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NZ556598A - Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors

Info

Publication number
NZ556598A
NZ556598A NZ556598A NZ55659800A NZ556598A NZ 556598 A NZ556598 A NZ 556598A NZ 556598 A NZ556598 A NZ 556598A NZ 55659800 A NZ55659800 A NZ 55659800A NZ 556598 A NZ556598 A NZ 556598A
Authority
NZ
New Zealand
Prior art keywords
phenyl
trifluoromethyl
urea
acid
substituted
Prior art date
Application number
NZ556598A
Inventor
Bernd Reidl
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
Original Assignee
Bayer Pharmaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27381740&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NZ556598(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Bayer Pharmaceuticals Corp filed Critical Bayer Pharmaceuticals Corp
Publication of NZ556598A publication Critical patent/NZ556598A/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
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    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07C275/28—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
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    • C07C275/30—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 halogen atoms, or by nitro or nitroso groups
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    • C07C275/28—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
    • 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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    • C07C275/32—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
    • 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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Abstract

Omega-carboxyaryl substituted diphenyl ureas are disclosed which are useful as raf kinase inhibitors. This disclosure also relates to the use of a group of these aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Description

New Zealand Paient Spedficaiion for Paient Number 556598 NEW ZEALAND *10054174627* PATENTS ACT 1953 55 6 5 9 8 COMPLETE SPECIFICATION This specification is divided out of New Zealand Patent Specification 544840 (hereinafter referred to as "that invention") Davies Collison Cave Reference: 20261538 APPLICANT(S) Bayer Corporation 100 Bayer Road, Pittsburgh, Pennsylvania 15205-9741, United States of America My/Our contact address is: My/Our address for service is: DAVIES COLLISON CAVE 255 Elizabeth Street G.P.O. Box 3876 Sydney 2000 New South Wales, AUSTRALIA Telephone: 61 2 9293 1000 Facsimile 61 2 9262 1080 Email: svdmail@davies.com.au DAVIES COLLISON CAVE c/- James & Wells Level 9, James & Wells Tower 56 Cawley Street Private Bag 11907 DX CP 34005 Ellerslie Auckland NEW ZEALAND INVENTION TITLE: "Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors" We, Bayer Corporation hereby declare the invention for which we pray that a patent be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement: \ 9 JUL W [ECEj^- EOl P:\WPDOCS\Hjw\Letters\Jul-07\20261538 DIV.doc -18/7/07 5 6 5 9 8 a-Carboxyaryi substituted diphenyl ureas as raf kinase inhibitors This application is a divisional of New Zealand Patent Application 544840, which in turn is a divisional of New Zealand Patent Application 534209, which in turn is a divisional of New Zealand Patent Application 513079, the entire disclosure of which is incorporated herein by reference.
Field of the Invention This and/or that 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 pll"" oncogene is a major contributor to the development and progression of human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann. Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP-bound activated and a GDP-bound resting form is strictly controlled by ras' endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This ieads to the cancerous growth of the cells which carry these mutants (Magnuson et 3!. Semirt. Cancer 3iol. • 1994. 247-53). It has been shown that inhibiting the effect of active ras by inhibiting ihc rut' kinase signaling pathway by administration of deactivating antibodies '.0 raf kinase or by co-expression of dominant negative raf kinase or dcminant negative MEK. the substrate of raf kinase, leads to the reversion of transformed cells to the norma] growth phenotype (see: Daurn et al. Trends Biochem. Sci. 1994,19, 474-80; Fndman et al. J. Biol. Chem. 1994, 269, 30105-8. Kolch et al. (Nature 1991, 349, 426-28) have further-indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated' in vitro and -in vivo with inhibition of the growth of a variety of human tumor types (Monia et ah, Nat. Med. 1996, 2, 668-75).
Summary of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase. Since the enzyme is a downstream effector of p21ras, the inhibitors are useful in pharmaceutical compositions for human or veterinary use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or cancerous cell growth mediated by raf kinase. In particular, the compounds are useful in the treatment of human or animal 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 enzyme raf kinase and also compounds, compositions and methods for the treatment of cancerous cell growth mediated by raf kinase wherein a compound of Formula I is administered or pharmaceutical^ acceptable salt thereof.
A-D-B (I) The invention as generally described relates to compounds of formula I in which Dis -NH-C(0)-NH-, T INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 18 MAR 2008 PCT/USOD/0064S 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, 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 aiyl 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 -SCbRu -C(0)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from Ns S and O and optionally halosubstituted, up to per halo, R, 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, is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 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 Rf 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 PCT/USOO/00648 b) Ra and Rb 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 0 and are optionally substituted by halogen; or c) one of Ra or Rb is -C(O)-, a C1-C5 divalent alkylene group or a substituted Cr Cs 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 Ll 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, -CO;R7, -C(0)NR7R7, -C(0)-R7, -N02, -OR7, -SR7, -NR7R7, -NR7C(0)0R7, -NR7C(0)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(0)R', -C(0)NR7R7, -OR7, -SR7, -NR7R7, -NO:, -NR7C(0)R7, -NR'C(0)0R7. 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 -0-, -S-. -N(R7)-, -<CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CHjXnS-, -(CH2)mN(R7)-, -0(CH2)m- CHX\ -CXV, -S-(CH2)m- and -N(R7)(CH2)m-, where m= 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z„i, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -CO;R . -C(0)R', -C(0)NR R . -NO:, -OR?, - SR7 -NR7R\ -NR7C(0)OR', -NR'C(0)R\ and a carbon based moiety of up to 4 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R', -COR7, -C(0)NR7R7, -OR7, -SR7, -N02, -NR7R7,-NR7C(0)R7, and -NR7C(0)0R7; wiih R7 as defined above.
According to an aspect of the invention as claimed there is provided compounds of formula I and the exemplified compounds. These compounds of formula I as claimed are A-D-B (I) or a pharmaceutical^ acceptable salt thereof, wherein D is -NH-C(0)-NH-, A is a substituted moiety of the formula: -L-M-L1, wherein L is a 5 or 6 membered cyclic structure bound directly to D, L1 is pyridinyl substituted by -C(0)Rx, and is optionally substituted with 1-3 additional substituents independently selected from the group consisting of R7 and halogen; wherein Rx is NRaRb and Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 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(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 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) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S aid 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 INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 8 MAR 2008 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 Ra or Rb is -C(O)-, a Cj-Cs 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 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; M is oxygen or sulfur; and 10 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, where when 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, 15 where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -C02R7, -C(0)NR7R7, -C(0)-R7, -N02, -OR7, -SR7 ,-NR7R7, -NR7C(0)0R7, -NR7C(0)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 20 substituents independently selected from the group consisting of -CN,-C02R7, -C(0)NR7R7, -OR7, -SR7, -NR7R7/ -N02, -NR7C(0)R7, -NR7C(0)0R7 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 -0-, -S-, -N(R7)-, -(CH2)m-, -C(O)-, -CH(OH)-, -(CH2)mO-, -(CH2)mS- , -(CH2)mN(R7)-, -0(CH2)m- CHX\ -CXa2-> -S-(CH2)rn- and -N(R7)(CH2)m-, where m = 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by 30 halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CNS -C02R7, -C(0)R7, - 5A ■ INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 8 MAR 2008 C(0)NR7R7, -NO2, -OR7, -SR7 -NR7R7, -NR7C(0)0R7 -NR7C(0)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, -C02R7, -COR7, -C(0)NR7R7, -OR7, -SR7, -N02, -NR7R7, -NR7C(0)R7, 5 and -NR7C(0)0R7, with R7 as defined above.
The invention as claimed further specifically relates to pharmaceutical!}' acceptable salts of the compounds of formula I and of the compounds of the examples, processes for their preparation, pharmaceutical compositions containing same and uses thereof. These and 10 other aspects, embodiments and preferments of the invention are set out in the description, examples and claims that follow.
In formula I, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms. For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-tnazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-,.4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyt, 3-, 4- or 5-isoxazolyi, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-y], 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazoiyl, l,2,3-oxadiazol-4- .or -5-yl, 1,2,4-oxadiazoI-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,2,4-oxadiazol-3- or -5-y3, 1,3,4-tbiadiazol-2- or-5-yl, l,3,4-thiadiazol-3- or-5-yl, l,2,3-thiadiazol-4- or-5-yl, 2-, 3-, 4-, 5-or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5- 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 2- 4-, 5-, 6- or 7-benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinoiinyl, 3-t 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-,' 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally optionally substituted ■v phenyl, 2- or 3-thienyl, 1,3,4-thiadiazoIyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyI or 5-thiazolyi, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1: -5B- INTELLECTUAL PROPERTY OFFICE OF N.2.
IT MAR 2008 methyl-3-pyrryI, l-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-l,2,4-thiadiazol-2- yi.
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, rm-butyl, etc.
Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl. - 5C- PCT/USOO/GO643 The term "cycloaikyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example, "C4 cycloalkyl" includes methyl substituted cycioprcpyl groups as well as cyclobutyl groups. The term "cycloalkyl", as used herein also includes saturated heterocyclic groups.
Suitable halogen groups include F, CI, 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 perse, of formula I.
The present invention is also directed to pharmaceuticaHy acceptable salts of formula I. Suitable pharmaceuticaHy acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hvdrobromic acid, sulfuric acid, phosphoric acid,methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfomc acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceuticaHy 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+: or Ba+2), the ammonium cation., as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, M/Z-diethylamine, /V.A'-dicyclohexylamine, lysine, pyridine, 7V,//-dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
A number of the compounds of Formula I possess asymmetric carbons and can therefor exist in racemic and optically active foims. 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 2ctive forrfi of compounds described in Formula I which possess raf inhibitory activity. 6 PCT/USOO/00648 General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the an 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, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations', VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines arc commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H: or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydriae (Rylander. Hydrogenation Methods', Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH.} (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a 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, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations', VCH Publishers: New York (1989)).
H2 / catalyst ^ (eg. Ni, Pd, Pt) ArN02 — ArNH2 \ M(0) y* (eg. Fe, Sn, Ca) Scheme 1 Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by eiectrophilic aromatic nitration using HNO-.. or an alternative NO:" source. Nitroaryls m3y be funiier elaborated prior to reduction. Thus, nitroaryls substituted with PCT/USOO/GQ643 hno3 Ar-H >«- ArN02 potential leaving groups (e.g. F, CI, 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). 0jN~-)r^ ArSH C y—F =J base ^^>~S-Ar B,-Af ^ R 7 _C J— SH CuO / base 3 Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroary! electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids 10 (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs ("Negishi reaction) to afford the biaryl (5). °2N\.r-% ArB(OR')2 OjN >1-* - R^=/ PcJ(O) 4 5 Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyi trifluoromethane in the presence of a fluoride source, such as tris( dimethyl amino )sulfonium difluorotrimethyisiliconats (TASF) leads to the corresponding trifluoroniethylsulfone (9). Alternatively, sulfonyl chioride 7 may be reduced to the arenetniol (10). for example with zinc amalgum. Reaction of thiol 10 with CHC1F; in the 8 FCT/USOO/00648 presence of base gives the difluoromethvl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO;,-acetic anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).
S02CI cisojh (Me2N)3S Me3SiF2 Me3SiCF3 CHCIF2 base SO2CF3 11 12 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 heteroaryi isocyanate may be synthesized from a heteroaryi amine by treatment with phosgene or a phosgene equivalent, such as trich'.oromethy! chlorofoimate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or 0 .V./V'-carbonyldiimidazole (CDJ). The isocyanate may also be derived from a heterocyclic carbcxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-iype rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be 9 WO 00742012 PCT/USOO/0064S subjected to Curtius-type rearrangements using diphenylp'nosphoryl azide (DPPA) or a similar reagent.
Ar1—NH2 13 H H 15 .
Ar X Ar' OH 16 17 Scheme IV Selected Methods of Non-Symmetrical Urea Formation Finally, ureas may be further manipulated using methods familiar to those skilled in the an.
The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term 'administration by injection' includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or. more compounds may be present in association with one or more nontoxic pharmaceuticaHy acceptable carriers and if desired other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-to.xic pharmaceuticaliy acceptable excipients which are suitable for the manufacture of (ablets These e.NCiDients may be, for example, inert diluents, such as calcium carbonate, sodium PCT/USOO/0 0648 carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disinteerating agents, for example, com starch, or aiginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl _p-hydroxvbenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting attorn. suspending agent and one or more preservatives. Suitable dispersing or wetting agents 11 PCT/USOO/00648 and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily 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 2s liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixture' 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 ma_y 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 glycols.
For al! regimens of use disclosed herein for compounds of Formula 1. the daily oral dosage reyimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daih dosage 12 PCT/USOO/0064S 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 i to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering 10 therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound 15 of Formula I or a pharmaceuticaHy 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 spepific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, 20 the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.
The entire enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Serial No. 60/1 15,877, 25 filed January 13, 1999 and non-provisional application Serial No. 09/257,266 filed February 25, 1999.
The compounds can be produced from known compounds (or from starting materials which, in turn, can be produced from known compounds), e.g., through the general preparative yo meihods shown below. The activity of a given compound to inhibit raf kinase .can be rotiiinelv assayed, e.g.. according to procedures disclosed below. The following examples 13 WO 00742012 PCT/USOO/00648 are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
EXAMPLES All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mniHg. 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-Ar'-(methylpolystyrene)carbodiiraide was purchased from Calbiochem-Novabiochem Corp. 3-ferf-Butylaniline, 5-/erf-butyl-2-methoxyaniline, 4-bromo-3-(trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniiine 2-methoxy-5- (trifluoromethyl)aniline, 4-fer:-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-0^ isocyanatobenzoate, Ar-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl fsocyanate 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-carbamovlphenoxy)-1 -nitrobenzene 25 (K. Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyi isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5-(trif!uoromethyi)phenyi isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described.
Thin-layer chromatography (TLC) was performed using Whatman1' pre-co3ted glass-backed silica ee! 60A F-254 250 urn plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) 14 PCT/US(K)/()0648 immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed bv heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenyIhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science® silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform infrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ("H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (5 0.00) or residual protonated solvent (CHCI3 6 7.26; MeOH 6 3.30; DMSO 5 2.49) as standard. Carbon (nC) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDClj 5 77.0; MeOD-dj; 5 49.0; DMSO-d$ 5 39.5) as s-andard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were ether obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacurnetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 |^A. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane or ammonia as the reagent gas (1x10"4 torr to 2.5x10"* torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10.amps until all traces of the sample disappeared ( ~-I-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-13 column, and a Finniean LCQ ion trap mass spectrometer with elecuospray ionization. Spectra were scanned from 120-S0G' amu using a variable ion time according to the number of ions in the source, Gas chromatography - ion selective mass spectra iGC-NiS) PCT/TJS00/Q0648 were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0,23 raM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.
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 atmosphere(s) BOC /err-butoxycarbonyl CDI 1,1 '-carbonyl diimidazole conc concentrated d day(s) dec decomposition DMAC iV,jV-dimethy lace t amide DMPU 1,3-dimethyl~3,4,5,6-tetrahydro-2( lH)-pyrimidinone DMF A^AT-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI l-(3-dimethylaminopropyl)-3-ethylcarbcdiimide EtOAc ethyl acetate EtOH ethanol (100%) Et20 diethyl ether Et3N triethyiamine h hour(s) HOBT 1-hvdroxybenzotriazole /jf-CPBA 3-chloropcroxybenzoic acid.
MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) 16 temp. temperature THF tetrahydrofuran TFA triiluoroAcOH Tf trifluoromethanesulfonyl 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-metboxynaphtbaIeoe.
C02Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydrosy-2-naphthoate (10.1 g, 50.1 mmol) and K1CO3 (7.96 g, 57.6 mmoi) in DMF (200 mLj was stirred at room temp, for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. 15 overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO,#), 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) 6 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app tT >8.09 Hz, 1H), 7.44 (s, 1H), 7.53 20 (app t, >8.09 Hz, 1H), 7.84 (d, >8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
Step 2. 3-Methoxy-2-naphtboic acid A solution of methyl 3-methoxy-2-naphthoate (6.2S g, 29.10 mmol) and water (10 mL) in VleOH (100 mL) at room temp, was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol) The mixture was heated 31 the reflux temp, for 3 n, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc <2 \ 111,1 PCT/USO0/0O648 mL). The combined organic layers were washed with a saturated NaC! solution, dried (MgSO.i) 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-ds) 6 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 5 7.S3 (d, >8.09 Hz, IH), 7.91 (d,>8.09 Hz, JH), 8.19 (s, IH), 12.83 (br s, IH). 9\ • OMe H ^ Step 3. 2-(/V-(Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and EtjN (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp, for 15 min., then treated with a 10 solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp., benzyl alcohol (2.06 mL, 20 mmol) -was added via syringe. The mixture was then warmed to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a 15 saturated NaCl solution, dried (MgSO^) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAcy86% hexane) to give 2-{N-(carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR 0 (DMSO-d6) 5 3.89 (s, 3H), 5.17 (s, 2H), 7.27r7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, IH), 8.76 (s,lH).
OMe Step 4. 2-Amino-3-metboxynaphthalene A slurry of 2-(JV-(carbobenzyloxv)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a atm (balloon) at room temp, overnight. The resulting mixture was filtered through Celite4" and concentrated under reduced pressure to give 2-arnino-3-methoxynaphiha!ene as a paie pink powder (2.JQ g.
!S WO 00/4201: PCT/USOO/0064S 85%): 1 H-NMR (DMSO-d6) 5 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, 7=8.0 Hz, IH), 7.56 (d, >3.0 Hz, IH); EI-MS m/z 173 (M+).
A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of4-(2-.iV-Methylcarbamyl-4-pyridyloiy)aniline O CK ^ , NHMe N ^ Step la. Synthesis of 4-ch]oro-jV-methyl-2-pyridinecarboxamide via the Menisci reaction Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in AT-methylformamide (250 mL) at room temp, was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H^Oj (30% wt in H2O, 17 mL) followed by FeSO.r7H2Q (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp, for 1 h, then wanned slowly over 4 h to 45 °C.
When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with HiO (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were ^ combined, dried (MgS04) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized, at 0 CC over 72 h to give 4-chloro-Ar-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtO Ac/50% hexane) R/0.50; "H NMR (CDCh) 8 3.04 (d, 7=5.1 Hz, 3H), 7.43 (dd, >5.4, 2.4 Hz, IH), 7.96 (br s, IH), 8.21 (s, IH), 8.44 (d,>5.1 Hz, 1 H); CI-MS m/z 171 ((M+Hf).
Cl- -a HCI Step lb. Synthesis of 4-ch!oropvridine-2-carbony| chloride HCI salt via picoiinic acid 19 P CT/Us00/0<3648 Anhydrous DMF (6.0 ml) was slowly added to SOCl2 (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 CC (vigorous S02 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 HCI salt as a yellow-orange solid (92.0 g, 89%).
Anh DMF (10.0 mL) was slowly added to SOClj (300 mL) at 40-48 °C. The solution was stirred at that temp, range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous SO; 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 HCI 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 CC. The contents were stirred at room temp, for 45 min., cooled to 5 °C and treated with Et20 (200. mL) dropwise. The resulting solids were filtered, washed with EbO (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2- carboxylate HCI salt as a white solid (110 g, 65%): mp 108-112 °C; 'H-NMR (DMSO-d&) 6 3.SS (s, 3H); 7.82 (dd, >5.5, 2.2 Hz, IH); 8.08 (d, >2.2 Hz, IH); 8.63 (d, >5.5 Hz. IH); 10.68 <br s, IH); HPLC ES-MS m/z 172 ((M+Hf).
O OMe Step 2. Synthesis of methyl 4-cbioropyridine-2-carboxylate HCI salt WO 00/42012 PCT/USQ0/QQ64S 0 'NHMe N Step 3a. Synthesis of 4-chloro-A-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carhqxyIate A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 42S mmol) in 5 MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp, below 5 °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 ^ L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na2S04) and concentrated under reduced pressure to afford 4-chloro-/V-methyl-2-10 pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C; 'H-NMR (DMSO-d6) 5 2.81 (s, 3H), 7.74 (dd, >5.1, 2.2 Hz, IH), 8.00 (d, J= 2.2, IH), 8.61 (d, J=5.1 Hz, IH), 8.85 (brd, IH); CI-MS mh 171 ((M+H)+).
O - "NHMe N Step 3b. Synthesis of 4-cbloro-/V-methyl-2-pyridiaecarboxamide from 4-15 chloropyridine-2-carbonyI chloride 4-Chloropyridine-2-carbonyl chloride HCI salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C. The resulting mixture was stored at 3 ®C for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate 20 was washed with a saturated NaCl solution (2 x 100 mL), dried (NajSO-t) and concentrated under reduced pressure to provide 4-chloro-jV-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.
O r^V'NHMe H->N Step 4. Synthesis of 4-(2-(,V-methylcarbamoyl)-4-pyridyloxy)aniline A solution of 4-amincpheno! (9.60 g. 88.0 mmo!) in anh. DMF (150 mL) was treated with potassium /trf-butoxiae (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred al 21 PCT/tlSO0/'OO648 room temp, for 2 h. The contents were treated with 4-chloro-/V-methyI-2-pyridinecarboxamide (15.0 g, S7.9 mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp, and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with 5 EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4 x 1000 mL), dried (l^SO.;) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(/V-methylcarbamoyl)-4-pyridy!oxy)aniline as a light-brown solid 17.9 g, 84%): 'H-NMR (DMSO-d6) 5 2.77 (d, 7=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB* quartet, 7=8.4 Hz, 4H), 7.06 (dd, 7=5.5, 2.5 Hz. 10 IH), 7.33 (d, 7=2.5 Hz, IH), 8.44 (d, 7=5.5 Hz, IH), 8.73 (br d, IH); HPLC ES-MS m/z 244 ((M+H)*)- A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-{4-Aminophenoxy)isoiudoline-l,3-dione NH O Step 1. Synthesis of 5-hydroxyisoindoiine-l,3-dione | To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated 20 at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp, and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN HCI solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-25 hydroxyisoindoline-l,3-dione as a pale yellow powder as product (3.24 g, 72%): !H NMR (DMSO-d6) 5 7.00-7.03 (m, 2H), 7.56 (d, 7=9.3Hz, 1H). wo 00/42032 pct/us00/q 06-48 O Step 2. Synthesis of 5-{4-nitrophenoxy)isoindoline-l,3-dione o2n nh To a stirring slurry ofNaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-l,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 Tt 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 (MgSOO and concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindoline-l,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) R/0.28; IH NMR (DMSO-d6) 5 7.32 (d, >12 Hz, 2H), 7.52-7.57 (m, 2H), 7,89(d, 7=7.8 Hz, IH), 8.29 (d, 7=9 Hz, 2H), 11.43 (br s, IH); CI--MS m/z 285 ((M+Hf, 100%).
A solution of 5-(4-nitrophenoxy)isoindoline-l,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp, for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindoline-l,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtO Ac/50% hexane) R/0.27; lH NMR (DMSO-d6) 5 5.14 (br s, 2H), 6.62 (d, 7=8,7 Hz, 2H), 6.84 (d, 7=8.7 Hz. 2H), 7.03 (d, 7=2.1 Hz, IH), 7.23 (dd, IH), 7.75 (d, 7=8.4 Hz, IH), 11.02 (s, IH); HPLC ES-MS m/z 255 ((M+H)\l00%).
O Step 3. Synthesis of 5-(4-aminophenoxy)isoindoline-l,3-dione a4.
Genera! Method for the Synthesis of Pvrrolylanilines. Synthesis of 5-terr-Butvl-2-(2,5-dimethylpyrrolyl)aniline 23 no2 Step 1. Synthesis of l-(4-/£^butyl-2'nitropbenyl)-2,5-dimethylpyrroIe To a stirring solution of 2-nitro-4-rerf-butylani]ine (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (O.ImL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The 5 reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2CI; (10 mL) and sequentially washed with a IN HCI solution (15 mL), a IN NaOH solution (15 mL) and a saturaied NaCl solution (15mL). dried ( MgSO„) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiOj; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give l-(4-rer/-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtO Ac/85% hexane) R/ 0.67; 'H NMR (CDCI3) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, IH), 7.62 (dd, IH), 7.88 (d, J=2.4 Hz, IH); CI-MS m/z 273 ((M+Hf, 50%).
A slurry of l-(4-iert-butyl-2-nitrophenyl)-2,5-dimethyipyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an Hj atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-/erf--butyl-2-(2,5-dimethyipyrrclyl)aniline as yellowish solids (0.30 g, 20 99%): TLC (10% EtOAc/90% hexane) R/0.43; 'H NMR (CDCh) 5 1.28 (s,9H), 1.87-1.91 (m. EH). 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
N Step 2. Synthesis of 5~tert—Butyl-2-(2,5-dimethylpyrrolyl)aniline 24 PCT/USOO/0064S AS. General Method for the Synthesis of Anilines from Anilines by Nucleopbilic Aromatic Substitution. Synthesis of 4- (2-(A-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt 0 ;0„ NHMe H,N- T HC, Me A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium /err-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-jV-methyl-2-pyridinecajboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp, and diluted with 10 water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCl solution (200 mL), dried (MgS04) and concentrated under reduced pressure. The residual black oil was treated with Et20 (50 mL) and sonicated. The solution was then treated with HCI (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 15 filtration from solution and stored under anaerobic conditions at 0 °C prior to use: lH NMR (DMSO-dfi) 5 2.41 (s, 3H), 2.78 (d, 7=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, 7=8.5, 2.6 Hz, IH), 7.23 (dd, 7=5.5, 2.6 Hz, IH), 7.26 (d, 7=2.6 Hz, IH), 7.55 (d, 7=2.6 Hz, IH), 7.64 (d, ^ 7=8.8 Hz, IH). 8.55 (d, >5.9 Hz, IH), 8.99 (q, 7=4.8 Hz, IH).
A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N- Protection, Nucleophilic Aromatric Substitution and Deprotection. Synthesis of 4-(2-(A/,-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline ,OH CI Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-chioro-4-nitrophenol (10.0 g, 58.0 mmoi) and trifluoroacetic anhydride (20 mL). This gray slum- stirred ai room temp, for 6 d. The iron was filtered from solution and the PCT/USOO/00648 remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added a saturated NaHCO;. solution (50 mL). The solid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined"was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCl solution (125 mL), dried (MgSOa) and concentrated under reduced pressure. The 'H NMR (DMSO-d^) 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 was taken on to the next step without further purification.
A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium ferf-butoxsde (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-,V-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 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 residua] brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4-(2-(/>/-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol). o Step 2: Synthesis of 4-(2-(JV-Methylcarbamoyl)-4-pyridyloxy)-2-chloropbenyl (222-trifluoro)acetamide O Step 3. Synthesis of4-(2-(.V-Methy|carbamoyl)-4-pyridyloxy)-2-chloroaniiine 26 PCT/USOO/00648 A solution of crude 4-(2-(jV-Methylcarbamoyl)-4-pyridyIoxy)-2-chlcrophenyl (222-trifluoro)acetaraide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The-green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield 4-(2-(A;-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR (DMSO-de) 5 2.77 (d, 7=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, >8.5, 2.6 Hz, IH), 6.76 (d, >2.6 Hz, IH), 7.03 (d, >8.5 Hz, IH), 7.07 (dd, >5.5, 2.6, Hz, IH), 7.27 (d, >2.6 Hz, IH), 8.46 (d, >5.5 Hz, IH), 8.75 (q, >4.8, IH).
A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of A suspension of 3-chloro-6-(N-acetyl)-4-(trifluoromethyl)anisole (4.00 g, 14.95 mmol) in a 6M HCI solution (24 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 CH2CI2 (3 x 50 mL). The combined organics were dried (MgSO^t) 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-da) 5 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8. General Method for Synthesis of {o-Alko.xy-o}-carboxyphenyl Anilines. 4-Cbloro-2-methoxy-5-(trifluoromethyl)aniline CF3 OMe Synthesis of 4-(3-(A-Metbylcarbarnoly)-4-methoxyphenoxy)aniline.
O Step 1. 4-{3-Methoxyc3rbonyl-4-methoxyphenoxy)-l-nitrobenzene: 27 PC77USOO/00648 To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from 2,5-dihvdroxybenzoic acid in a manner analogous to that described in Method A13, Step 1,12 mmol) in acetone (50 mL) was added K2CO3 (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 Si02l and purified by column chromatography (50% EtOAc i 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 g): mp 115-118 °C.
'VY^h |l I 02N' ^ ^^OMe 10 Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-methoxycavbonyl-4-methoxyphenoxy)-l-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp, overnight and then heated at. the reflux temp, for 4 h. The resulting mixture was cooled to room temp, and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous 15 mixture was made acidic with a IN HCI solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSOj) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g).
O ,0.
NHMe 02N" ^ ^ "OMe Step 3. 4-(3-0V-Methylcarbamoly)-4-methoxyphenoxy)-l-aitrobcnzene: To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l -nitrobenzene (0.50 g, 1.75 mmol) in CH2CI2 (12 mL) was added SOCI2 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp, for IB h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 25 mmol) in portions (CAUTION: gas evolution), and stirred at room temp, for 4 n. The resulting mixture was treated with a IN NaOH solution, then extracted with CH-CI- (25 rr.L). 28 PCT/USOO/0064S The organic layer was dried (NajSOa) and concentrated under reduced pressure to give 4-(3-(jV-methylcaibamolv)-4-inethoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95%).
Step 4. 4-(3-(Ar-MethylcarbamoIy)-4-methoxyphenaxy)aniline: A sluny of 4-(3-(jV-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene (0.78 g, 2.60 mmol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under I atm of H2 (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-(/V~methylcarbamoIy)-4-methoxyphenoxy)aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) R/0.36.
A9. General Method for Preparation of co-Alkylphthalimide-containing Anilines. Synthesis of 5-(4-Aminopheijoxy)-2-methylisoindoline-l,3-dione o Step 1. Synthesis of 5-(4-Nitrophenoxy)-2-metbylisoindoIine-l,3-dione: A slurry of 5-(4-nitrophenoxy)isoindoline-l,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp, for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The .resulting mixture was stirred at room temp, overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-20 1,3-dion.e as a bright yellow solid (0.87 g, 83%): TLC (35% EtO Ac/6 5% hexane) R/ 0.61. h2n v|— Me O 29 PCT/USOQ/0064S Step 2. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-<iioae: A slurry of nitrophenoxy)-2-methyIisoindoline-l,3-dione (0.87 g, 2.7S mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 aim 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 SiOi (60% EtOAc/40% hexane) to afford 5-(4-aminopherioxy)-2-methylisoindoIine-l,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) R^0.27.
^ A10. General Method for Synthesis of co-Carbamoylaryl Anilines Through !0 Reaction of to-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-{2-(yY-(2-morpholiD-4-ylethyl)carbamoyl)pyridyloxy)ani]ine Step 1. Synthesis of 4-Chloro-2-(Ar-(2-morpholin-4-ylethyl)carbamoyl)pyridiDe 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" (MgSOa)- and concentrated under reduced pressure to 20 afford 4-chloro-2-(A/-(2-morpholin-4-ylethyl)carbamoyl)pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeQH/90% EtOAc) Rf 0.50.
X¥XZ*~-*-0 H2N PCT/USOO/09648 Step 2. Synthesis of 4-(2-(;V-(2-MorphoIin~4-ylethy])carbamoyi)pyridyloxy)aniline. i A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium rerr-butoxide (0.53 a, 4.75 mol) in DMF (8 mL) was stirred at room temp, for 2 h, then was sequentially treated with 4-chloro-2-(Ar-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K2CO3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layeT was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCl solution (3 x 25 mL) and concentrated under reduced pressure. 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) R/0.32.
All. General Method for the Reduction of Nitroarenes to Arylamines.
A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mrnol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2CI2) Rr 0.44 (streaking).
A12. General Method for tbe Synthesis of Isoindolinone-Containing Anilines.
Synthesis of 4-(l-Oxoisoindolin-5-yloxy)aniIine.
Synthesis of 4-{3-Carboxyphen<vxy)aniline.
O o 31 PCT/USOO/00648 Step 1. Synthesis of 5-hydroxyisoindolin-l-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 (1.1 Kg SiOz; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-l-one (3.77 g): TLC (100% EtOAc) R/0.17; HPLC ES-MS m/z 150((M+H)+). f 02N' o io Step 2. Synthesis of 4-(l-isoiBdolinon-5-ytoxy)-l-nitrobenzeije To a slurry of NaH (Q.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-l-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp, and was stirred for 45 min., then 4-fluoro-l-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise 15 until a precipitate formed. The resulting solids were collected to give 4-(l-isomdolinon-5-yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) RyO.35.
NH O W Step 3. Synthesis of 4-(l-oxoisoindolin-5-yIoxy)aniline A slurry of 4-(l-isoindolinon-5-yIoxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C 20 (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford 4-( 1 -oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) Ry-0.15.
A13. General Method for the Synthesis of co-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reductioo.
Synthesis of 4-(3-iY-Methylcarbamoyipbenoxy)aniline. 32 PCT/USOO/00648 oj*' ~ "Of"" Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene A mixture of 4-fluoro-l-nitrobenzene (16 mL, 150 mmol), ethyl 3-hy<iroxybenzoate 25 g, 5 150 mmol) and K2CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp, overnight, cooled to room temp, and treated with water (250 mL). The resulting mixture was k extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed ; with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried fN^SCU) and concentrated under reduced pressure. The residue was purified by column chromatography 10 (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene as an oil (38 g). 03N Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g, 17.9 ^ mmol) in a 3:1 THF/water solution (75 mL).was added a solution LiOH-HjO (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCI 20 solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)-l-nitrobenzene (4.40 g, 95%).
O °YrT^NHMe 02N' PCT/USOO/OQ648 Step 3. Synthesis of 4-(3-(A-methylcarbamoyi)phenoxy)-l-nitrobenzene A mixture of 4-(3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCI'HCI (3.63 g, 18.6 mmol), /v-nnethylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2CI2 (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 IM HCI solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic, phases were washed with a saturated NaCl solution (50 mL), dried (Na2S04), and concentrated under reduced pressure to give 4-(3-(jV-methylcarbamoyl)phenoxy)-l-nitrobenzene as an oil (1.89 g).
O Step 4. Synthesis of 4-(3-(Ar-methylcarbamoyl)phenoxy)aniline A slurry of 4-(3-(/V-methylcarbamoyl)phenoxy)~l-nitrobenzene (1.89 g, 6.95 mmol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred under an H2 arm (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% CH2CI2). The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aniline as a yellow solid (0.95 g, 56%).
A14. General Method for the Synthesis of ©-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-3-(5-Methylcarbamoyl)pyridyloxy)aniline O Step 1. Synthesis of 4-(3-{5-methoxycarbonyl)pyridvloxy)-l-nitrobenzene To 2 slurry ofNaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hvdroxynicoiinate (2.0 g. 13.1 mmo!) in DMF (10 mL). The resulting mixture was added ic a 34 PCTAJSQQ/00648 solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 CC overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The oraanic phase was concentrated under reduced pressure. The residue was purified by column 5 chromatography (30% EtOAc/70% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.60 g).
Step 2. Synthesis of 4-(3-(5-metboxycarboDyl)pyridyloxy)aniline A slurry of 4-(3-(5-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmol) and 10 10% Pd/C in MeOH/EtOAc was stirred under an Hs 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% EtC)Ac/50% hexane) to afford 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline (0.28 g, 60%): 'H NMR (CDCI3) 5 3.92 (s, 3H), 6.71 (d, O OMe 2H), 6.89 (d, 2H), 7.73 (, IH), 8.51 (d, IH), 8.87 (d, IH).
PCT/USOO/0O64S A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction. Synthesis of 4-(3-Methylsuifamoylpbenoxy)aniline. q, ,o ''S"NH(v1e Step 1. Synthesis of jV-methyI-3-bromobenzenesulfonamide 5 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 HCI solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases 10 were sequentially washed with water (2 x 25 mL) and a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure to give /V-methylo-bromobenzenesulfonamide as a white solid (2.8 g, 99%).
V NHMe Step 2. Synthesis of 4-{3-(A-metbylsulfamoyI)phenylox7)ben2ene To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and Cul (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, lOmmol), and the resulting mixture was stirred at the reflux temp, overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCI solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially 20 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO.»), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(W-methylsulfamoyl)phenyloxy)ben2ene (0.30 g).
O, ,0 r\ c fj^Y "NHMe 0?N 36 PCT/USOG/00648 Step 3. Synthesis of 4-(3-(A-methy]su]famoyl)phenyloxy)-l-nitrobenzeDe To a solution of 4-(3-(.;V-methylsulfamoy])phenvlcxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10°C was added NaNOj (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 NaCl solution (10 mL), dried (MgSOj) and concentrated under reduced pressure to give 4-(3-(Af-methylsulfamoy])phenyloxy)-l-nitrobenzene (0.20 g). This material carried on to the next step without further purification.
A slurry of 4-(3-(jV-methylsulfamoyl)phenyloxy)-1 -nitrobenzene (0.30 g) and 10% Pd/C (0.03G g) in EtOAc (20 mL) was stirred under an H2 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-(A^-methylsulfamoyI)phenyloxy)aniline (0.070 g).
Al6. Modification of co-ketones. Synthesis of 4-(4-(l-(A/- To a slurry of 4-(4-acetylphenoxy)aniline HCI salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine 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-('l-(;V-methoxy)iminoethy!) phenoxvaniline HCI salt as a Srep 4. Synthesis of 4-(3-(JV-methylsulfamoyl)pheoyloxy)ani]ine methoxy)immoethyI)pbenoxyaniIjne HCI salt. 3" PCT/USOO/0064S yellow solid (0.S5 g): TLC (50% EtOAc/50% pet. ether) R/0.78; 'H NMR (DMSO-d6)5 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257.((M+H)+). a17. Synthesis of N-(a-SilyloxyaIkyl)amides. Synthesis of 4-(4-(2-(A'-(2- Triisopropylsi]yioxy)ethylcarbamoyi)pyridyloxyaniline.
^ Step 1. 4-Chloro-A'-(2-trii5opropyIsilyIoxy)ethyIpyridine-2-carboxamide To a solution of 4-chloro-jV-(2-hydroxyethyl)pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added 10 triisopropylsilyl chloride (1.59 g, S.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 £tOAc (3x10 mL). The combined organic phases were dried (MgSOo), and concentrated under reduced pressure to afford 4-15 chloro-2-(A''-(2-triisopropylsi3yloxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification. y- -h2n Step 2. 4-(4-(2-(jY-(2-Triisopropylsilyloxy)ethyIcarbamoyl)pyridyloxyaniline To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added 20 potassium rerf-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 K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 SC overnight. An additional portion of potassium /ert-butoxide (0.34 g, 3 mmol, 25 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The mixture was cooled to 0 °C with an ice/water baih, then water (approx. 1 mL) was slowly added Uropwise. The organic layer was extracted with EtOAc (3x10 mL). The combined 38 PCT/USOO/OQ64S organic layers were washed with a saturated NaCl solution (20 mL), dried (MgSO*) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO?; 30% EtOAc/ 70% pet ether) to afford 4-(4-(2-(/V-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 5 38%).
A18. Synthesis of 2-PryidinecarboxvIate Esters via Oxidation of 2- Methylpyridines. Synthesis of 4-(5-(2- methoxycarbonyl)pyridyloxy)aniline. °2N n Step 1. 4-(5-(2-Methyl)pyridyIoxy)-l-nitrobenzene.
A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), l-fiuoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K2CO3 (15 g, 1S3 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room 15 temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCl solution ((100 mL), dried (MgSOj) and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene as a brown solid (12.3 g).
If _ JvJ W jL^-OMe ozn n y O Step 2, Synthesis of 4-(5-(2-MetboxycarbonyI)pyridyloxy)-l-nitrobenzene.
A mixture of 4-(5-(2-methyl)pyridyloxy)-l -nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered , then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The 25 solution was treated with a conc HCI solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a 1 N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially 39 WO 00/42012 PCT/USOO/00648 washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), cried (MgSOj) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCH; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.70 g). ,0. r d ,OMe ° Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.
^ A slurry of 4-(5~(2-methoxycarbonyI)pyridyloxy)-l-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 Hi atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite1', and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S1O2; 70% EtOAc/30% hexane) to give 4-(5-(2- methoxycarbonyl)pvridyloxy)aniline (0.40 g).
AJ9. Synthesis of to-Sulfonylpfaenyl Anilines. Synthesis of 4-(4- MethyIsuIfonylphenyoxy)aniIine. 0,N V Step 1. 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-!-nitrobenzene (2.0 g, 7.7 mmol) in CH2CI2 (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 IN NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgSOa), and concentrated under reduced pressure to give 4-(4-methvlsulfonyiphenoxy)-l-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsulfonylphenoxy)-l-aniline: 4-(4-Methylsulfonyiphenoxv)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method A IS. slop-?. 40 PCT /USQO/9064 8 B Svnthesis of Urea Precursors ■ \ Bl. General Method for the Synthesis of Isocyanates from Anilines Using \ CDI. Synthesis of 4-Bromo-3-(trifiuoromethyl)pbenyl Isocyanate.
CFa nh2-hc! Step 1. Synthesis of 4-bromo-3-(trifluoromethyl)aniline HCI salt To a solution of 4-bromo-3-(trifluorcmethyl)aniline (64 g, 267 mmo!) in EhQ (500 mL) was added an HCI solution (1 M in Et^Q; 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 Et20 {50 mL) and to afford 4-bromo-3-(trifluoromethyl)aniline HCI salt (73 g , 10 98%). cf3 Br> NCO Step 2. Synthesis of 4-bromo-3-(trifluoromethyl)phenyl isocyanate A suspension of 4-bromo-3-(trifluoromethyl)aniline HCI salt (36.8 g, 133 mmol) in toluene 15 (27S 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 CH2CI2 (500 mL), then concentrated under reduced pressure. The CH^Cl; treatment/concentration protocol was repeated and resulting 20 amber oil was stored at -20 °C for 16 h, to afford 4-bromo-3-(trifluoromethyl)pheny! isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (1VT).
C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of!V-{4-Cbloro-3-(trifluoromethy|)phenvl)-A'"- (4-(2-(,V-methyfcarbamoyl)-4-pyridyloxy)phenyl) Urea 41 PCT/USOQ/0064S cf3 0 C,^S> n -nhme n n h h A solution of 4-chloro-3-(trifluoromethyI)phenyl isocyanate (14.60 g, 65.90 mmol) in CH>C1;> (35 mL) was added dropwise to a suspension of 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2CI2 (35 mL) at 0 °C. The 5 resulting mixture was stirred at room temp, for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2CI1 (2 x 30 mL) and dried under reduced ) pressure (approximately 1 mmHg) to afford //-(4-ch'oro-3-(trifluoromethyl)phenyl)-Af '-(4-(2-(jV-methylcarbamoyl)-4-pyridy|oxy)phenyI) urea as an off-white solid (28.5 g, 93%): mp 207-209 °C; *H-NMR (DMSO-d6) 6 2.77 (d, 7=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, 7=2.5 Hz, 10 IH), 7.62 (m, 4H), 8.11 (d, .7=2.5 Hz, IH), 8.49 (d, 7=5.5 Hz, IH), 8.77 (br d, IH), 8.99 (s, IH), 9.21 (s, IH); HPLC ES-MS m/z 465 ((M+H)+).
Clb. General Method for the Synthesis Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A7-(4-Bromo-3-(trifluoromethy!)phenyl)-Ar-15 (4-(2-(Af-methylcarbamoyI)-4-pyridyloxy)phenyl) Urea CF3 O n A solution of 4-bromo-3-(trifluoromethyl)phenyl isocyanate (Method Bl, Step 2; 8.0 g, 30.1 mmol) in CH2C12 (80 mL) was added dropwise to a solution of 4-(2-(;V-methy!carbamoyl)-4-pyridy!oxy)aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2CI2 (40 mL) at 0 eC. The 20 resulting mixture was stirred at room temp, for 16 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 50 mL) and dried under reduced pressure (approximately 1 mmHg) at 40 °C to afford A,-(4-bromo-3-(trifluoromethyl)phenyl}-iV'-(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g. 90%): mp 203-205 ®C; 'H-NMR (DMSO-d6) 5 2.77 (d, >4.8 Hz, 3H). 7.16 (m. 3H). 7.37 {d. 25 7=2.5 Hz, IH). 7.58 (m, 3H), 7.77 (d, >8.8 Hz, IH), 8.11 (d. >2.5 Hz. IH). 8.49 id. 7=5.5 Hz,- 1H), S.77 (br d. l'H). 8.99 (s. IH), 9.21 (s. 1H);H?LC ES-MS m/z 509 ((M-Hf l. 42 PCT/USO0/Q0648 Clc.
General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of /V-(4-Chloro-3-(trifIuoromethyl)phenyl)-A''-(2-metbyI-4-(2-(N-methyIcarbamoyl)(4-pyridyloxy))phenyl) Urea <?F3 0 CI NHMe H h Me A solution of 2-methyl-4-(2-(N-methy]carbamoyl)(4-pyridyloxy))aniline (Method A5; 0.11 g, 0.45 mmol) in CH2CI2 (1 mL) was treated with EtjN (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 (3x5 mL). The combined organic layers were dried (MgSO<t) 10 and concentrated under reduced pressure to yield A'-(4-chIoro-3-(trifluoromexhyl)phenyl)-/V- (2-rnethyl-4-(2-(N-methylcarbamoyl)(4-pyridyloxy))phenyi) urea as a brown oil (0.11 g, 0.22 mmol): 'H NMR (DMSO-d6) 5 2.27 (s, 3H), 2.77 (d, >4.8 Hz, 3H), 7.03 (dd, >8.5, 2.6 Hz, IH), 7.11 (d, >2.9 Hz, IH), 7.15 (dd, >5.5, 2.6, Hz, IH), 7.38 (d, >2.6 Hz, IH), 7.62 (app d, >2.6 Hz, 2H), 7.84 (d, 7=8.8 Hz, IH), 8.12 (s, IH), 8.17 (s, IH); 8.50 (d, >5.5 Hz, IH), 15 8.78 (q, >5.2, IH), 9.52 (s, IH); HPLC ES-MS m/z 479 ((M+Hf).
Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH2CI2 (308 mL) was added /7-phenvlenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp, for 1 h, treated with CH2CI2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture 25 of EtOAc (110 mL) and MeOH (15mL), and the clear solution was washed with a 0.05 N HC! solution. The organic layer was concentrated under reduced pressure to afford impure with an Aniline. Synthesis ofiV-(4-Chloro-3-(trifluoromethyI)phenyl)-W-(4-aminophenyl) Urea 9f3 h h 43 PCT7USOO/00648 /V-(4-chloro-3-(trifluoromethyl)phenyi)-.V-{4-arninopheriyi) urea (3.3 g): iLC (100% EtOAc) R/0.72.
Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of A~{4-Chloro-3-(trifluoromethyl)phenyl)~/V'-(4-ethoxycarbonylphenyl) Urea O O (^V^OEt w H h / To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2CJ2 (30 mL) was added 4-chloro-3-(trifluoromethyl)aniline (3.21 g, 16.4 mmol), and the solution was stirred at 10 room temp, overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to afford A'-(4-chloro-3-(trifluoromethyl)phenyl)-jV'-(4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 57%): TLC (40% EtOAc/60% hexane) R/0.44.
Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of /V-(4-Cbloro-3-(trifluoromethyI)phenyl)-Ar'- (3-carboxy phenyl) Urea cf3 o i o oh - h h To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (1.21g, 5.46 rnmol) in CH2CI2 (8 mL) was added 4-(3-carboxyphenoxy)aniline (Method All; 0.81 g, 5.76 mmol) and the 20 resulting mixture was stirred at room temp, overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1:1 EtOAc,'Tiexane solution to give A'-(4-chloro-3-(trifluoromethyl)phenyl)-,V-(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..Y'- Carbonvl Diimidazole Followed bv Addition of a Second Aniline. 44 PCT/USOQ/OC64S Synthesis of/V-(2-Methoxy-5-(tri.fluoromethy])pbenyl)-.'V'-(4-(2-(.'Y-methykarbamoyl)-4-pyridyloxy)phenyi) Urea r»»j H H OMe To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2CI2 (15 mL) at 0 °C 5 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-(2-(Ar-methylcarbamoyi)-4-^ pyridyloxy)aniline (0.18 g). The resulting yellow solution was stined at room temp, for 72 h, then was treated with HiO (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution 10 (100 mL), dried (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 iV-(2-methoxy-5-(trifluoromethyl)phenyl)-15 N'-(4-(2-(Ar-met.hykarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) Rf 0.62; lH NMR (DMSO-d*) 5 2.76 (d, 7=4.S Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, 7=4.8 Hz, IH), 9.55 (s, 1 H); FAB-MS m/z 461 P ((M+H)*).
C2b. General Method for Urea Synthesis by Reaction of an Aniline wiih ;Y,A"- Carbonyl Diimidazole Followed by Addition of a Second Aniline. Symmetrical Urea's as Side Products of a A^'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2-(Ar-methylcarbamoyl)-4-pyridvloxy)phenyl) Urea O O MeHN' " O H H 45 PCTAJS00/QG64S To a stimng solution of 3-arnino-2-methoxyquinoline (0.14 g) in anhydrous CH;C1; (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-(/V-methylcarbamoyl)-4-pyridylQxy)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 NaCl solution (100 ml), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)phenyi) urea (0.081 g, 44%): TLC (100% EtOAc) R/0.50; 'H NMR (DMSO-d6) 5 2.76 (d, .7=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, >5.4 Hz, IH), 8.75 (d, >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 To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2CI2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-l,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. - The resulting mixture was stirred for 12 h, then was treated with CH2CI2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCI solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSOd) and concentrated under reduced pressure to afford A-(2-methoxy-5-(trifiuoromethyl)phenyl-A''-(4-(l,3-dioxoisoindolin-5-yloxy)phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) R/0.50; 'H NMR (DMSO-d6) 5 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, IH), 8.53 (br s, 2H), 9.57 (s, IH), i 1.27 fbrs. IH): HPLC ES-MS 472.0 ({M-Hf. 100%). with an Aniline. Synthesis of A-(2-Methoxy-5-(trifluoromethyl)phenyl-/V'-(4-(l>3-dioxoisoindolin-5-yloxy)phenyl) Urea o 46 C2d. General Method for Urea Synthesis by Reaction of an Aniline with Carbonvl Diimidazole Followed by Addition of a Second Aniline. Synthesis of ;\-(5-(rerr-ButyI)-2-(2,5-diraethylpyrrolyf)phenyl)-A"-(4-(2-(/V-methylcarbartioyl)-4-pyridylo:iy)phenyI) Urea To a stirring solution of CDI (0.21 g, 1.30 mmol) in CH:C12 (2 mL) was added 5-(rerr-buiyl)-2-(2,5-dimethylp>Trolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp, for 4 h, then 4-(2-(?V-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmol) was then added in one portion. The resulting 10 mixture was heated at 36 °C overnight, then cooled to room temp, and diluted with EtOAc (5 mL). The resulting mixture was sequentially washed with water (15 mL) and a IN HCI solution (15mL), dried (MgSOj), and filtered through a pad of silica gel (50 g) to afford N-{5-(/err-butyl)-2-(2,5-dimethylpyTTolyl)phenyl)-/V'-(4-(2-(A-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0,033 g, 24%): TLC (40% EtOAc/60% hexane) 15 R/ 0.24; lH NMR (acetone-d6) 5 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, IH), 7.51-7.58 (m, 3H), 8.43 (d, >5.4HZ, IH), 8.57 (d, 7=2.1 Hz; IH), 8.80 (br s, IH); HPLC ES-MS 512 ((M+H)\ 100%).
C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichlorcethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial 25 was capped and heat at SO °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.). followed bv diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting 47 PCT/USOO/00648 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 Ar-(2-Melhoxy-5-(trifluorometbyOphenyO-iy'-^-^^jV-metbylcarbamoyl^-pyridyloxy^beijyl) Urea To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH:C1: (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-5-(trifiuoromethyl)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-(/vr-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 NaHCOj solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgS04), and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and' absorbed onto Si02 (100 g). Column chromatography (300 g SiOz; gradient from 1% Et3N/33% EtOAc/66% hexane to 1% EtjN/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of Ar-(2-methoxy-5-(trifluoromethyl)phenyl)-/V'-(4-(2-(A;-methyicarbamoyl)-4-pyridyloxy)phenyl) urea (0.44 g): TLC (1% EtjN/99% EtOAc) R/ 0.40. 4S PCT/US00/Q0648 D. Inter-conversion of Ureas Dla. Conversion of ©-Aminophenyl Ureas into co-(Arovlamino)phenyl Ureas.
Synthesis of yV-(4-Chloro-3-((trifhioromethyl)phenyl)-./V"-(4-(3-methoxycarbonylpbenyI)carboxyaminopheny!) Urea CF, To a solution of 7V-(4-chIoro-3-((trifluoromethyl)phenyl)-Ar'-(4-aminophenyl) urea (Method ) Cld; 0.050 g, 1.52 mmol), mo/io-methyl isophthalate (0.25 g, I.3S mmol), HOBT-HjO (0.4] g, 3.03 mmol) and /V-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI *HC1 (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp, overnight, 10 diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHCC>3 solution (25 mL). The organic layer was dried (Na2SC>4) and concentrated under reduced pressure. The resulting solids were triturated wi'h an EtOAc solution (80% EtOAc/20% hexane) to give Ar-(4-chloro-3-((tr;f]uoromethyl)phenyl)-/V'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% 15 EtOAc/20% hexane) R/0.75.
Dlb. Conversion of co-Carboxyphenyl Ureas into ©-(Arylcarbamoyl)phenyl ^ Ureas. Synthesis of /V-(4-Chloro-3-((trifluoromethyI)phenyl)-./V'-{4-(3- methylcarbamoylphenyl)carbamoylpbenyl) Urea To a solution of Ar-(4-chloro-3-((trifluoromethyl)phenyl)-/v"-(4-(3-methyicarbamoylphenyt) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBT'HjO (0.14 g, 1.07 mmol), and /v'-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCI*HC1 (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 (lOmL), and extracted with EtOAc (25 mL). The organic phase was concentrated 49 PCTAJS00/0064S undeT 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/3(3% hexane to 10% MeOH/90% EtOAc) to give /Y-{4-chloro-3-((trifluoromethyl)phenyl)-A'"-(4-(3--methylcarbamoylphenyl)carbamoyiphenyl) urea as a white solid (0.097 g, 41%): mp 225-5 229; TLC (100% EtOAc) R/0.23.
D1 c. Combinatorial Approach to the Conversion of co-Carboxyphenyl Ureas into (o-(Arylcarbamoyl)phenyl Ureas. Synthesis of jV-(4-Ch]oro-3-((trifluoromethyl)phenyl)-A"-(4-(N-(3-(N-(3-^10 pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) Urea X* A mixture of A/-(4-chloro-3-((trifluoroir.,;thyl)phex\yl)-iVr'-(3-caiboxyphervyl) urea (Method Clf; 0.030 g, 0.067 mmol) and /V-cyc]6he.\yl-Ar'-(methylpolystyTene)carbodiimide (55 mg) in 15 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CHjC12 (I M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then ^ treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were ? treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture was 20 stirred at 36 °C for 72 h, then cooled to room temp, and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded iV-(4-chloro-3-((trifluoromethyl)phenyl)-Ar,-(4-(N-(3-(N-(3- pyridyl)carbamoy!)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R/0.12.
D2. Conversion of co-Carboalkoxyaryl Ureas into o-Carbamoylaryf Ureas.
Synthesis of .V-(4-Chloro-3-((trinuoroniethyl)pbenyl)-;V'-(4-(3-methyicarbamoylphenyi)carboxyaminophenyl) Urea 50 PCT/US00/9O648 CI NHMe H H To a sample of jV-(4-chloro-3-((trifiuoromethyl)phenyl)-iV'-(4-(3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 ml, 1.7 mmol) and the resulting mixture was stirred at room temp, overnight, then concentrated 5 under reduced pressure to give //-(4-ch]oro-3-((trifluoromethyI)phenyl)-jV"-(4-(3-methylcarbamoylphenyl)carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% 0 EtOAc) R/0.35.
D3. Conversion of oCarboaikoxyaryl Ureas into co-Carboxyaryl Ureas.
Synthesis of AL(4-Chloro-3-((trifluoromethyl)phenyl)-./V'-{4- To a slurry of Ar-(4-chloro-3-((trifluoromethyl)phenyl)-A,'-(4-ethoxycarbonylphenyI) 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 HCI 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)-A'"-(4-carboxyphenyl) urea as a white solid (5.05 g, 92%).
D4. General Method for the Conversion of co-AIkoxy Esters into co-AIkyl Amides, Synthesis of j\-(4-Cbloro-3-((trifluoromethyl)phenyl)-/V'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxypbenyl) Urea carboxyphenyl) Urea H H H H 51 PCT/US00/CQ648 Step 1. Synthesis of jV-(4-Chloro-3-(trjfluoromethyi)phenyl)-/V'-((4-(3-(5-carboxypyridyl) oxyphenyl) Urea A^4-Chloro-3-(trifiuoromethyl)phenyl)-A'"-((4-(3-(5-methoxycarbanylpyridyl)oxypheny!) 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 AL(4-chIoro-3-{trifluoromethyl)phenyl)-Ar'-((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 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 m(4-chloro-3-(irifluoromethyl)phenyl)-Ar,-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%). h h Step 2. Synthesis of Ar-(4-chloro-3-(trifluoromethyl)phenyI)-jV'-((4-(3-(5-(2- dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea A mixture of //-(4-chloro-3-(trifluoromethyl)phenyl)-JV'-((4-(3-(5- carboxypyridyl)oxypbenyl) urea (0.050 g, 0.011 mmol), A^-dirnethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), jV-methylmorpholine (0.035 g, 0.28 mmol), 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 Et^O dropwise to give A-(4-chloro-3-(trifluoromethyl)phenyl)-Ar'-((4-(3-(5-(2-dimethylaminoethyl)carbamoyl)pyridyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: 'H NMR (DMSQ-d6) 5 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 2H), 8.05 (s, IH), 8.43 (s, IH), 8.58 (t, IH), 8.69 (s. IH). S.90 (s, IH)". 9.14 (s. IH); HPLC ES-MS m/z 522 ((M-H)").
PCT7US00/QG648 D5. General Method for the Deprotection of i\'-(o>-Silyloxyalkyl)amides.
Synthesis of iV-(4-Chloro-3-((trifluoromethyl)pbenyl)-/Y'-{4-(4-(2-(A-(2-bydroxy)ethylcarbamoyl)pyridytoxyphenyl) Urea. 9f3 - 9 y.
To a solution of Ar-(4-chloro-3-((trif]uorornethyl)phenyl)-/V'-(4-(4-(2-(/V-(2-triisopropylsilvloxy) ethylcarbamovljpyridyloxyphenyl) urea (prepared in a manner ^ analogous to Method CI a; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (] .0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3x10 10 mL). The combined organic layers were dried (MgSO*) and concentrated under reduced pressure. The residue was purified by column chromatography (SiOi; gradient from 100% hexane to 40% EtOAc/60% hexane) to give JV-(4-chlort-3-((trinuorornethyl)phenyl)-.V-(4-(4-(2-(Ar-(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-Af-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, 3-/er/-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-//-Methylcarbamoylphenoxy)anilme to afford the urea.
Entry 2: 4-Fluoro-l-nitrobenzene and /7-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxyjanili-ne. According to Method C3, 3-ferr-butylaniline was reacted with bis(iric'nloromeihvl) carbonate followed by 4-(4-aceiy!phenoxy)aniiine lo afford the urea. 53 PCT/USOQ/00648 Entry 3; According to Method C2d, 3-/en'-butylaniline was treated with CDI, followed by 4-(3-jV-melhylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 4: 5-/err-Butyl-2-methoxyaniline was converted to 5-/er/-butyl-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Ar-Methylcarbamoylphenoxy)aniline, prepared according to Method A13, was reacted with the isocyanate according to Method Cla to afford the urea. ^10 Entry 5: According to Method C2d, 5-rerr-butyl-2-methoxyaniline was reacted with CDI followed by 4-{3-Ar-methylcarbamoyl)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 6: 5-(4-Aminophenoxy)isoindoline-l,3-dione was prepared according to Method A3. 15 According to Method 2d, 5-ferr-butyl-2-methoxyaniline was reacted with CDI followed by 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.
Entry 7: 4-(l-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. According to Method 2d, 5-ferr-butyl-2-methoxyaniline was reacted with CDI followed by 4-(l-oxoisoindoIin-5-yloxy)aniline to afford the urea.
Entry 8: 4-(3-iV-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-Ar-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)-5-nitropyridine was reduced to 4-(4-acetylphenoxv)-5-aminopyridine. 2-Methoxy->(trifluoromethyl)aniiine was convened to 2-methoxy-5-50 (trifluorornethy!}pheriyl isocyanate according to Method Bl. The isocyanate was reacted with 4-{4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea. 54 PCT/US00;0064S Entry 10: 4-Fluoro-l-nitrobenzene and /?-hydroxyacetophencne were reacted according to Method A13, Step 1 to afford the 4-(4-acety]pheno.xy)-]-nitrobenzene. 4-(4-AcetyIphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline. According to Method C3, 5-(trifIuoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-{4-acetylphenoxy)ani!ine to afford the urea.
Entry 11: 4-Chloro-/V-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3 a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(-2-(/V-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethy])aniline was reacted with phosgene followed bv 3-(-2-(jV-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 12: 4-Ch!nropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-^-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-Ar-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-jV-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-{Ar-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2a, 2-methoxy-5-(trifluoromethyl)ani]ine was reacted with CDI followed by 4-(2-(A'-methvlcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 14: 4-Chlorapyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chioro-2-pyridinecarboxamide was reacted with 4-aminophenoi according to Method A2. Step 4 using DMAC in place of DMF to give 4-(2-carbamoyI-4-pyridyloxy)aniline. According to Method PCT/USOO/00648 C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamovl-4-pyndyloxy)aniline to afford the urea.
Entry 15: According to Method C2d, 5-(triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4-(3-Ar-methylcarbamoyI)-4-methoxyphenoxy)aniline, which had been prepared according to Method A8, to afford the urea.
Entry 16: 4-(2-(/V-Methylcarbamoyl)-4-pyridyloxy)-2-methyIani]ine was synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. The isocyanate was reacted with 4-(2-(//-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method Clc to afford the urea.
Entry 17: 4-(2-(Af-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(jV-methy!carbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method Cla to afford the urea.
Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chioro-AT-methyS-2-pyriciinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(//-metbylcarbamoyl)-4-pyridyIoxy)-4-methyianiline. 5-(Trifluoroinethyl)-2-methbxyaniline was converted into 5-(trifluoromethy])-2-methoxyphenyl isocyanate according to Method Bl. 5-{Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(2-(jV-rnethylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method Cla 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-(V-ethyl-2-pyridinecarboxamide was reacted with 4-aninopher.ol according to Method A2, Step 4 to give 4-(2-(A;-ethylc2rbannoyl)-4-pyridyloxy )aniline. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifiuoromethyi)- PCT/USOO/00648 2-mcthoxyphenyl isocyanate was reacted with 4-(2-(jV-ethylcarbamoyl)-4-pyridyloxyjaniIine according to Method Cla to afford the urea.
Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-yV-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(/v'-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluororaethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(Ar-methyIcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method C1 a to afford the urea.
Entry 21: 4-(4-Methylthiophenoxy)-l -nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-l-aniline. According 15 to Method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea. was reduced to 4-{3-According to Method Cla, 5-reacted with 4-(3- Entry 23: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. 5-(Trif]uoromethy])-2-methoxyani]ine was converted into 5-(trifluoromethyl)-2-25 methoxyphenyl isocyanate according to Method Bl. 5-{Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoIine-l,3-dione according to Method C1 a to afford the urea.
Entry 24: 4-Chloropyridine-2-carbonyI chloride was reacted with dimethyiamine according 30 to Method A2. Step 3b. The resulting 4-chicro-/V.;V^dimethyl-2-pyricinecarbcxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-I2-I.Y..V-dimethylcarbamoyl)-4-pyridyloxy)ani!tne. 5-(Trifluoromethy!}-2-methoxyaniline u as Entry 22: 4-(3-carbamoylphenoxy)-l-nitrobenzene carbamoylphenoxy)anilin-e according to Method A15, Step 4 (trif]uoromethyI)~2-methoxyphenyl isocyanate was carbamoylphenoxy)aniline to afford the urea. ■' 57 PCTAJSOO/00648 convened into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted wiih 4-(2-{/V,A-dimethylcarbamoy!)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 25: 4-(l-OxoisoindoIin-5-yloxy)aniline was synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(l-oxoisoindolino-yloxy)aniline according to Method C2d to afford the urea.
Entry 26: 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 A13, Step 4 to afford 4-(4-acetylphenoxy)aniIine, which was converted to the 4-(4-(l-(Ar-methoxy)iminoethyl)phenoxyaniline HCI salt according to Method A16. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoroiriethyl)-2-methoxyphenyl isocyanate according to Method BL 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-{l-(A-rnethoxy)immoethyl)phenoxyaniline HCI salt to Method Cla to afford the urea.
Entry 27; 4-Chloro-A-methylpyridinecarboxamide 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-(/V-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyI isocyanate was reacted with 4-(4-(2-(.V-methylcarbamoyl)phenylthio)aniline according to Method Cla to afford the urea.
Entiy 28: 5-{4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. 5-(Trifmoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoroinethyl)-2-methoxyphenyl isocyanate was reacted with 5-{4-aminophenoxy)-2-methylisoindoIine-lt3-dione according to Method Cla to afford the urea.
Emr/ 29: 4-Chloro-vV-methylpyricinecarboxamide was synthesized as described in Method A2. Slep 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method 53 PCT/USOO/00648 A2, Step 4 to give 3-(4-(2-(jV-methylcarbamcyl)phenylthio)aniline. 5-(Trifiuoromethyl)-2-methcxyaniline was converted into 5-{trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-Tnethoxyphenyl isocyanate was reacted with 3-(4-{2-(jV-methylcarbamoyl)phertylthio)aniline according to Method Cla 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-jV-isopropyl-2-pyridinecarboxamide .was reacted with 4-aminophenoI according to Method A2, Step 4 to give 4-(2-(A'-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-{Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyi)-2-methoxyphenyl isocyanate was reacted with 4-(2-(/V-isopropyicarbamoyl)-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 31: 4-(3-{5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-metboxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyi isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycaxbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. Ar-(5-(Trifluoromethvl)-2-methoxypheiiyl)-/vr'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-arninoethyl)morpholine to afford the amide according to Method D4, Step 2.
Entry 32: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. A^-{5-(Trif]uoromethyl)-2-methoxypheny!)-Ar-{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. 59 PCT/USOOV00648 Entry 33: 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxypheny! isocyanate according to Method Bl. 5-(Trifluoromethyi)-2-methoxypheny! isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method Cla to afford the urea. .V-(5-(Trifluoromethyl)-2-methoxyphenyl)-/V'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N'./V-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 34: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifiuoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxvphenoxy)aniline was reacted with 5-(triflucromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifiUoromethyl)-2-methoxyphenyl)-.V'-(3-carboxyphenyl) urea, which was coupled with 3-arninopyridine according to Method Die.
Entry 35: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-{trifluoromethyl)-2-methoxypheny] isocyanate according to Method Clf to afford N-(5-{trifluoromethyl)-2-methoxyphenyl)-A''-(3-carboxypheny!) urea, which was coupled with N-(4-fluorophenyl)piperazine according to Method Die.
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethy])-2-methoxyaniline was converted into 5-(trifluoromethy])-2-methoxypheny] isocyanate according to Method Bl. 4-(3-Carboxvphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford jV-(5-(trifluoromethyl)-2-methox>rphenyl)-iV"-(3-carbox>pheny!) urea, which was coupled with 4-fluoroaniline according to Method Die.
Entry 37: 4-(3-Carboxyphenoxy)aniiir.e was synthesized according to Method All. 5-(Trifluororneihyl)-2-methoxyaniiine was converted into 5-(trif!uoromethyl)-2-methoxyphenyl 60 PCT/US00/0064S isocyanate according to Method Bl. 4-{3-Carboxyphenoxy)ani]ine was reacted with 5-(trifIuoromethy!)-2-methoxvphenyl isocyanate according to Method Clf to afford ,V-(5-(triiluoromethyl}-2-methoxyphenyl)-A7'-(3-carboxypheny]) urea, which was coupled with 4-(dimethyiamino)aniline according to Method Die.
Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifiuorornethyl)-2-rnethoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyI isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford ;V-(5-(trifluoromethyl)-2-methoxypheny])-Ar'-(3-carboxypheny]) urea, which was coupled with 5-a_mino-2-rnethoxypyridine according to Method Die.
Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-iV'-(3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method Die.
Entry 40: 4-(3-Carboxyphenoxy)aniiine was synthesized according to Method All. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford /V-(5-<trifluoromethyl)-2-methoxyphenyl)-Ar'-(3-carboxyphenyl) urea, which was coupled with N-(2-pyridyl)pipera2ine according to Method Die.
Entry 41: 4-(3-{ALMethylcarbamoyl)phenoxy)aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3-(trifiuoromethyl)aniline was convened to the isocyanate, then reacted with 4-(3-(;V-Methylcarbamoyl)phenoxy)aniline to afford the urea. 61 PCT/USOO/00648 Entry 42: 4-(2-,V-Methylcarbamyl-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-3-(trif!uoromethyI)phenyl isocyanate was reacted with 4-(2-A'-methyIcarbamyl-4-pyridyloxy)aniline according to Method Cla to afford the urea.
Entry 43: 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 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluorornethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to •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 15 form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyIoxy)aniIine to afford the urea.
Entry 45: 4-Chloro-Ar-methyl-2-pyridinecarboxamide, which was synthesized according to 20 Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to -form 3-(-2-{Ar-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trii]uoromethyl)phenyl isocyanate was reacted with 3-(2-(/V-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entiy 46: 5-(4-Aminophenoxy)isoindoline-l,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-l,3-dione to afford the urea.
Entry 47: 4-(2-(/V-Methylcarbarnoy!)-4-pyridyloxy)-2-methy!aniliue was synthesized }0 according to Method A5. According to Method Clc, 4-chloro-3-(!rifluorornethyl)pheny! isocvanate was reacted with 5-<4-aminophenoxy)isoindoHne-l,3-dione to afford the urea. 62 PCT/USOO/0064S Entry 4S: 4-(3-A-Methy3sulfarnoyl)phenyloxy)ani3ine was synthesized according to Method A15. According to Method Cla, 4-chloro-3-(trifiuoromethyl)phenyl isocyanate was reacted with 4-(3-/V-methy!su]famoyl)phenyloxy)aniiine to afford the urea.
Entry 49: 4-(2-(//-MethylcarbamoyI)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(>V-methylcarbamoyI)-4-pyridyloxy)-2-chIoroaniline to afford the urea.
Entry 50: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-//-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(jV-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-[2-(N-methy!carbamoyl)-4-pyridy3oxy)-4-methylaniline to afford the urea.
Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-jV-ethy 1-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(//-ethylcarbamoyl)-4-. pyridyloxy)aniIine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was rcacted with 4-(2-(iV-ethylcarbamoyl)-4-pyridy!oxy)aniline to afford the urea.
Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-/V-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(iV-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)pheny] isocyanate was reacted with 4-(2-(/V-methyicarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 53: 4-(4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method A19. Step 1 to give 4-{4-methylsulfonylphenoxyVl-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methyisuIfony!phenoxv)-l-aniline. According, to Method Cla, 4-chloro-3-{trifluoromethyl)pheny 1 isocyanate was reacted with 4-{4-meihylsulfonyiphenoxy)-1 -aniline io afford the urea. wo 00/42012 PCTYUS00/[)O648 Entry 54: 4-Bromobenzenesulfony] chloride was reacted with methylamine according to Method A15, Step 1 to afford A-methyl-4-bromobenzenesulfonamide. /V-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(Ar-methylsulfamoyl)phenoxy)benzene.
Methylsulfamoyi)phenoxy)benzene was converted into 4-(4-(;V-methyisulfamoyl)pherioxy)-1-nitrobenzene according to Method AI5, Step 3. 4-(4-(//-Methylsulfamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(4-A^-methylsulfamoy!)phenyloxy)ajailine according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluorornethyl)phenyl. isocyanate was reacted with 4-(3-jV-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Entry 55: 5-Hydroxy-2-methylpyridine was coupled with ]-fluoro-4-nitrobenzene according to Method AI8, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A1S, Step 2 to give 4-(5-{2-methoxycarbonyl)pyridyloxy)-l -nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)ani]ine. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method Cla to afford the urea.
Entry 56: 5-Hydroxy-2-methy3pvridine was coupled with l-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene. ' The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyI)pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)ani!ine. The aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method Cla to give vV-(4-chloro-3-(trifluoromethyi)phenyl)-/V'-(4-{2-{methoxycarbonyl)-5-pyridyloxy)phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to afford A-(4-chloro-3-(trifluoromethyl)phenyl)-/V'-(4-(2-(:V-rnethylcarbamoyl)-5-pyridyloxy)phenyl) urea.
Entry 57: ,V-(4-Chloro-3-(tnfluoromethyl)phenyl-,\".(4-aminophenyi) urea was orepared according to Method Cld. JV-(4-Chloro-3-(tnflucromethyl)phenyi-/V,"-(4-aminophenyl) urea was coupied with «io/;o-methyl isophthalate according to Method Dla to afford the urea. 64 PCT/L'SOO/00643 Entry 5S: Ar-(4-Chloro-3-(trif3uoromethyl)pheny]-A'T,-(4-aminophenyl) urea was prepared according to Method Cld. Ar-(4-Chloro-3-(trif3uoromethyl)phenyl-/V'-(4-aminopnenyl) urea was coupled with mono-methyl isophthalate according to Method Dla to afford .V-(4-chloro-3-(trifluoromethyl)phenyl-Ar,-(4-(3-methoxycarbony3phenyl)carboxyaminophenyl) urea. According to Method D2, AL(4-ch]oro-3-(trifIuoromethyl)phenyl-/V'-(4-(3-methoxycarbonylphenyl)carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.
Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-JV,A|r-dimethyl-2-pyTidinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2 dimethylcarbamoyl)-4-pyridyloxy)anilrae. According to Method Cla, 4-chloro-3-(trifluoromethy])phenyl isocyanate was reacted with 4-(2-(Ar,/V-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the area.
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 converted to the 4-(4-(l-(N-methoxy)iminoethyl) phenoxyaniline HCI salt according to Method A16. According to Method Cla, 4-ch]oro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
Entry 61: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l -nitrobenzene was -coupled with 4-(2-aminoethyI)morpholme according to Method A13, Step 3 to give 4-(3-(;V-(2-morpholinylethyl)carbamoy])phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(A'-(2-morphoIinylethyI)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-{/v'-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chJoro-3-(tri fluoro methy I )p heny 1 isocyanate was reacted with 4-(3-(.V-(2-morphoiiny!ethyl)carbamoy|)phenoxy)aniline to afford the urea. 65 PCT/USOO/00648 Entry 62: 4-{3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-{3-Carboxyphenoxy)-]-nitrobenzene was coupled with l-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(A-(2-piperidylethyl)carbamoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-{3-(A"-(2- piperidylethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-(.V-<2-piperidylethyi)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(iV-(2-piperidylethyl)carbamoyl)phenoxy)aniline to afford the urea. ao Entry 63: 4-(3-CarboXyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(A-(tetrahydrofurylmethyl)carbarnoyl)phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(Ar-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-l-nitrobenzene was reduced to 4-(3-15 (A-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline. According to Method Cla, 4-chloro-3-(trifluoroinethyl)phenyl isocyanate was reacted with 4-(3-(A'-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.
Entry 64: 4-(3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, 20 Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyl-l-^ ethylpyrrolidine according to Method. A13, Step 3 to give 4-(3-(A'-((l-methylpyrrolidinyl)methyl)carbamoyi}phenoxy)-l-nitrobenzene. According to Method A13 Step 4, 4-(3-(Ar-((l-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-l -nitrobenzene was reduced to 4-(3-(Ar-((l-methylpyrrolidinyl)methyl)carbamoyI)phenoxy)aniline. According to 25 Method Cla, 4-chloro-3-{trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(/V-(( 1 -methylpyrTolidinyl)methyl)carbamoyl)phenoxy)aniiine to afford the UTea.
Entr>' 65: 4-ChIoro-A-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method 30 A2, Step 4 to give 4-(4-(2-(A'-methylcarbamoyl)phenylthio)ani]ine, According to Method Cla. 4-chlorG-3-(tnf!ucromelhyl)phenyl isocyanate was reacted wuh 4-(4-(2-<.V-meihylcarbamoy!)phenylthio)aniline to afford the urea. 66 PCT/L'SOO/00648 Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-A'-isopropyl-2-pyridinecarboxarnide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(;V-isopropylcarbarnoyl)-4-pyridyloxy)aniline. According to Method Cla, 4-chloro-3-(trifiuoromethyl)phenyl isocyanate was reacted with 4-(2-(.V-isopropvlcarbamoyl)-4-pyridyloxy)aniIine to afford the urea.
Entry 67: A-(4-Chloro-3-(trifluoromethyl)phenyl-Ar'-(4-ethGxycarbonylphenyl) urea was synthesized according to Method Cle. Ar-{4-Chloro-3-(trifluorornethyl)phenyl-iV"-(4-ethoxycarbonylphenyl) urea was saponified according to Method D3 to give jV-(4-chloro-3-(trifluoromethyl)phenyl-//'-(4-carboxyphenyI) urea. Ar-(4-Chloro-3-(trifluoromethyl)phenyl-Ar'-(4-carboxyphenyl) urea was coupled with 3-methy)carb"amoylaniline according to Method Dlb to give Ar-(4-chloro-3-(trifluoromethy])phenyl-Ar (4-(3- methvlcaib^moyiphenyl)carbamoylphenyl) urea.
Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline-l,3-dione was synthesized according to Method A9. According to Method Cla, 4-ch]oro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-{4-aminophenoxy)-2-methyiisoindoline-l,3-dione to afford the urea.
Entry 69: 4-Chloro-A-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-(/'/-methylcarbamoy])phenylthio)axxiiine. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-methyIcarbamoyl)phenylthio)aniline to afford the urea.
Entry 70: 4-(2-(Ar-(2-Morpholin-4-ylethyl)carbamovl)pyridyloxy)aniline was synthesized according to Method A10. According to Method Cla, 4-chloro-3-(trif]uorcmeihyl)phenyI isocyanate was reacted with 4-(2-(.V-(2-morpholin-4-ylethy\)caTbamoyi)pyridyloxy)ani]ine to afford the urea. 67 PCT/US00/GG648 Entry 71: 4-(3-(5-Methoxycarbonyl)pyridy]oxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethy])-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyI)pyridyloxy)aniline according to Method Cla to afford the urea. ,V-(4-Chloro-3-(trifluoromethyl)phenyl)-iV'-(4-(3-(5-methoxycarbony]pyridyI)oxy)phenyi) 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)pyridyIoxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trif]uoromethyl)phenyI isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)ani]ine according to Method Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-A"-(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 Cla to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-/V'-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with A.A-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
Entry 74: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-A-(2-triisopropylsiiyloxy)ethylpyridine-2-carboxamide. 4-Chioro-Ar-{2- triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-{4-(2-(/V-(2-triisopropylsiIyloxy)ethyIcarbamoyl)pyridyloxyaniline. According to Method Cla, 4-chloro-3-(trifiuoromethyl)pheny! isocyanate was reacted with 4-(4-(2-(A-(2-triisopropyIsilyloxy)ethylcarbamoyl) pyridyloxyaniline to afford A'-{4-chloro-3-((irifluoromeihy!)phenyl)-/V"-(4-(4-(2-(;V-{2-tnisopropyl5i!yloxy) ethylcarbamoyOpyridyloxyphenyl) urea. 68 PCT/US00/fiO64S Entry 75: 4-(3-Carboxyphenoxy)ajiiline was synthesized according to Method All. 4-Chioro-3-(trif3uoromethyl)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 Die.
Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-{4~ acetylphenyl)piperazine according to Method Die.
Entry 77: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifiuoromethyl)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 Die.
Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-(dimethylarnino)aniline according to Method Die.
Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chioro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniIine according to Method Clf to afford the urea, which was coupled with A-phenylethylenediamme according to Method Die.
Entry 80: 4-{3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-Chloro-3-(trifluoromethy!)pheny] isocyanate was reacted with 4-(3-caiboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 2-methoxyethvlamine according to Method Die.
Entry 81: 4-(3-Carboxyphenoxy)aniiine was synthesized according to Method All. 4-C'nloro-3-lirinuoromeihy!)pheny! isocyanate was reacted with 4-(3-carboxyphenoxy)aniSir!e 69 PCT/USOO/00648 according to Method Clf to afford the urea, which was coupled with 5-ainino-2-methoxypyridine according to Method Die.
Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All. 4-5 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniIine according to Method Clf to afford the urea, which was coupled with 4-morpholinoajiiline according to Method Die.
* Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1. 4-10 Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with jV-{2-pyridyl)piperazine according to Method DI c.
• Entry 84: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with 2-15 hydroxyethylarnine according to Method A2, Step 3b to form 4-chloro-A''-(2-triisopropylsi3yloxy)ethylpyndine-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-(/vr-(2-triisopropylsilyloxy)ethylcarbamoy])pyridyloxyaniline. According to Method Cla, 4-chIoro-20 3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(/vr-(2-® triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give Ar-(4-chloro-3-((tn f! uorom ethyl)phenyl)-./V '-(4-(4-{2-(A-(2- triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford Ar-(4-chloro-3-((trifluoromethyl)phenyl)-/v"-(4-(4-(2-(JV-(2-25 bydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.
Entry 85: 4-(2-(Ar-Methyicarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyi)phenyi isocyanate according to Method Bl. According to Method Cla, 4-30 brorno-3-(trifiUoromethyl)phenyl isocyanate was reacted with 4-(2-(.V-metbylc2rbarnoy!)-4-pyridvioxy)ani!ine to afford the urea. 70 PCTAJSOO/00648 Entry 86: 4-(2-(A-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)ani]ine was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trif]uoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-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-Af-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(A-methyIcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A7-methylcarbamoyl)-4-pyridyloxy)-3-chloroamline to afford the urea.
Entry 88: 4-ChJoropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-//-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(jV-ethyicarbamoyl)-4-pyridyloxy)ani]ine. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 89: 4-Chloro-/v'-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-(;V-methylcarbamoyl)-4-pyridyloxy)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-(trif]uoromethyl)phenyl isocyanate was reacted with 3-(•2-(A;-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 90: According to Method A2, Step 4, 5-arnino-2-methyiphenol was rcacted with 4-chloro-.V-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2. Step 3b, to give 3-{2-(/V-methy]carbamoyl)-4-pyridyloxy)-4-meiby!aniline. 4-Bromo-?- PCTAJSQO/00648 (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyI)phenyl isocyanate according to Method Bi. According to Method Cla, 4-bromo-3-{trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(/V-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
Entry 91: 4-Chloropyridine-2-carbonyI chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chlorQ-//,Mdiniethyl-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 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-^-(/^iV-dimethylcarbamoyl^-pyridyloxyJaniline to afford the urea.
Entry 92: 4-Chloro-/V-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-amino'hiophenol according to Method A2, Step 4 to give 4-(4-(2-(//<-methylcarbamoy3)pher,ylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(/V-methylcarbamoyl)phenylthio)aniline to afford the urea.
Entry 93: 4-Chloro-iV-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-(Ar-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-{trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(Af-meihylcarbaTTioyl)phenyhhio)aniline to afford the urea.
Entry 94: 4-(2-(iV-(2-Morpbolin-4-yiethy])carbamoyl)p>Tidyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-{irifluoronnethyl)ani]ine was converted into 4-bromo-3-{trifluoromethyl)phenyi isocyanate according to Method B I. According to Method C la, 4- PCT/USQO/00648 bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(A-(2-Morpholin-4-ylethyl)carbamoy!)pyridyloxy)ani]ine to afford the urea.
Entry 95: 4-(2-(A/-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5-(trif]uoromethy])aniline was synthesized according to Method Al. 4-Chloro-2-methoxy-5-(trif]uoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trif]uoromethyi)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethy!)phenyl isocyanate was reacted with 4-(2-(//-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 96: 4-(2-{A'-Methylcarbamoyl)-4-pyridyloxy)-2-ch]oroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method Al. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniliiie was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-niethoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)-2-ch]oroaniline afford the urea.
Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-A-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(A-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 Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(/V-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
Entry 98: 4-Chloro-A'-methyl-2-pyridinecarboxarnide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminopheno! according to Method A2, Step 4 to form 3-{-2-(A;-methylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-metho\v-5- (trif!uoromethyl)aniline W2S synthesized according to Method Al. 4-Chloro-2-methoxy-5-(trifluorornethyl)aniiins was convened into 4-chloro-2-rnethoxy-5-{trifIuoron:cth} l)phcnyl isocyanate according to Method B!. According "to Method Cla. 4-chloro-2-mcthoxy-5- PCT/USOQ/0064S (trifluoromethyl)phenyl isocyanate as was reacted with 3-(-2-(Af-methylcarbarnoyi)-4-pvridyloxy)aniline to afford the urea.
Entry 99: 4-Ch]oropyridine-2-carbonyi 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-(/V-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trif]uoromethyl)aniline was synthesized according to Method Al. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chIoro-2-methoxy-5-(trif]uoromethyl)phenyl isocyanate was reacted with 4-(2-(Ar-ethyicarbamoyl)-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-ch)oro-A',Af-dimethy]-2-pyridinecarboxaniide was reacted with 4-aminophenol according to Method Al, Step 4 to give 4-(2-{N.N~ dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method Al. 4-Chloro-2-methoxy-5-(trifiuoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method Bl. According to Method Cla, 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(jY,Ar-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Entry 101: 4-Chloro-Ar-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-(Af-methylcarbamayl)-4-pyridyloxy)aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method Al. According to Method C3, 2-amino-3-raethoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
Entry 102: 4-(2-(.V-Methyicarbamoy!)-4-pyndyicxy)aniline w2s synthesized according to Melhod A2. 5-.rerr-Butyl-2-(2,5-dimethylpyrTolyl)aniline was synthesized according to PCT/USOO/00648 Method A4. 5-terr-Butyl-2-(2,>dimethyipyrrolyl)ani]ine was rcacted with CDI followed by 4-(2-{A?-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
Entry 103: 4-ChlonWv-methyI-2-pyridinecarboxamide was synthesized according to Method A2. Step 3b. 4-Chloro-/v-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(vV-methylcarbamoyI)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)aniIine afforded bis(4-(2-(/V-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 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.
WO 00/42012 PCT/USQO/0064S Table 1, 3-terr-ButyIpbenyl Ureas Entry R mp (°C) HPLC fmin.) TLC Rr TLC Solvent System Mass Spec. [Source] Synth. Method 1 0 NH -o~o" 0.22 50% EtOAc / 50% hexane 418 (M-h)+ (HPLC ES-MS) A13 C3 2 -oo< 0.5S 50% EtOAc / 50% hexane 403 (M+H)-r (HPLC ES-MS) A!3 C3 3 Vnh ^y0^=y0:i 133-135 0.68 100°/o EtOAc 448 (M-*-H)+ (FAB) A8 C2d Table 2. -/err-Butyl-2-methoxyphenyl Ureas R-NAN H H OMe Entry R mp CC) hplc (min.) tlc Rr tlc Solvent System Mass Spcc. fSourccl Symh. Method 4 0, vNH -o~o Me .93 448 (M+H)+ (HPLC ES-MS) AI3 Bl Cla Vhh ■ _^y0_^_0re 120-122 0.67 100% EtOAc 478 (M+H)+ (FAB) A8 C2d 6 -o*os vnh Y 0 0.40 50% E'.OAc >! 50% hexane 460 (M-H)-(HPLC ES-MS) A3 C2cl 76 wo 00/4201: PCT/USOO/00648 7 0.79 50% EtOAc / 50% hexane 446 (M+H}+ (HPLC ES-MS) A12 C2d Table 3. 5-{TrifiuorometbyI)-2-methoxyphenyl Ureas Entrv R mp f°C) HPLC (min.) TLC Rr TLC Solvent Svstem Mass Spec. fSourcel Synth. Method 8 0 f—NH -o~o " 250 (dec) 460 (M+H)+ <FAB) A13 C2a 9 -Q-kh 206-208 C 54 % MeOH f 90% CH2C1 2 446 (M+H)+ (HPLC ES-MS) A3 step 2, A8 step 4, Bl, Cla 0.33 50% EtOAc / 50% pet ether 445 (M-rH)-i- (HPLC ES-MS) A13 C3 U -f\ . Vnh \=={ r={ Me 0.20 2% Et3N/ 98% EtOAc 461 <M+H)+ (HPLC ES-MS) A2 C4 12 -Q ^-NH, 0-O 0.27 1% Et3W 99% EtOAc 447 (M+H)+ (HPLC ES-MS) A2 C4 i3 0 V—NH r~\ We 0.62 100% EtOAc 461 (M+H)+ (FAB) A2 C2a 14 0 ^-NH: j(3~0~O 114- 117 0.40 1% Et3NV 99% E:OAc 447 (M+H)-(FAB) A2 C4 77 PCT/USQO/00648 o Vnh 232-235 0.5-1 100% EtOAc 490 (M+H)+ (FAB) AS C2d lo O Me \—NH y-\ Me 210-213 0.29 % MeOH / 45% EtOAc / 50% pet ether 475 (M^-H)+ (HPLC ES-MS) A 5 Bl Clc 17 o CI V-NH * 187-188 0.17 50% EtOAc / 50% pet ether 495 (M-*-H)+ (HPLC ES-MS) A6 Bl Cla IS ——(f y~Me ^—NHj °-0 0.48 100% EtOAc 475 (M+H)+ (HPLC ES-MS) A2 step 4, Bl Cla 19 0 V-NH 194-196 0.31 % MeOH 145% EtOAc ! 50% pet ether 475 (M+H)+ (HPLC ES-MS) A2 Bl Cla O CI V-NH -c5—O * 214-216 0.25 % MeOH / 45% EtOAc / 50% pet ether 495 (M+H)+ (HPLC ES-MS) A2 Cla 21 -O-O't 208-210 0.30 50% EtOAc / 50% hexane 481 (M+H)+ (HPLC ES-MS) A19 C2a 22 0 V-NH2 —/*—^^ y 188-190 0.30 70% EtOAc / 50% hexane 447 (M+H)+ (HPLC ES-MS) A15. step 4, Cla 23 ^ZV°-O^f0 VNH 0 0.50 70% EtOAc / 30% hexane 472 (M-K)+ (FAB) A3 Bl Cla 24 0 Me "V-N -CV0~C/ 203-205 0.13 100% EiOAc 479 (M-H)- (HPLC ES-MS) A2 Bl Cla PCT/USOO/0064S —( v0- \^NH 0.09 75% EtOAc / 25% hexane 458 (M+H)-r (HPLC ES-MS) A12 C2d 26 MeOi *\==}~ ^Me 169- 171 0.67 50% EtOAc 150% pet ether 474 (M-H)+ (HPLC ES-MS) A13 step 1, A13 step 4, A16, Bl Cla 27 O v-NH 218-219 0.40 50% EtOAc / 50% pet ether 477 (M+H)+ (HPLC ES-MS) A2 step 3b, A2 step 4, Bl, Cla 28 ^w^0_o-^° v-NMe 0 212-214 0.30 40% EtOAc ( 60% hexane A9 Bl Cla 29 -f\ vnh r={ Me s~v/ 0.33 50% EtOAc / 50% pet ether 474 (M+H)+ (HPLC ES-MS) A2 step 3b, A 2 step 4, Bl, Cla Q v-NH -&*<> PM 210-211 A2 Bl Cla 31 .
O v-NH -ok5 ""k —0 210-204 0.43 % MeOH / CH2C1 2 A14 Bl Cla D4 32 vNH -0~q ™ 247-249 0.57 % MeOH 1 CH2C1 2 A14 Bl Cla D4 3 3 \ /°~~\ " /N_M€ \=/ ^—N Me 217-219 0.07 % MeOH / CH2C1 A14 Bl Cla D4 79 PCT/USOO/00648 34 0 VNH -0°-Q t> 0.11 70% EtOAc / 30% hexane All Bl Clf Die o —N 0.3S 70% EtOAc / 30% hexane All Bl Clf Die 36 F—/ V-NH \=/ \=o 0.77 70% EtOAc / 30% hexane All Bl Clf Die 37 Me ^— y^o -<X) 0.58 70% EtOAc / 30% hexane All Bl Clf Die 38 MeO—V—NH -w^° -0°-0 0.58 70% EtOAc / 30% hexane All Bl Clf Die 39 O N—/' V-NH \ f \=J Wq -0-°-Q 0.17 70% EtOAc / 30% hexane All Bl Clf Die 40 y~^\ ~O^0_O 0.21 70% EtOAc / 30% hexane All Bl Clf Die Table 4. 3-{Trifluorometbyl)-4-cbloropbenyl Ureas I ct p ° 11 "j H H 80 PCT/USOO/0O648 Entrj R mp CQ HPLC (min.) TLC Rr TLC Solvent System Mass Spec. [Source! Synth. Method 41 I 0 V-NH 1 -OK5 " 163- 165 0.08 50% EtOAc/ 50% pet ether 464 (M+H)+ (HPLC ES-MS) A13 C3 42 0 VNH -0°-0 Me 215 0.06 50% EtOAc/ 50% pet ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 43 o VNH2 -O~0_O' 0.10 50% EtOAc/ 50% pet ether 451 (M+H)+ (HPLC ES-MS) A2 Cla 44 —VNH2 °~0I 0.25 % EtOAc/ 70% pet ether 451 (M+HK (HPLC ES-MS) A2 Cla 45 —^ \ V-NH \=< /={ Me 0.31 % EtOAc/ 70% pet ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 46 O 176-179 0.23 40% EtOAc/ 60% hexane 476 (M+H)+ <FAB) A3 Cla 47 0 Me f—NH -CKO' Me 0.29 % MeOH/ 45% EtOAc/ 50% pet ether 478 <M+H)+ (HPLC ES-MS) A5 Clc 48 P "S-NH -o-&" 206-209 A15 Cla 49 0 CI V-NH _r^ Me 147-151 0.22 50% EtOAc/ 50% pet ether 499 (M+H)+ (HPLC ES-MS) A6 Cla 50 —$ \—Me ^—NH W rJ, Me °~\J* ' 0.54 100% EtOAc 479 (M-Hh (HPLC ES-MS) A2 Cla : WO 00/4201: 51 v Vnh -0°-CN Et 187-189 0.33 % MeOH' 45% EtOAc/ 50% pet ether 479 (M+H)+ (HPLC ES-MS) A2 Cla 52 ° CI VNH 219 0.18 % MeOH/ 45% EtOAc/ 50% pet ether 499 (M+H)+ (HPLC ES-MS) A2 Cla 53 -cy'-o^z 246-248 0.30 50% EtOAc/ 50% hexane 485 (M+H)-*- (HPLC ES-MS) A19, Cla 54 -o-ok, Me 196-200 0.30 70% EtOAc/ 30% hexane) 502 (M+H)+ (HPLC ES-MS) A15 Cla 55 O -O-^P" 228-230 0.30 % EtOAc/ 70% CH2C12 466 (M+H)+ (HPLC ES-MS) 56 Me 238-245 57 221-222 0.75 80% EtOAc/ 20% hexane 492 (M+H)+ (FAB) Cld Dla 58 0 V-nh <y^o Me 247 0.35 100% EtOAc Cld Dla D2 59 O Me -OO "■ 198-200 0.09 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla 60 MeO 158-160 0.64 50% EtOAc/ 50% pet ether 61 °V V-NH // s\ / — \ ^ '*■ -Lr°\i O N—0 195-197 0.39 % MeOH/ CH2C1 2 A13 Cla 82 wo 00/4201: PCT/USOO,00648 i 62 0 Vnh -0-°-0 170-172 0.52 % MeOH/ CH2CI 2 Ai3 Cla 63 168-171 0.39 % MeOH/ CH2C1 2 A13 Cla 64 0 Et _ J^"NwS ^>o-0 ^ 176-177 0.35 % MeOH/ CH2C1 2 A13 Cla 65 v V-NH -O-O Me 130-133 487 (M+H)+ (HPLC ES-MS) A2 Bl Cla 66 ° V-NH -(H> 'Pr" 155 A2 Cla 67 0 y—NH O^O * 225-229 0.23 100% EtOAc Cle D3 Dlb 68 -<w^0^(Vf0 V^NMe O 234-236 0.29 40% EtOAc/ 60% hexane A 9 Cla 69 -O Vnh \ /r==\ Me 0.48 50% EtOAc/ 50% pet ether 481 (M+H)+ (HPLC ES-MS) 70 0 Vnh —\~^ ^ N— W Q x—O 0.46 % MeOH/ 95% CH2C12 564 (M-H)+ (HPLC ES-MS) A10 Cla 83 PCT/USOO/00648 71 0 Vnh \-0 199-201 0.50 % MeOR/ CH2C1 2 AU Cla D4 72 0 Vnh O--Q Me 235-237 0.55 % MeOH/ CH2C1 2 A14 Cla d4 73 o V-nh —,N_Me \=/ N Me 200-201 0.21 50% MeOH/ CH2C1 2 A14 Cla D4 74 ov Vnh OSi(Pr-i)3 \=/ v_N 145-148 75 \=/- \=o 0.12 70% EtOAc/ 30% hexane 527 (M+H)+ (HPLC ES-MS) All Clf die 76 p Me-4 Q "Qo 0.18 70% EtOAc/ 30% hexane All Clf die 77 f—f ^—nh V/^p=o -0°-0 0.74 70% EtOAc/ 30% hexane All Clf die 78 Me-N_fyNH Me — /==® -O~0-O 0.5S 70% EtOAc/ 30% hexane All Clf Die 84 PCT/XJSOO,'00648 79 vnh 0.47 70% EtOAc/ 30% hexane 569 (M+H)+ (HPLC ES-MS) All Clf Die 80 \-NH 0.18 70% EtOAc/ 30% hexane 50S (M+H)-r (HPLC ES-MS) Al 1 Clf Die 81 MeO~NH \=J y=o 0.58 70% EtOAc/ 30% hexane 557 (M*H)+ (HPLC ES-MS) All Clf Die 82 O sN—<f~v-NH v_/ \=/. 0.37 70% EtOAc/ 30% hexane 611 (M-H)+ (HPLC ES-MS) All Clf Die 83 q o —N v=o -o""0~o 0.19 70% EtOAc/ 30% hexane All Clf Die 84 0 v-NH 0°"<jN ^ ^OH 179-183 A2 A17 Cla D5 Table 5. 3-(Trifluoromethyl)-4-broniopheByi Ureas S5 PCT/USOO/O 0648 Entry R mp ra HPLC (mLn.l TLC R/ TLC Solvent Svstem Mass Spec. rSourcel Synth. Method 85 V-nh -o-oMe 186-1S7 0.13 50% EtOAc/ 50% pet ether 509 (M-H)+ (HPLC ES-MS) A2 Bl Cla 86 0 a Vnh -&--Q" 150-152 0.31 50% EtOAc/ 50% pet ether 545 (M+H)+ (HPLC ES-MS) A6 Bl Cla 87 0 ci Vnh -6~o * 217-219 0.16 50% EtOAc/ 50% pet ether 545 (M+H)+ (HPLC ES-MS) A2 Bl Cla 88 0 Vnh -Ch^G* * 183-184 0.31 50% EtOAc/ 50% pet ether 525 (M+H)+ (HPLC ES-MS) A 2 Bl Cla 89 —Vnh \=\ s=\ Me °"A^N 0.21 50% EtOAc/ 50% pet ether 511 (M+H)+ (HPLC ES-MS) A2 Bl Cla 90 —<f V-Me Vnh ^=\ r={ Me 0.28 50% EtOAc/ 50% pet ether 525 (M+H)+ (HPLC ES-MS) A2 Bl Cla 91 O Me -0~C/ 214-216 0.2 s 50% EtOAc/ 50% pet ether 522 (M+H)+ (HPLC ES-MS) A2 Bl Cla 92 o Vnh -o-oMe 0.47 50% EtOAc/ 50% pet ether 527 (M+H)+ (HPLC ES-MS) A2 step 3 b.
A2 step 4, Bl.
Cla 93 —( \ Vnh /=r\ S • 0.46 50% EtOAc/ 50% pet ether 527 (M+H)+ (HPLC ES-MS) A2 SJep 3 b.
A2 step 4.
Bl.
Cla So PCT/US00/9O64S Table 6. 5-(Trifluorometliyl)^4-chloro-2-methoxypheny] Ureas Enrrv R nip CC) HPLC (min.) TLC Rr TLC Solvent System Mass Spec. fSourcel Synth. Method 95 0 v- NH -<x>me 140-144 0.29.
% MeOH/ 45% EtOAc/ 50% pet ether 495 (M+H)+ (HPLC ES-MS) A2 A7 Bl Cla 96. 0 CI y—NH y~\_ _/=< Me 244-245 0.39 % MeOH/ 45% EtOAc/ 50% pet ether 529 (M+H)+ (HPLC ES-MS) A6 A7 Bl Cla 97 o CI y—NH 220-221 0.25 % MeOH/ 45% EtOAc/ 50% pet ether 529 (M+H)+ (HPLC ES-MS) A2 A7 Bl Cla 93 -f~\ Vnh \=( /r={ Me ■K_^N 0.27 % MeOH/ 45% EtOAc/ 50% pet ether 495 (M+H)+ (HPLC ES-MS) A2 A7 Bl Cla •99 0. v-nh <x>a 180-181 0.52 % MeOH/' 45% EtOAc/ 50% pel ether 509 (M+H)-!- (HPLC ES-MS) A2 A7 Bl Cla 100 0 v-NH /T\ r=( Pr"i 162-165 A2 A 7 Bl Cla 87 Table?. Additional Ureas Er.tr,' R mp CC) HPLC (min.) TLC R, TLC Solvent System Mass Spec. fSourcel Synth. Method ] ^ 0 Si! o r^:^°Y^r NH ww u m Ai, H h OMe 162- 165 - Al A2 C3 102 o nh vLnAnJUJ Me il H h mev vwe 0.10 50% EtOAc/ 50% hexane 442 (M+H)+ {HPLC ES-MS) A2 a4 C2d 103 0 1 HN NH 0 0 o 0 J? ^ NH-Me Me-NH 125-130 0.24 40% EtOAc/ 60% hexane 512 (M+H)* (FAB) A2 C2b The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (44)

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. 88A INTELLECTUAL PROPERTY OFFICE OF N.2. 1 8 MAR 2008 RECEIVED P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 finaLdoc -15/3/08 The Claims Defining the Invention are as Follows:
1. A compound of Formula I: A-D-B (I) or a pharmaceuticaHy acceptable salt thereof, wherein D is -NH-C(0)-NH-, A is a substituted moiety of the formula: -L-M-L1, wherein L is a 5 or 6 membered cyclic structure bound directly to D, L1 is pyridinyl substituted by -C(0)Rx, and is optionally substituted with 1-3 additional substituents independently selected from the group consisting of R7 and halogen; wherein Rx is NRaRb and Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 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(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 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) Ra and Rb 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 Ra or Rb 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 INTELLECTUAL PROPERTY . g9 . OFFICE OF N.Z. 1 b MAR 2008 a eo cj w en P:\WPDOCS\HjvASpecs 2\Raf kinase NZ 556598 finaldoc - 15/3/08 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; M is oxygen or sulfur; and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryi 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, where when 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, -C02R7, -C(0)NR7R7, -C(0)-R7, -N02, -OR7, -SR7 ,-NR7R7, -NR7C(0)0R7, -NR7C(0)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,-C02R7, -C(0)NR7R7, -OR7, -SR7, -NR7R7, -NO* -NR7C(0)R7, -NR7C(0)0R7 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 -0-, -S-, -N(R7)-, -(CH2)m-, -C(0)-, -CH(OH)-, -(CH2)mO-, -(CH2)raS-, -(CH2)mN(R7)-, -0(CH2)m- CHXa-, -CXa2-, -S-(CH2)m- and -N(R7)(CH2)m-, where m = 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, -C02R7, -C(0)R7, -C(0)NR7R7, -N02) -OR7, -SR7 -NR7R7, -NR7C(0)0R7, -NR7C(0)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(0)NR7R7, -OR7, -SR7, -N02, -NR7R7, -NR7C(0)R7, and -NR7C(0)0R7, with R7 as defined above. INTELLECTUAL PROPERTY OFFICE OF N.2. 1 8 MAR 2008 RECEIVED P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 final.doc - 15/3/08
2. A compound according to claim 1, wherein L is phenyl, optionally substituted by halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl up to perhaloalkyl and C1-C3 alkoxy.
3. A compound according to claim 1, wherein L is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C5 linear or branched alkyl, C1-C5 linear or branched haloalkyl up to perhalo, C1-C3 alkoxy and halogen.
4. A compound according to claim 3, wherein the substituents of L are selected from the group consisting of methyl, triflouromethyl, tert-butyl, methoxy, CI, and F.
5. A compound according to any one of claims 1-4, wherein L is phenyl, optionally substituted with chlorine or methyl substituents
6. A compound according to any one of claims 1-3, wherein L is phenyl, optionally substituted by halogen up to perhalo.
7. A compound according to any one of claims 1-6, wherein L is phenyl.
8. A compound according to any one of claims 1-7, wherein Ra and Rb are a) independently hydrogen, C1-C10 alkyl, C6 aryl, pyridinyl, substituted C1-10 alkyl, substituted C6 aryl, substituted pyridinyl, -phenylpiperazine(pyridinyl), -phenylmorpholinyl, -ethylmorpholinyl, -ethylpiperidyl, -methyl pyrrolidinyl, -methyl tetrahydrofuryl, or -C2H4NH(phenyl); where when Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, -N(CH3)2, C(-Cio alkyl, C1-C10 alkoxy, halosubstituted C^ alkyl, or -OSi(Pr-i)3; or -91 - iNTEilEC^AUPROPEfnY OFFICE OF N.Z. 1 Si MAR 2008 P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 fmaLdoc - 15/3/08 b) Ra and Rb together form piperazine or a substituted piperazine with substituents selected from the group consisting of halogen, hydroxy, Cmo alkyl, pyridinyl, Cmo alkoxy, C6 aryl, halo substituted C6 aryl, and N-(4-acetylphenyl).
9. A compound according to any one of claims 1-7, wherein Ra and Rb are independently hydrogen, Ci-Cio alkyl, C6 aryl, pyridinyl, substituted Cmo alkyl, substituted C6 aryl, or substituted pyridinyl.
10. A compound according to any one of claims 1-7, wherein Ra and Rb are independently hydrogen or CrC6 alkyl.
11. A compound according to any one of claims 1-7, wherein Ra and Rb are independently hydrogen, methyl, ethyl or propyl.
12. A compound according to any one of claims 1-11, where Ra is hydrogen and Rb is methyl
13. A compound according to any one of claims 1-11, where when Ra and Rb are a substituted group, they are substituted by halogen up to per halo.
14. A compound according to any one of claims 1-13, wherein M is sulfur.
15. A compound according to any one of claims 1-13, wherein M is oxygen.
16. A compound of any one of claims 1-15, wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by -OH.
17. A compound according to any one of claims 1-16, wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen. INTELLECTUAL PROPERTY OFFICE OF N,Z. 13 MAR 2008 RECEIVED P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 fmaLdoc ■ 15/3/08
18. A compound according to any one of claims 1-17, wherein B is an unsuhstituted phenyl group or a phenyl group substituted by a substituent selected from the group consisting of halogen up to per halo and Wn wherein W and n are as defined in claim 1.
19. A compound according to any one of claims 1-17, wherein B is phenyl, substituted with 1-3 substituents independently selected from the group consisting of halogen; C|-C<5 linear or branched alkyl, optionally substituted with 1-3 halogen substituents; and Ci-Cg linear or branched alkoxy.
20. A compound according to any one of claims 1-17, wherein B is phenyl, substituted with 1-3 substituents independently selected from the group consisting of chlorine, Ci-Q alkoxy and up to per halo substituted C1-C6 alkyl.
21. A compound according to claim 18, wherein the substituents of B are selected from the group consisting of methyl, triflouromethyl, tert-butyl, methoxy, CI, and F.
22. A compound according to claim 18, wherein the substituents for B are selected from the group consisting of up to per halo substituted CpCe alkyl and halogen.
23. A compound according to claim 18, where B is substituted by trifluoromethyl and chlorine or bromine.
24. A compound according to any one of claims 1-19, wherein B is phenyl, substituted by trifluoromethyl or tert-butyl, and optionally additional substituents selected from the group consisting of halogen up to per halo, and Wn where n is 0-3, and each W is independently selected from the group consisting of Ci-Cio alkyl, Cj-Cio alkoxy, C6 aryl, pyridinyl, and substituted Ci-Cio alkyl, substituted by one or more substituents independently selected from the group consisting of halogen up to per halo. INTELLECTUAL PROPERTY OFFICE OF N.Z. 15 MAR 2008 RECEIVE!) P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 fmaLdoc - 15/3/08
25. A compound according to claim 24, wherein the optionally additional substituents for B are selected from the group consisting of up to per halo substituted Ci-C6 alkyl and halogen.
26. A compound according to claims 24, wherein the optionally additional substituents for B are selected from the group consisting of halogen and methoxy.
27. A compound according to any one of claims 1-26, wherein L1 is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of Ci-C6 alkyl, halogen and Ci-C6 alkoxy.
28. A compound according to claim 27, wherein the optional substituents on L1 are selected from the group consisting of methyl, triflouromethyl, methoxy, CI and F.
29. A compound selected from the group consisting of 3-tot-butyl phenyl ureas of Table 1 above; 5-tert- butyl-2-methoxyphenyl ureas of Table 2 above; 5-(trifluoromethyl)-2-phenyl ureas of Table 3 above; 3-(trifluoromethyl)-4-chlorophenyl ureas of Table 4 above; 3-(trifluoromethyl)-4-bromophenyl ureas of Table 5 above; 5-(trifluoromethyl)-4-chloro-2-methoxyphenyl ureas of Table 6 above; and ureas 101-103 in Table 7 above or a pharmaceuticaHy acceptable salt thereof.
30. A compound selected from the group consisting of the 3-?er*-butyl phenyl ureas: /V-(3-terMjutylphenyl)-./V-(4-(3-(/V-methylcarbamoyl)phenoxy)phenyl urea (1) and N-(3-tert-butylphenyl)-7V-(4-(4-acetylphenoxy)phenyl urea (2); the 5-/e^/-butyl-2-methoxyphenyl ureas: //-(5-fe^butyl-2-methoxyphenyl)-jV'-(4-( 1,3 -dioxoisoindolin-5-yloxy)phenyl)urea (6), A'-(5-re^-butyl-2-methoxyphenyl)-7V-(4-(l-oxoisoindo]in-5-yloxy)phenyl) urea (7), INTELLECTUAL PROPERTY - 94 - QWRCE OF N.Z. 18 MAR 2008 P:\WPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 final,doc - 15/3/08 jV-(5-tert-butyl-2-methoxyphenyl)-/V-(4-(4-methoxy-3-(JV-methylcarbamoyl)phenoxy) phenyl) urea (5) and Ar-(5-/er/-butyl-2-methoxyphenyl)-An-(4-(3-(/V-methylcarbamoyl)phenoxy)phenyl) urea (4); the 2-methoxy-5-(trifluoromethyl) phenyl ureas: jV-(2 -methoxy-5 -(trifluoromethyl)pheny 1 )-A"-(3 -(2 -carbamoyl -4-pyridyloxy)phenyl) urea (12), JV-(2-methoxy-5-(trifluoromethyl)phenyl)-A"-C3-(2-(Ar-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (11), 7V-(2-methoxy-5-(trifluoromethyl)phenyl)-J/V-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea (14), 7V-(2-methoxy-5-(trifluoromethyl)phenyl)-jVv-(4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (13), JV-(2-methoxy-5-(trifluoromethyl)phenyl)-7V,-(4-(2-(iV-methylcarbamoyl)-4-pyridylthio)phenyl) urea (27), 7V-(2-methoxy-5-(trifluoromethyl)phenyl)-An-(2-chloro-4-(2-(JV-methylcarbamoyl)(4-pyridyloxy))phenyl) urea (17), and Ar-(2-methoxy-5-(trifluoromethyl)phenyl)-Ar'-(3-chloro-4-(2-(/V-methylcarbamoyl)(4-pyridyloxy))phenyl) urea (20); the 4-chloro-3-(trifluoromethyl) phenyl ureas: jV-(4-chloro-3-(trifluoromethyl)phenyl)-W-(3-(2-carbamoyl-4-pyridyloxy)phenyl) urea (44), N-(4-chloro-3-(trifluoromethyl)phenyl)-/V'-(3-(2-(A'-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (45), Ar-(4-chloro-3-(trifluoromethyl)phenyl)-A"-(4-(2-carbamoyl-4-pyridyloxy)phenyl) urea (43), Af-(4-chloro-3-(trifluoromethyl)phenyl)-A^'-(4-(2-(A^-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (42) and Ar-(4-chloro-3-(trifluoromethyl)phenyl)-Ar'-(2-chloro-4-(2-(A^-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (49); INTELLECTUAL PROPERTY OFFICE OF N.Z. "93" 18 MAR 2008 RECEIVED P:\WPDOCS\Hrw\Specs 2VRafkinase NZ 556598 ffoaLdoc -15/3/08 the 4-bromo-3-(trifluoromethyl) phenyl ureas: 7V-(4-bromo-3-(trifluoromethyl)phenyl)-Ar,-(3-(2-(jY-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (89), J/V-(4-bromo-3-(trifIuoromethyl)phenyI)-./V-(4-(2-(/V-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (85), 7V-(4-bromo-3-(trifluoromethyl)phenyl)-/V-(3-(2-(N-methylcarbamoyl)-4-pyridy]thio) phenyl) urea (93), J/V-(4-bromo-3-(trifluoromethyl)phenyl)-/V-(2-chloro-4-(2-(jV-methylcarbamoyl)(4-pyridyloxy))phenyl) urea (86) and 7V-(4-bromo-3-(trifluoromethyl)phenyl)-jV-(3-chloro-4-(2-(/V-methylcarbamoyl)(4-pyridyloxy)) phenyl) urea (87); and the 2-methoxy-4-chloro-5-(trifluoromethyl)phenyl ureas: JV-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-/V-(3-(2-(A<'-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (98), A^-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-A''-(4-(2-(A^-methylcarbamoyl)-4-pyridyloxy)phenyl) urea (95), Af-(2-methoxy-4-chloro-5-(trifluoromethy])phenyl)-/V-(2-ch3oro-4-(2-(jV-methylcarbamoyl)(4-pyridyloxy))phenyl) urea (96) and Af-(2-methoxy-4-chloro-5-(trifluoromethyl)phenyl)-/V'-(3-ch]oro-4-(2-(yV-methylcarbamoyl)(4-pyridyloxy))phenyl) urea (97) or a pharmaceuticaHy acceptable salt thereof.
31. A compound which is Ar-(4-chloro-3-(trifluoromethyl)phenyl)-Ar'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula: CF. O CI A i i o NH, H H INTELLECTUAL PROPERTY OFFICE OF N.Z. -96- 1 *| MAR 2008 MECETVED P:\WPDOCS\Hjw\Specs2\RafkinaseNZ556598 fmaLdoc- 15/3/08 or a pharmaceuticaHy acceptable salt thereof.
32. A compound which is /Vr-(4-chloro-3-(trifluoromethyl)phenyl)-A^'-(4-(2-(Ar-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the formula: CI N N I I H H or a pharmaceuticaHy acceptable salt thereof.
33. A pharmaceuticaHy acceptable salt of a compound of any one of claims 1-32 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.
34. A pharmaceuticaHy acceptable salt of a compound of any one of claims 29-32 which is a basic salt of an organic acid or an inorganic acid which is 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 or mandelic acid. fELLECTUAL PROPERTY OFFICE OF N.2. 97' 1 I MAK 2008 P:\WPDOCS\IBw\Specs 2\Raf kinase NZ 556598 finaldoc - 14/7/08
35. A pharmaceuticaHy acceptable salt according to claims 34 which is a tosylate salt of AL(4-chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula: h H
36. A pharmaceuticaHy acceptable salt according to claims 34 which is a tosylate salt of Ar-(4-chloro-3-(trifluoromethyl)phenyl)-//'-(4-(2-(A-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the formula: ■A i i H H
37. A pharmaceutical composition comprising a compound of any one of claims 1-32 or a pharmaceuticaHy acceptable salt of any one of claims 33-36, and a physiologically acceptable carrier.
38. Use of a compound of any one of claims 1-32 or a pharmaceuticaHy acceptable salt of any one of claims 33-36 in the manufacture of a medicament for the treatment of a cancerous cell growth mediated by raf kinase.
39. Use of a compound of any one of claims 1-32 or a pharmaceuticaHy acceptable salt of any one of claims 33-36 in the manufacture of a medicament for the treatment of a tumour or solid cancer. IPONZ 17 JUL 2008 -98- P:VWPDOCS\Hjw\Specs 2\Raf kinase NZ 556598 final.doc -14/7/08
40. Use of a compound of any one of claims 1-32 or a pharmaceuticaHy acceptable salt of any one of claims 33-36 in the manufacture of a medicament for the treatment of carcinomas, myeloid disorders or adenomas.
41. Use of claim 40 for the treatment of carcinoma of the lung, pancreas, thyroid, bladder or colon.
42. Use of claim 40 for the treatment of myeloid leukaemia or villous colon adenoma.
43. Use of any one of claims 38-42 wherein the compound is a pharmaceuticaHy acceptable salt of iV-(4-chloro-3-(trifluoromethyl)phenyl)-jV'-(4-(2-carbamoyl-4-pyridyloxy) phenyl) urea of the formula: Af-(4-chloro-3-(trifluoromethyl)phenyl)-A^'-(4-(2-(iV-methylcarbamoyl)-4-pyridyloxy) phenyl) urea of the formula:
44. Use of claim 43 wherein the salt is a tosylate salt. IPQNZ 17 JUL 2008 -99-
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