CA2549558C - 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
CA2549558C
CA2549558C CA2549558A CA2549558A CA2549558C CA 2549558 C CA2549558 C CA 2549558C CA 2549558 A CA2549558 A CA 2549558A CA 2549558 A CA2549558 A CA 2549558A CA 2549558 C CA2549558 C CA 2549558C
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Prior art keywords
substituted
phenyl
acid
heteroatoms selected
halogen
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CA2549558A
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French (fr)
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CA2549558A1 (en
Inventor
Bernd Riedl
Jacques Dumas
Uday Khire
Timothy B. Lowinger
William J. Scott
Roger A. Smith
Jill E. Wood
Mary-Katherine Monahan
Reina Natero
Joel Renick
Robert N. Sibley
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Bayer Healthcare LLC
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Bayer Healthcare LLC
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Priority claimed from CA002359510A external-priority patent/CA2359510C/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • 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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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C275/32—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
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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
    • C07C275/36—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 with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
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    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • 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
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Abstract

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.

Description

' ' 69676-8D
w-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors This is a divisional application of Canadian Patent Application No. 2,359,510 filed on January 12, 2000.
Field of the Invention 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 p2lras oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 300 of all human cancers (Bolton et al. Ann. Rep.
Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al.
Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer Biol. 1994, 5, 247-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-expression of dominant negative raf kinase or dominant negative MEK, the substrate of ' ' 69676-8D

raf l:inase, leads to the r°version of transformed cells to the norn~al gro~~t phenotype !.~ee~
Daum et a1. 1 rends Biocnem. ~ci. 1994, 19, 4?4-80; i-ridman et al. J. Biol.
Cnem. 1994, ?69, 36106-8. k~olch et a1. (l~'azure 1991, ~~9, 426-~'8) have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncooenes.
Similarly, inhibition of raf kinase (by antisense oligodeoxynucieotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., ~r'at_ Med. 1996, ?, 668-76).
Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase.
Since the en..,~yme is a downstream effector of p21'~5, the inhibitors are useful in pharmaceu~~ical 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 ~5 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., 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 ?~ mammals. Thus, the invention is directed to compounds which inhibit the en:
yme 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 then eof.
f ' ' 69676-8D
According to one aspect of the parent application, there is provided a compound selected from the group consisting of:
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, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, 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, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and 2a r ' ' 69676-8D
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
According to one aspect of the present divisional application, there is provided a compound of Formula (I):
A-D-B ( I ) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, 2b t 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 I-3; and each cyclic structure of L and L' 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, wherein L' is substituted by at least one substituent selected from the group consisting of -SOzRx, -C(O)Rx arid -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 O and optionally halosubstituted, up to per halo, RZ is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteraatoms 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;
RX is RZ or NReRb where Re and Rb are a) independently hydrogen, 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 O and are optionally substituted by halogen, or -OSi(Rr)3 where R~ is hydrogen or a carbon based moiety of up to 24 carbon ?5 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 O and are optionally substituted by halogen; or r WO 00!42012 PCT/US00/00648 b) Ra and Rb together form a 5-7 member heterocyclic structure of I-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, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C{0)-, a C~-CS divalent allcylene group or a substituted C,-CS divalent alkylene group bound to the moiety L to forma cyclic structure with at least 5 members, wherein the substituents of the substituted Ct-CS 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 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, -C02R', -C(O)NR'R', -C(O)-R', -N02, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -COzR', -C(O)R', -C(O)NR'R', -OR', -SR', -2o NR'R', -NOz, -NR'C(0)R', -NR'C(O)OR'. 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 O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R')-, -(CHZ)m-, -C(O)-, -CH(OH)-, -(CHZ)m0-, -(CHz)mS-, -{CHz)mN(R')-, -O(CHz)m CHXa-, -CXa2-, -S-(CHZ)m and -N(R')(CH2)m-, where m= 1-3,.
and Xa is halogen; and Ar is a S- 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 Zn~, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO~R', -C(O)R , -C(O)NR-R .
;~JO~, -ORS, - SR' -NR'R'. -NR'C(O)OR', -NR'C(O)R', and a carbon based moiety of up t«
-t t ' 69676-8D
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, -COzR~, -CORD, -C (0) NR~R7, -ORS, -SRS, -NOz, -NR~R~, -NR~C (0) R~, and -NR'C (0) OR', with R' as defined above, with a proviso that the compound is not a compound selected from the group consisting of:
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, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, 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, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, r ' ' 69676-8D
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
5a r ' 69676-8D
In formula I, suitable hetaryl groups include, but are not limited to, ~~-12 carbon-atom aromatic rings or ring systems containing i-'' -inks, at least one of which i~
aromatic, in which one or mare, 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 e~:ample, B can be 2- or 3-furyl, 2- or 3-thienyl, Z- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or S-imidazolyl, 3-,.4- or S-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or ~-isoxazolyl, 2-, 4- or S-thiazolyl, ~-, 4- or S-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -~-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or S-tetrazolyl, 1,2,3-oradiazol-4- or.
-5-yl, 1,2,4-oxadiazol-3- or -S-yl, 1,3,4-thiadiazol-2- or -S-yl, 1,2,4-oxadiazol-3- or -S-yl, 1,3,4-Jo thiadiazol-2- or -S-yl, 1,3,4-thiadiazol-3- or -S-yl, 1,2,3-thiadiazol-4-or -5-yl, 2-, 3-, 4-, S-or 6-?H-thiopyranyl, 2-,. 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, S-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, S-, 6- or 7-indolyl, 1-, ?-, 4- or S-benzimidazolyl, 1-, 3-, 4-, S-, 6- or 7-benzopyrazolyl, ?-, 4-, S-, 6-or 7=benzoxazolyl, 3-, 4-, S- 6-~or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, S-, 6'- or 7-b~nzisothiazolyl, 2-, 4-, S-, 6- or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoIinyl, 1-, 3-, 4-, S-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-; 4- or g-carbazolyl, 1-, 2-, 3-, 4-, S-, 6-, 7-, B-or 9-acridinyl, or 2-, 4-, S-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyi, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or S-thiazolyl, etc. For example, B can be 4-methyl-phenyl, S-methyl-2-thienyl, 4-methyl-2-thienyl, 1-?o methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or S-methyl-1,2,4-thiadiazol-2-y 1.
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, rert-butyl, etc.
? 5 Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl.
5b r ' ~~676-8 The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C9 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.
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, 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, furmaric acid, malefic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+, Na+ or K+), alkaline earth cations (e . g. , Mg+2, Ca+2 or Ba~2) , the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium _ ..676-8 cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane {DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
According to another aspect of the present invention, there is provided a compound selected from the group consisting of: 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, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3 (trifluoromethyl)phenyl) -N'- (2-chloro-4- (2- (N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N- (4-bromo-3- (trifluoromethyl) phenyl) -N' - (3- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N- (4-bromo-3- (trifluoromethyl)phenyl) -N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, 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, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-6a ' ..676-8 methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.
6b r WO 00/42012 PCT/US00l0064S
General Pr~arative 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 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, 3'd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic 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 Hz 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 LiAIH4 (Seyden-Penne.
Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH
Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3'd Ed.;
John Wiley: New York (I985). Larock. Comprehensive Organic Transformations;
VCH
Publishers: New York (1989)).
H2 / catalyst (eg. Ni, Pd, Pt) ArN02 ~H ~ ~ ArNH2 (eg. Fe, Sri, Ca) Scheme 1 Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using H'VO:, or an alternative N0~ source. Nitroaryls may be further elaborated prior to reduction. Thus.
nitroanUs substituted with WO 00!42012 PCT/US00/00648 Ar-H '- ArNOz 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).
OzN .
ArSH
base t' ~ ~ S-Ar OzN R/-\ Br-Ar j~SH
Cu0 / base 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 (Suzuki reactions, exemplified below), aryltins (Stifle reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
OzN ArB(OR')2 O2N
Pd 0 ~ j \ Ar R

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 source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyi trif7uoromethane in the presence of a fluoride source, such as tris(dimethylarnino)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 CHC1F~ in the WO 00!42012 PCT/US00/00648 presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.
Zh. Org. Khim. 1970, 6, (Sb8).

i KF
Zn(Hg) R 8 ~~ R 10 (Me2N)3S Me3SiF2 CHCIF2 Me3SiCF3 base S02CF3 SCHFZ .
~ ~ R 9 W ' R 11 Iol /, v 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 o 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 subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.
Are-NH2 13 COCI2 .
H2N-Ar2 Are-NCO, -T Ar~~N~N.A~

O O
ArI~X Ar~~OH
16 . 17 Scheme 1V 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, parenteraily, 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.
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 'u preparations. Tablets contain the active ingredient in admixture with non-twit pharmaceutically acceptable excipients which are suitable for the manufacture oi' tshlrts.
These excipients may be, for example, inert diluents, such as calcium carbonate. sodium ' t0 WO 00/4201'_ PCT/US00/00648 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 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 to ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate_ or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylerle oxide with fatty acids, for example polyoxyethylene stearate, or condensation 2o products of ethylene oxide with long chain aliphatic aleohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the ~u addition of water provide the active ingredient in admixture with a dispersing or wetting a'cnt, suspending a'ent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.
Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be l0 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 ail or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal 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 glycois.
For all regimens of use disclosed herein for compounds of Formula I, the daily ural ~fosayc regimen will preferably be from O.OI to ?00 mg/Kg of total body weight. The daily ~iosa=;c 65~ 76-8 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 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 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, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.

~ ,~ 6_ ~ ~6-8 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 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 13a are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at t 0 approximately 1 S 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.
Commercial grade reagents and solvents were used without further purification.
N
cyclohexyl-N'-(methyipolystyrene)carbodiimide was purchased from Calbiochem-Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline 2-methoxy-5-(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)-1-nitrobenzene (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761 b), 3-tert-butylphenyl isocyanate (0. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trifluoromethyI)phenyl isocyanate (K. Inukai et al. 3P 42,025,067; IBID Kogyo Kagaku ZCiSS~II 70, 1967, 491 ) have previously been described.
Thin-layer chromatography (TLC) was performed using Whatmanq~ pre-coated glass-backed silica gel 60A F-254 250 um plates. Visualization of plates was effected by one or more of~
ths: foliowin~ techniques: (a) ultraviolet illumination, {b) exposure to iodine vapor. (c) WO 00/42012 PCT/L~S00/00648 immersion of the plate in a IO% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, andior (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science' silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer.
l0 Proton (tH) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or residual protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO b 2.49) as standard.
Carbon (~3C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 b 77.0; MeOD-d3; b 49.0; DMSO-db b 39:5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra.
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Paekard 5989A mass spectrometer equipped with a Vaeumetrics Desorption Chemical Ionization Probe for sample introduction.
The ion source was maintained at 250 °C. Electron impact ionization was performed with zo electron energy of 70 eV and a trap current of 300 uA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of .fast atom bombardment were obtained using a Kratas 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 ( I x 10'~ torr to 2.5x 10'' torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held, at l0.amps until all traces of the sample disappeared ( --1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable waselen~th detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray .o ionization. Spectra were scanned from 1?0-800 amu using a variable ion time accouin~; to the number of ions in the source. Gas chromatography - ion selective mass spectral I<~C-~15t i5 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an methyl silicone column (0.33 mM coating; 25 m x 0.2 mrn) and a Hewlett Packard Mass Selective Detector (ionization energy 70 eV), Elemental analyses are conducted by Robertson Mierolit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS
consistent with assigned structures.
. List of Abbreviations and Acronyms:

AcOH acetic acid anh anhydrous atm atmospheres) BOC tert-butoxycarbonyl CDI , l,i'-carbonyl diimidazole cone concentrated d days) dec decomposition DMAC N,N dimethylacetamide .

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2o DMF N,N dimethylformamide DMSO dimethylsulfoxide ' .

DPPA diphenylphosphoryl azide EDCI 1-{3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) EtZQ diethyl ether Et3N triethylamine h hours) HOBT 1-hydroxybenzotriazole .o m-CPBA 3-chloroperoxybenzoic acid :~teOH methanol pet. Lther petroleum ether (boiling range 30-60 C) temp. temperature THF tetrahydrofuran TFA trifluoroAcOH
Tf trifluoromethanesulfonyl S
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.
COzMe OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (I0.1 g, 50.1 mmol) and KzC03 {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.
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 NaCI
solution (100 mL), dried (MgS04), 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-d6) S 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J--8.09 Hz, 1H), 7.44 (s, 1 H), 7.53 (app t, J--8.09 Hz, 1H), 7.84 (d,.l--8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
f /

OMe Step 2. 3-Methoxy-Z-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL1 in MeOH ( 100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 3s.-1 mmol).
The mixture was heated at the re flux temp. for 3 h, cooled to room temp., an~i ma~l~ amlic with a l0°,'o citric acid solution. The resulting solution was e~ttracted with EtO.ar t'_' v 1~»~
n WO OO14201? PCT/US00/00648 mL). The combined organic layers were washed with a saturated NaCI solution, dried {MgSOa) 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-d6) b 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 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).
O
W
y.
OMe Step 3. ?-{N-(Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-metlioxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6 mmol) in anh toluene ~ (70 mL) was stirred at . room temp. for 15 min., then treated with a 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. ARer cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 rnmol)wvas 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 saturated NaCI solution, dried (MgS04) 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-db) b 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 {s, 1 H), 8.76 (s, 1H).
_ . 1 w ~I
NHZ
OMe Step 4. 2-Amino-3-methoxynaphthalene-A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10°!0 Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a Hz atrn (balloon) at room temp.
overni;ht. The resulting mixture was filtered through Celite~' and concentrated under reduced pressure to give , Z-amino-3-methoxynaphthalene as a pale pink powder ('_.-10 g.
~8 WO 00/4201? PCT/L1S00100648 85%): ~H-NMR (DMSO-db) 8 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.I6 (m, 2H), 7.43 (d, J--8.0 Hz, 1H), 7.56 (d, J--8.0 Hz, 1H); EI-MS m/z 173 (M+).
A2. Synthesis of w-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis .of, 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline O
CI ~ NHMe ~N
Step la. Synthesis of 4-chloro-IV methyl-2-pyridinecarboxamide via the Menisci reaction to 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.
HZSOa (3.55 mL) to generate an exotherm. To this mixture was added HZ02 (30%
wt in HzO, 17 mL) followed by FeS04~7HZ0 (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 Hi0 (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 NaCI solution (3 x 150 mL), then they were combined, dried (MgS04) and filtered througli,a pad of silica gel with the aid of EtOAc. The 2o resulting brown oil was purified by column chromatography (gradient from 50% EtOAcl50%
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; iH NMR (CDC13) 8 3.04 (d, J--5.1 Hz, 3H), 7.43 (dd, J--5.4, 2.4 Hz, 1H), 7.96 (br s, 1 H), 8.21 (s, 1H), 8.44 (d, ,l--5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).
O
CI ~ CI
I
~ N HCI
Step 1 b. Sythesis of 4-chforopyridine-2-carbonyl chloride HC! salt via picolinic acid WO 00/42012 PCT/US00/006~18 Anhydrous DMF (6.0 mL) was slowly added to SOCIz (180 mL) between 40°
and 50 °C.
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 SOZ evolution) for 16 h to generate a yellow solid precipitate. 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 (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°!°).
O
C! w -OMe ~ N HC!
Step 2. Synthesis of methyl 4-chloropyridine-2-carboxyiate HCl salt Anh DMF (10.0 mL) was slowly added to SOCl2 (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 SOz evolution) for 16 h to 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.
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 EtZO (200. mL) dropwise. The resulting solids were filtered, washed with Et~O (200 mL) and dried under reduced pressure at .35 °C to provide methyl 4-chloropyridine-2-z5 carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 °C;
'H-NMR (DMSO-db) b 3.88 (s, 3H); 7.82 (dd, J--5.5, 2.2 Hz, 1H); 8.08 (d, J--2.2 Hz, 1H); 8.68 (d, J--5.5 Hz, 1 H);
10.68 (br s, 1H); HPLC ES-MS m/~ 172 ((M+H)+).

O
NHMe ~N
Step 3a. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 428 mmol) in 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 NaCI solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C;
tH-NMR (DMSO-d6) 8 2.81 (s, 3H), 7.74 (dd, J--5.1, 2.2 Hz, 1 H), 8.00 (d, .I--2.2, 1 H), 8.61 (d, J--5.1 Hz, 1 H), 8.85 (br d, 1H); CI-MS m/z 171 ((M+H)+).
O
NHMe ~N
Step 3b. Synthesis of 4-chloro-N methyl-2-pyridinecarboxamide from 4-ehloropyridine-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 2o was washed with a saturated NaCI solution (2 x 100 mL), dried (Na2SOa) 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.
O
O
NHMe w <

Step 4. Synthesis of 4-(2-{N methylcarbamoyl)-4-pyridyloxy)aniline 3s A solution of ~-aminophenol (9.60 g, 88.0 mmol) in anh. DMF ( 150 mL) was treated with potassium rent-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at WO 00/4207? PCT/US00/00648 room temp, for 2 h. The contents were treated with 4-chloro-N methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K~C03 (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 EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI
solution (4 x 1000 mL), dried (Na2S04) 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%): 1H-NMR (DMSO-d6) s 2.77 (d, J--4.8 Hz, 3H), S.I7 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, J--8.4 Hz, 4H), 7.06 (dd, J--5.5, 2.5 Hz, l0 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 mh 244 ((M+H)+) A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of S-(4-Aminophenoxy)isoindoline-1,3-dione O
j ~NH
HO
O
Step 1. Synthesis of S-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, 2?.45 mmol). The resulting mixture was heated 2o at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for ? 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 1N NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a 1N HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%):
'H NMR
(DMSO-d6) 8 7.00-7.03 (m, 2H), 7.56 (d,J--9.3Hz, IH).
zz I \ 0 I \
OzN ~ O
NH

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 yellow-green mixture was allowed to return to room temp. and was stirred for 1 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 (MgS04) and concentrated under reduced pressure to give 5-{4-to nitrophenoxy)isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30%
EtOAc/70%
hexane) R~ 0.28; 1H NMR (DMSO-d6) 8 7.32 (d, J--12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89(d, ,~7.8 Hz, I H), 8.29 (d, J--9 Hz, 2H), 1 I .43 (br s, 1H); CI-MS m/z 285 ((M+H)+, 100%). , HZN ~ O
NH
O
Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-I,3-dione A solution of 5-(4-nitrophenoxy)isoindoline-1,3-dione (0.6 g, 2.11 mrnol) 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 SO mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give S-(4-2o aminophenoxy)isoindoline-I,3-dione as a brownish solid (0.4 g, 75%): TLC
(50%
EtOAc/SO% hexane) Rf 0.27; 'H NMR (DMSO-db) 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,.lH), 7.23 (dd, 1H), 7.75 (d, J
8.4 Hz, 1H), 11.02 {s, 1 H); HPLC ES-MS m/z 255 ((M+H)+, 100%).
?, A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline .

N
Step 1. Synthesis of l-(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 (I0 mL) was added AcOH (O.ImL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The 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 CH2Clz (10 mL) and sequentially washed with a 1N HCl solution (15 mL), a 1N NaOH solution (15 mL) and a saturated NaCI
solution (lSmL), dried ( MgS04) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g Si02;
gradient from 6%
l0 EtOAc/94% hexane to 25% EtOAc/75% hexane} to give 1-(4-tert-butyl-2-nitrophenyl}-2,S-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/8S%
hexane) Rf 0.67; ~ H NMR (CDCl3) d 1.34. (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1 H), 7.62 (dd, 1H), 7.88 (d, .I--2.4 Hz, 1H); Cl-MS m/z 273 ((M+H)+, 50%).
NHZ
N
Step 2. Synthesis of 5-tent-Butyl-Z-(2,5-dimethylpyrroiyl)aniline A slurry of 1-{4-tert-butyl-2-nitrophenyl)-2,S-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (O.OS6 g) and EtOAc (SO mL) under an HZ atmosphere {balloon) was stirred for 72 h, then filtered through a pad of Celite~. The filtrate was concentrated under reduced pressure to give S-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf0.43; ~H NMR (CDC13) b 1.28 (s, 9H), 1.87-1.91 (m. 8H). x.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, .1H}.

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 NHMe H2N ~ v . W N
HCI
Me 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 l0 water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (MgSO.,) and concentrated under reduced pressure. The residual black oil was treated with Et~O (50 mL) and sonicated. The solution was then treated with HCl ( 1 M in Et20; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by ..
filtration from solution and stored under anaerobic conditions at 0 °C
prior to use: ~ H NMR
(DMSO-d6) 8 2.41 (s, 3H), 2.78 (d, J--4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, .I--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, .~8.8 Hz, LH), 8.55 (d, J--5.9 Hz, 1H), 8.99 (q, J--4.8 Hz, 1H).
2o A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N
Protection, Nucleophiiic Aromafric Substitution and Deprotection.
Synthesis of 4-{2-(N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline a I ~ off Step 1: Synthesis of 3-Chloro-4-{2,2,2-trifluoroacetylamino)phenol ?s Iron (3.?4 ', 58..00 mmol) was added to stirring TFA (200 mL). To this slurry was added ?-chloro--l-nitrophenol ( 10.0 g. 58.0 mmol) and trifluoroacetic anhydride (?0 mL). This =~rsv slurn~ was stirred at room temp. for 6 d. The iron was f ltered from solution and the WO 00/d201? PCT/IJS00/00648 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 NaHCOz 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 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 NaCI solution {125 mL), dried (MgS04) and concentrated under reduced pressure. The'H NMR (DMSO-d6) 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 to was taken on to the next step without further purification.
O
O I ~ NHMe ~N .
CI
Step 2: Synthesis of 4-(2-(N Methyicarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chIoro-4-{2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 rmmol) in is 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 2o 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).
O
O ~ NHMe ~ ,N
HzN C) Step 3. Synthesis of 4-(2-(N-~tethylcarbamoyl)-4-pyridyloxy)-2-chloroaniline 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 nnL) was treated with a 1N
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) and the solvent was concentrated to yield 4-(2-{N Methylcarbamoyl)-4-pyridylox,y)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR
(DMSO-d6) 8 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, 1 H), 7.03 (d, ,I--8.5 Hz, 1 H), 7.07 (dd, J--5.5, 2.6, Hz, 1 H), 7.27 (d, J--2.6 Hz, 1 H), 8.46 (d, J--5.5 Hz, 1H), 8.75 (q, J--4.8, 1H).
to A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline CI
NHz OMe A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoroniethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCI solution (2.4 mL) was heated at the reflux temp. for 1 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 NaHC03 solution until the solution was basic. The organic layer was extracted with CHZClZ (3 x 50 mL). The combined organics were dried (MgS04) and concentrated under reduced pressure to yield 4-chloro-2-methoxy-5-(trifluoromethyl)aniline as a brown oil (3.20 g, 14.2 mmol): 'H
NMR (DMSO-d6) b 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of co-Alkoxy-co-carboxyphenyl Anilines.
Synthesis of 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline.
O
O
OMe OZN ~OMe Step 1. 4-(3-Ntethoxycarbonyi-4-methoxyphenoxy)-1-nitrobenzene:

WO 00/4201?

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 KZC03 (5 g) and dimethyl sulfate (3.5 mL).
The resulting mixture was heated at the reflux temp. overnight, then cooled ,to room temp. and filtered through a pad of Celite~. The resulting solution was concentrated under reduced pressure, absorbed onto SiOz, and purified by column chromatography (SO% EtOAc 'i SO%
hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g): mp 11 S-118 °C.
O
O
\ ~ ~ % off OZN OMe 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 (SO mL), and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was-dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (1.04 g).
O
O
\ I . , % NHMe 02N OMe Step 3. 4-{3-(N Methylcarbantioly)-4-methoxyphenoxy)-1-nitrobenzene:
To a solution of 4-(3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CI-hCl2 (12 mL) was added SOC12 (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 CHZC12 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 ?s mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a 1 N NaOH solution, then extracted with CH~C1~ (? S mL).
z8 The organic layer was dried (Na2S04) and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene as a yellow solid (0.50 g, 95%).
O
O
I j NHMe H2N OMe Step 4. 4-(3-(N Methylcarbamoly)-4-methoxyphenoxy)aniline:
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 (SS mL) was stirred under 1 atm of HZ
(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% Et3N/99.9% EtOAc) Rf0.36.
to A9. General Method for Preparation of w-Alkylphthalimide-containing Anilines. Synthesis of 5-(4-Aminopheiaoxy}-2-methylisoindoline-1,3-dione O
O
N-Me OZN
O
Step '1. Synthesis of 5-(4-Nitrophenoxy)-2-methylisoindoline-1,3-dione:
A slurry of S-(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-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
O
O
~ I I r N-Me O

WO 00/420i2 PCT/US00/00648 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~ (balloon) overnight. The resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure.
The resulting yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si02 (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) Rf0.27.
A10. General Method for Synthesis of co-Carbamoylaryl Anilines Through to Reaction of w-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-{2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline O
CI
~O
N NON
Step 1. Synthesis of 4-Chloro-2-(N (2-morpholin-4-ylethyl)carbamoyl)pyridine ~5 To a solution of methyl 4-chloropyridine-2-carboxylate HCI 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 (MgS04)- and concentrated under reduced pressure to 3o afford 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil ( 1.25 g, 95%): TLC ( 10% MeOH/90% EtOAc) R~ 0.50.
O
O
~ N N~N

Step 2. Synthesis of 4-(?-(N {2-Morphoiin-4-ylethyl)carbamoyI)pyridyloxy)an iline.
A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 moI) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-chIoro-2-(N {2-mozpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and (0.31 g, 2.Z6 mmol). The resulting mixture was heated at 75 °C
overnight, cooled to room temp., and separated between EtOAc (2S mL) and a saturated NaC1 solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCI solution (3 x 2S mL) and concentrated under reduced pressure.
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) Rf0.32.
A11. General Method for the Reduction of Nitroarenes to Arylamines, Synthesis of 4-(3-Carboxyphenoxy)aniline.
O
O OH

A slurry of 4-(3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10%
Pd/C (0.50 g) in MeOH (120 mL) was stirred under an Hz atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of CeIite~, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10%
MeOH/90%
CH~CIz) Rf 0.44 (streaking).
A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.
Synthesis of 4-(1-~xoisoindotin-5-yloxy)aniline.
HO
~NH
O

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 repeated on the same scale and the combined oily residue was purified by column chromatography (l.l Kg SiOz; gradient from 60% EtOAc/40% hexane to 25%
MeOH/7~%
EtOAc) to give S-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf0.17;
HPLC ES-MS mlz 1S0 ((M+H)+).
O
I , ~ I NH
OzN
O
to Step 2. Synthesis of 4-{1-isoindotinon-5-yloxy)-1-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added S-hydroxyisoindolin=1-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 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) Rf0.35.

I , ~ I NH

O
Step 3. Synthesis of 4-{1-oxoisoindolin-5-ytoxy)aniline A slurry of 4-(1-isoindolinon-S-yloxy)-1-nitrobenzene (2,12 g, 7.8 mmol) and i0% Pd/C
(0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of CeIite~. The filtrate was concentrated under reduced pressure to afford 4-( 1-oxoisoindolin-S-yloxy)aniline as a dark yellow solid: TLC ( 100% EtOAc} Rf 0.15.
A13. General Method for the Synthesis of co-Carhamoyt Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-(3-N Methytcarbamoylphenoxy)anitine.

O
O ~ OEt 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, 150 mmol) and KZC03 (41 g, 300 mrnol) 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 NaCI solution (2 x 100 mL), dried (Na~S04) and concentrated under reduced pressure. The residue was purified by column chromatography (IO% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g)~

OH
~ r w t5 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~H20 (1.50 g, .35.8 mmol) in water (36 mL). The resulting mixture was heated at SO °C
overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1 M HCl solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-I-nitrobenzene (4.40 g, 95%).
.O
NHMe 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~HC1 (3.63 ~, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmoI) in CH~Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under 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 NaCI
solution (50 mL), dried (Na2SOa), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil {1.89 g).
O
O ~ NHMe ~ i w 1 HZN
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 mmoI) and S%
Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an HI atm (balloon) overnight. The resulting mixture was filtered through a pad of Celite~ and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95%
CH2Clz).
The resulting oil solidified under vacuum overnight to give 4-(3-(N
methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
2o A14. General Method for the Synthesis of ~-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.
Synthesis of 4-3-(S-Methylcarbamoyl)pyridyloxy)aniline O
O -~ ' oArte 2s Step i. 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 S-hvdroxvnicotinate (2.0 5, 13.1 mmol) in DMF ( 10 mL). The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DIvIF (10 mL) and the resulting mixture was heated at 70 °C overnijht, 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 chromatography (30% EtOAc/70% hexane) to afford 4-(3-{5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
O
O ~ I OMe HZN N
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 l0 10% Pd/C in MeOH/EtOAc was stirred under an HZ 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 (CDCl3) 8 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1 H), 8.51 (d, 1 H), 8.87 (d, 1 H).

A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.
Synthesis of 4-(3-Methylsulfamoylphenoxy)aniline.
O~ ,O
Br / I S~ NHMe Step 1. Synthesis of N methyl-3-bromobenzenesulfonarnide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 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 1o were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure to~ give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
O ,O
~ O , I S~NHMe Step 2. Synthesis of 4-(3-(N methylsulfamoyl)phenyloxy)benzene To a slurry of phenol (1.9 g, 20 mmoi), K2C03 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N methyl-3-bromobenzenesulfonamide (2.5 g, 1 Ommol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (SO mL) and a 1 N ~HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x SO mL). The combined organic phases' were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04), 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).
O, ,O
O , I S~NHMe OZN

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 NaN02 (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 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 NaCI solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material cazried on to the next step without further purification.
p NHMe 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 HZ atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite~. The filtrate was concentrated under 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 w-ketones. Synthesis of 4-(4-(1-(N
methoxy)iininoethyl)phenoxyaniline HCl salt.
N.O~
HCI I
HzN

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 mrnol) in a mixture of EtOH (10 mL) and pyridine ( 1.0 mL) was added O-methylhydroxylamine HCi 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 concentrated under reduced pressure. The resulting solids were triturated with water ( 10 mL) and washed with water to give 4-(4-(1-(N-methoxy)iminoethyl) phenoxyaniline HCl salt as yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf0.78; ~H NMR (DMSO-d6) 8 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257.((M+H)+).
A17. Synthesis of N (co-Silyloxyalkyl)amides. Synthesis of 4-(4-{2-(N (2-Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
O
CI , H~O.Si N
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 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 (MgS04), 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.
O
° / N''~'O.Si v N H

Step 2. 4-(4-(2-(N (2-Triisopropyisilyloxy)ethyicarbamoyl)pyridyloxyani;line To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added 2o 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, 1 equiv.) in DMF (4 mL) was added followed by KZC03 (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, 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.
1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL)_ The combined WO 00/42012 " PCT/US00/00648 organic layers were washed with a saturated NaCl solution (20 mL), dried (I~fgSOa) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (Si02; 30% EtOAcJ 70% pet ether) to afford 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%). -A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2-Methylpyridines. Synthesis of . 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.
. I ~ o ~- I

Step 1. 4-(S-(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.), KzC03 (25 g, 183 mmoI, 2.0 equiv.) in DMF (100 mL) was heated at the reflex temperature overnight. The resulting mixture was cooled to room 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 NaCI solution ((100 mL), dried (MgS04} and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).
O
O.Me OZN N
O
zo 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, 3.4 equiv.) in pyridine (20 mL) was heated at the reflex 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 solution was treated with a cone HCI solution (7 mL), then heated at the reflex temperature for 3 h, cooled to room temperature and concentrated under reduced pressure.
The residue was separated between lrtOAc (50 mL) and a 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgSOa) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-I-nitrobenzene (0.70 g).
\ O /
OMe O
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 Hz atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite~, l0 and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 70% EtOAc/30% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).
A19. Synthesis of co-Sulfonylphenyl Anilines. Synthesis of 4-(4-I S Methylsulfonylphenyoxy)aniline.
O
.Me Step 1. 4-(4-Methylsulfonylphenoxy)-1=nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-1-nitrobenzene (2.0 g, .7.7 mmol) in CH2C12 (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 20 5 h. The reaction mixture was treated with a IN NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.I g).
z5 Step 2. 4-(4-Methylsulfonylphenoxy)-1-aniline: 4-(4-Methylsulfonylphenoxy)-nitrobenzene was reduced to the aniline in a manner analogous to that described W lethod -~ 18, step 3.

WO 00/42012 PCT/USOOi00648 g, Synthesis of Urea Precursors gl, General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synth\;sis of 4-Bromo-3-(trifluoromethyi)phenyl Isocyanate.

Br ~
NHZ~HCI
Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCI salt To a solution of 4-bromo-3-(trifluoromethyl)aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution {1 M in EtzO; 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 EtzO (50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCl salt (73 g , l0 98%).

Br Nco.
Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (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 CHZCIz (500 mL), then concentrated under reduced pressure. The CHzCl2 treatmentlconcentration protocol was repeated and resulting 2o 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 2~ with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyi)phenyl)-N'-(4-(2-{N-methvlcarbamoyl)-4-pyridvloxy)phenyl) Urea 4t CI ~ J O ~ I O I w NHMe .~ N
N N
H H
A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate ( 14.60 g, 65.90 mmol) in CHzCIz (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 CHZCIz (35 mL) at 0 °C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration; then washed with CHZCIz (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N (4-chIoro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-rriethylcarbamoyl)-4-pyridyloxy)phenyl) urea as an off white solid (28.5 g, 93%): mp 207-209 °C; iH-NMR (DMSO-db) b 2.77 (d,.J 4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J--2.5 Hz, 1 H), 7.62 (m, 4H), 8.11 (d, J--2.5 Hz, I H), 8.49 (d, J=5.5 Hz, 1 H), 8.77 (br d, 1 H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H)+).
Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with as Aniline. Synthesis of N (4-Bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea Br \ I ~ \ I O , N NHMe N N
H H v A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2;
8.0 g, 30.1 mmol) in CHZCIZ (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 CHZC12 (40 mL) at 0 °C. The 2o resulting mixture was stirred at room temp. for 16 h. The resulting yellow solids were removed by filtration, then washed with CHzCI2 (2 x 50 mL) and dried under reduced pressure (approximately 1 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-d6) 8 2.77 (d, J--4.8 Hz, 3H), 7.16 (m, 3H ), 7.37 (d, ZS J--2.5 Hz, 1H), 7.58 (m, 3H), 7.77 (d, J--8.8 Hz, 1H), 8.11 (d, J 2.5 Hz, IH). 8.-19 (d. J=s.s Hz; 1 H), 8.77 (br d, 1 H), 8.99 (s, 1 H), 9.21 (s, 1 H); HPLC ES-MS m/ 509 ((:fit-H )' ) ~2 CI c. 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 CI i ~ Q / ~ C ! w NHMe ~N~N ~ ~ N
H H Me A solution of 2-methyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CHzCl2 (1 mI,) was treated with Et3N (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 (MgSOa) 0 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 (O.I 1 g, 0.22 mmol): 'H NMR (DMSO-d6) 8 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, ,~2.6 Hz, 1H), 7.62 (app d, J--2.6 Hz, 2H), 7.84 (d, J--8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J--5.5 Hz, .1H), t5 8.78 (q, J--5.2, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H)+).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(triflnoromethyl)phenyl)-N'-(4-aminophenyl) Urea ' . CF3 CI I ~ o , I NH2 i N N

To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2Clz (308 ri~L) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CHzCl2 ( 100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture z5 of EtOAc ( 110 mL) and MeOH ( lSmL), and the clear solution was washed with a 0.0~ '~
HCl solution. The organic layer was concentrated under reduced pressure to afford impure N-(4-chloro-3-{trifluoromethyl)phenyl)-N'-(4-aminophenyl) urea (3.3 g); TLC
(100°~0 EtOAc) Rf 0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N (4-Chloro-3-(trifluoromethyI)phenyl)-lY'-(4-ethoxycarbonylphenyl) Urea CI I ~ O .~ I OEt N~N
H H
To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CHZCIz (30 mL) was added 4-chloro-3-(trifluoromethyl)aniIine (3.21 g, 16.4 mmol), and the solution was stirred at 1o room temp. overnight. The resulting slurry was diluted with CHzCIz (SO 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) Rf0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate 15 with an Aniline. Synthesis of N (4-Chloro-3-(triflnoromethyl)phenyl)-N'-(3-carboxyphenyl) Urea Ct ( ~ O i I O I i OH
N N
H H
To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 mmol) in CHZCIz (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method A11; 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 I :I EtOAc/hexane solution to give N (4-chloro-3-(trifluoromethyl)phenyl)-N'-{3-carboxyphenyl) urea as an off white solid (1.21 g, 76%).
C2a. General Method for Urea Synthesis by Reaction of an Aniline with ;v,.W-Carbonyl Diimidazole Followed by Addition of a Second Aniline.

Synthesis of N {2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-{N
methylcarbamoyl)-4-pyridyloxy)phenyI) Urea O ~ ~ O ( ~ NHMe W ~ ~ ~N
~N N
OMe H H
To a solution of Z-methoxy-5-{trifluoromethyl)aniline (0.15 g) in anh CHzClz (15 mL) at 0 °C
was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4-(Z-(N
methylcarbamoyl)-4-pyridyloxy)aniline (O.IB g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with HZO ( 125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL), The combined organics were washed with a saturated NaCI
solution l0 (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. 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)-N'-(4-(Z-(N methylcarbamoyI)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%):
TLC (I00% EtOAc) Rf 0.62; ~H NMR (DMSO-d6) 8 Z.76 (d, J--4.8 Hz, 3H), 3.96 (s, 3H), -7.1-7.6 and 8.4-8.6 , (m, I lH}, 8.75 (d, J--4.8 Hz, IH), 9.55 (s, I H); FAB-MS m/z 461 ((M+H)+) ~ v zo C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,lV'-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 O O
MeHN N i O \ I O I ~ O I ~ NHMe ~ ~N
N N
H H

To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CHzCh ( 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 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 NaCI 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-to pyridyloxy)phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf0.50;'H NMR
(DMSO-db) b 2.76 {d, J--5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, ,I--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 with an Aniline. Synthesis ofN (2-Methoxy-S-(trif3uoromethyl)phenyI-N'-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl) Urea O I W O. ( W
OMe H H N O
O
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2ClZ (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step Zo 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for i 2 h, then was treated with CHzCIz (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCI solution (15 mL) and a saturated NaCI solution (I5 mL), dried (MgS04) and concentrated under reduced pressure to afford N (2-methoxy-S-(trifluoromethyl)phenyl-N'-(4-{1,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 'H NMR (DMSO-d6) 8 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, 3=8.7 Hz, 1 H), 8.53 (br s, 2H), 9.57 (s, 1 H), l 1.27 (br s, 1 H); HPLC ES-MS 472.0 ((M+H)~, 100%).
.16 C2d. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline.
Synthesis of N (5-(tert-Butyl)-2-(2,5-dimethylpyrrolyi)phenyl)-N'-(4-(2-{N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea p O ~ ~ O, , ~ NHMe _ ,N
-N N
N H H
\ /
To a stirring solution of CDI (0.21g, 1.30 inmol) in CHZCIz (2 mL) was added 5-(tert-butyi)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 nltnol) 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 1o 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 1 N HCi solution ( lSmL), dried (MgS04), and filtered through a pad of silica gel (50 g) to afford N-(S-(tert-butyl)-2-(2,5-dimethylpyrolyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyioxy)phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40%
EtOAc/60% hexane) i5 Rf 0.24; ~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. I Hz,-1 H), 8.80 (br s, 1H); HPLC ES-MS 512 ((M+H)+, 100%).
C3. Combinatorial Method for the Synthesis of biphenyl Ureas Using 20 Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M).
This solution was added to a $ mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyI) carbonate solution (0.12 M in dichloroethana, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 tnL, 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 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followW
by diisopropyiethylamine (0.3~ M in dichloroethane, 0.2 mL, 1.2 equiv.). The ~esuitin;

mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.
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-S-(triflaoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) Urea O ~ I O I ~ NHMe ~N
'N N
OMe N
To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CHZCIa to (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-S-{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;
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 NaHC03 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCI
solution, combined, dried (MgS04), and concentrated under reduced pressure. The resulting pink-2o brown residue was dissolved in MeOH and absorbed onto SiOz {100 g). Column chromatography (300 g SiOz; gradient from 1% Et3N/33% EtOAc/66% hexane to 1%
Et3N/99% EtOAc to 1 % Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 4S °C gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of N (2-methoxy-S-(trifluoromethyl)phenyl)-N'-(4-(2-(N methylcarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% Et3N/99%
EtOAc) Rf 0.40.

D. lnterconversion of Ureas Dla. Conversion of cc-Aminophenyl Ureas into m-(Aroylamino)phenyl Ureas.
Synthesis of N (4-Chloro-3-{(trifluoromethyl)phenyl)-N'-{4-(3-methoxycarbonylphenyl)carboxyaminophenyl) Urea Cl ~ O , N ~ I OMe I ~ ~ w I O o N N
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 mrnol), HOBT~Hz0 (0.41 g, 3.03 mmol) and N methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI ~HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp.
overnight;
diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (NazS04) 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%
EtOAc/20% hexane) R~0.75.
Dlb. Conversion of ~-Carboxyphenyl Ureas into ~-(Aryicarbamoyl)phenyl Ureas. Synthesis of N (4-Chloro-3-{(trifluoromethyl)phenyl)-N'-(4-(3-methylcarbamoylphenyl)carbamoyiphenyl) Urea CFg O
Ci ~ ~ , N w I NHMe I / N~N ~ I H O
' 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~H20 (0.14 g, 1.07 mmol), and N metiiylmorpholine (O.SmL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI~HCl (0.10 g, 0.53 mmol). The resulting mixture was allowed to warm to room temp. and was stirred overnight. The resulting mixture was treated with water ( 1 OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated 1~0 00/4201: PCT/USOO/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 225-229; TLC ( 100% EtOAc) Rf 0.23.
Dlc. Combinatorial Approach to the Conversion of w-Carboxyphenyl Ureas into w-(Arylcarbamoyl)phenyl Ureas. Synthesis of N {4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(N-(3-(N-(3-1o pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea w CI ~ 0 ~ N \ I ~ ~N
I ~ . ~ w I. H O I i 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 rng) in 1,2-dichloroethane ( 1 mL) visas treated with a solution of 3-anunopyridine in CHzCl2 ( 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)styrane) (0.040 g) and the resulting ~
mixture was 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-((trifluoromethyI)phenyl)-N'-(4-(N-(3-(N-{3-pyridyl)carbamoyI)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70%
EtOAc/30%
hexane) Rf 0.12.
D2. Conversion of w-CarboalkoYyaryl Ureas into cu-Carbamoylaryl Ureas.
Synthesis of N (4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-methyicarbamoylphenyl)carboxyaminophenyl) Urea H
CI ~ 0 , N ~ I NHMe ~ I O O
~N N
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 under reduced pressure to give N (4-chloro-3-((trifluoromethyl)phenyl)-N'-(4-(3-rnethylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC
( 100%
EtOAc) Rf0.35.
D3. Conversion of co-Carboalkoxyaryl Ureas into cu-Carboxyaryl Ureas.
to Synthesis ofN:(4-Chloro-3-{(trifluoromethyl)phenyl)-N'-(4-carboxyphenyl) Urea CJ I ~ O ~ I OH
N~N \
H H
To a slurry of N (4-chloro-3-((trifluoromethyi)phenyl)-N'-(4-ethoxycarbonylphenyl) urea {Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH
solution (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%).
zo D4. General Method for the Conversion of c~-Alkoxy Esters into c~-Alkyl Amides.
Synthesis of N (4-Chloro-3-{(trifluoromethyl)phenyl)-N'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyt)oxyphenyl) Urea C! , I O I ~ O , I OH
w ~ w ~N N N
H H

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-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2} in a manner analogous to Method Cla. A suspension of N (4-chloro-3-(trifluorornethyl)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 HCI solution. The resulting to 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, 71%).
CF3 O ~
C! , I O I ~ O ~ I H~N\
~ ~ ~ w N N N
H H
Step 2. Synthesis of N (4-chloro-3-(triflnoromethyI)phenyl)-N'-({4-{3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyi)oxyphenyl) urea A mixture of N {4-chloro-3-(trifluoromethyl)phenyl}-N'-((4-(3-(5-carboxypyridyI)oxyphenyl) urea (0.050 g, 0.011 mmol), N,N
dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, O.I7 mmol), N methylmorpholine (0.035 g, 0.28 mmol), 2o 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 (MgS04) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH2CI2 (approximately 2 mL). The resulting solution was treated with EtZO dropwise to give N-(4-chloro-3-(trifluorornethyl)phenyl)-N'-{(4-(3-(5-{2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: 'H NMR (DMSO-d6) 8 2.10 s, 6H), 3.26 (s, H ), 7.03 (d, 2H), 7.~2 (d, 2H), 7,60 (m, 3H), 8.05 {s, IH), 8.43 (s, IH), 8.58 (t, IH), 8.69 (s. 1H). 8.90 (s, 1 H), 9.14 (s, 1 H); HPLC ES-MS m/c 522 ((M+H)+).

D5. General Method for the Deprotection of N {m-Silyloxyalkyl)amides.
Synthesis of N {4-Chloro-3-((trifluoromethyl)phenyl)-N'-(4-(4-{2-(N (2-hydroxy)ethylcarbamoyl)pyridyloxyphenyl) Urea.

CI ~. C ~ O , N~O.Si / ~ N
H H
To a solution of N {4-chloro-3-{(trifluoromethyl)phenyl)-N'-(4-(4-{2-(N {Z-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 S min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 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%).
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) Entry 1: 4-(3-N Methylcarbamoylphenoxy)aniline was prepared according to Method A13.
According to Method C3, 3-terl-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-{3-N Methylcarbamoylphenoxy)aniline to afford the urea.
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)-1-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 Lhe urea.

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.
s Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-N Methylcarbamoylphenoxy)aniline, prepared according to Method AI3, was reacted with the isocyanate according to Method CI a to afford the urea.
to 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.
is 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, S-tert-butyl-2-methoxyaniline was reacted with CDI
followed by 4-20 (1-oxoisoindoIin-s-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.
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)-S-nitropyridine was reduced to 4-(4-acetylphenoxy)-aminopyridine. ~ 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with ~-(4-acetylphenoxy}-5-aminopyridine according to Method Cla to afford the urea.

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)-I-nitrobenzene was reduced according to Method A13, Step 4 to afford ~ 4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifluoromethyl)-2-methoxybutylaniline 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 to DMAC in place of DMF to give 3-(-2-(N methylcarbamoyl)-4-pyzidyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyI)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 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.
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-(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 HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-.o pyridinecarboxamide was reacted with 4-aminophenol according to Method A2.
Step -l usin;
DMAC in place of DMF to give 4-(2-carbamoyi-4-pyridyloxy)aniline. According to Vlzthod 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 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-to (trifluoromethyl)-2-methoxyphenyl i ocyanate according to Method B1. The isocyanate was reacted with 4-(2-(N methylcarbamoyl)-4-pyridyloxy}-2-methylaniline according to Method C 1 c to afford the urea.
Entry 17: 4-(2-{N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. S-(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 C 1 a to afford the urea.
z0 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 B1. 5-(Trifluoromethyi)-2-methoxyphenyl isocyanate was reacted with 3-{2-{N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C 1 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 3o with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridvloxy)aniline. 5-(Trifluoromethyl)-2-methaxyaniline was convened into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-{2-{N ethylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 20: 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. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. S-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method 1 o C 1 a 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-methylsulfonyiphenoxy)-1-aniline.
According 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 Ai 5, Step 4. According to Method C 1 a, 5-z0 (trifluoroinethyl)-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-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-{4-aminophenoxy)isoindoline-1,3-dione according to Method C 1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according 3o to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboaamide was reacted with 4-aminophenol according to Method A2, Step 4 to give -1-t'_-t.~~..~~-dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl}-2-metho~cyanilinc w as convened into 5-{trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-{2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 25: 4-(I-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-{Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-oxoisoindoli:n-5-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to 1o 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 B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(1-(N methoxy)iminoethyl)phenoxyaniline HCl salt to Method Cla to afford ttze 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 2o 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 B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-{2-(N methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
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 B 1. 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.
3o Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A?. Step 3b. 'The chloropyridine was reacted with 3-aminothiophenol according to :~tetho~l A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyI)phenylthio)aniline. 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 3-(4-{2-(N-methylcarbamoyl)phenylthio)aniline according to Method C 1 a to afford the urea.
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 converted into S-(trifluoromethyl}-2-methoxyphenyl isocyanate according to Method B l . 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N
isopropylcarbamoyl)-4-pyridyloxy)aniline according to Method C 1 a to afford the urea.
Entry 31: 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 B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C I a to afford the urea. N-{5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(5-methoxycarbonylpyridyI)oxy)phenyl) urea was saponified according to Method D4, Step l, 2o and the corresponding acid was coupled with 4-(2-aminoethyl)rnorpholine 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-methoxyaniiine was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N'-(4-(3-(S-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step I, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.

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 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 N,N dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
1o Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5 (Trifluoromethyl)-2-methoxyaniIine was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5 {trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (5 (trifluoromethyi)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 3 asninopyridine according to Method D 1 c.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.

(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-. (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N
(4-fluorophenyl)piperazine according~to Method Dlc.
Entry 36: 4-(3-Carboxyphenoxy)aniIine was synthesized according to Method A11.

(Trifluoromethyl)-2-methoxyaniline w.as converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N (5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Dlc.
:0 Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.
~-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl WO 00/42013 PCT/US00/OOb43 isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with S-(trifluoromethyl)-2-rnethoxyphenyl isocyanate according to Method C 1 f to afford N-(S-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyI) urea, which was coupled with 4-(dimethylamino)aniline according to Method D 1 c.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyI)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C 1 f to afford N-(S-to (trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with S-amino-2-methoxypyridine according to Method D 1 c.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.
S-(Trifluoromethyl}-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl t5 isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(S-(trifluoromethyl)-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method Dlc.
2o Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. S-(Trifluoromethyl)-2-methoxyaniline was converted into S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with S-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(S-(trifluoromethyl}-2-methoxyphenyl)-N'-(3-carboxyphenyl) urea, which was coupled with N-2S (2-pyridyl)piperazine according to Method D 1 c.
Entry 41: 4-(3-(N Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A 13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was convened to the isocyanate, then reacted with,4-(3-(N Methylcarbamoyl)phenoxy)aniline to afford the urea.
bl Entry 42: 4-(2-N Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-3-(trifluoromethyI)phenyl isocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C1 a to afford the urea.
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-(trifluoromethyI)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to 1 o 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 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 2o Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N methylcarbamoyl)-4-pyridyloxy)aniIine. According to Method Cla, 4-chloro-3-(trifluorornethyl)phenyl isocyanate was reacted with 3-(2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
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 with 5-(4-aminophenoxy)isoizidoline-1,3-dione to afford the urea.
Entry 47: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized :o according to Method A5. According to Method C 1 c, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-I,3-dione to afford the urea.

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.
Entry 49: 4-(2-{N Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-{2-(N methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
1o Entry 50: According to Method A2, Step 4, S-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.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethyiamine 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 C 1 a, 4-chloro-3-(trifluoromethyl)phenyl 2o 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 Method C 1 a, 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 A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-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 -1-(-1-methylsulfonylphenoxy)-1-aniline to afford the urea.

Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method AIS, 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-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N
methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-{N
Methylsulfamoyl)phenoxy)-1-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.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with I-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 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 C 1 a to afford the urea.
Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according 2o to Method AIB, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene. ' The rriethylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyI)pyridyloxy)-I-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-z5 (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.
:o Entry 57: ;'V-(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 the urea.

WO 00/42012 PCT/'US00/00648 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 D 1 a to afford N (4-chloro-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.
to Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenoI according to Method A2, Step 4 to give 4-(2-(N,N
dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3 (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-{N,N
dimethylcarbamoyl)-4 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 2o converted to the 4-(4-(1-(N methoxy)iminoethyl) phenoxyaniline HCI salt according to Method A 16. According to Method C l a, 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, 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-(Z-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method C 1 a; 4-chloro-3-:o (trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(?-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.

Entry 62: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-{3-Carboxyphenoxy)-I-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 AI3 Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyi)phenoxy)-I-nitrobenzene was reduced to 4-{3-(N (?-piperidylethyl)carbamoyI)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniIine to afford the urea.
to Entry 63: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N (tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(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)-1-nitrobenzene was synthesized according to Method A13, 2o Step ?. 4-{3-Carboxyphenoxy)-I-nitrobenzene was coupled with 2-aminomethyl-I-ethylpyrrolidine according to Method. A13, Step 3 to give 4-(3-(N ((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A 13 Step 4, 4-{3-(N ((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-{N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
According to z5 Method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-{( I -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 3o A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method Cla, .1-chloro-3-(tri~uoromethyl)phenyl isocyanate was reacted wtth .i-(.1-(?-(.'~'-methyicarbamoyl)phenylthio)aniline to afford the urea.

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
isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method C 1 a, 4-chloro-(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 synthesized according to Method C1 e. 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-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.
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 C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-{2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N {2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.

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-(S- .
methoxycarbonyl)pyridyloxy)aniline according to Method Cl a to afford the urea. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(3-(5-methoxycarbonyipyridyl)oxy)phenyl) urea 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-(5-1 o methoxycarbonyl)pyridyloxy)aniline according to Method C 1 a 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.
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 C 1 a 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 2o N,N 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-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 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-t4-(?-(,N-(?-triisopropylsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-~-((trifluoromethyl)phenyl)-N'-{4-(4-(2-(N-(2-triisopropylsilyloxy) ethvlcarbamoyl)pyridyloxyphenyl) urea.

Entry 75: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11.

Chloio-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Dlc.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

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.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

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 D 1 c.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

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 Dlc.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A
11. 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
phenylethylenediam'ine according to Method Dlc.
Entry 80: 4-{3-Carboxyphenoxy)aniline was synthesized according to Method A
11. 4-Chloro-3-(trifluoromethyI)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f to afford the urea, which was coupled with 2-methoxyethylamine according to Method D 1 c.
Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 5-amino-2-methoxypyridine according to Method Dlc.
Entry 82: 4-{3-Carboxyphenoxy)aniline was synthesized according to Method All.

Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-{3-carboxyphenoxy)ariiline according to Method Clf to afford the urea, which was coupled with 4-morpholinoaniline according to Method D 1 c.
Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method ~A
11. 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 (2-pyridyl)pipera2ine according to Method D 1 c.
Entry 84: 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-triisopropylsilyloxy)ethylpyridine-2-carboxainide 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-3-(trifluoromethyl)phenyl ~ isocyanate . was reacted. with 4-(4-(2-(N (2-triisopropylsilyloxy)ethyicarbamoyl)pyridyloxjraniline 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-hydroxy)ethylcarbamoyI)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)phenyi isocyanate according to Method B 1. According to Method C 1 a, 4 3o~ bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4 pyridyloxy)aniline to afford the urea.
~o 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 B 1. According to Method C 1 a, 4 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-{2-{N
methylcarbamoyl)-4 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-pyridinecarboxarnide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-{N methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-l0 (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.
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 B.1. According to Method C I a, 4-2o 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 tv Method A2, Step 4 to form 3-(-2-(N methylcarbamvyl)-4-pyridyloxy)aniline. 4-Bromo-3-{trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1.
According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
3o Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with -t-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Vtcthod A3, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. -1-Bromo- ~-WO 00/4201? PCT/US00/00648 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyI)phenyl isocyanate was reacted with 3-{2-(N-methylcarbamoyl}-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-. dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-{trifluoromethyl)aniline was 1o converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
According to Method Cla, 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 meihylpyridinecarboxamide was synthesized as described in Method 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 B1. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N methylcarbamoyl)phenylthio)aniline to afford the 2o 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-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyI
isocyanate according to ~ Method B 1. According to Method C 1 a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyI)phenylthio)aniline to afford the urea.
Entry 94: 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was convened into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method C1 a, ~l-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 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 B 1.
According to Method C 1 a, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-{N-methylcarbamoyl)-4-pyridyIoxy)aniline to afford the urea.
l0 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 convened into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyariate according to Method B
1.
1S 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 2o 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 AZ, Step 4 to form 3-{-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxv-5-o (trif3uoromethyl)aniline was synthesized according to Method A7. 4-Chloro-?-methow-s-(trifluoromethyl)aniline was convened into 4-chloro-2-methoxy-5-(trifluoromcthvl)phcnvl isocyanate according to Method B1. According to Method Cla, 4-chloro-?-mcthoxv-~-(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 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-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B
1.
to 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-N,N dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-S-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-S-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N 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 form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method A1. According to Method C3, 2-amino-3-methoxynaphthaiene was reacted with bis(trichloromethyl) carbonate followed by 3-{-2-(N
methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
Entry 102: 4-(2-(N-Methyicarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-tent-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to 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 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)-~-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-methyicarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.
Listed in the Tables below are compounds which have been synthesized according to the Detailed Experimental Procedures given above:
Tables 2o 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.

Tabte 1. 3-teri-Butylphenyl Ureas O
R.N~N /
N H
TLC Mass mp HPLC TLC SolventSpec. Synth.

EntryR (C) (min.)R, 5 Source Method stem 1 0 0.22 50% 418 A 13 NH EtOAc(M+H)+

\ - Me /50% (HPLC
O \ ~ hexaneES-MS) 2 O 0,58 50% 403 A 13 ~ ~ O \ ~ EtOAc(M+H)+ C3 Me /50% (HPLC

hexaneES-MS) 3 O I33- 0.68 100% 448 A8 C2d NH I35 EtOAc(M+H)+

Me ~O \ ~ OMe Table Z. 5-tert-Butyl-2-methoxyphenyl Ureas O
R.N~N /
H H OMe TLC Mass mp HPLC TLC SolventSpec. Synth.

En R (C) (min.)Rr S Source Method stem 4 O 5.93 448 A 13 NH
(M+H)+ B 1 \ -. Me (HPLC Cla ~O \ ~ ES-MS) O 120- 0.67 100% 478 A8 NH 122 EtOAc(M+H)+ C2d \ Me (FAB) ~O \ ~ OMe 6 ~ \ O 0.40 50% 460 A3 O \ ~ EtOAc(MTH)- C2d NH /50% (HPLC

hexaneES-'4S) O

7 ~ \ 0.7950% 446 A 12 O

O EtOAc (M+H)+C2d \ ~

NH / 50% (HPLC

hexaneES-MS

Table 3. 5-{Trifluoromethyl)-2-methoxyphenyl Ureas F F F
O
R_N~N
H H OMe TLC Mass ' mp HPLC TLC Solvent~ Spec.Synth.

En R (C) (min.)Rr S SourceMethod stem NH (dec) (M+H)+C2a ., Me (FAB) ~O \

9 O 206- 0.54 10% 446 A3 step 208 ~ MeOH (M+H)+2, N Me /
90% (HPLC A8 step -CH2C1ES-MS)4, 2 Bi, Cla I / \ - O 0.33 50% 445 A I
0 ~O \ ~ EtOAc(M+Hr-3 C3 Me /50% (HPLC

pet ES-MS) ether 11 O 0.20 2% 461 A2 ~ \ . Et3N/(M+H)+C4 NH

INe 98% (HPLC

O \ ~N
EtOAcES-MS) 12 O 0.27 1 447 A2 %

/ \ Et3N/(M+H)+C4 99% (HPLC

O \ / N EtOAcES-MS) 13 O 0.62 100% 461 A2 C2a NH EtOAc(M+H)+

/ \ Me (FAB) ~O \ /N
14 O ~ 114- 0.40 1% 447 A2 NH2 li7 Et3N/(M+H)+C4 99% (FAB) O \ /N
EtOAc wo 00/42012 PCT/US00/00648 15 O 232- 0.54 100% 490 A8 C2d NH 235 EtOAc (M+H)+
Me (FAB) ~O ~ ~ OMe 16 O 210- 0.29 5% 475 AS
Me NH 213 MeOH (M+H)~ BI Clc O ~ / N Me EtOAc ESPMS) / 50 /°
pet ether 17 O 187- 0.17 50% 49S A6 C! NH 188 EtOAc (M+H)+ B1 Cla / N Me pe0°~° EHPMS) ether 18 ~ ~ O 0.48 100% 475 AZ step Me NHy EtOAc (M+H)+ 4, (HPLC B1 Cla O ~ ~ N ES-MS) 19 O 194- 0.31 5% 475 A2 NH 196 MeOH (M+H)+ BI Cla O. ~ ~N, ,Et . EtOAc E~S~-MS) _ / SO%
pet ether 20 . O Z 14- 0.25 S% 49S AZ C 1 a CI NH 216 MeOH (M+H)+
_ / 45%
Me (HPLC
O N EtOAc ES-MS) ~ ~ / SO%
pet ether 21 _ O 208- 0.30 50% 481 A19 C2a O ~ ~ S' O 210 EtOAc (M+H)+
Me /S0% (HPLC
hexane ES-MS
22 O 188- 0.30 70% 447 A 1 S, NHZ 190 EtOAc (M+H)+ step 4, _ / 50% (HPLC C 1 a hexane ES-MS) 23 ~ ~ - O 0.50 70% 472 A3 EtOAc (M+H)+ B 1 C 1 a NH / 30% (FAB) hexane O
24 0 Me 203- 0.13 100% 479 A? B.i N 205 EtOAc (M+H)+ Cla ~Me (HPLC
N ES-V1S) 78.

2S /'\ - - O - p.09 75% 4S8 A12 O \ ~ EtOAc (M+H)+ C2d NH 125% (HPLC
hexane ES-MS) 26 Me0 169- 0.67 50% 474 A I 3 / \ _ N 171 EtOAc (M+H)+ stepl, O \ / ~ / SO% (HPLC A13 step Me pet ES-MS) 4, ether A 16, Cla 27 O 218- 0.40 SO% 477 A2 step NH 219 EtOAc (M+H)+ 3b, \ Me / 50% (HPLC A2 step ~S N pet ES-MS) 4, \ / ether B 1, Cla 28 / \ - O 2IZ- 0.30 40% A9 O \ / 214 EtOAc BI Cla NMe / b0%
hexane O
29 ~ \ O 0.33 50% 474 A2 step NH EtOAc (M+H)+ 3b, Me I 50% (HPLC A2 step w S N pet ES-MS) 4, ether B1, Cla NH Zil B1 \ _ ~Pr-I ' Cla ~O ~ /N
31 O 210- 0.43 10% A 14 NH 204 MeOH B1 / \ / Cla O \ / N _ CH2C1 D4 O
32 O 247- 0.57 10% A14 NH 249 ~ MeOH B1 / \ -- Me. / Cla p \ / CH2C1 D4 ~/ N 2 33 O 217- 0.07 10% A14 NH 219 MeOH B I
CIa / \ O \ / ~N-M CH2CI D4 N Me 2 34 O 0.11 70% A l l N H EtOAc B 1 _ / 30% C 1 f ~ O ~ ~ ~ \ N hexane D 1 c 3j F 0.38 70% All EtOAc B 1 / 30% Clf hexane D i c N
'-N
O
O
36 ~ ~ 0.77 70% All F~NH EtOAc B1 O / 30% Clf - hexane D 1 c ~O
37 Me~ 0.58 70% All N ~ ~ NH EtOAc B1 Me O / 30% Clf _ ~ hexane D 1 c O
38 N 0.58 70% All Me0 ~ ~ NH EtOAc B1 O / 30% Clf _ hexane D 1 c O ~ ~
39 ~ ~ ~ . 0.17 70% All ~N NH v EtOAc B1 O / 30% C l f - hexane D 1 c O
40 N ~'--~ 0.21 70% A 11 N N . ~ ~ NH EtOAc B 1 O / 30% Clf _ hexane D l c Table 4. 3-(Trifluoromethyl)-4-chlorophenyl Ureas F
F F
O ~ CI
R.N~N I i H H

TLC Mass mp HPLC TLC Solvent Spec. Synth.
Entry R I (°C) (min.) R~ Svstem Sourcel Method 41 , O. 163- 0.08 50% 464 A 13 NH 165 EtOAcI ~ (M+H)+ C3 \ _ [~e 50% pet (HPLC
O \ / ether ES-MS) 42 O 215 0.06 50% 465 AZ
NH EtOAc/ (M+H)+ Cla (yle 50% pet (HPLC
\ O - N ether ES-MS) 43 O 0.10 50% 451 A2 NHy EtOAc/ (M+H)+ Cla \ O N eth°erpet ESPMS) 44 ~ \ O 0.25 30% 451 A2 NHy EtOAc/ (M+H)+ C 1 a 70% pet (HPLC
w O \ /N _ ether ES-MS) 45 / \ O 0.31 30% 465 A2 NH EtOAc/ (M+H)+ Cla Me 70% pet (HPLC
p ~ - ether ES-MS) 46 ~ \ - ~ . 17b- 0.23 40% 476 A3 O \ ~ 179 EtOAcI (M+H)+ C 1 a NH 60% (FAB) hexane O
47 O O.Z9 S% 478 AS
Me NH . MeOH/ (M+H)+ Clc _ j~ye ~ 45% (HPLC
O \ / N ~ EtOAc/ ES-MS) 50% pet ether 48 O' ~O 206- A15 'S-NH 209 Cla \ - Me ~O \
49 O 147- 0.22 50% 499 Ab CI NH 151 EtOAc/ (M+H)+ Cla \ O \ N Me therpet ESPMS) 50 ~ \ O 0.54 100% 479 A2 Me NH EtOAc (i~I~H)~ Cia ~Me (HPLC I
ES-~1S ) O ~ /N

51 O 187- 0.33 5% 479 A2 NH 189 MeOH/ (M+H)+ Cla ~Et 45% (HPLC
/ ~ O N EtOAc/ ES-MS) / 50% pet ether 52 O 219 0.18 5% 499 A2 CI NH MeOH/ (M+H)+ C 1 a _ 45%
/ ~ O ~ / N Me EtOAc/ E1S~-MS) 50% pet ether 53 - O 24b- 0.30 50% 485 A19, Cla / ~ O ~ ~ ~5r0 248 EtOAc/ (M+H)+
Me 50% (HPLC
hexane ES-MS
54 - O 196- 0.30 70% 502 A 15 / ~ O ~ ~ S=O 200 EtOAc/ (M+H)+ Cla ~NH 30% (HPLC
Me hexane) ES-MS) 55 O 228- 0.30 30% 466 p 230 EtOAc/ (M+H)+
Me 70% (HPLC
/ ~ O ~ / N CH2C12 ES-MS) / ~ 0 ~ ~ 245 NH
Me 57 O 221- 0.75 80% 492 Cld p 222 EtOAc/ (M~H)+ Dia O _ jNe 20% {FAB) / ~ N \ / hexane 58 O 247 0.35 100% Cld NH ~ EtOAc Dla H .0 tvie D2 / ~ N ~ /
59 O Me 198- 0.09 100% 479 A2 200 EtOAc (M+H)+ C 1 a / ~ O \ N ~Me ESPMS) 60 Me0 158- 0.64 50%
/ ~ - / N I 60 EtOAc/
/ 50% pet Me ether 61 0 195- 0.39 10% A 13 NH 197 MeOH/ Cla O ~ / ~N. 2 62 O 170- 0.52 I 0% A I 3 NH I72 MeOH/ C 1 a O ~ / N 2 63 O 168- 0.39 10% A13 N~ 171 MeOH/ C 1 a ~O
64 O Et 17b- 0.35 10% A13 NH N 177 MeOH/ Cla / ~ CH2C1 O ~ / 2 NH 133 (M+H)+ Bl / ~ - Me (HPLC Cla ~S ~ /N ES-MS) NH Cla / ~ - ~Pr-i ~O ~ ~N
67 O 225- 0.23 100% C 1 a NH 229 EtOAc D3 / ~ H O -~ Me Dlb ~N ~ /
68 / ~ - O 234- 0.29 40% A9 O ~ / 236 EtOAc/ Cla NMe ~ 60%
hexane O
69 / \ O 0.48 50% 481 NH EtOAc/ (M+H)+
jNe 50% pet (HPLC
S ~ ~ N ether ES-MS) 70 O 0.46 5% 564 A10 NH MeOH/ (M+H)+ Cla - 95% (HPLC
O ~ ~ N ~N CH2C12 ES-MS) O

71 O 199- 0.50 10% A14 NH 201 MeOH/ Cla O ~ / N. 2 N

72 O 235- 0.55 10% A14 NH 237 MeOH/ Cla / ~ (Ne CH2C1 D4 73 O 200- 0.21 50% A 14 NH 201 IvIeOH/ Cla O ~ / ~N-Me 2 N Me O ~ / OSi(Pr-i)3 N
75 N ~ 0.12 70% 527 A 11 ~NH EtOAc/
0 30% (M+H)+ Clf (HPLC D i c / \ - ' hexane ES-MS) O ~. /
76 O 0.18 70% A11 Me EtOAc/ C1 f 30% D l c hexane N
N
O
77 / ' 0.74 70% A 1 1 F~ NH EtOAc/ C l f O 30% D 1 c - hexane ~O ~ /
78 Me 0.58 70% All 'N / ~ NH EtOAc/ Cl f Me O 30% Dlc _ hexane /

WO 00/42012 PCT/US00/OOb48 79 O 0.47 70% 569 All NH EtOAc/ (M+H)+ Clf _ ~ 30% (HPLC Dlc / ~ O NH hexane ES-MS) g0 O 0.18 70% 508 A11 NH EtOAc/ (M+H)+ C 1 f 30% (HPLC D 1 c / ~ O ~ ~ OMe . hexane ES-M5) 81 N 0.58 70% 557 All Me0 / ~ NH EtOAc/ (M+H)+ Clf Q 30% (HPLC Dlc _ hexane ES-MS) O
82 ~ ~ ~ 0.37 70% 611 A11 NH .
O 30% c/ (M+H)+ Clf (HPLC D 1 c - hexane ES-MS) O
83 0.19 70% A 11 ~ / N EtOAc/ ~ C 1 f 30% D 1 c N~ hexane ~~N
O
O ~ ~.

_ Cla / ~ O ' / N OH DS
Table 5. 3-(Trifluoromethyl)-4-bromop6enyl Ureas F F F
O ~ Br R.N~N ( /
H H

wo oo/azol~

TLC Mass mp HPLC TLC Solvent Spec. Synth.
Entry R (°C) (min.) R, S stem (Source Method 85 O 186- 0.13 50% 509 A2 NH 187 EtOAc/ (M+H)+ BI
- Me 50% pet (HPLC ES- Cla / N ether MS) 86 0 150- 0.31 50% 545 A6 CI NH 152 EtOAcI (M+H)+ B1 Me SO% pet (HPLC ES- Cla O ~ ~ N ether MS) 87 O 217- 0.16 50% 545 A2 CI NH 219 EtOAc/ (M+HN- BI
Me 50% pet . (HPLC ES- Cla ~ N ether MS) 88 O 183- 0.31 50% 525 AZ
NH 184 EtOAc/ (M+H)+ BI
~Et SO% pet (HPLC ES- Cla O ~ / N ether MS) 89 ~ ~ O 0.21 50% 511 A2 NH EtOAc/ (M+H)+ B 1 Me - SO% pet (HPLC ES- Cla O ~ / N ether MS) 90 / \ O 0.28 50% 525 A2 Me NH EtOAc/ (M+H)+ B1 Me SO% pet (HPLC ES- CIa O ~ / N ether MS) 91 0 Me 214- 0.28 SO% 522 A2 N 216 EtOAcI (M+H)+ B 1 Me SO% pet (HPLC ES- Cla ~O ~ / N ether MS) 92 O 0.47 50% 527 A2 step NH EtOAc/ (IvI+H)+ 3b.
Me 50% pet (HPLC ES- A2 step ~S ~ / N ether MS) 4, B1, Cla 93 ~ ~ 0 0.46 SO% 527 AZ step NH EtOAc/ (M+H)+ 3b.
- Me 50% pet (HPLC ES- A2 step S ~ ~ N ether MS) 4, Bt.
Cla 94 O 14S- 0.415% A10 NH 150 MeOH/ B

~ 9S% Cla - \

O . ~ / N
O

Table 6. 5-(Triflnoromethyi}-4-chloro-2-methoxyphenyl Ureas F F F
0 ~ CI
R.N~N ~ /
H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth.
En R (°C) (min.) R S stcm Source Method 9S O 140- 0.29 S% . 495 A2 NH 144 MeOH/ (M~H)+ A7 jNe 4S% (HPLC Bl O ~ ~ N EtOAc/ ES-MS) C i a SO% pet ether 96 O 244- 0.39 S% 529 A6 CI NH 24S MeOH/ (M+H)+ A7 O ~ / N Me EtOAc/ EMS MS) C 1 a SO% pet ether 97 O 220- 0.25 S% 529 A2 CI NH 221 MeOH/ (M+H)+ A7 O ~ /N Me . EtOAc/ ESA-MS) Cla SO% pet ether 98 ~ ~ O 0.27 S% 495 A2 NH MeOHJ (M+H)+ A7 j,~e 45% (HPLC B I
EtOAc/ ES-MS) C 1 a 0 ~ / N SO% pet ether '99 O 180- 0.52 S% S09 A2 NH 181 ' MeOH/ (M+H)+ A7 O ~ / N .Et EtOAc/ ESPMS) C 1 a 50 /o pet ether . ~Pr-i B 1 ~ 0 ~ /N C1a Table 7. Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth.
En I R (°C) (min.) R S ste r v m Source Method 101 I w O 162-~ I O ~ I I ~ NH C3 i N~N W i Me OMe H H
102 0.10 50% 442 A2 ~~~ O EtOAc/ (M+H)+ A4 ~O~~NH SO% (HPLC C2d N N ~ I I~~ N Me hexane ES-MS) H H
Me 'N/ Me 103 O 12S- 0.24 40% 512 A2 HN~NH I30 EtOAc/ (M+H)+ C2b 60% (FAB) / ~ hexane O O
/ \.
O O
NH-Me Me-NH
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.
l0 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.
8s

Claims (65)

1. 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-L1)q , where L is a 5 or 6 membered cyclic structure bound directly to D, L1 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 L1 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, wherein L1 is substituted by at least one substituent selected from the group consisting of -SO2R x, -C(O)R x and -C(NR y) R z, R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, R z is hydrogen or 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 D and are optionally substituted by halogen;
R x is R z or NR a R b where R a and R b are a) independently hydrogen, 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 O and are optionally substituted by halogen, or -OSi(R f)3 where R f is hydrogen or a carbon based moiety of up to 24 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 O and are optionally substituted by halogen; or b) R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-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 C1-C5 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 O and are optionally substituted by halogen;
where B is substituted, L is substituted or L1 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, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, - (CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m-, -CHX a-, -CX a2-, -S-(CH2)m- and -N(R7) (CH2)m-, where m = 1-3, and X a 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 n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O) R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, and -NR7C(O)OR7, with R7 as defined above;

with a proviso that the compound is not a compound selected from the group consisting of:

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, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, 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, N-(4-bromo-3-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(2-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl)urea, or a pharmaceutically acceptable salt thereof.
2. A compound as in claim 1 wherein:
Ry is hydrogen, C1-to alkyl, C1_lo alkoxy, C3-to cycloalkyl having 0-3 heteroatoms, CZ-to alkenyl, C1-Zo alkenoyl, C6_12 aryl, C3_12 hetaryl having 1-3 heteroatoms selected from N, S and 0, C~_z4 aralkyl, C~_z9 alkaryl, substituted C1-to alkyl, substituted C1-to alkoxy, substituted Cs-to cycloalkyl having 0-3 heteroatoms selected from N, S and 0, substituted C6-C19 aryl, substituted C3_12 hetaryl having 1-3 heteroatoms selected from N, S and 0, substituted C~_29 alkaryl or substituted C~_24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, 91a R2 is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-3 heteroatoms, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from S, N and O, C7-24 alkaryl, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C6-C14 aryl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from S, N and O, substituted C3-12 hetaryl having 1-3 heteroatoms selected from S, N and O, substituted C7-24 alkaryl or substituted C7-24 aralkyl where R z is a substituted group, it is substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 91b alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C3-C12 hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from O, N and S, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)Rg, R a and R b are, a) independently hydrogen, a carbon based moiety selected from to group consisting of C1-C10 alkyl, C1-C10 alkoxy, C3-10cycloalkyl, C2-10 alkenyl, C1-10 alkenoyl, C6-12 aryl, C3-12 hetaryl having 1-3 heteroatoms selected from O, N and S, C3-12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, C7-12 aralkyl, C7-C24 alkaryl, substituted C1-10 alkyl, substituted C1-10 alkoxy, substituted C3-10 cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C6-12 aryl, substituted C3-12 hetaryl having 1-3 heteroatoms selected from N, S
and O, substituted C7-24 aralkyl, substituted C7-24 alkaryl, where R a and R b are a substituted group, they are substituted by halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)R g; or -OSi(R f)3 where R f is hydrogen, C1-10 alkyl, C1-10 alkoxy, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-12 aryl, C3-C12 hetaryl having 1-3 heteroatoms selected from O, S and N, C7-24 aralkyl, substituted C1-10 alkyl, substituted C1-C10 alkoxy, substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C3-C12 heteraryl having 1-3 hetervatoms selected from O, S, and N, substituted C6-12 aryl, and substituted C7-24 alkaryl, where R f is a substituted group it is substituted halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl. C7 -C24 alkaryl, C7 -C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)R g, or b) R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-10 alkoxy, C6-12 aryl, C7 -C24 alkaryl, C7 -C24 aralkyl, halo substituted C1-6 alkyl up to per halo alkyl, halo substituted C6-C12 aryl up to per halo aryl, halo substituted C3-C12 cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)R g, or c)- one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-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 C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, C1-10 alkyl, C3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C3-12 hetaryl having 1-3 heteroatoms selected from N, S and O, C1-alkoxy, C6-12 aryl, C7 -C24 alkaryl, C7 -C24 aralkyl, C1-6 halo substituted alkyl up to per halo alkyl, C6-C12 halo substituted aryl up to per halo aryl, C3-C12 halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3-C12 hetaryl up to per halo heteraryl, halo substituted C7-C24 aralkyl up to per halo aralkyl, halo substituted C7-C24 alkaryl up to per halo alkaryl, and -C(O)R g, where R g is C1-10 alkyl; -CN, -CO2R d, -OR d, -SR d, -NO2, -C(O) R c. -NR d R
c. -NR j C(O)OR e and -NR d C(O)R e, and R d and R e are independently selected from the group consisting of hydrogen, C1-10, alkyl, C1-10 alkoxy, C3-10 cycloalkyl having 0-
3 heteroatoms selected from O, N and S, C6-12 aryl, C3- C12 hetaryl with 1-3 heteroatoms selected from O, N
and S and C7 -C24 aralkyl, C7 -C24 alkaryl, up to per halo substituted C1-C10 alkyl, up to per halo substituted C3 -C10 cycloalkyl having 0-3 heteroatoms selected from O, N
and S, up to per halo substituted C6 -C14 aryl, up to per halo substituted C3 -C12 hetaryl having 1-3 heteroatoms selected from O, N, and S, halo substituted C7-C24 alkaryl up to per halo alkaryl, and up to per halo substituted C7-C24 aralkyl, W is independently selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, C1-C10 alkyl, C1-alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C7-C24 alkaryl, C7 -C24 aralkyl, C3-C12 heteroaryl having 1-3 heteroatoms selected from O, N and S, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C3-C12 hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C7-C24 aralkyl, substituted C7-C24 alkaryl, substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-Ar;
R7 is independently selected from H, C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, S and N, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7-C14 alkaryl, C7 -C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per-halosubstituted C6-C14 aryl, up to per-halosubstituted C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C7-C24 aralkyl, up to per-halosubstituted C7-C24 alkaryl, and up to per-halosubstituted C4-C23 alkheteroaryl; and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, - SR7 -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, C1-C10 alkyl, alkoxy, C2-C10 alkenyl, C1-C10 alkenoyl, C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, C6-C14 aryl, C3-C13 hetaryl having 1-3 heteroatoms selected from O, N and S, C7C24 alkaryl, C7 -C24 aralkyl, C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C1-C10 alkyl, substituted C1-C10 alkoxy, substituted C2-C10 alkenyl, substituted C1-C10 alkenoyl, substituted C3-C10 cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C6-C12 aryl, substituted C7-C24 alkaryl, substituted C7-C24 aralkyl and substituted C4-C23 alkheteroaryl having 1-3 heteroatoms selected from O, N
and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, and -NR7C(O)OR7.
3. A compound as in claim 1 wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a 2-, -S-{CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen and R7 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.
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 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
and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from 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, 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, C1-C10 alkyl, C1-C10 alkoxy, -OH, up to per halo substituted C1-C10 alkyl, up to per halo substituted C1-C10 alkoxy or phenyl substituted by halogen up to per halo.
9. A compound of claim 1, wherein L, the six member cyclic structure bound 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 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 L1 comprises a 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 L1 is phenyl, pyridinyl or pyrimidinyl.
13. A compound of claim 3, wherein said substituted cyclic moiety L1 is phenyl, pyridinyl or pyrimidinyl.
14. A compound of claim 6, wherein said substituted cyclic moiety L1 is phenyl, pyridinyl or pyrimidinyl.
15. A compound of claim 8, wherein said substituted cyclic moiety L1 is phenyl, pyridinyl or pyrimidinyl.
16. A compound of claim 9, wherein said substituted cyclic moiety L1 is phenyl, pyridinyl or pyrimidinyl.
17. A compound of claim 10, wherein said substituted cyclic moiety L1 is phenyl, pyridinyl or pyrimidinyl.
18. A compound of claim 14, wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by 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 -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O 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 -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen and R74 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O 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 -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen and R7 is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to per halo.
22. A compound of claim 1 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
23. A compound of claim 13 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
24. A compound of claim 18 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
25. A compound of claim 19 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
26. A compound of claim 20 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
27. A compound of claim 21 wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C1-C10 alkyl, up to per halo substituted C1-C10 alkyl, -CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
28. A compound of claim 1 wherein L1 is substituted by -C(O)R x.
29. A compound of claim 1 wherein L1 is substituted by -SO2R x.
30. A compound of claim 1 wherein L1 is substituted only by -C(O)R x.
31. A compound of claim 1 wherein L1 is substituted only by -SO2R x.
32. A compound of claim 1 wherein L1 is substituted by -C(O)R x or -SO2R x.
wherein R x is NR o R b.
33. A compound of claim 13 wherein L1 is substituted by -C(O)R x or -SO2R x, wherein R x is NR a R b, and R a and R b are a) independently hydrogen, 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 O and are optionally substituted by halogen, or -OSi(R f)3 where R f is hydrogen or a carbon based moiety of up to 24 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 O and are optionally substituted by halogen; or b) R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R a or R b 15 -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-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 C1-C5 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 O and are optionally substituted by halogen.
34. A compound of claim 18 wherein L1 is substituted by -C(O)R x or -SO2R x, wherein R x is NR a R b and R a and R b are independently hydrogen or 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 O and are optionally substituted by halogen.
35. A compound of claim 19 wherein L1 is substituted by -C(O)R x, wherein R x is NR a R b and R a and R b are independently hydrogen or 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 O and are optionally substituted by halogen.
36. A compound of claim 20 wherein L1 is substituted by -C(O)R x or -SO2R x, wherein R x is NR a R b and R a and R b are independently hydrogen or 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 O and are optionally substituted by halogen.
37. A compound of claim 21 wherein L1 is substituted by -C(O)R x or -SO2R x, wherein R x is NR a R b and R a and R b are independently hydrogen or 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 O and are optionally substituted by halogen.
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-L1)q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L1 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 L1 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, wherein L1 is substituted by at least one substituent selected from the group consisting of -SO2R x, -C(O)R x and -C(NR y)R z, R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, R z is hydrogen or 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 O and are optionally substituted by halogen;
R x is R z or NR a R b where R a and R b are a) independently hydrogen, 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 O and are optionally substituted by halogen, or -OSi(R f)3 where R f is hydrogen or a carbon based moiety of up to 24 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 O and are optionally substituted by halogen; or b) R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R a, or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-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 C1-C5 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 O and are optionally substituted by halogen;
where B is substituted, L is substituted or L1 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, -CO2R7-, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, and X a 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, up to per-halo, and optionally substituted by Z n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -NO2, -OR7, - SR7 -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by one or more substituents are selected from the group consisting of -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, and -NR7C(O)OR7, with R7 as defined above; and wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m-CHX a-. -CX a-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, X a is halogen.
39. 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-L1)q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L1 comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group 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 L1 is substituted by at least one substituent selected from the group consisting of -SO2R x, -C(O)R x and -C(NR y)R z, R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and;
R z is hydrogen or a carbon based moiety of up to 34 carbon atoms optionally containing heteroatoms selected from N, S and O arid optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
R x is R z or NR a R b where R a and R b are a) independently hydrogen, 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 O and are optionally substituted by halogen, or -OSi(R f)3 where R f is hydrogen or a carbon based moiety of up to 24 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 O and are optionally substituted by halogen; or b) R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R a or R b is -C(O)-, a C1-C5 divalent alkylene group or a substituted C1-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 C1-C5 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 O and are optionally substituted by halogen;
where B is substituted, L is substituted or L1 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, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, -SR7, -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7, -NO2, -NR7C(O)R7, -NR7C(O)OR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q is -O-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m- CHX a-, -CX a2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, and X a 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, up to per-halo, and optionally substituted by Z n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, NO2, -OR7, - SR7 -NR7R7, -NR7C(O)OR7, -NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O
and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R7, -COR7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7, -NR7C(O)R7, and -NR7C(O)OR7; and wherein M is one or more bridging groups selected from the group consisting of -O-, -S-, -N(R7)-, -(CH2)m,- -C(O)-, -CH(OH)-, -(CH2)m O-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m-CHX a-, -CX b2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m=1-3, X a is halogen.
40. 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-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 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 substituents for L1, are selected from the group consisting of C1-C10 alkyl up to per halo substituted C1-C10 alkyl, CN, OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
45. A compound as in claim 39 wherein substituents for B and L and additional substituents for L1, are selected from the group consisting of C1-C10 alkyl up to per halo substituted C1-C10 alkyl, CN, -OH, halogen, C1-C10 alkoxy and up to per halo substituted C1-C10 alkoxy.
46. A compound of claim 38 wherein L1 is substituted by C(O)R x or SO2R x.
47. A compound of claim 39 wherein L1 is substituted by C(O)R x or SO2R x.
48. A compound of claim 46 wherein R x is NR a R b and R a and R b are independently hydrogen and 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 O and are optionally substituted by halogen.
49. A compound of claim 47 wherein R x is NR a R b and R a and R b are independently hydrogen and 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 O and are optionally substituted by halogen.
50. A compound of claim 1 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, 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 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline canons, alkaline earth canons, the ammonium cation, aliphatic 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, 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 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 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), 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 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline canons, alkaline earth cations, the ammonium cation, aliphatic 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, 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 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 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, 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 substituted ammonium cations and aromatic substituted ammonium cations.
55. 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;
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-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, 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, 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 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea.
56. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
57. A pharmaceutical composition comprising a compound of claim 2 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
58. A pharmaceutical composition comprising a compound of claim 33 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
59. A pharmaceutical composition comprising a compound of claim 38 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
60. A pharmaceutical composition comprising a compound of claim 39 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
61. The pharmaceutical composition according to claim 56, which is for the treatment of a cancerous cell growth mediated by raf kinase.
62. The pharmaceutical composition according to claim 58, which is for the treatment of a cancerous cell growth mediated by raf kinase.
63. The pharmaceutical composition according to claim 59, which is for the treatment of a cancerous cell growth mediated by raf kinase.
64. The pharmaceutical composition according to claim 60, which is for the treatment of a cancerous cell growth mediated by raf kinase.
65. A pharmaceutical composition comprising 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;
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-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, 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, 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 N-(2-methoxy-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea;
the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas:
N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea, and N-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-N'-(3-chloro-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyl) urea, and a physiologically acceptable carrier, for the treatment of a cancerous cell growth mediated by raf kinase.
CA2549558A 1999-01-13 2000-01-12 Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Expired - Lifetime CA2549558C (en)

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