1. Synthesis of 4 -Chloro- 2
-(N-(
2 -morpholin-4-ylethyl)carbamoyl)pyridine 5 To a solution of methyl 4 -chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4
-(
2 -aminoethyl)morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO 4 ) and concentrated under reduced pressure to o afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rr 0.50. 0 lIiZz 0'1 " N-'.r\
H
2 N O N NO 30 WO 00/42012 PCT/USOO/00648 Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4 ylethyl)carbamoyl)pyridyloxy)aniline. A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4 5 chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K 2 CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 *C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. 10 The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4 ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, 65%): TLC (10% MeOH/90% EtOAc) Rf 0.32. Al1. General Method for the Reduction of Nitroarenes to Arylamines. 15 Synthesis of 4-(3-Carboxyphenoxy)aniline. 0 0~ OH
H
2 NO A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite*, then concentrated under reduced pressure to 20 afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90%
CH
2 Cl 2 ) Rf 0.44 (streaking). A12. General Method for the Synthesis of Isoindolinone-Containing Anilines. Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline. HO I NH 25 0 31 WO 00/42012 PCT/US0O/00648 Step 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was 5 repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO 2 ; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES MS m/z 150 ((M+H)*). I NH 0 2 N O NH 0 10 Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 'C was added 5-hydroxyisoindolin-l one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70 'C for 3 h. The mixture was cooled to 0 *C and treated with water dropwise 15 until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5 yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35. I I NH
H
2 N 0 Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline A slurry of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C 20 (0.20 g) in EtOH (50 mL) was stirred under an H 2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite*. The filtrate was concentrated under reduced pressure to afford 4-(l oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) Rf 0.15. A13. General Method for the Synthesis of o-Carbamoyl Anilines via EDCI 25 Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-(3-N-Methylcarbamoylphenoxy)aniline. 32 WO 00/42012 PCTIUSOO/00648 0 O0 OEt 0 2 N" ID Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 5 150 mmol) and K 2
CO
3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na 2
SO
4 ) and concentrated under reduced pressure. The residue was purified by column chromatography 10 (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g). 0 0~ OH 0 2 N O0 O 15 Step 2. Synthesis of 4-(3-carboxyphenoxy)-1-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH-H 2 0 (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 *C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a IM HCI 20 solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%). '0 O2N NHMe 0 2 N3 33 WO 00/42012 PCT/USOO/00648 Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI-HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH 2
C
2 (45 mL) was stirred at room temp. for 3 d, then concentrated under 5 reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na 2 SO4), and concentrated under reduced pressure to give 4-(3-(N methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g). 0 -~ NHMe 10 H 2 N Step 4. Synthesis of 4-(3-(N-methylcarbamoyl)phenoxy)aniline A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H 2 atm (balloon) overnight. The 15 resulting mixture was filtered through a pad of Celite* and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH 2 Cl 2 ). The resulting oil solidified under vacuum overnight to give 4-(3-(N methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%). 20 A14. General Method for the Synthesis of co-Carbamoyl Anilines via EDCI Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline O O OMe 0 2 N N 25 Step 1. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5 hydroxvnicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a 34 WO 00/42012 PCT/USOO/00648 solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column 5 chromatography (30% EtOAc/70% hexane) to afford 4
-(
3 -(5-methoxycarbonyl)pyridyloxy) 1-nitrobenzene (0.60 g). 0 0 - 0 OMe
H
2 N ON Step 2. Synthesis of 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g, 2.20 mmol) and 10 10% Pd/C in MeOH/EtOAc was stirred under an H 2 atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 1H NMR (CDCla) 8 3.92 (s, 3H), 6.71 (d, 15 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, IH). 35 WO 00/42012 PCT/USOO/00648 A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction. Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline. 00 Br '/NHMe Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide 5 To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 0 C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases 10 were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give N-methyl-3 bromobenzenesulfonamide as a white solid (2.8 g, 99%). 0"0 0 S NHMe Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene 15 To a slurry of phenol (1.9 g, 20 mmol), K 2
CO
3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially 20 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N methylsulfamoyl)phenyloxy)benzene (0.30 g). 0 2 NHMe 0 2 N 36 WO 00/42012 PCT/USOO/00648 Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 C was added NaNO 2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at -10 'C for 1 h, then was allowed to warm to room temp., and was 5 concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.20 g). This material carried on to the next step without further purification. 0"0 0 -~ NHMe 10
H
2 N O Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline A slurry of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite*. The filtrate was concentrated under 15 reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)aniline (0.070 g). A16. Modification of co-ketones. Synthesis of 4-(4-(1-(N methoxy)iminoethyl)phenoxyaniline HCl salt. HCI N 20
H
2 N To a slurry of 4-(4-acetylphenoxy)aniline HCl salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine HCl salt (0.65 g,.7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and 25 concentrated under reduced pressure. The resulting solids were triturated with water (10 nL) and washed with water to give 4-(4-(l-(N-methoxy)iminoethyl) phenoxyaniline HCI salt as a 37 WO 00/42012 PCT/USOO/00648 yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf 0.78; 'H NMR (DMSO-d 6 ) 6 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H)*). A17. Synthesis of N-(o-Silyloxyalkyl)amides. Synthesis of 4-(4-(2-(N-(2 5 Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. O CI N NH Step 1. 4 -Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide To a solution of 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added 10 triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO 4 ), and concentrated under reduced pressure to afford 4 15 chloro-2-(N-(2-triisopropylsilyloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification. 00
H
2 N O NSi Step 2. 4
-(
4
-(
2
-(N-(
2 -Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added 20 potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4-chloro-2-(N-(2 triisopropylsilyloxy)ethyl)pyridinecarboxamide (2.32 g, 6 mmol, I equiv.) in DMF (4 mL) was added followed by K 2 C0 3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 'C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 25 0.5 equiv.) was then added and the mixture was stirred at 80 *C an additional 4 h. The mixture was cooled to 0 'C with an ice/water bath, then water (approx. I mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined 38 WO 00/42012 PCT/USOO/00648 organic layers were washed with a saturated NaCl solution (20 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO 2 ; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 5 38%). A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2 Methylpyridines. Synthesis of 4-(5-(2 methoxycarbonyl)pyridyloxy)aniline. 0 10 0 2 N N Step 1. 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K 2
CO
3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room 15 temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCl solution ((100 mL), dried (MgSO 4 ) and concentrated under reduced pressure to give 4 (5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g). 02NN OMe 0 20 Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-1-nitrobenzene. A mixture of 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The 25 solution was treated with a conc HCl solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a IN NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially 39 WO 00/42012 PCT/USOO/00648 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 50% EtOAc/50% hexane) to afford 4 -(5-( 2 -methoxycarbonyl)pyridyloxy)-1 nitrobenzene (0.70 g). H2'OOMe
H
2 NN 5 0 Step 3. Synthesis of 4 -(5-( 2 -Methoxycarbonyl)pyridyloxy)aniline. A slurry of 4 -(5-( 2 -methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.50 g) and 10% Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite*), 10 and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; 70% EtOAc/30% hexane) to give 4-(5-(2 methoxycarbonyl)pyridyloxy)aniline (0.40 g). A19. Synthesis of -Sulfonylphenyl Anilines. Synthesis of 4-(4 15 Methylsulfonylphenyoxy)aniline. 0 0 2 N Me Step 1. 4
-(
4 -Methylsulfonylphenoxy)-1-nitrobenzene: To a solution of 4-(4 methylthiophenoxy)-1-nitrobenzene (2.0 g, 7.7 mmol) in CH 2 Cl 2 (75 mL) at 0 *C was slowly added m-CPBA (57-86%, 4.0 g), and the reaction mixture was stirred at room temperature for o 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 ), and concentrated under reduced pressure to give 4 (4-methylsulfonylphenoxy)- 1 -nitrobenzene as a solid (2.1 g). 5 Step 2. 4-(4-Methylsulfonylphenoxy)-1 -aniline: 4-(4-Methylsulfonylphenoxy)- I nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A lS. step 3. 40 WO 00/42012 PCTIUSOO/00648 B. Synthesis of Urea Precursors BI. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synthesis of 4-Bromo-3-(trifluoromethyl)phenyl Isocyanate.
CF
3 Br N H 2 -H OC 5 Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCl salt To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et 2 0 (500 mL) was added an HCl solution (1 M in Et 2 0; 300 mL) dropwise and the resulting mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et 2 0 (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g, 10 98%).
CF
3 Br ~NCO Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HCI salt (36.8 g, 133 mmol) in toluene 15 (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH 2 Cl 2 (500 mL), then concentrated under reduced pressure. The CH 2 C1 2 treatment/concentration protocol was repeated and resulting 20 amber oil was stored at -20 'C for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M*). C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 25 with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenvl)-N' (4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea 41 WO 00/42012 PCTIUSOO/00648
CF
3 CN NHMe iN N H H A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 g, 65.90 mmol) in CH 2 Cl 2 (35 mL) was added dropwise to a suspension of 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH 2 Cl 2 (35 mL) at 0 IC. The 5 resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH 2 Cl 2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mnmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2 (N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off-white solid (28.5 g, 93%): mp 207-209 'C; 'H-NMR (DMSO-d 6 ) 8 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 10 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, IH), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)*). Cib. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl)phenyl)-N' 15 (4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF
3 0 Br N N NHMe N N H H A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method BI, Step 2; 8.0 g, 30.1 mmol) in CH 2
C
2 (80 mL) was added dropwise to a solution of 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH 2 Cl 2 (40 mL) at 0 'C. The 20 resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CH 2 Cl 2 (2 x 50 mL) and dried under reduced pressure (approximately I mmHg) at 40 *C to afford N-(4-bromo-3-(trifluoromethyl)phenyl) N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, 90%): mp 203-205 'C; 'H-NMR (DMSO-d 6 ) 6 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 25 J=2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, IH), 8.11 (d, J=2.5 Hz, I H). 8.49 (d. J=5.5 Hz, I H), 8.77 (br d, I H), 8.99 (s, I H), 9.21 (s, I H); HPLC ES-MS m/: 509 ((M-H)'). 42 WO 00/42012 PCT/USOO/00648 Cic. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N' (2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) Urea
CF
3 0 C1 0 O NHMe H H Me 5 A solution of 2-methyl-4-(2-(N-methylcarbanoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH 2 Cl 2 (1 mL) was treated with Et 3 N (0.16 mL) and 4-chloro-3 (trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO 4 ) 10 and concentrated under reduced pressure to yield N-(4-chloro-3-(trifluoromethyl)phenyl)-N' (2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil (0.11 g, 0.22 mmol): 'H NMR (DMSO-d 6 ) 5 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5, 2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, IH), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, IH); 8.50 (d, J=5.5 Hz, IH), 15 8.78 (q, J=5.2, IH), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)*). CId. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N' (4-aminophenyl) Urea
CF
3 CI 0 ~ NH 2 Cl& N N N 20 H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in
CH
2 Cl 2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for I h, treated with CH 2 Cl 2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture 25 of EtOAc (110 mL) and MeOH (I5mL), and the clear solution was washed with a 0.05 N HCI solution. The organic layer was concentrated under reduced pressure to afford impure 43 WO 00/42012 PCT/USOO/00648 N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (3.3 g): TLC (100% EtOAc) Rf 0.72. Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 5 with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N' (4-ethoxycarbonylphenyl) Urea
CF
3 0 CI 0~ QEt C N NOt H H To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at 10 room temp. overnight. The resulting slurry was diluted with CH 2 Cl 2 (50 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf 0.44. Cf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 15 with an Aniline. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N' (3-carboxyphenyl) Urea
CF
3 O CI N N O OH H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CH 2
CI
2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the 20 resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 EtOAc/hexane solution to give N-(4 chloro-3-(trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%). 2 5 C2a. General Method for Urea Synthesis by Reaction of an Aniline with N,V' Carbonyl Diimidazole Followed by Addition of a Second Aniline. 44 WO 00/42012 PCT/USOO/00648 Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF
3 0 -~ 01 ~NHMe N N OMeH H To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH 2 Cl 2 (15 mL) at 0 C 5 was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over I h, was stirred at room temp. for 16 h, then was treated with 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H 2 0 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution 10 (100 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl) 15 N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) Rf 0.62; 'H NMR (DMSO-d 6 ) 8 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (in, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m/z 461 ((M+H)*). 20 C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,N' Carbonyl Diimidazole Followed by Addition of a Second Aniline. Symmetrical Urea's as Side Products of a N,N'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) Urea 0 0 MeHN O N NHMe N NN H H 45 WO 00/42012 PCT/USOO/00648 To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 (15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2 (N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g). The resulting yellow solution stirred at 5 room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCl solution (100 ml), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)-4 10 pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf 0.50; 1H NMR (DMSO-d 6 ) 6 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H),, 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H)*). C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 15 with an Aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl-N' (4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea
CF
3 0 0 N N 0 OMeH H NH 0 To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 Cl 2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 20 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH 2 C1 2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO 4 ) and concentrated under reduced pressure to afford N-(2-methoxy-5 (trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 25 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 'H NMR (DMSO-d 6 ) 6 3.95 (s, 3H), 7.31 7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, IH), 8.53 (br s, 2H), 9.57 (s, IH), 11.27 (br s, I H); HPLC ES-MS 472.0 ((M+H)*, 100%). 46 WO 00/42012 PCTIUSOO/00648 C2d. General Method for Urea Synthesis by Reaction of an Aniline with NN' Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of N-(5-(tert-Butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-( 4
-(
2 (N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea 0 N NNHMe N H H 5 To a stirring solution of CDI (0.21g, 1.30 mmol) in CH 2 Cl 2 (2 mL) was added 5-(tert-butyl) 2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in one portion. The resulting 10 mixture was heated at 36 *C overnight, then cooled to room temp. and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HCI solution (15mL), dried (MgSO 4 ), and filtered through a pad of silica gel (50 g) to afford N-(5 (tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) 15 Rf 0.24; 1 H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, 1H), 8.57 (d, J=2.lHz, 1H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)*, 100%). C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using 20 Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate 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 25 was capped and heat at 80 'C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting 47 WO 00/42012 PCT/USOO/00648 mixture was heated at 80 0 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. 5 C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N-(2-Methoxy-5 (trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea
CF
3 0 N0 N ONHMe N ) N 1 N OMe H H To a stirring solution of phosgene (1.9 M in toluene; 2.07 mLO.21g, 1.30 mmol) in CH 2 Cl 2 10 (20 mL) at 0 *C was added anh pyridine (0.32 mL) followed by 2-methoxy-5 (trifluoromethyl)aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 15 0.30 g) and the resulting suspension was heated at 80 *C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgSO 4 ), and concentrated under reduced pressure. The resulting pink 20 brown residue was dissolved in MeOH and absorbed onto SiO 2 (100 g). Column chromatography (300 g SiO 2 ; gradient from 1% Et 3 N/33% EtOAc/66% hexane to 1% Et 3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 'C gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4 25 (2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et 3 N/99% EtOAc) Rf 0.40. 48 WO 00/42012 PCT/USOO/00648 D. Interconversion of Ureas Dia. Conversion of c-Aminophenyl Ureas into o-(Aroylamino)phenyl Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methoxycarbonylphenyl)carboxyaminophenyl) Urea
CF
3 H CI 0 N W-. Oe N ,N N0 0 5 H H To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBT-H 2 0 (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI -HCI (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight, 10 diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHCO 3 solution (25 mL). The organic layer was dried (Na 2
SO
4 ) and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% 15 EtOAc/20% hexane) Rf 0.75. D1b. Conversion of o-Carboxyphenyl Ureas into o-(Arylcarbamoyl)phenyl Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methylcarbamoylphenyl)carbamoylphenyl) Urea CI N NHMe N Ne 20 H H To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT-H 2 0 (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 'C was added EDCI-HCl (0.10 g, 0.53 mmol). The resulting mixture was 25 allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water (1OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated 49 WO 00/42012 PCTIUSOO/00648 under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 ,methylcarbamoylphenyl)carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225 5 229; TLC (100% EtOAc) Rf 0.23. Dlc. Combinatorial Approach to the Conversion of co-Carboxyphenyl Ureas into o-(Arylcarbamoyl)phenyl Ureas. Synthesis of N-(4-Chloro-3 ((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3 10 pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea
CF
3 0 -~ H C1 0 e ~ N N N ClN N N N H H A mixture of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'-(methylpolystyrene)carbodiimide (55 mg) in 15 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH 2 Cl 2 (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 *C overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was 20 stirred at 36 *C for 72 h, then cooled 'to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3 pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) Rf 0.12. 25 D2. Conversion of o-Carboalkoxyaryl Ureas into o-Carbamoylaryl Ureas. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methylcarbamoylphenyl)carboxyaminophenyl) Urea 50 WO 00/42012 PCTUSOO/00648
CF
3 H CI N N y NHMe N U'N00 H H To a sample of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated 5 under reduced pressure to give N-( 4 -chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3 methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35. D3. Conversion of co-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas. 10 Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4 carboxyphenyl) Urea
CF
3 0 CI 0~ Q - OH Cl&N N O H H To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution 15 (2.5 N, 10 mL, 23 mmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCl solution to adjust the pH to 2 to 3. The resulting solids were collected and dried under reduced pressure to give N-(4-chloro-3 ((trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%). 20 D4. General Method for the Conversion of co-Alkoxy Esters into co-Alkyl Amides. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-((4-(3-(5-(2 dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) Urea
CF
3 0 CI 0 "" " OH N N N H H 51 WO 00/42012 PCT/USOO/00648 Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5 carboxypyridyl) oxyphenyl) Urea N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-methoxycarbonylpyridyl)oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5 5 methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5 methoxycarbonylpyridyl)oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting 10 precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N-(4-chloro-3 (trifluoromethyl)phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 7 1%).
CF
3 O N N N H H 15 Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2 dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-(5 carboxypyridyl)oxyphenyl) urea (0.050 g, 0.011 mmol), NN-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol), 20 and EDCI-HCl (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp. overnight. The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH 2 Cl 2 (approximately 2 mL). The resulting solution was treated with Et 2 0 dropwise to give N-(4-chloro-3 25 (trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: 'H NMR (DMSO-d,) 8 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (in, 3H), 8.05 (s, I H), 8.43 (s, 1H), 8.58 (t, IH), 8.69 (s, I H), 8.90 (s, I H), 9.14 (s, I H); HPLC ES-MS m/z 522 ((M+H)*). 52 WO 00/42012 PCT/USOO/00648 D5. General Method for the Deprotection of N-(-Silyloxyalkyl)amides. Synthesis of N-(4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2 hydroxy)ethylarbamoyl)pyridyloxyphenyl) Urea.
CF
3 0 N NN H H 5 To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2 triisopropylsilyloxy) ethylcarbamoyl)pyridyloxyphenyl) urea (prepared in a manner analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 10 mL). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 ; gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4 (4-(2-(N-(2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea as a white solid (0.019 g, 10%). 15 Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above: Syntheses of Exemplified Compounds (see Tables for compound characterization) 20 Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. 25 Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy) I-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4 acetylphenoxy)aniline. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea. 53 WO 00/42012 PCT/USOO/00648 Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI, followed by 4 (3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea. 5 Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B1. 4-(3-N-Methylcarbamoylphenoxy)aniline, prepared according to Method A13, was reacted with the isocyanate according to Method Cla to afford the urea. 10 Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea. Entry 6: 5-(4-Aminophenoxy)isoindoline-1,3-dione was prepared according to Method A3. 15 According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 5 (4-aminophenoxy)isoindoline-1,3-dione to afford the urea. Entry 7: 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4 20 (1-oxoisoindolin-5-yloxy)aniline to afford the urea. Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea. 25 Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4 acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5 aminopyridine. 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5 30 (trifluoromethyl)phenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method CIa to afford the urea. 54 WO 00/42012 PCTIUSOO/00648 Entry 10: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. 4-(4-Acetylphenoxy) 1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4 acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline 5 was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea. Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using 10 DMAC in place of DMF to give 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia 15 according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2 pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2 carbamoyl-4-pyridyloxy)aniline to afford the urea. 20 Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5 25 (trifluoromethyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2 s0 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method 55 WO 00/42012 PCT/USOO/00648 C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2 carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with 5 CDI followed by 4-(3-N-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea. Entry 16: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5 10 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method Cl c to afford the urea. Entry 17: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized 15 according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5 (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl) 4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea. 20 Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was 25 reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method Cl a to afford the urea. Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted 30 with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4 pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5 (trifluoronethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl) 56 WO 00/42012 PCT/USOO/00648 2-methoxyphenyl isocyanate was reacted with 4
-(
2 -(N-ethylcarbamoyl)-4-pyridyloxy)ani line according to Method CIa to afford the urea. Entry 20: According to Method A2, Step 4, 4 -amino-2-chlorophenol was reacted with 4 5 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4
-(
2 -(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-meihylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method 10 CIa to afford the urea. Entry 21: 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4
-(
4 -methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4
-(
4 -methylsulfonylphenoxy)-1-aniline. According 15 to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4 methylsulfonylphenoxy)-1-aniline to afford the urea. Entry 22: 4-(3-carbamoylphenoxy)- 1 -nitrobenzene was reduced to 4-(3 carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method Cla, 5 20 (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3 carbamoylphenoxy)aniline to afford the urea. Entry 23: 5-( 4 -Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2 25 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-( 4 -aminophenoxy)isoindoline-1,3-dione according to Method CIa to afford the urea. Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according 0 to Method A2, Step 3b. The resulting 4 -chloro-NN-dimethyl-2-pyridinecarboxanide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-2-(...
dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Tri fluoromethyl)-2-methoxyani line n as 57 WO 00/42012 PCTIUSOO/00648 converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5 (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(NN dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea. 5 Entry 25: 4 -(1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5 (Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-oxoisoindolin-5 yloxy)aniline according to Method C2d to afford the urea. Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to 10 Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method A13, Step 4 to afford 4
-(
4 -acetylphenoxy)aniline, which was converted to the 4 -(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl) 2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl 15 isocyanate was reacted with 4
-(
4 -(1-(N-methoxy)iminoethyl)phenoxyaniline HC salt to Method C Ia to afford the urea. Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 20 A2, Step 4 to give 4
-(
4
-(
2 -(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2 methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method CIa to afford the urea. 25 Entry 28: 5-( 4 -Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione according to Method Cl a to afford the urea. 30 Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method 58 WO 00/42012 PCT/USOO/00648 A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2 methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3
-(
4 -(2-(N-methylcarbamoyl)phenylthio)aniline according to Method CIa to afford the urea. 5 Entry 30: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4 -chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was 10 converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5 (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea. Entry 31: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method 15 A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5 methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, 20 and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2. Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2 25 methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4
-(
3 -(5-methoxycarbonyl)pyridyloxy)aniline according to Method CIa to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5 methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 0 to afford the amide. 59 WO 00/42012 PCT/USOO/00648 Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2 methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to 5 Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5 methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with NN-dimethylethylenediamine according to Method D4, Step 2 to afford the amide. 10 Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al1. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method CIf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 3 15 aminopyridine according to Method DIc. Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al1. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 20 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Cif to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N (4-fluorophenyl)piperazine according to Method DIc. Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5 25 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4 fluoroaniline according to Method DIc. 30 Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5 (Tri fluoromethyl)-2-methoxyani line was converted into 5-(trifluoromethyl)-2-methoxyphenyl 60 WO 00/42012 PCT/USOO/00648 isocyanate according to Method Bl. 4
-(
3 -Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4 (dimethylamino)aniline according to Method Dlc. 5 Entry 38: 4 -(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5 (Tri fluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4
-(
3 -Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 10 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 5 amino-2-methoxypyridine according to Method Dlc. Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl 15 isocyanate according to Method Bl. 4 -(3-Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4 morpholinoaniline according to Method DIc. 20 Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 5 (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4
-(
3 -Carboxyphenoxy)aniline was reacted with 5 (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5 (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N 25 (2-pyridyl)piperazine according to Method DIc. Entry 41: 4 -(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A13. According to Method C3, 4 -chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4
-(
3 -(N-Methylcarbamoyl)phenoxy)aniline to afford the urea. 30 61 WO 00/42012 PCT/USOO/00648 Entry 42: 4
-(
2 -N-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to Method A2. 4 -Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-N methylcarbamyl-4-pyridyloxy)aniline according to Method CIa to afford the urea. 5 Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4 -chloro-2-pyridinecarboxamide. 4-Chloro-2 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4
-(
2 -carbamoyl-4-pyridyloxy)aniline to 10 afford the urea. Entry 44: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4 -chloro-2-pyridinecarboxamide. 4-Chloro-2 pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to 15 form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 3
-(
2 -carbamoyl-4-pyridyloxy)aniline to afford the urea. Entry 45: 4 -Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to 20 Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3
-(-
2 -(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro 3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. 25 Entry 46: 5-(4-Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. According to Method Cla, 4 -chloro-3-(trifluoromethyl)phenyl isocyanate was reacted wifh 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea. Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized 30 according to Method A5. According to Method Clc, 4 -chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea. 62 WO 00/42012 PCT/USOO/00648 Entry 48: 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method A15. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea. 5 Entry 49: 4 -(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea. 10 Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea. 15 Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4 pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl 20 isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4 -(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to 25 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea. Entry 53: 4-(4-Methylthiophenoxy)- 1 -nitrobenzene was oxidized according to Method A 19, Step I to give 4-(4-methylsulfonylphenoxy)-I-nitrobenzene. The nitrobenzene was reduced 3o according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4 niethylsulfonylphenoxy)- I-aniline to afford the urea. 63 WO 00/42012 PCTIUSOO/00648 Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4 bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N 5 Methylsulfamoyl)phenoxy)benzene was converted into 4 -(4-(N-methylsulfamoyl)phenoxy) 1-nitrobenzene according to Method A15, Step 3. 4 -(4-(N-Methylsulfamoyl)phenoxy)-l nitrobenzene was reduced to 4-( 4 -N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea. 10 Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4 -(5-( 2 -Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4 -(5-( 2 -methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The 15 nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2 methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3 (trifluoromethyl)phenyl isocyanate according to Method CIa to afford the urea. Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according 20 to Method A18, Step 1 to give 4 -(5-( 2 -Methyl)pyridyloxy)-1-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4 -(5-( 2 -methoxycarbonyl)pyridyloxy)-1-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2 methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3 25 (trifluoromethyl)phenyl isocyanate according to Method Cla to give N-(4-chloro-3 (trifluoromethyl)phenyl)-N'-( 4
-(
2 -(methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3 (trifluoromethyl)phenyl)-N'-(4-( 2 -(N-methylcarbamoyl)-5-pyridyloxy)phenyl) urea. 310 Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method DIa to afford the urea. 64 WO 00/42012 PCT/USOO/00648 Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford N-(4-chloro 5 3-(trifluoromethyl)phenyl-N'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea. According to Method D2, N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3 methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide. 10 Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(NN dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(NN-dimethylcarbamoyl)-4 15 pyridyloxy)aniline to afford the urea. Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was 20 converted to the 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl salt according to Method A16. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea. Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, 25 Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was - coupled with 4-(2 aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2 morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4 (3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2 morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3 30 (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2 morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea. 65 WO 00/42012 PCTIUS0O/00648 Entry 62: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1 nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2 5 piperidylethyl)carbamoyl)phenoxy)- 1 -nitrobenzene was reduced to 4-(3-(N-(2 piperidylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2 piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea. 10 Entry 63: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3 15 (N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N (tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea. Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, 20 Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyl-l ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((l methylpyrrolidinyl)methyl)carbamoyl)phenoxy)- 1 -nitrobenzene. According to Method A 13 Step 4, 4-(3-(N-((I-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to4-(3-(N-((I-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline. According to 25 Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1 methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea. Entry 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 30 A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method CIa, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(.
nethylcarbamoyl)phenylthio)aniline to afford the urea. 66 WO 00/42012 PCTIUSOO/00648 Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4 -chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N 5 isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. Entry 67: N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4-ethoxycarbonylphenyl) urea was 10 synthesized according to Method Cle. N-(4-Chloro-3-(trifluoromethyl)phenyl-N'-(4 ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N-(4-chloro-3 (trifluoromethyl)phenyl-N'-(4-carboxyphenyl) urea. N-(4-Chloro-3-(trifluoromethyl)phenyl N'-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3 15 methylcarbamoylphenyl)carbamoylphenyl) urea. Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea. 20 Entry 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N 25 methylcarbamoyl)phenylthio)aniline to afford the urea. Entry 70: 4
-(
2 -(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method AlO. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
2
-(N-(
2 -morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to 30 afford the urea. 67 WO 00/42012 PCT/USOO/00648 Entry 71: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(4 Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea 5 was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide. Entry 72: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5 10 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5 (Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide. 15 Entry 73: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. N-(5 (Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 20 NN-dimethylethylenediamine according to Method D4, Step 2 to afford the amide. Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2 hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2 triisopropylsilyloxy)ethylpyridine-2-carboxamide. - 4-Chloro-N-(2 25 triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method C I a, 4-chloro 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-( 2 triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3 30 ((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2-triisopropylsilyloxy) ethvlcarbamoyl)pyridyloxyphenyl) urea. 68 WO 00/42012 PCT/USOO/00648 Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5 methoxycarbonyl)pyridyloxy)aniline according to Method Cif to afford the urea, which was coupled with 3-aminopyridine according to Method Dic. 5 Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A 1l. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(4 acetylphenyl)piperazine according to Method Dlc. 10 Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-fluoroaniline according to Method D1c. 15 Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4 (dimethylamino)aniline according to Method Dic. 20 Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N phenylethylenediamine according to Method Dic. 25 Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Cl f to afford the urea, which was coupled with 2-methoxyethylamine according to Method DIc. 30 Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)ani line 69 WO 00/42012 PCTUSOO/00648 according to Method Clf to afford the urea, which was coupled with 5-amino-2 methoxypyridine according to Method DIc. Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4 5 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
3 -carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method DIc. Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4 10 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
3 -carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(2-pyridyl)piperazine according to Method Dic. Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2 15 hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2 triisopropylsilyloxy)ethylpyridine-2-carboxamide. 4-Chloro-N-(2 triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline. According to Method Cla, 4-chloro 20 3-(trifluoromethyl)phenyl isocyanate was reacted. with 4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4-chloro-3 ((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford N-(4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-(2-(N-(2 25 hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea. Entry 85: 4
-(
2 -(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3 (trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4 30 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. 70 WO 00/42012 PCT/US0O/00648 Entry 86: 4
-(
2 -(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3 (trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4 5 pyridyloxy)-2-chloroaniline to afford the urea. Entry 87: According to Method A2, Step 4, 4 -amino-2-chlorophenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4
-(
2 -(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3 10 (trifluoromethyl)aniline was converted into 4 -bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
2 -(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea. 15 Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4 -chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4 pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3 (trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method C 1 a, 4 20 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to 25 form 3 -(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)ani line was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method CIa, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3 (-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. 30 Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 4-Brono-3 71 WO 00/42012 PCT/USOO/00648 (trifluoromethyl)aniline was converted into 4 -bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4 -bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3
-(
2 -(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea. 5 Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4 -chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(NN dimethylcarbamoyl)-4-pyridyloxy)aniline. 4 -Bromo-3-(trifluoromethyl)aniline was 10 converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method CIa, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4 (2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 92: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method 15 A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4
-(
4
-(
2 -(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3 (trifluoromethyl)aniline was converted into 4 -bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
4
-(
2 -(N-methylcarbamoyl)phenylthio)aniline to afford the 20 urea. Entry 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3
-(
4
-(
2 -(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3 25 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3
-(
4
-(
2 -(N-methylcarbamoyl)phenylthio)aniline to afford the urea. 30 Entry 94: 4
-(
2 -(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A1O. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo 3-(trifluoromethyl)phenyl isocyanate according to Method BI. According to Method CIa, 4 72 WO 00/42012 PCT/USOO/00648 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4 ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea. Entry 95: 4
-(
2 -(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to 5 Method A2. 4 -Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4 -Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2 methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4 -chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4 (2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. 10 Entry 96: 4
-(
2 -(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4 -Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4 -Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. 15 According to Method Cla, 4 -chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4
-(
2 -(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea. Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4 chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method 20 A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2 methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2 methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5 (trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4 chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N 25 methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea. Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3
-(-
2 -(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxv-5 30 (trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxv-5 (trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoronethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5 73 WO 00/42012 PCT/US0O/00648 (trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(N-methylcarbamoyl)-4 pyridyloxy)aniline to afford the urea. Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to 5 Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4 pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)pheny isocyanate according to Method Bl. 10 According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was 15 reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(NN dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl 20 isocyanate was reacted with 4-(2-(NN-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea. Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to 25 form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method Al. According to Method C3, 2-amino-3 methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniline to form the urea. 30 Entry 102: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5 -tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to 74 WO 00/42012 PCT/USOO/00648 Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea. Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method 5 A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2 methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea. 10 Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above: 15 Tables 20 The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables. 75 WO 00/42012 PCTIUSOO/00648 Table 1. 3-tert-Butylphenyl Ureas O RN N H H TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R ('C) (min.) Rr System [Source] Method 1 0.22 50% 418 A13 C3 NH EtOAc (M+H)+ - Me /50% (HPLC O hexane ES-MS) 2 0 0.58 50% 403 A13 C3 o EtOAc (M+H)+ Me /50% (HPLC hexane ES-MS) 3 0 133- 0.68 100% 448 A8 C2d NH 135 EtOAc (M+H)+ - Me (FAB) O-& OMe 5 Table 2. 5-tert-Butyl-2-methoxyphenyl Ureas R'N N H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R ('C) (min.) Rr System [Source] Method 4 0 5.93 448 A13 NH (M+H)+ BI - Me (HPLC Cla O- ES-MS) 5 120- 0.67 100% 478 A8 NH 122 EtOAc (M+H)+ C2d - Me (FAB) o OMe 6 0 0.40 50% 460 A3 EtOAc (M,-H)- C2d NH /50% (HPLC hexane ES-MS) 0 76 WO 00/42012 PCT/US00/00648 7 - 0.79 50% 446 Al2 O EtOAc (M+H)+ C2d NH /50% (HPLC hexane ES-MS) Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas F F F R'N N H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R ('C) (min.) Rr System [Source] Method 8 0 250 460 A13 NH (dec) (M+H)+ C2a - Me (FAB) 9 0 206- 0.54 10% 446 A3 step 0 208 MeOH (M+H)+ 2, NDMe /90% (HPLC A8 step CH2Cl ES-MS) 4, 2 B1, Cla 10 0 0.33 50% 445 A13 C3 O EtOAc (M+H)+ 1Me /50% (HPLC pet ES-MS) f ether 11 0 0.20 2% 461 A2 NH Et3N/ (M+H)+ C4 - Me 98% (HPLC O el N EtOAc ES-MS) 12 0 0.27 1% 447 A2
NH
2 Et3N/ (M+H)+ C4 99% (HPLC O N EtOAc ES-MS) 13 0 0.62 100% 461 A2 C2a NH EtOAc (M+H)+ - Me (FAB) 14 0 114- 0.40 1% 447 A2
NH
2 117 Et3N/ (M+H)+ C4
-
99% (FAB) -- a 0 N EtOAc 77 WO 00/42012 PCT/USOO/00648 15 0 232- 0.54 100% 490 A8 C2d NH 235 EtOAc (M+H)+ - Me (FAB) -& OMe 16 0 210- 0.29 5% 475 A5 Me NH 213 MeOH (M+H)+ BI Clc Me /45% (HPLC 0 N EtOAc ES-MS) /50% pet ether 17 0 187- 0.17 50% 495 A6 CI NH 188 EtOAc (M+H)+ BI Cla - Me /50% (HPLC O N pet ES-MS) / _ether 18 0 0.48 100% 475 A2 step Me NH 2 EtOAc (M+H)+ 4, (HPLC BI Cla 0 /N ES-MS) 19 0 194- 0.31 5% 475 A2 NH 196 MeOH (M+H)+ BI Cla Et /45% (HPLC O N EtOAc ES-MS) - /50% pet ether 20 0 214- 0.25 5% 495 A2 Cla Cl NH 216 MeOH (M+H)+ - Me /45% (HPLC O l N EtOAc ES-MS) /50% pet ether 21 0 208- 0.30 50% 481 A19 C2a 0 S:::0 210 EtOAc (M+H)+ - Me /50% (HPLC hexane ES-MS) 22 0 188- 0.30 70% 447 A15,
NH
2 190 EtOAc (M+H)+ step 4, /50% (HPLC Cla O Ihexane ES-MS) 23 0.50 70% 472 A3 o EtOAc (M+H)+ BI Cla NH /30% (FAB) hexane 0 24 0 Me 203- 0.13 100% 479 A2 BI N 205 EtOAc (M-H)+ Cla - Me (HPLC O N ES-MS) 78 WO 00/42012 PCT/US00/00648 25 0.09 75% 458 A12 O5EtOAc (M+H)+ C2d NH /25% (HPLC hexane ES-MS) 26 Me, 169- 0.67 50% 474 A13 N 171 EtOAc (M+H)+ step, 0 1 ~ / 50% (HPLC A13 step O Me pet ES-MS) 4, ether A16, B1 Cla 27 0 218- 0.40 50% 477 A2 step NH 219 EtOAc (M+H)+ 3b, 'Me /50% (HPLC A2 step S- N pet ES-MS) 4, N ether B1, Cla 28 212- 0.30 40% A9 O 214 EtOAc B1 Cla NMe /60% hexane 29 0 0.33 50% 474 A2 step NH EtOAc (M+H)+ 3b, - 'Me / 50% (HPLC A2 step S pet ES-MS) 4, / tether BI, Cla 30 0 210- A2 NH 211 B1 - Pr-i Cla 31 0 210- 0.43 10% A14 NH 204 MeOH B1 / Cla 0 / N CH2C1 D4 N 2 0 32 0 247- 0.57 10% A14 NH 249 MeOH B1 - Me /Cla O CH2C1 D4 - N2 33 0 217- 0.07 10% A14 NH 219 MeOH B1 Cla O N-ME CH2CI D4 N Me2 79 WO 00/42012 PCT/USOO/00648 34 0 0.11 70% All NH EtOAc BI / \ 0 \/30% Cif O N hexane Dic 35 F 0.38 70% All EtOAc B1 /30% Cif hexane Dlc N O N 36 0.77 70% All F / \ NH EtOAc BI 0 /30% Clf hexane Dlc - 0 37 Me, 0.58 70% All N NH EtOAc B1 Me' 0 /30% Clf hexane Dlc 38 N 0.58 70% All MeO NH EtOAc B1 0 /30% Cif hexane Dlc 39/\ 0.17 70% All 0 N NH EtOAc BI 0 /30% Cif hexane Dlc 40 N 0.21 70% All C N N - ' NH EtOAc BI 0 /30% Clf hexane Dlc Table 4. 3-(Trifluoromethyl)-4-chlorophenyl Ureas F F 0 c R' N N H H 80 WO 00/42012 PCT/USOO/00648 TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (*C) (min.) Rr System [Source] Method 41 0 163- 0.08 50% 464 A13 NH 165 EtOAc/ (M+H)+ C3 Me 50% pet (HPLC ether ES-MS) 42 0 215 0.06 50% 465 A2 NH EtOAc/ (M+H)+ Cla - Me 50% pet (HPLC O N ether ES-MS) 43 0 0.10 50% 451 A2
NH
2 EtOAc/ (M+H)+ Cla
-
50% pet (HPLC O N ether ES-MS) 44 0 0.25 30% 451 A2
NH
2 EtOAc/ (M+H)+ Cla 70% pet (HPLC O e l N ether ES-MS) 45 0 0.31 30% 465 A2 NH EtOAc/ (M+H)+ Cla - - 'Me 70% pet (HPLC O\ N ether ES-MS) 46 176- 0.23 40% 476 A3 0 179 EtOAc/ (M+H)+ Cla NH 60% (FAB) hexane 47 0.29 5% 478 A5 Me NH MeOH/ (M+H)+ Clc Me 45% (HPLC N EtOAc/ ES-MS) 50% pet ether 48 O 0 206- A 15 '-NH 209 Cla O Me 49 0 147- 0.22 50% 499 A6 CI NH 151 EtOAc/ (M+H)+ Cla Me 50% pet (HPLC O N ether ES-MS) 50 0 0.54 100% 479 A2 Me NH EtOAc (Mi-H)- Cla - - Me (HPLC 0 N ES-MS) 81 WO 00/42012 PCT/US0O/00648 51 0 187- 0.33 5% 479 A2 NH 189 MeOHI (M+H)+ Cla - Et 45% (HPLC O/ 0 N EtOAc/ ES-MS) 50% pet ether 52 0 219 0.18 5% 499 A2 Cl NH MeOH/ (M+H)+ Cla Me 45% (HPLC - NEtOAc/ ES-MS) 50% pet ether 53 0 246- 0.30 50% 485 A19, Cla o \ ,::: 248 EtOAc/ (M+H)+ Me 50% (HPLC Me _ hexane ES-MS) 54 0 196- 0.30 70% 502 A15 0 :::0 200 EtOAc/ (M+H)+ Cla - -a llNH 30% (HPLC Me' hexane) ES-MS) 55 0 228- 0.30 30% 466 0 230 EtOAc/ (M+H)+ - Me 70% (HPLC O CH2C12 ES-MS) 56 -N 0 238 56 a O NH Me 57 0 221- 0.75 80% 492 Cld q 222 EtOAc/ (M+H)+ Dla H - Me 20% (FAB) N hexane 58 247 0.35 100% Cld NH EtOAc Dla H - Me D2 59 0 Me 198- 0.09 100% 479 A2 N, 200 EtOAc (M+H)+ Cla - Me (HPLC O l N ES-MS) 60 MeO 158- 0.64 50% N 160 EtOAc/ 0 50% pet - 0 / Me ether .61 0 195- 0.39 10% A13 NH 197 MeOH/ Cla CH2Cl O N 2 82 WO 00/42012 PCTIUSOO/00648 62 0 170- 0.52 10% A13 NH 172 MeOH/ Cla CH2C1 O N 2 63 0 168- 0.39 10% A13 NH O 171 MeOH/ Cla CH2C1 0 2 64 0 Et 176- 0.35 10% A13 NH N 177 MeOH/ Cla CH2C1 O 2 65 0 130- 487 A2 NH 133 (M+H)+ BI - Me (HPLC Cla S l N ES-MS) 66 0 155 A2 NH Cla 0 - Pr-i 67 0 225- 0.23 100% Cle NH 229 EtOAc D3 H O' Me Dlb 68 234- 0.29 40% A9 O 236 EtOAc/ Cla NMe 60% hexane 0 69 0 0.48 50% 481 NH EtOAc/ (M+H)+ - Me 50% pet (HPLC S\ ether ES-MS) 70 0 0.46 5% 564 AlO NH MeOH/ (M+H)+ Cla 95% (HPLC - O N N CH2CI2 ES-MS) 0 83 WO 00/42012 PCT/US0O/00648 71 0 199- 0.50 10% A14 NH 201 MeOH/ Cla CH2C1 D4 0 N 2 N 0 72 0 235- 0.55 10% A14 NH 237 MeOH/ Cla - Me CH2C1 D4 O- 2 N 73 0 200- 0.21 50% A14 NH 201 MeOH/ Cla CH2C1 D4 O N-Me 2 N Me 74 0 145 NH 148 / O N I \/ OSi(Pr-i) 3 - N 75 N 0.12 70% 527 All NH EtOAc/ (M+H)+ Cif 0 30% (HPLC Dlc - hexane ES-MS) 76 0 0.18 70% All Me EtOAc/ Cif 30% Dlc hexane N O N 0 77 0.74 70% All F NH EtOAc/ Cif 0 30% Dlc hexane 78 Me 0.58 70% All N NH EtOAc/ Cif Me 0 30% Dlc hexane 84 WO 00/42012 PCTIUSOO/00648 79 O 0.47 70% 569 All NH EtOAc/ (M+H)+ Clf 30% (HPLC Dic 0 NH hexane ES-MS) 80 0 0.18 70% 508 All NH EtOAc/ (M+H)+ Clf 30% (HPLC Dic OMe hexane ES-MS) 81 N 0.58 70% 557 All MeO NH EtOAc/ (M+H)+ Clf O 30% (HPLC Dlc hexane ES-MS) 82 0.37 70% 611 All 0 N NH EtOAc/ (M+H)+ Clf 0 30% (HPLC Dlc hexane ES-MS) 83 0.19 70% All N EtOAc/ Clf 30% Dlc N hexane N O00 84 0 179- A2 NH 183 A17
-
Cla OHe D5 O /N OHCa Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas F F OBr R'N N H H 85 WO 00/42012 PCTIUSOO/00648 TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R ( C) (min.) Rr System [Source] Method 85 0 186- 0.13 50% 509 A2 NH 187 EtOAc/ (M+H)+ BI - Me 50% pet (HPLC ES- Cla O N ether MS) 86 0 150- 0.31 50% 545 A6 CI NH 152 EtOAc/ (M+H)+ BI - Me 50% pet (HPLC ES- Cla O N ether MS) 87 0 217- 0.16 50% 545 A2 Cl NH 219 EtOAc/ (M+H)+ BI Me 50% pet (HPLC ES- Cla 0 /ether MS) 88 0 183- 0.31 50% 525 A2 NH 184 EtOAc/ (M+H)+ BI Et 50% pet (HPLC ES- Cla o N ether MS) 89 0 0.21 50% 511 A2 NH EtOAc/ (M+H)+ BI - Me 50% pet (HPLC ES- Cla e N ether MS) 90 0 0.28 50% 525 A2 Me NH EtOAc/ (M+H)+ B1 'Me 50% pet (HPLC ES- Cla o N ether MS) 91 0 Me 214- 0.28 50% 522 A2 N 216 EtOAc/ (M+H)+ BI - Me 50% pet (HPLC ES- Cla O- ether MS) 92 0 0.47 50% 527 A2 step NH EtOAc/ (M+H)+ 3b, Me 50% pet (HPLC ES- A2 step S \,N ether MS) 4, Bi1, Cla 93 0 0.46 50% 527 A2 step NH EtOAc/ (M+H)+ 3b, - 'Me 50% pet (HPLC ES- A2 step S N ether MS) 4, BI, Cla 86 WO 00/42012 PCT/US0O/00648 94 0 145- 0.41 5% AlO NH 150 MeOH/ BI 95% Cla O N CH2C12 0 Table 6. 5-(Trifluoromethyl)-4-chloro-2-methoxyphenyl Ureas F F F O CI R' N N C1 H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (C) (min.) R, System [Source] Method 95 0 140- 0.29, 5% 495 A2 NH 144 MeOH/ (M+H)+ A7 - Me 45% (HPLC BI O N EtOAc/ ES-MS) Cla 50% pet ether 96 0 244- 0.39 5% 529 A6 Cl NH 245 MeOH/ (M+H)+ A7 - Me 45% (HPLC BI N EtOAc/ ES-MS) Cla 50% pet ether 97 0 220- 0.25 5% 529 A2 CI NH 221 MeOH/ (M+H)+ A7 - Me 45% (HPLC BI O N EtOAc/ ES-MS) Cla 50% pet ether 98 0 0.27 5% 495 A2 NH MeOH/ (M+H)+ A7 - Me 45% (HPLC BI O N EtOAc/ ES-MS) Cla 50% pet I ether '99 0 180- 0.52 5% 509 A2 NH 181 MeOH/ (M+H)+ A7 Et 45% (HPLC BI O \ 1 N EtOAc/ ES-MS) Cla
-
50% pet ether 100 0 162- A2 NH 165 A7 O Pr-i BI N Cla 87 WO 00/42012 PCT/US0O/00648 Table 7. Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R *C) (min.) R, System rSourcel Method 101 0 162- Al 0 NH 165 A2 JM C3 N Na OMeH H 102 0.10 50% 442 A2 0 0 EtOAc/ (M+H)+ A4 0 NH 50% (HPLC C2d N N - N Me hexane ES-MS) H H Me N Me 103 0 125- 0.24 40% 512 A2 HN NH 130 EtOAc/ (M+H)+ C2b 60% (FAB) hexane 0 0 O 0 NH-Me Me-NH 5 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. 0 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. 88

Claims (67)

1. A compound of Formula I: A-D-B (I) 5 or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L' )q , where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least 10 one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, 15 wherein L' is substituted by at least one substituent selected from the group consisting of -SO 2 Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, 20 Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is R 2 or NRaRb where Ra and Rb are 25 a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and 89 WO 00/42012 PCT/USOO/00648 carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rf) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted 5 by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 10 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a CI-C 5 divalent alkylene group or a substituted C 1 C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 15 members, wherein the substituents of the substituted Ci-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the 20 substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)NR 7 R 7 , -C(O)-R', -NO 2 , -OR 7 , -SR 7 , -NR 7 R', -N 7 C(O)OR 7 , -NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected 25 from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , -OR 7 , -SR, NR 7 R 7 , -NO 2 , -NR7C(O)R 7 , -NR'C(O)OR 7 and halogen up to per-halo; with each R' independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, 90 WO 00/42012 PCT/USOO/00648 wherein Q is -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -(CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa 2 -, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the 5 group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zi, wherein nI is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)R', -C(O)NR 7 R 7 , NO 2 , -OR 7 , - SR7 -NR R', -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally 10 substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R 7 , COR 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NO 2 , -NR 7 R 7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 , with R 7 as defined above.
2. A compound as in claim 1 wherein: 15 Ry is hydrogen, CI. 1 0 alkyl, C 1 . 1 0 alkoxy, C 3 . 10 cycloalkyl having 0-3 heteroatoms, C 2 . 1o alkenyl, C 1 . 1 0 alkenoyl, C 6 - 12 aryl, C 312 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 7 - 24 aralkyl, C 7 - 24 alkaryl, substituted C 1 . 1 0 alkyl, substituted C 1 . 1 0 alkoxy, substituted C 3 . 10 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, substituted C 6 -C 14 aryl, substituted C 3 . 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C 7 . 24 20 alkaryl or substituted C 7 -C 24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, Rz is hydrogen, C 1 . 1 0 alkyl, CI. 1 0 alkoxy, C 3 . 10 cycloalkyl having 0-3 heteroatom, C 2 -1o alkenyl, CI. 1 0 alkenoyl, C6- 1 2 aryl, C 3 -C 12 hetaryl having 1-3 heteroatoms selected from, S, N 25 and 0, C 7 . 24 alkaryl , C 7 - 24 aralkyl, substituted C 1 . 1 0 alkyl, substituted CI. 1 0 alkoxy, substituted C 6 -C 1 4 aryl, substituted C 3 -Cio cycloalkyl having 0-3 heteroatoms selected from S, N and 0, substituted C 3 . 12 hetaryl having 1-3 heteroatoms selected from S, N and 0, substituted C7. 4 alkaryl or substituted C 7 -C 2 4 aralkyl where Rz is a substituted group, it is substituted by halogen up to per halo, hydroxy, C 1 . 1 o alkyl, C 3 . 12 cycloalkyl having 0-3 heteroatoms selected o from 0, S and N, C. 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1 . 1 91 WO 00/42012 PCT/USOO/00648 alkoxy, C 6 - 12 aryl, CI- 6 halo substituted alkyl up to per halo alkyl, C 6 -C 1 2 halo substituted aryl up to per halo aryl, C 3 -C 12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and 0, halo substituted C 3 -C 1 2 hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from 0, N and S, halo substituted C 7 -C 24 aralkyl up to per 5 halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(O)Rg, Ra and Rb are, a) independently hydrogen, a carbon based moiety selected from te group consisting of C 1 -Clo alkyl, C 1 10 CIO alkoxy, C 3 . 10 cycloalkyl, C 2 -Io alkenyl, C 1 . 10 alkenoyl, C 6 - 12 aryl, C 3 - 1 2 hetaryl having 1-3 heteroatoms selected from 0, N and S, C 3 - 12 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, C 7 - 24 aralkyl, C7-C 24 alkaryl, substituted CI- 10 alkyl, substituted C1. 1 0 alkoxy, substituted C 3 - 1 0 cycloalkyl, having 0-3 heteroatoms selected from N, S and 0, substituted C 6 . 12 aryl, substituted C 3 - 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted 15 C 7 - 24 aralkyl, substituted C 7 - 24 alkaryl, where Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, C 1 . 1 0 alkyl, C 3 - 12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 3 - 12 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1 . 1 0 alkoxy, C 6 - 12 aryl, C 1 - 6 halo substituted alkyl up to per halo alkyl, C 6 -C] 2 halo substituted aryl up to per halo aryl, C 3 -C 12 halo substituted cycloalkyl having 0-3 heteroatoms 2o selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -CI 2 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(0)R9 ; or -OSi(R) 3 where Rf is hydrogen, CI. 10 alkyl, C 1 . 1 0 alkoxy, C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 - 12 aryl, C 3 -C 12 hetaryl having 1-3 5 heteroatoms selected from 0, S and N, C 7 - 24 aralkyl, substituted C 1.10 alkyl, substituted C 1 CIO alkoxy, substituted C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, substituted C 3 -C 12 heteraryl having 1-3 heteroatoms selected from 0, S, and N, substituted C 6 - 12 aryl, and substituted C 7 - 24 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo, hydroxy, CI. 1 o alkyl, C 3 . 1 2 cycloalkyl having 0-3 heteroatoms selected o from 0, S and N, C,.1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1 . 1 0 alkoxy, Ci2 aryl, C 7 -C- 4 alkaryl, C 7 -C 24 aralkyl, CI. 6 halo substituted alkyl up to per halo 92 WO 00/42012 PCT/USOO/00648 alkyl, C 6 -CI 2 halo substituted aryl up to per halo aryl, C 3 -C 12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -C 1 2 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and -C(O)Rg, 5 or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 with substituents selected from the group consisting of halogen up to per halo, hydroxy, C 1 .i 0 alkyl, C 3 - 12 cycloalkyl having 0-3 10 heteroatoms selected from 0, S and N, C 3 - 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1 . 1 0 alkoxy, C 6 - 12 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, halo substituted C, - 6 alkyl up to per halo alkyl, halo substituted C 6 -C 12 aryl up to per halo aryl, halo substituted C 3 -C 12 cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -C 12 hetaryl up to per halo heteraryl, halo substituted C 7 -C 2 4 aralkyl up to per 15 halo aralkyl, halo substituted C 7 -C 2 4 alkaryl up to per halo alkaryl, and -C(O)Rg, or c) one of Ra or Rb is -C(O)-, a CI-C 5 divalent alkylene group or a substituted Cj C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 20 members, wherein the substituents of the substituted C 1 -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, CI. 1 0 alkyl, C 3 - 12 cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 3 - 1 2 hetaryl having 1-3 heteroatoms selected from N, S and 0, C 1 . 1o alkoxy, C 6 - 1 2 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 1 . 6 halo substituted alkyl up to per halo 25 alkyl, C 6 -C 1 2 halo substituted aryl up to per halo aryl, C 3 -Ci 2 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and 0, up to per halo cycloalkyl, halo substituted C 3 -C 12 hetaryl up to per halo heteraryl, halo substituted C 7 -C 24 aralkyl up to per halo aralkyl, halo substituted C 7 -C 2 4 alkaryl up to per halo alkaryl, and -C(O)Rg, where Rg is CI. 1 0 alkyl; -CN, -CO 2 Rd, -OR 4 I, -SRd, -NO 2 , -C(O) Re, -NR,,R,. 30 NRd C(O)ORe and -NRd C(O)Re, and Rd and Re are independently selected from the group 93 WO 00/42012 PCT/USOO/00648 consisting of hydrogen, C 1 . 10 , alkyl, C 1 . 1 0 alkoxy, C 3 . 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, C 6 - 1 2 aryl, C 3 - C 1 2 hetaryl with 1-3 heteroatoms selected from 0, N and S and C 7 -C 24 aralkyl, C 7 -C 24 alkaryl, up to per halo substituted CI-Cio alkyl, up to per halo substituted C 3 -CIO cycloalkyl having 0-3 heteroatoms selected from 0, N and S, up to 5 per halo substituted C 6 -C 14 aryl, up to per halo substituted C 3 -C 1 2 hetaryl having 1-3 heteroatoms selected from 0, N, and S, halo substituted C 7 -C 24 alkaryl up to per halo alkaryl, and up to per halo substituted C 7 -C 24 aralkyl, W is independently selected from the group consisting of -CN, -CO 2 R 7 , -C(O)NR 7 R 7 , 10 -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , Ci-Co alkyl, CI-Co alkoxy, C 2 -Cio alkenyl, CI-C 1 o alkenoyl, C 3 -Cio cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 3 -C 12 heteroaryl having 1-3 heteroatoms selected from 0, N and S, C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted C 1 -C 10 alkyl, substituted C 1 -Ci 0 alkoxy, substituted C 2 -Cio 15 alkenyl, substituted C 1 -Clo alkenoyl, substituted C 3 -C 1 O cycloalkyl having 0-3 heteroatoms selected from 0, N and S, substituted C 6 -C 12 aryl, substituted C 3 -C 1 2 hetaryl having 1-3 heteroatoms selected from 0, N and S, substituted C 7 -C 24 aralkyl, substituted C 7 -C 24 alkaryl, substituted C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, and -Q Ar; 20 R 7 is independently selected from H, C 1 -C 10 alkyl, CI-Cio alkoxy, C 2 -Cio alkenyl, Ci CIO alkenoyl, C 3 -Cio cycloalkyl having 0-3 heteroatoms selected from 0, S and N, C 6 -C 4 aryl, C 3 -C 1 3 hetaryl having 1-3 heteroatoms selected from 0, N and S, C 7 -C 1 4 alkaryl, C 7 -C 24 aralkyl, C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, up to per 25 halosubstituted C 1 -C 1 0 alkyl, up to per-halosubstituted C 3 -C 10 cycloalkyl having 0-3 heteroatoms selected from 0, N and S, up to per-halosubstituted C 6 -C 14 aryl, up to per halosubstituted C 3 -C 13 hetaryl having 1-3 heteroatoms selected from 0, N and S, up to per halosubstituted C 7 -C 24 aralkyl, up to per-halosubstituted C7-C 24 alkaryl, and up to per halosubstituted C 4 -C 2 3 alkheteroaryl; and 0 94 WO 00/42012 PCTIUSOO/00648 each Z is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)R, -C(O)NR 7 R 7 , -NO 2 , -OR', - SR 7 -NR 7 R 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , C 1 -C 10 alkyl, Ci-CI 0 alkoxy, C 2 -Clo alkenyl, C 1 -C 10 alkenoyl, C 3 -Cio cycloalkyl having 0-3 heteroatoms selected from 0, N and S, C 6 -C 14 aryl, C 3 -C 3 hetaryl having 1-3 heteroatoms selected from 0, N and 5 S, C 7 -C 24 alkaryl, C 7 -C 24 aralkyl, C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N and S, substituted CI-Clo alkyl, substituted C 1 -C 10 alkoxy, substituted C 2 -Ci 0 alkenyl, substituted CI-Cio alkenoyl, substituted C 3 -Co cycloalkyl having 0-3 heteroatoms selected from 0, N and S, substituted C 6 -C 1 2 aryl, substituted C 7 -C 24 alkaryl, substituted C 7 -C 24 aralkyl and substituted C 4 -C 23 alkheteroaryl having 1-3 heteroatoms selected from 0, N 10 and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of -CN, -C0 2 R 7 , -COR 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NO 2 , -NR 7 R 7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 .
3. A compound as in claim I wherein M is one or more bridging groups selected 15 from the group consisting of -0-, -S-, -N(R')-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, (CH 2 )mS., -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa 2 , -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen and R 7 is as defined in claim 1.
4. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by-OH. 20
5. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
6. A compound of claim 1 wherein B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety 25 having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl moiety being carbon.
7. A compound of claim 1 wherein B of Formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W 3o and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from 95 WO 00/42012 PCT/USOO/00648 the group constituting of halogen and Wn, whereas W and n are as defined in Claim 1, or a substituted pyridyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1.
8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group, 5 a substituted pyrimidinyl group, or substituted pyrridyl group substituted 1 to 3 times by 1 or more substituents selected from the group consisting of -CN, halogen, C 1 -C 1 o alkyl, C 1 -Co alkoxy, -OH, up to per halo substituted CI-CIO alkyl, up to per halo substituted C 1 -CIO alkoxy or phenyl substituted by halogen up to per halo.
9. A compound of claim 1, wherein L, the six member cyclic structure bound 10 directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wn wherein W and n are as defined in 15 claim 1.
10. A compound of claim 8, wherein L, the 6 member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.
11. A compound of claim 1, wherein said substituted cyclic moiety L' comprises a 20 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.
12. A compound of claim 1, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.
13. A compound of claim 3, wherein said substituted cyclic moiety L' is phenyl, 25 pyridinyl or pyrimidinyl.
14. A compound of claim 6, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.
15. A compound of claim 8, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl. 96 WO 00/42012 PCT/USOO/00648
16. A compound of claim 9, wherein said substituted cyclic moiety L' is phenyl, pyridinyl or pyrimidinyl.
17. A compound of claim 10, wherein said substituted cyclic moiety L, is phenyl, pyridinyl or pyrimidinyl. 5
18. A compound of claim 14, wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, (CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by 10 halogen up to per halo.
19. A compound of claim 15, wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, (CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, 15 optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo.
20. A compound of claim 16, wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -N(R')-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, (CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where 20 m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo.
21. A compound of claim 17, wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, 25 (CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen and R 7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen up to per halo.
22. A compound of claim I wherein L' is additionally substituted 1 to 3 times by 30 one or more substituents selected from the group consisting of CI-Clo alkyl, up to per halo 97 WO 00/42012 PCTUSOO/00648 substituted C-Cio alkyl, -CN, -OH, halogen, C 1 -Cio alkoxy and up to per halo substituted Cl C 1 0 alkoxy.
23. A compound of claim 13 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -Cio alkyl, up to per halo 5 substituted C 1 -C 10 alkyl, -CN, -OH, halogen, C-Clo alkoxy and up to per halo substituted C 1 C 1 0 alkoxy.
24. A compound of claim 18 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -Cio alkyl, up to per halo substituted Ci-Co alkyl, -CN, -OH, halogen, C-Cio alkoxy and up to per halo substituted Cl 10 C 10 alkoxy.
25. A compound of claim 19 wherein L' is additionally substituted I to 3 times by one or more substituents selected from the group consisting of C-Co alkyl, up to per halo substituted CI-C 10 alkyl, -CN, -OH, halogen, C-C 1 o alkoxy and up to per halo substituted CI C 1 0 alkoxy. 15
26. A compound of claim 20 wherein L' is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -Cio alkyl, up to per halo substituted C 1 -Co alkyl, -CN, -OH, halogen, Cr-Cio alkoxy and up to per halo substituted C CIo alkoxy.
27. A compound of claim 21 wherein L' is additionally substituted I to 3 times by 20 one or more substituents selected from the group consisting of CI-Cio alkyl, up to per halo substituted CI-Cio alkyl, -CN, -OH, halogen, C-Cio alkoxy and up to per halo substituted C CIo alkoxy.
28. A compound of claim I wherein L' is substituted by -C(O)R .
29. A compound of claim I wherein L' is substituted by -SO 2 R,. 5
30. A compound of claim 1 wherein L' is substituted only by -C(O)R,
31. A compound of claim I wherein L1 is substituted only by -SO 2 R,.
32. A compound of claim I wherein Ll is substituted by -C(O)R, or -SO 2 R,, wherein R, is NRaRb. 98 WO 00/42012 PCT/USOO/00648
33. A compound of claim 13 wherein L' is substituted by -C(O)Rx or -SO 2 Rx, wherein Rx is NRaRb, and Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing 5 heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(R) 3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted 10 by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 15 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a CI-Cs divalent alkylene group or a substituted C 1 C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 20 members, wherein the substituents of the substituted CI-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.
34. A compound of claim 18 wherein L' is substituted by -C(O)Rx or -S0 2 Rx, 25 wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen. 99 WO 00/42012 PCTIUSOO/00648
35. A compound of claim 19 wherein L' is substituted by -C(O)R,, wherein R, is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, 5 which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.
36. A compound of claim 20 wherein L' is substituted by -C(O)Rx or -S0 2 Rx, wherein R, is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and 10 optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.
37. A compound of claim 21 wherein L' is substituted by -C(O)Rx or -S0 2 Rx, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety 15 of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen. 20
38. A compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L' )q , 25 where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L, contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and 100 WO 00/42012 PCT/USOO/00648 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting 5 of -SO 2 Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally 10 containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; R, is Rz or NRaRb where Ra and Rb are a) independently hydrogen, 15 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(R) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon 20 atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 25 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of R, or Rb is -C(O)-, a CI-C 5 divalent alkylene group or a substituted C: 30 Ci divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 101 WO 00/42012 PCTIUSOO/00648 members, wherein the substituents of the substituted CI-C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; 5 where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)NR 7 R 7 , -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , -NWR 7 , -NR 7 C(0)OR 7 , -NR 7 C(O)R 7 , -Q-Ar, and 10 carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , -OR 7 , -SR', NR 7 R 7 , -NO 2 , -NR 7 C(O)R 7 , -NR 7 C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally 15 containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -(CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the 20 group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by ZI, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , NO 2 , -OR 7 , - SR 7 -NR 7 R 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally 25 substituted by one or more substituents are selected from the group consisting of -CN, CO 2 R 7 , -COR 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NO 2 , -NR 7 R 7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 , with R 7 as defined above; and wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -(CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m 30 CH Xa-, -CXar, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen. 102 WO 00/42012 PCTIUSOO/00648
39. A compound of Formula I: A-D-B (I) 5 or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L' )q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, LI comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group 10 having at least one atom, q is an integer of from 1-3; and B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein L is substituted by at least one substituent selected from the group consisting of -SO 2 R,, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally 15 containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, and ; Rz is hydrogen .or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain 20 heteroatoms selected from N, S and 0 and are optionally substituted by halogen; R, is R, or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and 25 carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rr) 3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which 103 WO 00/42012 PCT/USOO/00648 optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 5 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a CI-C 5 divalent alkylene group or a substituted C 1 C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 10 members, wherein the substituents of the substituted C 1 -C 5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the 15 substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C0 2 R 7 , -C(O)NR 7 R 7 , -C(O)-R 7 , -NO 2 , -OR 7 , -SR 7 , -NR 7 R 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected 20 from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO 2 R 7, -C(O)R 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7, NR 7 R 7 , -NO 2 , -NR 7 C(O)R 7 , -NR 7 C(0)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, 25 wherein Q is -0-, -S-, -N(R 7 )-, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -(CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m- CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, and Xa is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, 30 up to per-halo, and optionally substituted by ZnI, wherein nl is 0 to 3 and each Z is 104 WO 00/42012 PCT/USOO/00648 independently selected from the group consisting of -CN, -CO 2 R 7 , -C(O)R 7 , -C(O)NR 7 R 7 , NO 2 , -OR 7 , - SR' -NR 7 R 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R 7 , 5 COR 7 , -C(O)NR 7 R 7 , -OR 7 , -SR 7 , -NO 2 , -NR 7 R 7 , -NR 7 C(O)R 7 , and -NR 7 C(O)OR 7 ; and wherein M is one or more bridging groups selected from the group consisting of -0-, -S-, N(R 7) -, -(CH 2 )m-, -C(O)-, -CH(OH)-, -(CH 2 )mO-, -(CH 2 )mS-, -(CH 2 )mN(R 7 )-, -O(CH 2 )m CHXa-, -CXa2-, -S-(CH 2 )m- and -N(R 7 )(CH 2 )m-, where m= 1-3, Xa is halogen.
40. A compound as in claim 38 wherein the cyclic structures of B and L bound 10 directly to D are not substituted in the ortho position by-OH.
41. A compound as in claim 38 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
42. A compound as in claim 39 wherein the cyclic structures of B and L bound 15 directly to D are not substituted in the ortho position by-OH.
43. A compound as in claim 39 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
44. A compound as in claim 38 wherein substituents for B and L and additional 20 substituents for L', are selected from the group consisting of CI-CIO alkyl up to per halo substituted CI-Cio alkyl, CN, OH, halogen, C 1 -C 10 alkoxy and up to per halo substituted Cj C 1 0 alkoxy.
45. A compound as in claim 39 wherein substituents for B and L and additional substituents for L', are selected from the group consisting of C 1 -CIO alkyl up to per halo 25 substituted CI-Cio alkyl, CN, OH, halogen, CI-Cio alkoxy and up to per halo substituted CI CIO alkoxy.
46. A compound of claim 38 wherein L' is substituted by C(O)Rx or SO 2 R,.
47. A compound of claim 39 wherein L' is substituted by C(O)R, or SO 2 R,.
48. A compound of claim 46 wherein R, is NRaRb and Ra and Rb are 30 independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally 105 WO 00/42012 PCT/USOO/00648 containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen..
49. A compound of claim 47 wherein R, is NRaRb and Ra and Rb are 5 independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen.
50. A compound of claim 1 which is a pharmaceutically acceptable salt of a 10 compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, 15 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic 20 substituted ammonium cations and aromatic substituted ammonium cations.
51. A compound of claim 2 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, 25 methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), I-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and 106 WO 00/42012 PCTUSOO/00648 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
52. A compound of claim 33 which is a pharmaceutically acceptable salt of a 5 compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, 10 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic 15 substituted ammonium cations and aromatic substituted ammonium cations.
53. A compound of claim 38 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, 2o methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and 5 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
54. A compound of claim 39 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of 107 WO 00/42012 PCTIUSOO/00648 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, 5 trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic 10 substituted ammonium cations and aromatic substituted ammonium cations.
55. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of formula I , and a physiologically acceptable carrier.
56. A pharmaceutical composition comprising a compound of claim 2 consistent 15 with fQrmula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
57. A pharmaceutical composition comprising a compound of claim 33 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 20
58. A pharmaceutical composition comprising a compound of claim 38 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
59. A pharmaceutical composition comprising a compound of claim 39 consistent with formula I or a pharmaceutically acceptable salt thereof and a physiologically 25 acceptable carrier.
60. A compound selected from the group consisting of 3-tert butyl phenyl ureas of Table 1 above; 5-tert butyl-2-methoxyphenyl ureas of Table 2 above; 108 WO 00/42012 PCT/USOO/00648 5-(trifluoromethyl)-2 phenyl ureas of Table 3 above; 3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above; 3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above; 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and 5 ureas 101-103 in Table 7 above.
61. A compound selected from the group consisting of the 3-tert butyl phenyl ureas: N-(3-tert-butylphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and N-(3-tert-butylphenyl)-N'-(4-(4-acetylphenoxy)phenyl urea; 10 the 5-tert-butyl-2-methoxyphenyl ureas: N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1-oxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(4-methoxy-3-(N 15 methylcarbamoyl)phenoxy)phenyl) urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea; the 2-methoxy-5-trifluoromethyl)phenyl ureas: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, 20 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea, 25 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridylthio)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea and 109 WO 00/42012 PCTUSOO/00648 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N '-(3 -chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea; the 4-chloro-3-(trifluoromethyl)phenyI ureas: 5 N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N '-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-chloro-3 -(trifluoromethyl)phenyl)-N '-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and N-(4-chloro-3 -(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamnoyl)-4-pyridyloxy)phenyl) 10 urea. the 4-romo-3-(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, 15 N-( 4 -bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4pyridyloxy)phenyl) urea, N-( 4 -bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbaxnoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N-methylcarbamoyl)(4 20 pyridyloxy))phenyl) urea and N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(3-chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)pheny ureas: 25 N-(2-methoxy-4-chloro-5'-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea., N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea, N-(2 -methoxy-4-chloro-5 -(tri fluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N o methylcarbamoyl)(4-pyridyloxy))phenyl) urea and NV-(2-methoxy-4-chloro-5-(tri fluoromethyl)phenyl)-N -(3-chloro-4-(2-(N methylcarbamoyl)(4-pyridyloxy))phenyl) urea. 110 WO 00/42012 PCTIUSOO/00648
62. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 1.
63. A method for the treatment of a cancerous cell growth mediated by raf kinase, 5 comprising administering a compound of Formula I of claim 33.
64. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 38.
65. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 39. 10
66. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of 3-tert butyl phenyl ureas of Table 1 above; 5-tert butyl-2-methoxyphenyl ureas of Table 2 above; 5-(trifluoromethyl)-2 phenyl ureas of Table 3 above; 15 3-(trifluoromethyl) -4 chlorophenyl ureas of Table 4 above; 3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above; 5-(trifluoromethyl)-4-chloro-2 methoxyphenyl ureas of Table 6 above; and ureas 101-103 in Table 7 above.
67. A method for the treatment of a cancerous cell growth mediated by raf kinase, 0 comprising administrating a compound selected from the group consisting of the 3-tert butyl phenyl ureas: N-(3-tert-butylphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl urea and N-(3-tert-butylphenyl)-N'-(4-(4-acetylphenoxy)phenyl urea; :5 the 5-tert-butyl-2-methoxyphenyl ureas: N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(I-oxoisoindolin-5-yloxy)phenyl) urea, 11 1 WO 00/42012 PCT/USOO/00648 N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(4-methoxy-3-(N methylcarbamoyl)phenoxy)phenyl) urea and N-(5-tert-butyl-2-methoxyphenyl)-N'-(4-(3-(N-methylcarbamoyl)phenoxy)phenyl) urea; 5 the 2-methoxy-5-trifluoromethyl)phenyl ureas: N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbanoyl)-4 pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea, 10 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridyloxy)phenyl) urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4 pyridylthio)phenyl) urea, 15 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea and N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea; 20 the 4-chloro-3-(trifluoromethyl)phenyl ureas: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea and 25 N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea; the 4-romo-3-(trifluoromethyl)phenyl ureas: N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) 30 urea, N-(4-bromo-3 -(tri fluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, 112 WO 00/42012 PCTUSOO/00648 N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(3 -( 2 -(N-methylcarbamoyl)-4-pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-( 2 -chloro-4-(2-(N-methylcarbamoyl)(4 pyridyloxy))phenyl) urea and 5 N-(4-bromo-3-(trifluoromethyl)phenyl)-N '-(3 -chloro- 4 -(2-(N-methylcarbamoy)(4 pyridyloxy))phenyl) urea; and the 2-methoxy-4-chloro-5-(trifluoromethyl)pheny ureas: N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(3-(2-(N-methylcarbamoyl)-4 10 pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4. pyridyloxy)phenyl) urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N methylcarbamoyl)(4-pyridyloxy))phenyl) urea and 15 N-(2-methoxy-4-chloro-5-(trifluoromethy)pheny)-N'(3choro4(2-(N methylcarbamoyl)(4-pyridyloxy))phenyl) urea. 113
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