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Title:
$g(v)-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2000/042012
Kind Code:
A1
Abstract:
This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Inventors:
RIEDL BERND (DE)
DUMAS JACQUES (US)
KHIRE UDAY (US)
LOWINGER TIMOTHY B (JP)
SCOTT WILLIAM J (US)
SMITH ROGER A (US)
WOOD JILL E (US)
MONAHAN MARY-KATHERINE (US)
NATERO REINA (US)
RENICK JOEL (US)
SIBLEY ROBERT N (US)
Application Number:
PCT/US2000/000648
Publication Date:
July 20, 2000
Filing Date:
January 12, 2000
Export Citation:
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Assignee:
BAYER AG (US)
RIEDL BERND (DE)
DUMAS JACQUES (US)
KHIRE UDAY (US)
LOWINGER TIMOTHY B (JP)
SCOTT WILLIAM J (US)
SMITH ROGER A (US)
WOOD JILL E (US)
MONAHAN MARY KATHERINE (US)
NATERO REINA (US)
RENICK JOEL (US)
SIBLEY ROBERT N (US)
International Classes:
C07D295/12; A61K31/17; A61K31/18; A61K31/24; A61K31/341; A61K31/40; A61K31/4035; A61K31/44; A61K31/4406; A61K31/4409; A61K31/4439; A61K31/4453; A61K31/495; A61K31/496; A61K31/5355; A61K31/5375; A61K31/5377; A61P35/00; A61P43/00; C07C275/28; C07C275/30; C07C275/32; C07C275/36; C07C275/40; C07C291/12; C07C311/29; C07C317/22; C07D207/09; C07D209/46; C07D209/48; C07D213/74; C07D213/75; C07D213/79; C07D213/81; C07D213/82; C07D295/13; C07D295/135; C07D295/18; C07D295/192; C07D307/14; C07D401/12; C07F7/18; A61K; C07C; C07D; (IPC1-7): C07D211/78; C07D211/72; A61K31/33; A61K31/54; A61K31/535; A61K31/17; C07C275/20; C07C275/22; C07C275/24; C07C275/28
Domestic Patent References:
WO1998052558A11998-11-26
WO1998052559A11998-11-26
Foreign References:
Other References:
DATABASE HCAPLUS [online] DUMAS ET. AL.: "Inhibition of P38 kinase activity using substituted heterocyclic ureas.", XP002949801, Database accession no. 1999:425745
DATABASE HCAPLUS [online] DUMAS ET. AL.: "Preparation of pyrazolyl aryl areas and related compounds as P38 kinase inhibitors.", XP002949802, Database accession no. 1999:425744
DATABASE HCAPLUS [online] KURIK M. V. ET. AL.: "Optical properties of segmented oligourethane with azomethine terminal fragments.", XP002949803, accession no. STN Database accession no. 1997:624629
DATABASE HCAPLUS [online] KUBO ET. AL.: "Preparation quinoline and quinazoline derivaties inhibiting platelet-derived growth factor receptor autophosphorylation.", XP002949804, Database accession no. 1997:414195
DATABASE HCAPLUS [online] WINKLER ET. AL.: "Inhibitors of coenzyme A-independent transacylase induce apoptosis in human HL-60 cells,", XP002948805, Database accession no. 1996:702444
DATABASE HCAPLUS [online] CHUGAI PHARMACEUTICAL CO. LTD., JAPAN.: "Antitumor Benzophenone derivaties.", XP002949806, Database accession no. 1983:78152
DATABASE HCAPLUS [online] HIRT ET. AL.: "Tuberculostatic and cancerstatic polybasic ureas.", XP002949807, Database accession no. 1970:79046
DATABASE HCAPLUS [online] MILLER ET. AL.: "Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas.", XP002948808, Database accession no. 1999:421642
DATABASE HCAPLUS [online] DEARDEN ET. AL.: "Quantitative structure-biodegradability studies: an investigation of the MITI aromatic compound database.", XP002949809, Database accession no. 1997:613699
DATABASE HCAPLUS [online] BONWICK ET. AL.: "Production of murine monoclonal antibodies against sulcofuron and flucofuran by in-vitro immunization.", XP002949810, Database accession no. 1996:551868
See also references of EP 1140840A4
Attorney, Agent or Firm:
Traverso, Richard J. (White Zelano & Braniga, P.C. Arlington Courthouse Plaza 1 Suite 1400 2200 Clarendon Boulevard Arlington VA, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
1. A compound of Formula I: ADB (I) or a pharmaceutically acceptable salt thereof, wherein D isNHC (O)NH, A is a substituted moiety of up to 40 carbon atoms of the formula:L (ML') q, where L is a 5 or 6 membered cyclic structure bound directly to D, Ll 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 13; and each cyclic structure of L and Ll contains 04 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6member cyclic structure bound directly to D containing 04 members of the group consisting of nitrogen, oxygen and sulfur, wherein Ll is substituted by at least one substituent selected from the group consisting ofSO2Rx,C (O) R% andC (NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing 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; Rx 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 (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 57 member heterocyclic structure of 13 heteroatoms selected from N, S and O, or a substituted 57 member heterocyclic structure of 13 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 isC (O), a Clc5 divalent alkylene group or a substituted C C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted ClC5 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 L'is additionally substituted, the substituents are selected from the group consisting of halogen, up to perhalo, and Wn, where n is 03; wherein each W is independently selected from the group consisting ofCN,Co2R7, C (O) NR,C (0)R,N02,OR,SR,NR,NRC (0) OR,NRC (0) R\QAr, 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 ofCN,C02R,C (O) R7,C (O) NR7R7,oR7,SR7, NR7R7,NO2, NR7C(O)R7,(O)R7, NR7C(O)OR7 and halogen up to perhalo; with each R' independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q isO,S, N(R7), (CH2)m, C(O), CH(OH), (CH2)mO, (CH2)mS, (CH2) mN (R7),O (CH2) mCHXa,CXa2,S(CH2) mandN (R7) (CH2) m,(CH2) mN (R7),O (CH2) mCHXa,CXa2,S(CH2) mandN (R7) (CH2) m, where m= 13, and Xa is halogen; and Ar is a 5or 6member aromatic structure containing 02 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, <BR> <BR> <BR> <BR> up to perhalo, and optionally substituted by Zn), wherein nl is 0 to 3 and each Z is independently selected from the group consisting ofCN,C02R,C (O) R',C (O) NR'R, NO2, OR7, SR7 NR7R7, NR7C(O)OR7, NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting ofCN,CO2R', COR7, C(O)NR7R7, OR7, SR7, NO2, NR7R7, NR7C(O)R7, and NR7C(O)OR7, with R7 as defined above.
2. A compound as in claim 1 wherein: Ry is hydrogen, Cl lo alkyl, Cl o alkoxy, C3 10 cycloalkyl having 03 heteroatoms, C2 10 alkenyl, C110 alkenoyl, C612 aryl, C312 hetaryl having 13 heteroatoms selected from N, S and O, C7 24 aralkyl, C7 24 alkaryl, substituted Cl lo alkyl, substituted C110 alkoxy, substituted <BR> <BR> <BR> <BR> C310 cycloalkyl having 03 heteroatoms selected from N, S and O, substituted C6Cl4 aryl, substituted C3, 2 hetaryl having 13 heteroatoms selected from N, S and O, substituted C724 alkaryl or substituted C7C24 aralkyl, where Ry is a substituted group, it is substituted by halogen up to per halo, Rz is hydrogen, Cl lo alkyl, Cl 0 alkoxy, C3 10 cycloalkyl having 03 heteroatom, C210 alkenyl, C110 alkenoyl, C612 aryl, C3C12 hetaryl having 13 heteroatoms selected from, S, N and O, C7 24 alkaryl, C7 24 aralkyl, substituted C110 alkyl, substituted C110 alkoxy, substituted <BR> <BR> <BR> <BR> C6Cz4 aryl, substituted C3 _CIO cycloalkyl having 03 heteroatoms selected from S, N and O, substituted C312 hetaryl having 13 heteroatoms selected from S, N and O, substituted C ?. 24 alkaryl or substituted C7C24 aralkyl where Rz is a substituted group, it is substituted by halogen up to per halo, hydroxy, Cl. lo alkyl, C312 cycloalkyl having 03 heteroatoms selected from O. S and N, CR l2 hetaryl having 13 heteroatoms selected from N, S and O, C110 alkoxy, C6 12 aryl, C,6 halo substituted alkyl up to per halo alkyl, C6C2 halo substituted aryl up to per halo aryl, C3C, 2 halo substituted cycloalkyl up to per halo cycloalkyl having 03 heteroatoms selected from N, S and O, halo substituted C3CI2 hetaryl up to per halo hetaryl having 13 heteroatoms selected from O, N and S, halo substituted C7C24 aralkyl up to per halo aralkyl, halo substituted C7C24 alkaryl up to per halo alkaryl, andC (O) Rg, Ra and Rb are, a) independently hydrogen, a carbon based moiety selected from te group consisting of C1C, 0 alkyl, Cl C, o alkoxy, C310 cycloalkyl, C210 alkenyl, C110 alkenoyl, C6 12 aryl, C3 12 hetaryl having 13 heteroatoms selected from O, N and S, C3 12 cycloalkyl having 03 heteroatoms selected from <BR> <BR> <BR> <BR> N, S and O, C7 24 aralkyl, C7C24 alkaryl, substituted Cm o alkyl, substituted Cl 10 alkoxy, substituted C3 cycloalkyl, having 03 heteroatoms selected from N, S and O, substituted Ce <BR> <BR> <BR> <BR> 12 aryl, substituted C3_IZ hetaryl having 13 heteroatoms selected from N, S and O, substituted C7 24 aralkyl, substituted C7 24 alkaryl, where Ra and Rb are a substituted group, they are substituted by halogen up to per halo, hydroxy, Cl lo alkyl, C3l2 cycloalkyl having 03 heteroatoms selected from O, S and N, C3 hetaryl having 13 heteroatoms selected from N, S and O, C110 alkoxy, C612 aryl, C16 halo substituted alkyl up to per halo alkyl, C6CI2 2 halo substituted aryl up to per halo aryl, C3CI2 halo substituted cycloalkyl having 03 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3C, 2 hetaryl up to per halo heteraryl, halo substituted C7C24 aralkyl up to per halo aralkyl, halo substituted C7C24 alkaryl up to per halo alkaryl, andC (O) Rg; or OSi (Rf) 3 where Rf is hydrogen, C110 alkyl, C110 alkoxy, C3C10 cycloalkyl having 03 heteroatoms selected from O, S and N, C6) 2 aryl, C3Cl2 hetaryl having 13 <BR> <BR> <BR> <BR> heteroatoms selected from O, S and N, C724 aralkyl, substituted C 110 alkyl, substituted C1 Cl0 alkoxy, substituted C3Cz2 cycloalkyl having 03 heteroatoms selected from O, S and N, substituted C3C, 2 heteraryl having 13 heteroatoms selected from O, S, and N, substituted C6. l2 aryl, and substituted C7 24 alkaryl, where Rf is a substituted group it is substituted halogen up to per halo, hydroxy, Cl. o alkyl, C312 cycloalkyl having 03 heteroatoms selected from O, S and N, C312 hetaryl having 13 heteroatoms selected from N, S and O, C110 alkoxy, C612 aryl, C7C24 alkaryl, C7C24 aralkyl,C16 halo substituted alkyl up to per halo alkyl, C6Cl2 halo substituted aryl up to per halo aryl, C3CI2 halo substituted cycloalkyl having 03 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3Cl2 hetaryl up to per halo heteraryl, halo substituted C7C24 aralkyl up to per halo aralkyl, halo substituted C7C24 alkaryl up to per halo alkaryl, andC (O) Rg, or b) Ra and Rb together form a 57 member heterocyclic structure of 13 heteroatoms selected from N, S and O, or a substituted 57 member heterocyclic structure of 13 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C1_lo alkyl, C312 cycloalkyl having 03 heteroatoms selected from O, S and N, C312 hetaryl having 13 heteroatoms selected from N, <BR> <BR> <BR> S and O, Cl lo alkoxy, C6 12 aryl, C7C24 alkaryl, C7C24 aralkyl, halo substituted Cl 6 alkyl up to per halo alkyl, halo substituted C6C2 aryl up to per halo aryl, halo substituted C3Cz2 2 cycloalkyl having 03 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3Cl2 hetaryl up to per halo heteraryl, halo substituted C7C24 aralkyl up to per halo aralkyl, halo substituted C7C24 alkaryl up to per halo alkaryl, andC (O) Rg, or <BR> <BR> <BR> <BR> c) one of Ra or Rb isC (O), a Clc5 divalent alkylene group or a substituted Cl<BR> <BR> <BR> <BR> C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, <BR> <BR> <BR> <BR> wherein the substituents of the substituted Clc5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, Cl lo alkyl, C3 z2 cycloalkyl having 03 heteroatoms selected from O, S and N, C3, 2 hetaryl having 13 heteroatoms selected from N, S and O, C, <BR> <BR> <BR> s0 alkoxy, C6 s2 aryl, C7C24 alkaryl, C7C24 aralkyl, C1 6 halo substituted alkyl up to per halo alkyl, C6Cl2 halo substituted aryl up to per halo aryl, C3C, 2 halo substituted cycloalkyl having 03 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C3C, 2 hetaryl up to per halo heteraryl, halo substituted C7C24 aralkyl up to per halo aralkyl, halo substituted C7C24 alkaryl up to per halo alkaryl, andC (O) Rg, where Rg is Cl 0 alkyl ;CN,CO2Rd,ORd,SRd,NO2,C (O) R,NRtlR,. NRd C (O) ORe andNRd C (O) Re, and Rd and Re are independently selected from the group consisting of hydrogen, C110, alkyl, C110 alkoxy, C310 cycloalkyl having 03 heteroatoms <BR> <BR> <BR> selected from O, N and S, C6 2 aryl. C3Cu hetaryl with 13 heteroatoms selected from O, N<BR> <BR> <BR> <BR> <BR> and S and C7C24 aralkyl, C7C24 alkaryl, up to per halo substituted ClClo alkyl, up to per<BR> <BR> <BR> <BR> <BR> halo substituted C3Clo cycloalkyl having 03 heteroatoms selected from O, N and S, up to<BR> <BR> <BR> <BR> <BR> <BR> per halo substituted C6C14 aryl, up to per halo substituted C3Cl2 hetaryl having 13 heteroatoms selected from 0, N, and S, halo substituted C7C24 alkaryl up to per halo alkaryl, and up to per halo substituted C7C24 aralkyl, W is independently selected from the group consisting of CN, CO2R7, C(O)NR7R7, C (O)R7, NO2, OR7, SR7, NR7R7, NR7C(O)OR7, NR7C(O)R7, C1C10 alkyl, C1C10 alkoxy, C2C10 alkenyl, C1C10 alkenoyl, C3C10 cycloalkyl having 03 heteroatoms selected from O, S and N, C6C14 aryl, C7C24 alkaryl, C7C24 aralkyl, C3C12 heteroaryl having 13 heteroatoms selected from O, N and S, C4C23 alkheteroaryl having 13 heteroatoms selected from O, N and S, substituted ClClo alkyl, substituted ClClo alkoxy, substituted C2C, 0 <BR> <BR> <BR> <BR> alkenyl, substituted C1C10 alkenoyl, substituted C3CIo cycloalkyl having 03 heteroatoms selected from O, N and S, substituted C6Cl2 aryl, substituted C3Cl2 hetaryl having 13 heteroatoms selected from O, N and S, substituted C7C24 aralkyl, substituted C7C24 alkaryl, substituted C4C23 alkheteroaryl having 13 heteroatoms selected from O, N and S, andQ Ar; R7 is independently selected from H, C1C10 alkyl, C1C10 alkoxy, C2C10 alkenyl, C1 Clo alkenoyl, C3C10 cycloalkyl having 03 heteroatoms selected from O, S and N, C6C, 4 aryl, C3C13 hetaryl having 13 heteroatoms selected from O, N and S, C7C14 alkaryl, C7C24 aralkyl, C4C23 alkheteroaryl having 13 heteroatoms selected from O, N and S, up to per <BR> <BR> <BR> <BR> halosubstituted C1C10 alkyl, up to perhalosubstituted C3CIo cycloalkyl having 03 heteroatoms selected from O, N and S, up to perhalosubstituted C6Cl4 aryl, up to per <BR> <BR> <BR> <BR> halosubstituted C3cl3 hetaryl having 13 heteroatoms selected from O, N and S, up to per halosubstituted C7C24 aralkyl, up to perhalosubstituted C7C24 alkaryl, and up to per halosubstituted C4C23 alkheteroaryl; and each Z is independently selected from the group consisting ofCN,C02R',C (O) R', C (O) NR'R,NO2,OR',SR'NR'R',NR'C (O) OR,NR'C (O) R', C,Clo alkyl, CCa <BR> <BR> <BR> alkoxy, C2Clo alkenyl, ClClo alkenoyl, C3CIo cycloalkyl having 03 heteroatoms selected from 0, N and S, C6Ci4 aryl, C3C13 hetaryl having 13 heteroatoms selected from 0, N and S, C7C24 alkaryl, C7C24 aralkyl, C4C23 alkheteroaryl having 13 heteroatoms selected from 0, N and S, substituted ClClo alkyl, substituted ClClo alkoxy, substituted C2C, o alkenyl, <BR> <BR> <BR> <BR> substituted CClo alkenoyl, substituted C3CIo cycloalkyl having 03 heteroatoms selected from 0, N and S, substituted C6Cl2 aryl, substituted C7C24 alkaryl, substituted C7C24 aralkyl and substituted C4C23 alkheteroaryl having 13 heteroatoms selected from 0, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting ofCN,Co2R7,CoR7,C (o) NR7R7,oR7,SR7,NO2,NR7R7, NR7C (O) R7, andNR7C (O) OR7.
3. A compound as in claim 1 wherein M is one or more bridging groups selected from the group consisting ofO,S,N (R'), (CH2) m,C (O),CH (OH), (CH2) mO, (CH2) mS,(CH2) mN (R7), ~O (CH2) m~ CHXa,CXa2,S(CH2) mandN (R7) (CH2) m, where m= 13, Xa is halogen and R7is as defined in claim 1.
4. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position byOH.
5. A compound as in claim 1 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
6. A compound of claim 1 wherein B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulfur with the balance of the hetaryl moiety being carbon.
7. A compound of claim 1 wherein B of Formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1, a pyrimidinyl group substituted by a substituent selected from the group constituting of halogen and Wn, whereas W and n are as defined in Claim 1, or a substituted pyridyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1.
8. A compound of claim 6 wherein B of Formula I is a substituted phenyl group, a substituted pyrimidinyl group, or substituted pyrridyl group substituted 1 to 3 times by 1 or more substituents selected from the group consisting ofCN, halogen, CCo alkyl, CsClo alkoxy,OH, up to per halo substituted ClClo alkyl, up to per halo substituted ClClo alkoxy or phenyl substituted by halogen up to per halo.
9. A compound of claim 1, wherein L, the six member cyclic structure bound directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wn wherein W and n are as defined in claim 1.
10. A compound of claim 8, wherein L, the 6 member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group.
11. A compound of claim 1, wherein said substituted cyclic moiety L'comprises a 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulfur.
12. A compound of claim 1, wherein said substituted cyclic moiety L'is phenyl, pyridinyl or pyrimidinyl.
13. A compound of claim 3, wherein said substituted cyclic moiety L'is phenyl, pyridinyl or pyrimidinyl.
14. A compound of claim 6, wherein said substituted cyclic moiety L'is phenyl, pyridinyl or pyrimidinyl.
15. A compound of claim 8, wherein said substituted cyclic moiety L'is phenvl. pyridinyl or pyrimidinyl.
16. A compound of claim 9, wherein said substituted cyclic moiety Ll is phenyl, pyridinyl or pyrimidinyl.
17. A compound of claim 10, wherein said substituted cyclic moiety L'is phenyl, pyridinyl or pyrimidinyl.
18. A compound of claim 14, wherein M is one or more bridging groups selected from the group consisting ofO,S,N (R7),(CH2) m,C (O),CH (OH), ~ (CH2) mO~ <BR> <BR> <BR> (CH2)mS, (CH2) mN (R7), ~O (CH2) m~ CHXa,CXa2,S(CH2) mandN (R7) (CH2) m,(CH2) mN (R7), ~O (CH2) m~ CHXa,CXa2,S(CH2) mandN (R7) (CH2) m, where<BR> <BR> <BR> <BR> m= 13, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to per halo.
19. A compound of claim 15, wherein M is one or more bridging groups selected <BR> <BR> <BR> from the group consisting ofO,S,N (R), (CH2) m,C (O),CH (OH), (CH2) mO, (CH2)mS, (CH2)mN(R7), O (CH2) m CHXa,CXa2,S (CH2) m andN (R) (CH2) m,where <BR> <BR> <BR> m= 13, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to per halo.
20. A compound of claim 16, wherein M is one or more bridging groups selected <BR> <BR> <BR> from the group consisting ofO,S,N (R7),(CH2) m,C (O),CH (OH),(CH2) mO,<BR> <BR> <BR> <BR> (CH2) n, S, (CH2) n, N (R'),0 (CH CHX\CX'2,S (CH2 andN (R') (CH2), where<BR> <BR> <BR> <BR> <BR> m= 13, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to per halo.
21. A compound of claim 17, wherein M is one or more bridging groups selected <BR> <BR> <BR> from the group consisting ofO,S,N (R7),(CH2) m,C (O),CH (OH),(CH2) mO, (CH2)mS, (CH2)mN(R7), O(CH2)mCHXª, CXª2, S(CH2)m and N(R7)(CH2)m, where <BR> <BR> <BR> m= 13, Xa is halogen and R is hydrogen or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen up to per halo.
22. A compound of claim 1 wherein Ll is additionally substituted I to 3 times by one or more substituents selected from the group consisting of ClCIo alkyl, up to per halo substituted CsCio alkyl,CN,OH, halogen, Clcalo alkoxy and up to per halo substituted Cl C o alkoxy.
23. A compound of claim 13 wherein Ll is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of ClClo alkyl, up to per halo substituted ClClo alkyl,CN,OH, halogen, Clcl alkoxy and up to per halo substituted Cl C I o alkoxy.
24. A compound of claim 18 wherein Ll is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of ClClo alkyl, up to per halo substituted CClo alkyl,CN,OH, halogen, ClClo alkoxy and up to per halo substituted Cl CO alkoxy.
25. A compound of claim 19 wherein Ll is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of ClClo alkyl, up to per halo substituted CClO alkyl,CN,OH, halogen, Ccalo alkoxy and up to per halo substituted C I C I o alkoxy.
26. A compound of claim 20 wherein Ll is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of CClO alkyl, up to per halo substituted ClClo alkyl,CN,OH, halogen, CClo alkoxy and up to per halo substituted Cl C, o alkoxy.
27. A compound of claim 21 wherein Ll is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C,C, o alkyl, up to per halo substituted CiCio alkyl,CN,OH, halogen, ClClo alkoxy and up to per halo substituted Cl C o alkoxy.
28. A compound of claim 1 wherein Ll is substituted byC (O) Rx.
29. A compound of claim 1 wherein Ll is substituted bySOZRX.
30. A compound of claim 1 wherein L'is substituted only byC (O) R,.
31. A compound of claim 1 wherein L'is substituted only byS02Rx <BR> <BR> <BR> <BR>.
32. A compound of claim 1 wherein Ll is substituted byC (O) R, orSOrRx,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> wherein Rxis NRaRb.
33. A compound of claim 13 wherein Ll is substituted byC (O) Rx orS02Rx, 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 57 member heterocyclic structure of 13 heteroatoms selected from N, S and 0, or a substituted 57 member heterocyclic structure of 13 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 isC (O), a ClC5 divalent alkylene group or a substituted C C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 <BR> <BR> <BR> <BR> members, wherein the substituents of the substituted Clc5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen.
34. A compound of claim 18 wherein Ll is substituted byC (O) Rx orS02Rx, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen.
35. A compound of claim 19 wherein Ll is substituted byC (O) RX, wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 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. <BR> <BR> <BR> <BR> <P>.
36. A compound of claim 20 wherein Ll is substituted byC (O) Rx orSO2Rx,<BR> <BR> <BR> <BR> <BR> <BR> <BR> wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 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. <BR> <BR> <BR> <BR> <P>.
37. A compound of claim 21 wherein Ll is substituted byC (O) Rx orS02Rx,<BR> <BR> <BR> <BR> <BR> <BR> wherein Rx is NRaRb and Ra and Rb are independently hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen.
38. A compound of Formula I: ADB (I) or a pharmaceutically acceptable salt thereof, wherein D isNHC (O)NH, A is a substituted moiety of up to 40 carbon atoms of the formula:L (ML') q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L'comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 13; and each cyclic structure of L and L contains 04 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6member cyclic structure bound directly to D containing 04 members of the group consisting of nitrogen, oxygen and sulfur, wherein Ll is substituted by at least one substituent selected from the group consisting ofSO2Rx,C (O) Rx andC (NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing 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; Rx 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 (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 57 member heterocyclic structure of 13 heteroatoms selected from N, S and 0, or a substituted 57 member heterocyclic structure of 13 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or c) one of R, or Rb isC (O), a ClC5 divalent alkylene group or a substituted C ; C divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted Clc5 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 perhalo, and Wn, where n is 03; wherein each W is independently selected from the group consisting ofCN,C02R', C (O) NR7R7,C (o)R7,NO2,oR7,SR7,NR7R7,NR7C (o) oR7,NR7C (o) R7,QAr, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of CN, CO2R7, C(O)R7, C(O)NR7R7, OR7, SR7, NR7R7, NO2, NR7C(O)R7, NR7C(O)OR7 and halogen up to perhalo; with each R' independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, wherein Q isO,S,N (R7),(CH2) m,C (O),CH (OH),(CH2) mO,(CH2) mS, (CH2)mN(R7), O(CH2)mCHXª, CXª2, S(CH2)m and N(R7)(CH2)m, where m= 13, and Xa is halogen; Ar is a 5or 6member aromatic structure containing 02 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, <BR> <BR> <BR> up to perhalo, and optionally substituted by Znt, wherein nl is 0 to 3 and each Z is independently selected from the group consisting ofCN,Co2R7,C (O) R7,C (o) NR7R7, NO2,oR7,SR7NR7R7,NR7C (o) oR7,NR7C (o) R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents are selected from the group consisting ofCN, CO2R7, COR7, C(O)NR7R7, OR7, SR7, NO2, NR7R7, NR7C(O)R7, and NR7C(O)OR7, with R as defined above; and wherein M is one or more bridging groups selected from the group consisting ofO,S, N (R'), (CH,C (O),CH (OH), (CH2)0. (CH2) n, S, (CH2) n. N (R'),0 (CH2) CHXª, CXª2, S(CH2)m and N(R7)(CH2)m, where m= 13, Xa is halogen.
39. A compound of Formula I: ADB (I) or a pharmaceutically acceptable salt thereof, wherein D isNHC (O)NH, A is a substituted moiety of up to 40 carbon atoms of the formula:L (ML') q, where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 13; and B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein Ll is substituted by at least one substituent selected from the group consisting ofSO2Rx,C (O) RX andC (NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and; Rz 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; Rx 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 (R,) 3 where Rr is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 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 57 member heterocyclic structure of 13 heteroatoms selected from N, S and 0, or a substituted 57 member heterocyclic structure of 13 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 isC (O), a C)Cs divalent alkylene group or a substituted C <BR> <BR> <BR> <BR> 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 ClC5 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 perhalo, and Wn, where n is 03; wherein each W is independently selected from the group consisting ofCN,C02R7, C (O) NR7 R',C (O)R 7,N02,OR 7,SR 7, _NRIR7,NR'C (O) OR',NR'C (O) R 7,QAr, 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 ofCN,Co2R7,C (o) R7,C (o) NR7R7,oR7,SR7, NR7R7,NO2,NR7C (o) R7,NR7C (o) oR7 and halogen up to perhalo; 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, <BR> <BR> <BR> <BR> wherein Q isO,S,N (R'), (CH2) m,C (O),CH (OH), (CH2) mO, (CH2) mS,<BR> <BR> <BR> <BR> <BR> <BR> (CH2) mN (R7)sO(CH2) mN (R7)sO (CH2) mCHXawCXa2sS (CH2) mandN (R7) (CH2) m, where m= 13, and Xa is halogen; Ar is a 5or 6member aromatic structure containing 02 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, <BR> <BR> <BR> up to perhalo, and optionally substituted by Znl, wherein nl is 0 to 3 and each Z is independently selected from the group consisting ofCN,Co2R7,C (O) R',C (O) NR7R7, NO2, OR7, SR7 NR7R7, NR7C (O)OR7,NR7C (o) R7,(O)OR7,NR7C (o) R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of CN, CO2R7, COR7, C(O)NR7R7, OR7, SR7, NO2, NR7R7, NR7C(O)R7, and NR7C(O)OR7 ; and wherein M is one or more bridging groups selected from the group consisting of0,S, <BR> <BR> <BR> N (R7), ~ (CH2) m~C (O),CH (OH),(CH2) mO,(CH2) mS,(CH2) mN (R7), ~O (CH2) m~ CHX',CX'2,S (CH2) andN (R) (CH2) m, where m=13, Xa is halogen.
40. A compound as in claim 38 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position byOH.
41. A compound as in claim 38 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
42. A compound as in claim 39 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position byOH.
43. A compound as in claim 39 wherein the cyclic structures of B and L bound directly to D are not substituted in the ortho position by a moiety having an ionizable hydrogen and a pKa of 10 or less.
44. A compound as in claim 38 wherein substituents for B and L and additional substituents for L', are selected from the group consisting of C1C10 alkyl up to per halo substituted ClClO alkyl, CN, OH, halogen, ClClo alkoxy and up to per halo substituted C C ; o alkoxy.
45. A compound as in claim 39 wherein substituents for B and L and additional substituents for L', are selected from the group consisting of ClClo alkyl up to per halo substituted ClClo alkyl, CN, OH, halogen, ClClo alkoxy and up to per halo substituted Cl CIO alkoxy.
46. A compound of claim 38 wherein Ll is substituted by C (O) Rx or S02Rx.
47. A compound of claim 39 wherein Ll is substituted by C (O) Rx or SOrRx.
48. A compound of claim 46 wherein Rx is NRaRb and Ra and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen..
49. A compound of claim 47 wherein R, is NRaRb and Ra and Rb are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen.
50. A compound of claim 1 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, ptoluene sulphonic acid (tosylate salt), 1napthalene sulfonic acid, 2napthalene 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.
51. A compound of claim 2 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, ptoluene sulphonic acid (tosylate salt), 1napthalene sulfonic acid, 2napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid ; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
52. A compound of claim 33 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, ptoluene sulphonic acid (tosylate salt), 1napthalene sulfonic acid, 2napthalene 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.
53. A compound of claim 38 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, ptoluene sulphonic acid (tosylate salt), 1napthalene sulfonic acid, 2napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
54. A compound of claim 39 which is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, ptoluene sulphonic acid (tosylate salt), 1napthalene sulfonic acid, 2napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations.
55. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically acceptable carrier.
56. A pharmaceutical composition comprising a compound of claim 2 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
57. A pharmaceutical composition comprising a compound of claim 33 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
58. A pharmaceutical composition comprising a compound of claim 38 consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.
59. A pharmaceutical composition comprising a compound of claim 39 consistent with formula I or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier.
60. A compound selected from the group consisting of 3tert butyl phenyl ureas of Table 1 above; 5tert butyl2methoxyphenyl 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)4bromophenyl ureas of Table 5 above; 5 (trifluoromethyl)4chloro2 methoxyphenyl ureas of Table 6 above; and ureas 101103 in Table 7 above.
61. A compound selected from the group consisting of the 3tert butyl phenyl ureas: N(3tertbutylphenyl)N' (4 (3 (Nmethylcarbamoyl)(3tertbutylphenyl)N' (4 (3 (Nmethylcarbamoyl) phenoxy) phenyl urea and N (3tertbutylphenyl)N' (4 (4acetylphenoxy) phenyl urea; the 5tertbutyl2methoxyphenyl ureas: N(5tertbutyl2methoxyphenyl)N' (4 (1, 3dioxoisoindolin5yloxy)(5tertbutyl2methoxyphenyl)N' (4 (1, 3dioxoisoindolin5yloxy) phenyl) urea, N(5tertbutyl2methoxyphenyl)N' (4 (1oxoisoindolin5yloxy)(5tertbutyl2methoxyphenyl)N' (4 (1oxoisoindolin5yloxy) phenyl) urea, N(5tertbutyl2methoxyphenyl)N' (4 (4methoxy3 (N methylcarbamoyl) phenoxy) phenyl) urea and N(Stertbutyl2methoxyphenyl)N' (4 (3 (Nmethylcarbamoyl)(Stertbutyl2methoxyphenyl)N' (4 (3 (Nmethylcarbamoyl) phenoxy) phenyl) urea; the 2methoxy5trifluoromethyl) phenyl ureas: N (2methoxy5 (trifluoromethyl) phenyl)N' (3 (2carbamoyl4pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2carbamoyl4pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridylthio) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (2chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea and N (2methoxy5 (trifluoromethyl) phenyl)N' (3chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea; the 4chloro3 (trifluoromethyl) phenyl ureas: N (4chloro3 (trifluoromethyl) phenyl)N' (3 (2carbamoyl4pyridyloxy) phenyl) urea, <BR> <BR> <BR> <BR> N (4chloro3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, N (4chloro3 (trifluoromethyl) phenyl)N' (4 (2carbamoyl4pyridyloxy) phenyl) urea and <BR> <BR> <BR> <BR> N (4chloro3 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea. the 4romo3 (trifluoromethyl) phenyl ureas: N(4bromo3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridyloxy)(4bromo3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, <BR> <BR> <BR> <BR> N (4bromo3 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, <BR> <BR> <BR> <BR> N(4bromo3(trifluoromethyl) phenyl)N'(3(2(Nmethylcarbamoyl)4pyridylthio) phenyl) urea, N (4bromo3 (trifluoromethyl) phenyl)N' (2chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea and N(4bromo3 (trifluoromethyl) phenyl)N' (3chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea; and the 2methoxy4chloro5 (trifluoromethyl) phenyl ureas: N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (2chloro4 (2 (N methylcarbamoyl) (4pyridyloxy)) phenyl) urea and . N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (3chloro4 (2 (N methylcarbamoyl) (4pyridyloxy)) phenyl) urea.
62. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 1.
63. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 33.
64. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 38.
65. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administering a compound of Formula I of claim 39.
66. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of 3tert butyl phenyl ureas of Table 1 above; 5tert butyl2methoxyphenyl 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)4bromophenyl ureas of Table 5 above; 5 (trifluoromethyl)4chloro2 methoxyphenyl ureas of Table 6 above; and ureas 101103 in Table 7 above.
67. A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of the 3tert butyl phenyl ureas: N(3tertbutylphenyl)N' (4 (3 (Nmethylcarbamoyl)(3tertbutylphenyl)N' (4 (3 (Nmethylcarbamoyl) phenoxy) phenyl urea and N(3tertbutylphenyl)N' (4 (4acetylphenoxy)(3tertbutylphenyl)N' (4 (4acetylphenoxy) phenyl urea; the 5tertbutyl2methoxyphenyl ureas : <BR> <BR> <BR> :'' (5tertbutyl2methoxyphenyl)N' (4 (1, 3dioxoisoindolin5yloxy) phenyl) urea,<BR> <BR> <BR> <BR> N (5tettbutyl2methoxyphenyl)N' (4 (Ioxoisoindolin5yloxy) phenyl) urea, N(5tertbutyl2methoxyphenyl)N' (4 (4methoxy3 (N methylcarbamoyl) phenoxy) phenyl) urea and N(5tertbutyl2methoxyphenyl)N' (4 (3 (Nmethylcarbamoyl)(5tertbutyl2methoxyphenyl)N' (4 (3 (Nmethylcarbamoyl) phenoxy) phenyl) urea; the 2methoxy5trifluoromethyl) phenyl ureas: N (2methoxy5 (trifluoromethyl) phenyl)N' (3 (2carbamoyl4pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2carbamoyl4pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridylthio) phenyl) urea, N (2methoxy5 (trifluoromethyl) phenyl)N' (2chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea and N (2methoxy5 (trifluoromethyl) phenyl)N' (3chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea; the 4chloro3 (trifluoromethyl) phenyl ureas: N (4chloro3 (trifluoromethyl) phenyl)N' (3 (2carbamoyl4pyridyloxy) phenyl) urea, N(4chloro3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, N(4chloro3 (trifluoromethyl) phenyl)N' (4 (2carbamoyl4pyridyloxy)(4chloro3 (trifluoromethyl) phenyl)N' (4 (2carbamoyl4pyridyloxy) phenyl) urea and <BR> <BR> <BR> <BR> N (4chloro3 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea; the 4romo3 (trifluoromethyl) phenyl ureas: <BR> <BR> <BR> <BR> N (4bromo3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, <BR> <BR> <BR> <BR> N(4bromo3(tri fluoromethyl) phenyl)N'(4(2(Nmethylcarbamoyl)4pyridyloxy) phenyl) urea, N (4bromo3 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4pyridylthio) phenyl) urea, N(4bromo3(trifluoromethyl) phenyl)N'(2chloro4(2(Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea and N (4bromo3 (trifluoromethyl) phenyl)N' (3chloro4 (2 (Nmethylcarbamoyl) (4 pyridyloxy)) phenyl) urea; and the 2methoxy4chloro5 (trifluoromethyl) phenyl ureas: N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (3 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (4 (2 (Nmethylcarbamoyl)4 pyridyloxy) phenyl) urea, N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (2chloro4 (2 (N methylcarbamoyl) (4pyridyloxy)) phenyl) urea and N (2methoxy4chloro5 (trifluoromethyl) phenyl)N' (3chloro4 (2 (N methylcarbamoyl) (4pyridyloxy)) phenyl) urea.
Description:
co-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Cross-Reference to Related Applications This is a continuation-in-part of Serial No. 09/257,266 filed February 25,1999 and a continuation-in-part of Serial No. 60/115,877 filed January 13,1999.

Field of the Invention This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Background of the Invention The p21ra5 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. Bos. Cancer Res. 1989, 49,4682-9). In its normal, unmutated form, the ras protein is a key element of the signal transduction cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends Biochem. Sci. 1994,19,279-83).

Biochemically, ras is a guanine nucleotide binding protein, and cycling between a GTP- bound activated and a GDP-bound resting form is strictly controlled by ras'endogenous GTPase activity and other regulatory proteins. In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and, therefore, the protein delivers constitutive growth signals to downstream effectors such as the enzyme raf kinase. This leads to the cancerous growth of the cells which carry these mutants (Magnuson et al. Semin. Cancer <BR> <BR> <BR> Biol. 1994., 917-53). It has been shown that inhibiting the effect of active ras by inhibiting the raf kinase signaling pathway by administration of deactivating antibodies to raf kinase or by co-exprcssion of dominant negative raf kinase or dominant negative MEK, the substrate of

raf kinase, leads to the reversion of transformed cells to the normal growth phenotype (see: Daum et al. Trends Biochem. Sci. Fridman et al. J. Biol. Chem. 1994,269, 30105-8. Kolch et al. (Nature have further indicated that inhibition of raf expression by antisense RNA blocks cell proliferation in membrane-associated oncogenes.

Similarly, inhibition of raf kinase (by antisense oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the growth of a variety of human tumor types (Monia et al., Nat. Med. 1996,2,668-75).

Summarv of the Invention The present invention provides compounds which are inhibitors of the enzyme raf kinase.

Since the enzyme is a downstream effector of p21as, 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 pharmaceutically acceptable salt thereof.

A-D-B (I) ln formula 1, D is-NH-C (O)-NH-,

A is a substituted moiety of up to 40 carbon atoms of the formula:-L- (M-L') q where L is a 5 or 6 membered cyclic structure bound directly to D, L'comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and Ll contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein Ll is substituted by at least one substituent selected from the group consisting of-SO2Rx,-C (O) Rx and-C (NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, Rz 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; Rx 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 (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 0, 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 C)-Cs divalent alkylene group or a substituted Cl- <BR> <BR> <BR> <BR> 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 Cl-Cs divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 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,-C02R, <BR> <BR> <BR> -C (O) NR7R7-C (o)-R7,-NO2,-oR7-SR7,-NR7R7,-NR7C (o) oR7,-NR7C (o) R7,-Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of-CN,-Co2R7,-C (O) R7,-C (o) NR7R7,-oR7,-SR7,- NR7R7,-NO2,-NR7C (o) R7,-NR7C (o) oR7 and halogen up to per-halo; with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, <BR> <BR> <BR> <BR> <BR> wherein Q is-O-,-S-,-N (R7)-,-(CH2) m-,-C (O)-,-CH (OH)-,-(CH2) mO-,-(CH2) mS-,<BR> <BR> <BR> <BR> <BR> <BR> -(CH2) mN (R7)-, ~O (CH2) m~ CHXa-,-CXa2-,-S-(CH2) m-and-N (R7) (CH2) m-,(CH2) mN (R7)-, ~O (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 Znl, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of-CN,-C02R',-C (O) R,-C (O) NR'R'.- -NR O) OR-NR O) R', 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,-C02R",- <BR> <BR> <BR> COR 7, _C (O) NR7 R 7,-OR 7,-SR 7,-N02,-NR 7R 7, _NR7 C (O) R 7, and _NR7 C (O) OR 7, With R'as defined above.

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-triazinyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, <BR> <BR> <BR> <BR> 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 1,2,3-triazol-l-,-4-or-5- yl, 1,2,4-triazol-1-,-3-or-5-yl, 1-or 5-tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4- oxadiazol-3-or-5-yl, 1,3,4-thiadiazol-2-or-5-yl, 1,2,4-oxadiazol-3- or-5-yl, 1,3,4- thiadiazol-2-or-5-yl, 1,3,4-thiadiazol-3- or-5-yl, 1,2,3-thiadiazol-4- or-5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-or 4-4H-thiopyranyl, 3-or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-6-or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7- benzisothiazolyl, 2-, 4-, 5-, 6-or 7-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, or additionally optionally substituted phenyl, 2-or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, I- methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2- Yl Suitable alkyl groups and alkyl portions of groups, e. g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc. <BR> <BR> <BR> <P> Suitable arvl groups which do not contain heteroatoms include, for example. phcny)<BR> <BR> <BR> <BR> <BR> <BR> and 1-and'-napllthn l.

The term"cycloalkyl", as used herein, refers to cyclic structures with or without alkyl <BR> <BR> <BR> <BR> substituents such that, for example,"C4 cycloalkyl"includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term"cycloalkyl", as used herein also includes saturated heterocyclic groups.

Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i. e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.

The invention also relates to compounds per se, of formula I.

The present invention is also directed to pharmaceutically acceptable salts of formula I.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2- naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li+ Na+ or K+), alkaline earth cations (e. g., Mg+2, Ca+2 or Boa+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabiclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

A number of the compounds of Formula I possess asymmetric carbons and can therefor exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art. The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess raf inhibitory activity.

General Preparative Methods The compounds of Formula I may be prepared by the use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing 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 <BR> <BR> <BR> Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (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 <BR> <BR> <BR> 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) \ ArNO2 [H-] > ArNH2 \ (0) (eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using Ho-, or an alternative NO,-source. Nitroaryls may be further elaborated prior to reduction. Thus. nitroaryls substituted with potential leaving groups (e. g. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II). 3 R SeArs \ (' F Base S Ar bu-air Rj SH R 3 CuO/base 3

Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (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 trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris (dimethylamino) sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Altematively, sulfonyl chloride 7 may be reduced to the arenethiol (10). for example with zinc amalgum. Reaction of thiol 10 with CHCIFn in the presence of base gives the difluoromethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including Cr03-acetic anhydride (Sedova et al.

Zh. Org. Khim. 1970,6, (568). SOUCI /CIS03H, ;-R 7 KF \ Zn (Hg) SOzF SH S02F SH or 8 R 10 (Me2N) 3S Me3SiF2 CHCIF2 Me3SiCF3 base SO2CF3 SCHF2 v Ruz [O] S02CHF2 . R 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 heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene), or NN-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Scheme IV Selected Methods of Non-Symmetrical Urea Formation Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term'administration by injection'includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. One or more compounds may be present in association with one or more non- toxic pharmaceutically acceptable carriers and if desired other active ingredients.

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 palatale preparations. Tablets contain the active ingredient in admixture w ith non-toxic pharmaceuticaDy acceptable excipients which are suitable for the manufacture ol tahlcts These excipients may be, for example, inert diluents, such as calcium carbonaté, sodium

carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example, lecithin, or condensation products or an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents

and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e. g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For all regimens of use disclosed herein for compounds of Formula I) the daily oral dosage <BR> <BR> <BR> reginzen will preferably be from 0.01 to 200 mg/Kg of total body weight. The dai ! \ dosage

for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regime will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regime will preferably be from 0.1 to 200 mg administered between one to four times daily. The daily inhalation dosage regime will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be appreciated by one skilled in the art that the specific dose level for a given patient depends on a variety of factors, including specific activity of the compound administered, age, body weight, health, sex, diet, time and route of administration, rate of excretion, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, ie., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the condition undergoing therapy.

The entire enclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Serial No. 60/115,877, 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 methods shown below. The activity of a given compound to inhibit raf kinase can be <BR> <BR> <BR> routinelv assayed, e.., according to procedures disclosed below. The following examples

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 mmHg. Unless otherwise stated, the term'under high vacuum'refers to a vacuum of 0.4-1.0 mmHg.

All temperatures are-reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification. N- cyclohexyl-N'- (methylpolystyrene) carbodiimide was purchased from Calbiochem- Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl) aniline, 4-chloro-3- (trifluoromethyl) aniline 2-methoxy-5- (trifluoromethyl) aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4- isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5- (trifluoromethyl) aniline and 4-chloro-3- (trifluoromethyl) phenyl isocyanate were purchased and used without further purification.

Syntheses of 3-amino-2-methoxyquinoline (E. Cho et al. WO 98/00402; A. Cordi et al. EP <BR> <BR> <BR> <BR> 542,609; IBID Bioorg. Med Chem.. 4- (3-carbamoylphenoxy)-l-nitrobenzene (K. Ikawa Yakugaku Zasshi Chem. Abstr. butylphenyl isocyanate (O. Rohr et al. DE 2,436,108) and 2-methoxy-5- (trifluoromethyl) phenyl isocyanate (K. Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967,491) have previously been described.

Thin-layer chromatography (TLC) was performed using Whatman pre-coated glass-backed silica gel 60A F-254 250 um plates. Visualization of plates was effected by one or more of the tollos ing techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c)

immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 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 <BR> <BR> <BR> <BR> protonated solvent (CHCI3 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer <BR> <BR> <BR> <BR> with solvent (CDCl3 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction.

The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 ßA. 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 (1 x 10-4 torr to 2.5x 104 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared (-1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time accot to <BR> <BR> <BR> the number of ions in the source. Gas chromatography-ion selective mass spectra ( (, (-\1X >

were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.

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 tert-butoxycarbonyl CDI 1,1'-carbonyl diimidazole conc concentrated d day (s) dec decomposition DMAC N, N dimethylacetamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone DMF N, N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EDCI 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide EtOAc ethyl acetate EtOH ethanol (100%) Et2Q diethyl ether Et3N triethylamine h hour (s) HOBT 1-hydroxybenzotriazole nr-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C)

temp. temperature THF tetrahydrofuran TFA trifluoroAcOH 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-methoxynaphthalene.

Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K2CO3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room temp. overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2-naphthoate as an amber oil (10.30 g): lu- <BR> <BR> <BR> <BR> NMR (DMSO-d6) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).

Step 2.3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.29.10 mmol) and water and water MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 3.. l mmol) The mixture was heated at the reflux temp. for 3 h, cooled to room temp.. and made aod) c <BR> <BR> with a t0% citric acid solution. The resulting solution was extracted with EtOAc (2 \)""

mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%):'H-NMR (DMSO-d6) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).

Step 3.2-(N-(Carbobenzyloxy) amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et3N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a solution of DPPA (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The resulting mixture was heated at 80 °C for 2 h. 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 saturated NaCI solution, dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%):'H-NMR (DMSO-d6) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).

Step 4.2-Amino-3-methoxynaphthalene A slurry of 2- (N- (carbobenzyloxy) amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H2 atm (balloon) at room temp. overnight. The resulting mixture was filtered through Celitet and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40.

85%):'H-NMR (DMSO-d6) 6 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H); 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 of 4- (2-N-Methylcarbamyl-4-pyridyloxy) aniline Step la. Synthesis of 4-chloro-N-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 N-methylformamide (250 mL) at room temp. was added conc.

H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H202 (30% wt in H2O, 17 mL) followed by FeS04-7H20 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 °C.

When bubbling had subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCI solution (3 x 150 mL), then they were combined, dried (MgSO4) 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 °C over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50;'H NMR (CDC13) 8 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4,2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H) +). Step1 b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid

Anhydrous DMF (6.0 mL) was slowly added to SOC12 (180 mL) between 40° and 50 °C.

The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous 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%).

Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCl salt Anh DMF (10.0 mL) was slowly added to SOC12 (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 S02 evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (50 mL) and dried under high vacuum for 4 hours to afford 4-chloropyridine-2- carbonyl chloride HCl salt as an off-white solid (27.2 g, 16%). This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 °C. The contents were stirred at room temp. for 45 min., cooled to 5 °C and treated with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et, (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2- carboxylate HCl salt as a white solid (110 g, 65%): mp 108-112 °C;'H-NMR (DMSO-d6) 8<BR> 3.88 (s, 3H); 7.82 (dd, J=5.5,2.2 Hz, 1H); 8.08 (d, J=2.2 Hz, 1H); 8.68 (d, J=5.5 Hz, I H); 10.68 (br s, IH); HPLC ES-MS nilz 172 ((M+H) +).

Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4- chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCl salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5 °C. The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCI solution (500 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-chloro-N-methyl-2- pyridinecarboxamide as pale-yellow crystals (71.2 g, 97%): mp 41-43 °C ;'H-NMR (DMSO- d6) 8 2.81 (s, 3H), 7.74 (dd, J=5.1,2.2 Hz, 1H), 8.00 (d, J=2.2,1H), 8.61 (d, J=5.1 Hz, 1H), 8.85 (brd, 1H); CI-MS m/z 171 ((M+H) +).

Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4- chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 °C.

The resulting mixture was stored at 3'C for 4 h, then concentrated under reduced pressure.

The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCI solution (2 x 100 mL), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40 °C.

Step 4. Synthesis of 4- (2- (N-methylcarbamoyl)-4-pyridyloxy) aniline A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at

room temp. for 2 h. The contents were treated with 4-chloro-N-methyl-2- pyridinecarboxamide (15.0 g, 87.9 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 NaCI solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI solution (4 x 1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35 °C for 3 h to afford 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline as a light-brown solid 17.9 g, 84%):'H-NMR (DMSO-d6) 5 2.77 (d, J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64,6.86 (AA'BB'quartet, J=8.4 Hz, 4H), 7.06 (dd, J=5.5,2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ( (M+H) +).

A3. General Method for the Synthesis of Anilines by Nucleophilic Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5- (4- Aminophenoxy) isoindoline-1, 3-dione Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated 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 HCl solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5- hydroxyisoindoline-1,3-dione as a pale yellow powder as product (3.24 g, 72%): lH NMR (DMSO-d6) 8 7.00-7.03 (m, 2H), 7.56 (d, J=9.3Hz, 1H).

Step 2. Synthesis of 5- (4-nitrophenoxy) isoindoline-1,3-dione To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-1,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp. and was stirred for 1 h, then 1- fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to give 5- (4- nitrophenoxy) isoindoline-1,3-dione as a yellow solid (3.3 g, 62%): TLC (30% EtOAc/70% hexane) Rf 0.28; 1H NMR (DMSO-d6) 5 7.32 (d, J=12 Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 8.29 (d, J=9 Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H) +, 100%).

Step 3. Synthesis of 5- (4-aminophenoxy) isoindoline-1,3-dione A solution of 5- (4-nitrophenoxy) isoindoline-1,3-dione (0.6 g, 2.11 mmol) in conc. AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp. for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 5- (4- aminophenoxy) isoindoline-1,3-dione as a brownish solid (0.4 g, 75%): TLC (50% EtOAc/50% hexane) Rf 0.27;'H NMR (DMSO-d6) 8 5.14 (br s, 2H), 6.62 (d, J=8.7 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 7.03 (d, J=2.1 Hz, 1H), 7.23 (dd, IH), 7.75 (d, J=8.4 Hz, IH), 11.02 (s, 1H); HPLC ES-MS m/z 255 ( (M+H) +, 100%).

A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5-tert- Bu ty 1-2-(2, 5-dimethylpyrrolyl) aniline

Step 1. Synthesis of 1- (4-tert-butyl-2-nitrophenyl)-2, 5-dimethylpyrrole To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (O. ImL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2CI2 (10 mL) and sequentially washed with a I N HCI solution (15 mL), a IN NaOH solution (15 mL) and a saturated NaCI solution (15mL), dried (MgSO4) and concentrated under reduced pressure. The resulting <BR> <BR> <BR> orange-brown solids were purified via column chromatography (60 g Si02; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1- (4-tert-butyl-2-nitrophenyl)-2,5- dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67;'H NMR (CDCI3) d 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS mlz 273 ( (M+H) +, 50%).

Step 2. Synthesis of 5-tert--Butyl-2- (2, 5-dimethylpyrrolyl) aniline A slurry of 1- (4-tert-butyl-2-nitrophenyl)-2, 5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite@. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2- (2, 5-dimethylpyrrolyl) aniline as yellowish solids (0.30 g, <BR> <BR> <BR> 99%): TLC (10% EtOAc/90% hexane) Rf0.43;'H NMR (CDC13) 6 1.28 (s, 9H), 1.87-1.91 (m. 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, IH). A5. General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of 4- (2- (N Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt

A solution of 4-amino-3-methylphenol (5.45 g, 44.25 mmol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL). The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (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 filtration from solution and stored under anaerobic conditions at 0 °C prior to use: NMR <BR> <BR> <BR> <BR> (DMSO-d6) 6 2.41 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5,2.6 Hz, 1H), 7.23 (dd, J=5.5,2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 (q, J=4.8 Hz, 1H).

A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N- Protection, Nucleophilic Aromatric Substitution and Deprotection.

Synthesis of 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline Step 1: Synthesis of 3-Chloro-4- (2,2,2-trifluoroacetylamino) phenol <BR> <BR> Iron (3. 24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2- chloro-4-nitrophellol (10. 0,, 58.0 mmol) and trifluoroacetic anhydride (20 mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from solution and the

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 NaCI solution (125 mL), dried (MgS04) and concentrated under reduced pressure. The'H NMR (DMSO-d6) indicated a 1: 1 ratio of the nitrophenol starting material and the intended product 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol. The crude material was taken on to the next step without further purification.

Step 2: Synthesis of 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro) acetamide A solution of crude 3-chloro-4- (2,2,2-trifluoroacetylamino) phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the brownish black mixture was stirred at room temp. until the flask had cooled to room temp. The resulting mixture was treated with 4-chloro-N-methyl-2- pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222- trifluoro) acetamide as a yellow solid (8.59 g, 23.0 mmol).

Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline

A solution of crude 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222- trifluoro) acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 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- (N-Methylcarbamoyl)-4-pyridyloxy)-2- chloroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol):'H NMR (DMSO-d6) 6 2.77 (d, J=4.8 Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5,2.6 Hz, 1H), 6.76 (d, J=2.6 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 7.07 (dd, J=5.5,2.6, Hz, 1H), Hz, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.75 (q, J=4.8,1H).

A7. General Method for the Deprotection of an Acylated Aniline. Synthesis of 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline 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 (MgSO4) and concentrated under reduced pressure to yield 4- chloro-2-methoxy-5- (trifluoromethyl) aniline as a brown oil (3.20 g, 14.2 mmol): tH NMR (DMSO-d6) 6 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).

A8. General Method for Synthesis of co-Alkoxy-co-carboxyphenyl Anilines.

Synthesis of 4- (3- (N-Methylcarbamoly)-4-methoxyphenoxy) aniline.

Step 1.4- 1-4-methoxyphenoxZ)-1-nitrobenzene:

To a solution of 4- (3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from 2,5- dihydroxybenzoic acid in a manner analogous to that described in Method A 13, 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 Celte@. The resulting solution was concentrated under reduced pressure, absorbed onto Si02, 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.

Step 2.4- (3-Carboxy-4-methoxyphenoxy)-1-nitrobenzene: A mixture of 4- (3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp. overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4- (3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (1.04 g).

Step 3.4-(3-(N-Methylcarbamoly)-4-methoxyphenoxy)-1-nitrobenzene: To a solution of 4- (3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (0.50 g, 1.75 mmol) in CH2CI2 (12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in CH2CI2 (3 mL) then the resulting solution was treated with a methylamine solution (2.0 M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and stirred at room temp. for 4 h. The resulting mixture was treated with a IN NaOH solution, then extracted with CH2CI2 (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give 4- (3- (N-methylcarbamoly)-4-methoxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 95%).

Step 4.4- (3- (N-Methylcarbamoly)-4-methoxyphenoxy) aniline: A slurry of 4- (3- (N-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 1 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- (N-methylcarbamoly)-4-methoxyphenoxy) aniline as an off-white solid (0.68 g, 96%): TLC (0.1% Et3N/99.9% EtOAc) Rf 0.36.

A9. General Method for Preparation of co-Alkylphthalimide-containing Anilines. Synthesis of 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione Step 1. Synthesis of 5- (4-Nitrophenoxy)-2-methylisoindoline-1, 3-dione: A slurry of 5- (4-nitrophenoxy) isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to °C and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5- (4-nitrophenoxy)-2-methylisoindoline- 1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf 0.61.

Step 2. Synthesis of 5- (4-Aminophenoxy)-2-methylisoindoline-1,3-dione: A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) and 10% Pd/C (0.10 g) in MeOH was stirred under 1 atm of H2 (balloon) overnight. The resulting mixture was filtered through a pad of Celiez and concentrated under reduced pressure. The resulting <BR> <BR> <BR> yellow solids were dissolved in EtOAc (3 mL) and filtered through a plug of Si02 (60% EtOAc/40% hexane) to afford 5- (4-aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf 0.27.

A10. General Method for Synthesis of co-Carbamoylaryl Anilines Through Reaction of w-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N-(2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholin-4-ylethyl) carbamoyl) pyridine To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 mmol) in THF (20 mL) was added 4- (2-aminoethyl) morpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the reflux temp. for 20 h, cooled to room temp., and treated with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to afford 4-chloro-2- (N-(2-morpholin-4-ylethyl) carbamoyl) pyridine as a yellow oil (1.25 g, 95%): TLC (10% MeOH/90% EtOAc) Rf0.50.

Step 2. Synthesis of 4- (2- (N (2-Morpholin-4- ylethyl) carbamoyl) pyridyloxy) aniline. <BR> <BR> <BR> <P>A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4- chloro-2-(N-(2-morpholin-4-ylethyl) carbamoyl) pyridine (1. 22(N-(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 NaCI solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCI solution (3 x 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) Rf 0.32.

A11. General Method for the Reduction of Nitroarenes to Arylamines.

Synthesis of 4- (3-Carboxyphenoxy) aniline.

A slurry of 4- (3-carboxyphenoxy)-1-nitrobenzene (5.38 g, 20.7 mmol) and 10% Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celte, then concentrated under reduced pressure to afford 4- (3-carboxyphenoxy) aniline as a brown solid (2.26 g, 48%): TLC (10% MeOH/90% CH2CI2) Rf 0.44 (streaking).

A12. General Method for the Synthesis of Isoindolinone-Containing Anilines.

Synthesis of 4- (1-Oxoisoindolin-5-yloxy) aniline.

Step 1. Synthesis of 5-hydroxyisoindolin-1-one To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg Si02; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES- MS m/z 150 ((M+H) +).

Step 2. Synthesis of 4- (l-isoindolinon-5-yloxy)-l-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added 5-hydroxyisoindolin-l- one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4- (l-isoindolinon-5- yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0. 35.

Step 3. Synthesis of 4- (l-oxoisoindolin-5-yloxy) aniline A slurry of 4- (1-isoindolinon-5-yloxy)-1-nitrobenzene (2.12 g, 7.8 mmol) and 10% Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford 4- (1- oxoisoindolin-5-yloxy) aniline as a dark yellow solid: TLC (100% EtOAc} Rf 0.15.

A13. General Method for the Synthesis of-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4- (3-N-Methylcarbamoylphenoxy) aniline.

Step 1. Synthesis of 4- (3-ethoxycarbonylphenoxy)-l-nitrobenzene A mixture of 4-fluoro-1-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate 25 g, 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 extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4- (3-ethoxycarbonylphenoxy)-l-nitrobenzene as an oil (38 g).

Step 2. Synthesis of 4- (3-carboxyphenoxy)-1-nitrobenzene To a vigorously stirred mixture of 4- (3-ethoxycarbonylphenoxy)-1-nitrobenzene (5.14 g, 17.9 mmol) in a 3: 1 THF/water solution (75 mL) was added a solution LiOHH2O (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 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%).

Step 3. Synthesis of 4-(3-(N-methylcarbamoyl) phenoxy)-1 nitrobenzene A mixture of 4- (3-carboxyphenoxy)-l-nitrobenzene (3.72 g, 14.4 mmol), EDCIHCI (3.63 g, 18.6 mmol), N-methylmorpholine (1. 6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2C12 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M 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 NaCI solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4- (3- (N- methylcarbamoyl) phenoxy)-1-nitrobenzene as an oil (1.89 g).

Step 4. Synthesis of 4- (3- (N-methylcarbamoyl) phenoxy) aniline A slurry of 4- (3- (N-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 atm (balloon) overnight. The resulting mixture was filtered through a pad of Celitee and concentrated under reduced pressure. The residue was purified by column chromatography (5% MeOH/95% CH2C12).

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 co-Carbamoyl Anilines via EDCI- Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4-3- (5-Methylcarbamoyl) pyridyloxy) aniline

Step 1. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy)-l-nitrobenzene To a slurry of NaH (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5- hvdroxvnicotinate (2.0 g, 13.1 mmol) in DMF (10 mL). The resulting mixture was added to a

solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 °C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to afford 4- (3- (5-methoxycarbonyl) pyridyloxy)- 1-nitrobenzene (0. 60 g).

Step 2. Synthesis of 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline A slurry of 4- (3- (5-methoxycarbonyl) pyridyloxy)-l-nitrobenzene (0.60 g, 2.20 mmol) and 10% Pd/C in MeOH/EtOAc was stirred under an H2 atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% EtOAc/90% hexane to 30% EtOAc/70% hexane to 50% EtOAc/50% hexane) to afford 4- (3- (5- methoxycarbonyl) pyridyloxy) aniline (0.28 g, 60%): IH NMR (CDC13) 8 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H). A15. Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction.

Synthesis of 4- (3-Methylsulfamoylphenoxy) aniline.

Step 1. Synthesis of N-methyl-3-bromobenzenesulfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF (15 mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp. overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCl solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x 25 mL). The combined organic phases were sequentially washed with water (2 x 25 mL) and a saturated NaCI solution (25 mL), dried (MgS04) and concentrated under reduced pressure to give N-methyl-3- bromobenzenesulfonamide as a white solid (2.8 g, 99%).

Step 2. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene 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, 10mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4- (3- (N- methylsulfamoyl) phenyloxy) benzene (0.30 g).

Step 3. Synthesis of 4- (3- (N-methylsulfamoyl) pbenyloxy)-l-nitrobenzene To a solution of 4- (3- (N-methylsulfamoyl) phenyloxy) benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at-10°C was added NaN02 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at-10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgS04) and concentrated under reduced pressure to give 4- (3- (N-methylsulfamoyl) phenyloxy)-l-nitrobenzene (0.20 g). This material carried on to the next step without further purification.

Step 4. Synthesis of 4- (3- (N-methylsulfamoyl) phenyloxy) aniline A slurry of 4- (3- (N-methylsulfamoyl) phenyloxy)-l-nitrobenzene (0.30 g) and 10% Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celte@. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give 4- (3- (N-methylsulfamoyl) phenyloxy) aniline (0.070 g).

A16. Modification of co-ketones. Synthesis of 4- (4- (1- (N methoxy) iminoethyl) phenoxyaniline HCI salt. To a slurry of 4- (4-acetylphenoxy) aniline HCl salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine HC1 salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting solids were triturated with water (10 mL) and washed with water to give 4- (4- ( 1- (N-methoxy) iminoethyl) phenoxyaniline HCI salt as a

yellow solid (0.85 g): TLC (50% EtOAc/50% pet. ether) Rf 0.78;'H NMR (DMSO-d6) 8 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z 257 ((M+H) +).

A17. Synthesis of N (w-Silyloxyalkyl) amides. Synthesis of 4- (4- (2- (N (2- Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline.

Step 1.4-Chloro-N-(2-triisopropylsilyloxy) ethylpyridine-2-carboxamide To a solution of 4-chloro-N- (2-hydroxyethyl) pyridine-2-carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO4), and concentrated under reduced pressure to afford 4- chloro-2-(N-(2-triisopropylsilyloxy)(N-(2-triisopropylsilylo xy) ethyl) pyridinecarboxamide as an orange oil (2.32 g, 88%). This material was used in the next step without further purification.

Step 2.4- (4- (2- (N (2-Triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline To a solution of 4-hydroxyaniline (0. 70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm.

When this mixture had cooled to room temperature, a solution of 4-chloro-2- (N- (2- triisopropylsilyloxy) ethyl) pyridinecarboxamide (2.32 g, 6 mmol, 1 equiv.) in DMF (4 mL) was added followed by K2CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The mixture was cooled to 0 °C with an ice/water bath, then water (approx. 1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined

organic layers were washed with a saturated NaCI solution (20 mL), dried (MgS04) and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (Si02; 30% EtOAc/70% pet ether) to afford 4- (4- (2- (N- (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2- Methylpyridines. Synthesis of 4- (5- (2- methoxycarbonyl) pyridyloxy) aniline.

Step 1.4- (5- (2-Methyl) pyridyloxy)-l-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4-nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K2CO3 (25 g, 183 mmol, 2.0 equiv.) in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with water (2 x 100 mL) and a saturated NaCI solution ( (100 mL), dried (MgS04) and concentrated under reduced pressure to give 4- (5-(2-methyl) pyridyloxy)-1-nitrobenzene as a brown solid (12.3 g).

Step 2. Synthesis of 4- (5- (2-Methoxycarbonyl) pyridyloxy)-l-nitrobenzene.

A mixture of 4- (5- (2-methyl) pyridyloxy)-1-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered, then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The 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 I N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCI solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography <BR> <BR> (Si02; 50% EtOAc/50% hexane) to afford 4-(5-(2-methoxycarbonyl) pyridyloxy)-1- nitrobenzene (0.70 g).

Step 3. Synthesis of 4- (5- (2-Methoxycarbonyl) pyridyloxy) aniline.

A slurry of 4- (5- (2-methoxycarbonyl) 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 H2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Si02; 70% EtOAc/30% hexane) to give 4- (5- (2- methoxycarbonyl) pyridyloxy) aniline (0.40 g).

A19. Synthesis of so-Sulfonylphenyl Anilines. Synthesis of 4- (4- Methylsulfonylphenyoxy) aniline.

Step To a solution of 4- (4- methylthiophenoxy)-1-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 5 h. The reaction mixture was treated with a 1N NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4- (4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).

Step 4- (4-MethyIsuIfony) phenoxy)-) nitrobenzene was reduced to the aniline in a manner analogous to that described Method . S. step 3.

B. Synthesis of Urea Precursors B1. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synthesis of 4-Bromo-3- (trifluoromethyl) phenyl Isocyanate.

Step 1. Synthesis of 4-bromo-3- (trifluoromethyl) aniline HCI salt To a solution of 4-bromo-3- (trifluoromethyl) aniline (64 g, 267 mmol) in Et20 (500 mL) was added an HC1 solution (1 M in Et20; 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 HCl salt (73 g, 98%).

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 (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH2CI2 (500 mL), then concentrated under reduced pressure. The CH2CI2 treatment/concentration protocol was repeated and resulting amber oil was stored at-20 °C for 16 h, to afford 4-bromo-3- (trifluoromethyl) phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).

C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N- (4-Chloro-3- (trifluoromethyl) phenvi)-N'- (4-(2-(N-methylcarbamoyl)-4-pyridyloxy) phenyl) Urea

A solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (14.60 g, 65.90 mmol) in CH2CI2 (35 mL) was added dropwise to a suspension of 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline (Method A2, Step 4; 16.0 g, 65.77 mmol) in CH2CI2 (35 mL) at 0 °C. The resulting mixture was stirred at room temp. for 22 h. The resulting yellow solids were removed by filtration, then washed with CH2CI2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mmHg) to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea as an off-white solid (28.5 g, 93%): mp <BR> <BR> <BR> 207-209 °C ;'H-NMR (DMSO-d6) 8 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5 Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5 Hz, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 ((M+H) +).

Clb. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Bromo-3-(trifluoromethyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) Urea A solution of 4-bromo-3- (trifluoromethyl) phenyl isocyanate (Method B1, Step 2; 8.0 g, 30.1 mmol) in CH2CI2 (80 mL) was added dropwise to a solution of 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline (Method A2, Step 4; 7.0 g, 28.8 mmol) in CH2CI2 (40 mL) at 0 °C. The 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 N-(4-bromo-3-(trifluoromethyl)phenyl)- N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea as a pale-yellow solid (13.2 g. <BR> <BR> <BR> <P>90%): mp 203-205 °C ; IH-NMR (DMSO-d6) 6 2.77 (d, J=4.8 Hz, 3H), 7.16 (m, 3H), 7.37 (d.

J=2.5 Hz, IH), 7.58 (m, 3H), 7.77 (d, J=8.8 Hz, IH), 8.11 (d, J=2.5 Hz, I H) * 8. 49 (dw J=>. 5 Hz, I H), 8.77 (br d, I H), 8.99 (s, I H), 9.21 (s, I H); HPLCES-MS/r509 ( (M-H)').

Clc. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl) phenyl)-N'- (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) Urea

A solution of 2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) aniline (Method A5; 0.11 g, 0.45 mmol) in CH2CI2 (1 mL) was treated with Et3N (0.16 mL) and 4-chloro-3- (trifluoromethyl) phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water (5 mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure to yield N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- (2-methyl-4- (2- (N-methylcarbamoyl) (4-pyridyloxy)) phenyl) urea as a brown oil (0.11 g, 0.22 mmol):'H NMR (DMSO-d6) 8 2.27 (s, 3H), 2.77 (d, J=4.8 Hz, 3H), 7.03 (dd, J=8.5,2.6 Hz, 1 H), 7.11 (d, J=2.9 Hz, 1H), 7.15 (dd, J=5.5,2.6, Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.62 (app d, J=2.6 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.17 (s, 1H); 8.50 (d, J=5.5 Hz, 1H), 8.78 (q, J=5.2,1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 ((M+H) +).

Cld. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl) phenyl)-N'- (4-aminophenyl) Urea To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (2.27 g, 10.3 mmol) in CH2CI2 (308 mL) was added p-phenylenediamine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for 1 h, treated with CH2CI2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOH (15mol), and the clear solution was washed with a 0.05 N <BR> <BR> HCI solution. The organic layer was concentrated under reduced pressure to afford impure

N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- (4-aminophenyl) urea (3.3 g): TLC (100% EtOAc)Rf 0.72.

Cle. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl) phenyl)-N'- (4-ethoxycarbonylphenyl) Urea

To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH2CI2 (30 mL) was added 4-chloro-3- (trifluoromethyl) aniline (3.21 g, 16.4 mmol), and the solution was stirred at room temp. overnight. The resulting slurry was diluted with CH2CI2 (50 mL) and filtered to afford N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- (4-ethoxycarbonylphenyl) urea as a white solid (5.93 g, 97%): TLC (40% EtOAc/60% hexane) Rf 0.44.

Clf. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl) phenyl)-N'- (3-carboxyphenyl) Urea

To a solution of 4-chloro-3- (trifluoromethyl) phenyl isocyanate (1.21g, 5.46 mmol) in CH2CI2 (8 mL) was added 4- (3-carboxyphenoxy) aniline (Method All; 0.81 g, 5.76 mmol) and the resulting mixture was stirred at room temp. overnight, then treated with MeOH (8 mL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 EtOAc/hexane solution to give N- (4- chloro-3- (trifluoromethyl) phenyl)-N'- (3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).

C2a. General Method for Urea Synthesis by Reaction of an Aniline with/V. V- Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of N (2-Methoxy-5- (trifluoromethyl) phenyl)-N'- (4- (2- (N methylcarbamoyl)-4-pyridyloxy) phenyl) Urea

To a solution of 2-methoxy-5- (trifluoromethyl) aniline (0.15 g) in anh CH2CI2 (15 mL) at 0 °C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over I h, was stirred at room temp. for 16 h, then was treated with 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline (0.18 g). The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H20 (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCI solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl) phenyl)- N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea as a light tan solid (0.098 g, 30%): TLC (100% EtOAc) Rf 0.62;'H NMR (DMSO-d6) 8 2.76 (d, J=4.8 Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1 H); FAB-MS m/z 461 C2b. General Method for Urea Synthesis by Reaction of an Aniline with N, N'- Carbonyl Diimidazole Followed by Addition of a Second Aniline.

Symmetrical Urea's as Side Products of a N, N'-Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis (4- (2- (N-methylcarbamoyl)-4- pyridyloxy) phenyl) Urea

To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH2C12 (15 mL) at 0 C was added CDI (0.13 g). The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4- (2- (N-methylcarbamoyl)-4-pyridyloxy) aniline (0.18 g). The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCI solution (100 ml), dried (MgS04) and concentrated under reduced pressure.

The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis (4- (2- (N-methylcarbamoyl)-4- pyridyloxy) phenyl) urea (0.081 g, 44%): TLC (100% EtOAc) Rf0.50;'H NMR (DMSO-d6) 5 2.76 (d, J=5.1 Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4 Hz, 1H), 8.75 (d, J=4.8 Hz, 2H),.

8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H) +).

C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(2-Methoxy-5-(trifluoromethyl) phenyl-N'- (4- (1, 3-dioxoisoindolin-5-yloxy) phenyl) Urea 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-1,3-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 CH2C12 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HCI solution (15 mL) and a saturated NaCI solution (15 mL), dried (MgS04) and concentrated under reduced pressure to afford N-(2-methoxy-5- (trifluoromethyl) phenyl-N'- (4- (1, 3-dioxoisoindolin-5-yloxy) phenyl) urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50;'H NMR (DMSO-d6) 8 3.95 (s, 3H), 7.31- 7.10 (m, 6H), 7.57 (d, J=9.3Hz, 2H), 7.80 (d, J=8.7 Hz, IH), 8.53 (br s, 2H), 9.57 (s, IH), 1 I. 27 (br s, I H) ; HPLC ES-MS 472.0 ((M+H) +, 100%).

C2d. General Method for Urea Synthesis by Reaction of an Aniline with N, N'- Carbonyl Diimidazole Followed by Addition of a Second Aniline.

Synthesis of N-(5- (tert-Butyl)-2- (2, 5-dimethylpyrrolyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) Urea

To a stirring solution of CDI (0.21g, 1.30 mmol) in CH2CI2 (2 mL) was added 5- (tert-butyl)- 2- (2,5-dimethylpyrrolyl) aniline (Method A4, Step 2; 0.30 g, 1.24 mmol) in one portion. The resulting mixture was stirred at room temp. for 4 h, then 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline (0.065 g, 0.267mmol) was then added in one portion. The resulting 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 (MgS04), and filtered through a pad of silica gel (50 g) to afford N- (5- (tert-butyl)-2- (2,5-dimethylpyrrolyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-4- pyridyloxy) phenyl) urea as a yellowish solid (0.033 g, 24%): TLC (40% EtOAc/60% hexane) <BR> <BR> <BR> Rf 0.24;'H NMR (acetone-d6) 8 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, 1H), 8.57 (d, J=2.1 Hz, 1 H), 8.80 (br s, 1 H); 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 dichloroethane (1 mL). To this was added a bis (trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.) followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting

mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline. Synthesis of N-(2-Methoxy-5- (trifluoromethyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) Urea To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in CH2C12 (20 mL) at 0 °C was added anh pyridine (0.32 mL) followed by 2-methoxy-5- (trifluoromethyl) aniline (0.75 g). The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4- (2- (N-methylcarbamoyl)-4-pyridyloxy) aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHC03 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgS04), and concentrated under reduced pressure. The resulting pink- <BR> <BR> brown residue was dissolved in MeOH and absorbed onto Si02 (100 g). Column<BR> <BR> chromatography (300 g Si02; gradient from 1 % Et3N/33% EtOAc/66% hexane to 1% Et3N/99% EtOAc to 1% Et3N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of N (2-methoxy-5- (trifluoromethyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-4-pyridyloxy) phenyl) urea (0.44 g): TLC (1% Et3N/99% EtOAc) Rf 0.40.

D. Interconversion of Ureas Dia. Conversion of w-Aminophenyl Ureas into w- (Aroylamino) phenyl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromethyl) phenyl)-N'-(4-(3- methoxycarbonylphenyl) carboxyaminophenyl) Urea

To a solution of N- (4-chloro-3-((trifluoromethyl) phenyl)-N'-(4-aminophenyl) urea (Method Cld; 0.050 g, 1.52 mmol), mono-methyl isophthalate (0.25 g, 1.38 mmol), HOBTH20 (0.41 g, 3.03 mmol) and N-methylmorpholine (0.33 mL, 3.03 mmol) in DMF (8 mL) was added EDCI HCl (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight, diluted with EtOAc (25 mL) and sequentially washed with water (25 mL) and a saturated NaHC03 solution (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to give N-(4-chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (3- methoxycarbonylphenyl) carboxyaminophenyl) urea (0.27 g, 43%): mp 121-122; TLC (80% EtOAc/20% hexane) Rf 0.75.

Dlb. Conversion of co-Carboxyphenyl Ureas into (o- (Arylearbamoyl) phenyl Ureas. Synthesis of N-(4-Chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (3- methylcarbamoylphenyl) carbamoylphenyl) Urea To a solution of N-(4-chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (3-methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 mmol), 3-methylcarbamoylaniline (0.080 g, 0.53 mmol), HOBTH2O (0.14 g, 1.07 mmol), and N-methylmorpholine (0.5mL, 1.07 mmol) in DMF (3 mL) at 0 °C was added EDCIHCI (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 (I OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated

under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% EtOAc/30% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3-((trifluoromethyl) phenyl)-N'-(4-(3- . methylcarbamoylphenyl) carbamoylphenyl) urea as a white solid (0.097 g, 41%): mp 225- 229; TLC (100% EtOAc) Rf 0.23.

Dlc. Combinatorial Approach to the Conversion of-Carboxyphenyl Ureas into w- (Arylcarbamoyl) phenyl Ureas. Synthesis of N-(4-Chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (N- (3- (N- (3- pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) Urea A mixture of N- (4-chloro-3-((trifluoromethyl) phenyl)-N'-(3-carboxyphenyl) urea (Method Clf; 0.030 g, 0.067 mmol) and N-cyclohexyl-N'- (methylpolystyrene) carbodiimide (55 mg) in 1,2-dichloroethane (1 mL) was treated with a solution of 3-aminopyridine in CH2C12 (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility or turbidity, a small amount of DMSO was also added.) The resulting mixture was heated at 36 °C overnight. Turbid reactions were then treated with THF (1 mL) and heating was continued for 18 h. The resulting mixtures were treated with poly (4- (isocyanatomethyl) styrene) (0.040 g) and the resulting mixture was stirred at 36 °C for 72 h, then cooled to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (1 g). Concentration under reduced pressure afforded N- (4-chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (N- (3- (N- (3- pyridyl) carbamoyl) phenyl) carbamoyl) phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) Rf 0.12.

D2. Conversion of (o-Carboalkoxyaryl Ureas into w-Carbamoylaryl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromethyl) phenyl)-N'-(4-(3- methylcarbamoylphenyl) carboxyaminophenyl) Urea

To a sample of N-(4-chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (3-carbomethoxyphenyl) carboxyaminophenyl) urea (0.17 g, 0.34 mmol) was added methylamine (2 M in THF; 1 mL, 1.7 mmol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4-chloro-3-((trifluoromethyl) phenyl)-N'-(4-(3- methylcarbamoylphenyl) carboxyaminophenyl) urea as a white solid: mp 247; TLC (100% EtOAc) Rf 0.35.

D3. Conversion of c3-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas.

Synthesis of N-(4-Chloro-3-((trifluoromethyl) phenyl)-N'-(4- carboxyphenyl) Urea To a slurry of N- (4-chloro-3- ( (trifluoromethyl) phenyl)-N- (4-ethoxycarbonylphenyl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (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)-N'- (4-carboxyphenyl) urea as a white solid (5.05 g, 92%).

D4. General Method for the Conversion of co-Alkoxy Esters into so-Alkyl Amides.

Synthesis of N-(4-Chloro-3-((trifluoromethyl) phenyl)-N'-((4-(3-(5-(2- dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) Urea

Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl) phenyl)-N'-((4-(3-(5- carboxypyridyl) oxyphenyl) Urea N-(4-Chloro-3-(trifluoromethyl) phenyl)-N'-((4-(3-(5-methoxycarbonylpyndyl) oxyphenyl) urea was synthesized from 4-chloro-3- (trifluoromethyl) phenyl isocyanate and 4- (3- (5- methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N-(4-chloro-3-(trifluoromethyl) phenyl)-N'-((4-(3-(5- methoxycarbonylpyridyl) oxyphenyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, 2.5 mmol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a 1 N HCl solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolved in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N- (4-chloro-3- (trifluoromethyl) phenyl)-N'-((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.18 g, 71%).

Step 2. Synthesis of N-(4-chloro-3- (trifluoromethyl) phenyl)-N'- ( (4- (3- (5- (2- dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea A mixture of N-(4-chloro-3-(trifluoromethyl) phenyl)-N'-((4-(3-(5- carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), N, N-dimethylethylenediamine (0.22 mg, 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol), and EDCIHCl (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 Et20 dropwise to give N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- ( (4- (3- (5- (2-dimethylaminoethyl) carbamoyl) pyridyl) oxyphenyl) urea as a white precipitate (0.48 g, 84%: NMR (DMSO-d6) 8 2.10 s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1 H), 8.43 (s, 1 H), 8.58 (t, lH), 8.69 (s, 1 H). 8.90 (s, I H), 9.14 (s, I H); HPLC ES-MS m/z 522 ((M+H) +).

D5. General Method for the Deprotection of N-(w-Silyloxyalkyl) amides.

Synthesis of N-(4-Chloro-3-((trifluoromethyl) phenyl)-N'-(4-(4-(2-(N-(2- hydroxy) ethylcarbamoyl) pyridyloxyphenyl) Urea.

To a solution of N-(4-chloro-3-((trifluoromethyl) phenyl)-N'-(4-(4-(2-(N-(2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea (prepared in a manner analogous to Method Cla; 0.25 g, 0.37 mmol) in anh THF (2 mL) was tetrabutylammonium fluoride (1.0 M in THF; 2 mL). The mixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (Si02; gradient from 100% hexane to 40% EtOAc/60% hexane) to give N-(4-chloro-3-((trifluoromethyl) phenyl)-N'-(4- (4- (2- (N- (2-hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, 10%).

Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above: Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4- (3-N-Methylcarbamoylphenoxy) aniline was prepared according to Method A13. According to Method C3,3-tert-butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (3-N-Methylcarbamoylphenoxy) aniline to afford the urea.

Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-nitrobenzene. 4-(4-Acetylphenoxy)- 1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4- (4- acetylphenoxy) aniline. According to Method C3,3-tert-butylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to afford the urea.

Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDI, followed by 4- (3-N-methylcarbamoyl)-4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to afford the urea.

Entry 4: 5-tert-Butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate according to Method Bl. 4- (3-N-Methylcarbamoylphenoxy) aniline, prepared according to Method A 13, was reacted with the isocyanate according to Method Cla to afford the urea.

Entry 5: According to Method C2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4- (3-N-methylcarbamoyl)-4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to afford the urea.

Entry 6: 5- (4-Aminophenoxy) isoindoline-1,3-dione was prepared according to Method A3.

According to Method 2d, 5-tert-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-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4- (l-oxoisoindolin-5-yloxy) aniline to afford the urea.

Entry 8: 4- (3-N-Methylcarbamoylphenoxy) aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (3-N-methylcarbamoylphenoxy) aniline to afford the urea.

Entry 9: 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4- (4- acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4,4- (4-acetylphenoxy)-5-nitropyridine was reduced to 4- (4-acetylphenoxy)-5- aminopyridine. 2-Methoxy-5- (trifluoromethyl) aniline was converted to 2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method Bl. The isocyanate was reacted with 4- (4-acetylphenoxy)-5-aminopyridine according to Method Cla to afford the urea.

Entry 10: 4-Fluoro-l-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A 13, Step 1 to afford the 4- (4-acetylphenoxy)-1-nitrobenzene. 4- (4-Acetylphenoxy)- 1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4- (4- acetylphenoxy) aniline. According to Method C3,5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis (trichloromethyl) carbonate followed by 4- (4-acetylphenoxy) aniline to afford the urea.

Entry 11: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3- (-2- (N-methylcarbamoyl)-4-pyridyloxy) aniline. According to Method C4,2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 3- (-2- (N-methylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 12: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2- pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 3- (2- carbamoyl-4-pyridyloxy) aniline to afford the urea.

Entry 13: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4- (2- (N- methylcarbamoyl)-4-pyridyloxy) aniline. According to Method C2a, 2-methoxy-5- (trifluoromethyl) aniline was reacted with CDI followed by 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 14: 4-Chloropyridine-2-carbonyl chloride HC1 salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2- <BR> <BR> <BR> <BR> pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4- (2-carbamoyl-4-pyridyloxy) aniline. According to Methood

C4,2-methoxy-5- (trifluoromethyl) aniline was reacted with phosgene followed by 4- (2- carbamoyl-4-pyridyloxy) aniline to afford the urea.

Entry 15: According to Method C2d, 5- (triflouromethyl)-2-methoxyaniline was reacted with CDI followed by 4- (3-N-methylcarbamoyl)-4-methoxyphenoxy) aniline, which had been prepared according to Method A8, to afford the urea.

Entry 16: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5.5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method C 1 c to afford the urea.

Entry 17: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6.5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)- 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- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C 1 a to afford the urea.

Entry 19: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl)-4- pyridyloxy) aniline. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trinuoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5-(Trifluoromethyl)-

2-methoxyphenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy) aniline according to Method C1 a to afford the urea.

Entry 20: According to Method A2, Step 4,4-amino-2-chlorophenol was reacted with 4- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline according to Method Cla to afford the urea.

Entry 21: 4- (4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy)-1-aniline. According to Method Cla, 5- (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (4- methylsulfonylphenoxy)-l-aniline to afford the urea.

Entry 22: 4- (3-carbamoylphenoxy)-l-nitrobenzene was reduced to 4- (3- carbamoylphenoxy) aniline according to Method A15, Step 4. According to Method Cla, 5- (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (3- carbamoylphenoxy) aniline to afford the urea.

Entry 23: 5- (4-Aminophenoxy) isoindoline-1,3-dione was synthesized according to Method A3.5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2- methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione according to Method C 1 a to afford the urea.

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give4-<2-(.\..V- <BR> <BR> <BR> dimethylcarbamoyl)-4-pyridyloxy) aniline. 5- (Trifluoromethyl)-2-methoxyaniline w as

converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1.5- <BR> <BR> <BR> <BR> (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N, N- dimethylcarbamoyl)-4-pyridyloxy) aniline according to Method Cla to afford the urea.

Entry 25: 4- (1-Oxoisoindolin-5-yloxy) aniline was synthesized according to Method A12.5- (Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4- (1-oxoisoindolin-5- 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 A 13, Step 4 to afford 4- (4-acetylphenoxy) aniline, which was converted to the 4- (4-(1-(N-methoxy) iminoethyl) phenoxyaniline HCI salt according to Method A16.5- (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)- 2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (4-(1-(N-methoxy) iminoethyl) phenoxyaniline HCI salt to Method C 1 a to afford the urea.

Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (Trifluoromethyl)-2- methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline according to Method Cla to afford the urea.

Entry 28: 5- (4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9.5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2- methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5- (4-aminophenoxy)-2-methylisoindoline-1,3-dione according to Method C 1 a to afford the urea.

Entry 29: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described m Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method

A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 5- (Trifluoromethyl)-2- methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) 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-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N isopropylcarbamoyl)-4-pyridyloxy) aniline. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Bl. 5- (Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (2- (N isopropylcarbamoyl)-4-pyridyloxy) aniline according to Method Cla to afford the urea.

Entry 31: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2- methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N-(5- (Trifluoromethyl)-2-methoxyphenyl)-N'- (4- (3- (5- methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to afford the amide according to Method D4, Step 2.

Entry 32: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2- methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N- (5- (Trifluoromethyl)-2-methoxyphenyl)-N'- (4- (3- (5- methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.

Entry 33: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2- methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (3- (5-methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N- (5- (Trifluoromethyl)-2-methoxyphenyl)-N'- (4- (3- (5- methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.

Entry 34: 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-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with 3- aminopyridine according to Method Dite.

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-methoxyphenyl isocyanate according to Method Clf to afford N-(5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with N- (4-fluorophenyl) piperazine according to Method Dlc.

Entry 36: 4- (3-Carboxyphenoxy) 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-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with 4- fluoroaniline according to Method Dlc.

Entry 37: 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-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with 4- (dimethylamino) aniline according to Method Dlc.

Entry 38: 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-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with 5- amino-2-methoxypyridine according to Method Dlc.

Entry 39: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 5- (Trifluoromethyl)-2-methoxyaniline was converted into 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4- (3-Carboxyphenoxy) aniline was reacted with 5- (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with 4- morpholinoaniline according to Method Dite.

Entry 40: 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-methoxyphenyl isocyanate according to Method Clf to afford N- (5- (trifluoromethyl)-2-methoxyphenyl)-N'- (3-carboxyphenyl) urea, which was coupled with N- (2-pyridyl) piperazine according to Method Dite.

Entry 41: 4- (3- (N-Methylcarbamoyl) phenoxy) aniline was synthesized according to Method A 13. According to Method C3,4-chloro-3- (trifluoromethyl) aniline was converted to the isocyanate, then reacted with 4- (3- (N-Methylcarbamoyl) phenoxy) aniline to afford the urea.

Entry 42: 4- (2-N-Methylcarbamyl-4-pyridyloxy) aniline was synthesized according to Method A2.4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4-(2-lu- methylcarbamyl-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- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-carbamoyl-4-pyridyloxy) aniline to afford the urea.

Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2- pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (2-carbamoyl-4-pyridyloxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2-carbamoyl-4-pyridyloxy) aniline to afford the urea.

Entry 45: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (-2- (N-methylcarbamoyl)-4-pyridyloxy) aniline. According to Method Cla, 4-chloro- 3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 46: 5- (4-Aminophenoxy) isoindoline-1,3-dione was synthesized according to Method A3. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to afford the urea.

Entry 47: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. According to Method Clc, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy) isoindoline-1,3-dione to afford the urea.

Entry 48: 4- (3-N-Methylsulfamoyl) phenyloxy) aniline was synthesized according to Method A15. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-N-methylsulfamoyl) phenyloxy) aniline to afford the urea.

Entry 49: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method Cla, 4-chloro-3-(trifluoromethyl) phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.

Entry 50: According to Method A2, Step 4,5-amino-2-methylphenol was reacted with 4- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3- (2- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N- methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.

Entry 51: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl)-4- pyridyloxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 52: According to Method A2, Step 4,4-amino-2-chlorophenol was reacted with 4- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 53: 4- (4-Methylthiophenoxy)-l-nitrobenzene was oxidized according to Method A19, Step 1 to give 4- (4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4- (4-methylsulfonylphenoxy)-1-aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with4-(4- methylsulfonylphenoxy)-l-aniline to afford the urea.

Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4- bromobenzenesulfonamide was coupled with phenol according to Method Al5, Step 2 to afford 4- (4- (N-methylsulfamoyl) phenoxy) benzene. 4- (4- (N- Methylsulfamoyl) phenoxy) benzene was converted into 4- (4- (N-methylsulfamoyl) phenoxy)- 1-nitrobenzene according to Method A15, Step 3.4- (4- (N-Methylsulfamoyl) phenoxy)-l- nitrobenzene was reduced to 4- (4-N-methylsulfamoyl) phenyloxy) aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl) phenyl isocyanate was reacted with 4- (3-N methylsulfamoyl) phenyloxy) aniline to afford the urea.

Entry 55: 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4- (5- (2-Methyl) pyridyloxy)-l-nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4- (5- (2-methoxycarbonyl) pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4- (5- (2- methoxycarbonyl) pyridyloxy) aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method Cla to afford the urea.

Entry 56: 5-Hydroxy-2-methylpyridine was coupled with 1-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-methoxycarbonyl) pyridyloxy)-l-nitrobenzene. The nitrobenzene was reduced according the Method A18, Step 3 to give 4- (5- (2- methoxycarbonyl) pyridyloxy) aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl) phenyl isocyanate according to Method Cla to give N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- (4- (2- (methoxycarbonyl)-5-pyridyloxy) phenyl) urea. The methyl ester was reacted with methylamine according to Method D2 to afford N- (4-chloro-3- (trifluoromethyl) phenyl)-N'- (4- (2- (N-methylcarbamoyl)-5-pyridyloxy) phenyl) urea.

Entry 57 : N- (4-Chloro-3-(trifluoromethyl) phenyl-N-(4-aminophenyl) urea was prepared according to Method Cld. N- (4-Chloro-3- (trifluoromethyl) phenyl-N'- (4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method DIa to afford the urea.

Entry 58: N- (4-Chloro-3- (trifluoromethyl) phenyl-N'- (4-aminophenyl) urea was prepared according to Method Cld. N- (4-Chloro-3- (trifluoromethyl) phenyl-N'- (4-aminophenyl) urea was coupled with mono-methyl isophthalate according to Method Dl a to afford N- (4-chloro- 3- (trifluoromethyl) phenyl-N'- (4- (3-methoxycarbonylphenyl) carboxyaminophenyl) urea.

According to Method D2, N- (4-chloro-3- (trifluoromethyl) phenyl-N'- (4- (3- methoxycarbonylphenyl) carboxyaminophenyl) urea was reacted with methylamine to afford the corresponding methyl amide.

Entry 59: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N, N- dimethylcarbamoyl)-4-pyridyloxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4-(2-(N, N-dimethylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 60: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A 13, 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-(1-(N-methoxy) iminoethyl) phenoxyaniline HCl salt according to Method A 16. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4-acetylphenoxy) aniline to afford the urea.

Entry 61: 4- (3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A 13, Step 2.4- (3-Carboxyphenoxy)-1-nitrobenzene was. coupled with 4- (2- aminoethyl) morpholine according to Method A13, Step 3 to give 4- (3- (N (2- morpholinylethyl) carbamoyl) phenoxy)-l-nitrobenzene. According to Method A13 Step 4,4- (3-(N-(2-morpholinylethyl) carbamoyl) phenoxy)-1-nitrobenzene was reduced to 4- (3- (N- (2- morpholinylethyl) carbamoyl) phenoxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2- morpholinylethyl) carbamoyl) phenoxy) aniline to afford the urea.

Entry 62: 4- (3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A 13, Step 2.4- (3-Carboxyphenoxy)-l-nitrobenzene was coupled with 1- (2-aminoethyl) piperidine according to Method A13, Step 3 to give 4- (3- (N- (2-piperidylethyl) carbamoyl) phenoxy)-1- nitrobenzene. According to Method A13 Step 4,4- (3- (N- (2- piperidylethyl) carbamoyl) phenoxy)-1-nitrobenzene was reduced to 4- (3- (N- (2- piperidylethyl) carbamoyl) phenoxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (2- piperidylethyl) carbamoyl) phenoxy) aniline to afford the urea.

Entry 63: 4- (3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2.4- (3-Carboxyphenoxy)-l-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy)-1-nitrobenzene. According to Method A13 Step 4,4- (3- (N (tetrahydrofurylmethyl) carbamoyl) phenoxy)-1-nitrobenzene was reduced to 4- (3- (N-(tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline. According to Method Cla, 4-chloro- 3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- (tetrahydrofurylmethyl) carbamoyl) phenoxy) aniline to afford the urea.

Entry 64: 4- (3-Carboxyphenoxy)-l-nitrobenzene was synthesized according to Method A13, Step 2.4- (3-Carboxyphenoxy)-l-nitrobenzene was coupled with 2-aminomethyl-1- ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((I- methylpyrrolidinyl) methyl) carbamoyl) phenoxy)-1-nitrobenzene. According to Method A13 Step 4,4- (3- (N ( (1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy)-1-nitrobenzene was reduced to 4- (3- (N- ( (1-methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (N- ( (I- methylpyrrolidinyl) methyl) carbamoyl) phenoxy) aniline to afford the urea.

Entry 65: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method Cla 4-chloro-3-(trifluoromethyl) phenyl(trifluoromethyl) phenyl isocyanate was reacted with 4-(4* methylcarbamoyl) phenylthio) aniline to afford the urea.

Entry 66: 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N isopropylcarbamoyl)-4-pyridyloxy) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-isopropylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 67: N- (4-Chloro-3- (trifluoromethyl) phenyl-N'- (4-ethoxycarbonylphenyl) urea was synthesized according to Method Cle. N-(4-Chloro-3-(trifluoromethyl) phenyl-N'-(4- ethoxycarbonylphenyl) urea was saponified according to Method D3 to give N- (4-chloro-3- (trifluoromethyl) phenyl-N'- (4-carboxyphenyl) urea. N- (4-Chloro-3- (trifluoromethyl) phenyl- N'- (4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method Dlb to give N (4-chloro-3- (trifluoromethyl) phenyl-N'- (4- (3- methylcarbamoylphenyl) carbamoylphenyl) urea.

Entry 68: 5- (4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 5- (4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.

Entry 69: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N- methylcarbamoyl) phenylthio) aniline to afford the urea.

Entry 70: 4- (2- (N (2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A 10. According to Method Cla, 4-chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline to afford the urea.

Entry 71: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14.4-Chloro-3- (trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (3- (5- methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N- (4- Chloro-3- (trifluoromethyl) phenyl)-N'- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4- (2-aminoethyl) morpholine to afford the amide.

Entry 72: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14.4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5- methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N- (5- (Trifluoromethyl)-2-methoxyphenyl)-N'- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.

Entry 73: 4- (3- (5-Methoxycarbonyl) pyridyloxy) aniline was synthesized according to Method A14.4-Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5- methoxycarbonyl) pyridyloxy) aniline according to Method Cla to afford the urea. N- (5- (Trifluoromethyl)-2-methoxyphenyl)-N'- (4- (3- (5-methoxycarbonylpyridyl) oxy) phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N, N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.

Entry 74: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2- hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N- (2- triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N- (2- triisopropylsilyloxy) ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- (N- (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline. According to Method Cla. 4-chloro- 3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (,'V- (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline to afford N- (4-chloro-3- ((trifluoromethyl) phenyl)-N'- (4- (4- (2- (N- (2-triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Entry 75: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4- Chloro-3-(trifluoromethyl) phenyl(trifluoromethyl) phenyl isocyanate was reacted with 4- (3- (5- methoxycarbonyl) pyridyloxy) aniline according to Method Clf to afford the urea, which was coupled with 3-aminopyridine according to Method Dlc.

Entry 76: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method A 11.4- Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to afford the urea, which was coupled with N- (4- acetylphenyl) piperazine according to Method Dlc.

Entry 77: 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-fluoroaniline according to Method D 1 c.

Entry 78: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4- Chloro-3-(trifluoromethyl) phenyl(trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to afford the urea, which was coupled with 4- (dimethylamino) aniline according to Method Dlc.

Entry 79: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method 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- phenylethylenediamine according to Method Dlc.

Entry 80: 4- (3-Carboxyphenoxy) aniline was synthesized according to Method All. 4- Chloro-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (3-carboxyphenoxy) aniline according to Method Clf to afford the urea, which was coupled with 2-methoxyethylamine according to Method Dlc.

Entry 81: 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 5-amino-2- methoxypyridine according to Method Dlc.

Entry 82: 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-morpholinoaniline according to Method Dite.

Entry 83: 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 (2-pyridyl) piperazine according to Method Dlc.

Entry 84: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2- hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2- triisopropylsilyloxy) ethylpyridine-2-carboxamide. 4-Chloro-N-(2- triisopropylsilyloxy) ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4- (4- (2- (N (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline. According to Method Cla, 4-chloro- 3- (trifluoromethyl) phenyl isocyanate was reacted. with 4- (4- (2- (N (2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyaniline to give N- (4-chloro-3- ((trifluoromethyl) phenyl)-N'-(4-(4-(2-(N-(2- triisopropylsilyloxy) ethylcarbamoyl) pyridyloxyphenyl) urea. The urea was deprotected according to Method D5 to afford N-(4-chloro-3- ( (trifluoromethyl) phenyl)-N'- (4- (4- (2- (N-(2- hydroxy) ethylcarbamoyl) pyridyloxyphenyl) urea.

Entry 85: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy) aniline was synthesized according to Method A2.4-Bromo-3- (trifluoromethyl) aniline was converted to 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4- bromo-3-(trifluoromethyl)(trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 86: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6.4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4- bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4- pyridyloxy)-2-chloroaniline to afford the urea.

Entry 87: According to Method A2, Step 4,4-amino-2-chlorophenol was reacted with 4- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl)-4- pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4- bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 89: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) aniline. 4-Bromo-3-(trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method B I.

According to Method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (-2-(N-methylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 90: According to Method A2, Step 4,5-amino-2-methylphenol was reacted xith 1- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-melhylaniline. 4-Bronao-.-

(trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 3- (2- (N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.

Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N, N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N, N- dimethylcarbamoyl)-4-pyridyloxy) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl.

According to Method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N, N-dimethylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 92: 4-Chloro-N-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- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to afford the urea.

Entry 93: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo-3- (trifluoromethyl) phenyl isocyanate according to Method Bl. According to Method Cla, 4-bromo-3-(trifluoromethyl) phenyl isocyanate was reacted with 3- (4- (2- (N-methylcarbamoyl) phenylthio) aniline to afford the urea.

Entry 94: 4- (2-(N-(2-Morpholin-4-ylethyl) carbamoyl) pyridyloxy) aniline was synthesized according to Method A10. 4-Bromo-3- (trifluoromethyl) aniline was converted into 4-bromo- 3- (trifluoromethyl) phenyl isocyanate according to Method B I. According to Method Cla, 4-

bromo-3- (trifluoromethyl) phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4- ylethyl) carbamoyl) pyridyloxy) aniline to afford the urea.

Entry 95: 4- (2- (N-Methylcarbamoyl)-4-pyridyloxy) aniline was synthesized according to Method A2.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted into 4-chloro-2- methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B 1. According to Method Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 96: 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B 1.

According to Method Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline afford the urea.

Entry 97: According to Method A2, Step 4,4-amino-2-chlorophenol was reacted with 4- chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4- (2- (N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. 4-Chloro-2- methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2- methoxy-5- (trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B 1. According to Method Cla, 4- chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N- methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.

Entry 98: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to <BR> <BR> <BR> <BR> form 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2-methoxv-5- (trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5-(triíluoronacthyl) phet isocyanate according to Method Bl. According to Method C la, 4-chloro-2-methoxy-5-

(trifluoromethyl) phenyl isocyanate as was reacted with 3- (-2- (N-methylcarbamoyl)-4- pyridyloxy) aniline to afford the urea.

Entry 99: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4- (2- (N-ethylcarbamoyl)-4- pyridyloxy) aniline. 4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B 1.

According to Method Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2- (N-ethylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 100: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N, N- dimethylcarbamoyl)-4-pyridyloxy) aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl) aniline was synthesized according to Method A7.4-Chloro-2-methoxy-5- (trifluoromethyl) aniline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate according to Method B 1. According to Method Cla, 4-chloro-2-methoxy-5- (trifluoromethyl) phenyl isocyanate was reacted with 4- (2-(N, N-dimethylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 101: 4-Chloro-N-methyl-2-pyridinecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3- (-2- (N-methylcarbamoyl)-4-pyridyloxy) aniline. 2-Amino-3-methoxynaphthalene was synthesized as described Method A1. According to Method C3,2-amino-3- methoxynaphthalene was reacted with bis (trichloromethyl) carbonate followed by 3- (-2- (N- methylcarbamoyl)-4-pyridyloxy) aniline to form the urea.

Entry 102: 4- (2-(N-Methylcarbamoyl)-4-pyridyloxy) aniline was synthesized according to Method A2.5-ter/-Butyl-2- (2, 5-dimethylpyrrolyl) aniline was synthesized according to

Method A4.5-tert-Butyl-2- (2, 5-dimethylpyrrolyl) aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyndyloxy) aniline according(2-(N-methylcarbamoyl)-4-pyndyloxy) aniline according to Method C2d to afford the urea.

Entry 103: 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4- (2- (N methylcarbamoyl)-4-pyridyloxy) aniline. According to Method C2b, reaction of 3-amino-2- methoxyquinoline with CDI followed by 4- (2- (N-methylcarbamoyl)-4-pyridyloxy) aniline afforded bis (4- (2- (N-methylcarbamoyl)-4-pyridlyoxy) phenyl) urea.

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.

Table 1.

3-tert-Butylphenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (°C) (min.) Rf System [Sourcel Method 1 0 0.22 50% 418 A 13 C3 NH EtOAc (M+H) + -Me 150% (HPLC hexane ES-MS) 2 0 0. C3 0 EtOAc (M+H) + Me/50% (HPLC hexane ES-MS) 3 0 133-0.68 100% 448 A8 C2d NH 135 EtOAc (M+H) + -Me (FAB) 0-& OMe

Table 2.

5-tert-Butyl-2-methoxyphenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (°C) (min.) Rf System [Source] Method 4 0 5.93 448 A13 NH (M+H) + BI -Me (HPLC Cla ES-MS) 5 120-0.67 100% 478 A8 NH 122 EtOAc (M+H) + C2d -Me (FAB) O OMe 6 0.40 50% 460 A3 EtOAc (M-H) + C2d NH (HPLC hexane ES-MS) O 7 0 0.79 50% 446 A 12 7 EtOAc (M+H) + C2d nu H/50% (HPLC hexane ES-MS) Table 3. 5-(Trifluoromethyl)-2-methoxyphenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (°C) (min. Rf System [Source] Method 8 0 250 460 A 13 N H (dec) (M+H) + C2a -Me (FAB) po 9 fi5/=\, O 206-0.54 10% 446 A3 step +/\ 208 MeOH (M+H) + 2, N \/Me/90% (HPLC A8 step CH2CI ES-MS) 4, 2 Bl, Cla 10 0 0.33 50% 445 A13 C3 EtOAc (M+H) + Me/50% (HPLC pet ES-MS) ether 11 mS Os 0.20 2% 461 A2 NH Et3N/ (M+H) + C4 -me 98% (HPLC EtOAc ES-MS) \- 12 0 0. 27 1% 447 A2 NH2 Et3N/ (M+H) + C4 \= (HPLC EtOAc ES-MS) -eN nu00.62 100% 461 A2 C2a NH EtOAc (M+H) + Me (FAB) 0 N 14 114-0.40 1% 447 A2 NH2 117 Et3N/ (M+H) + C4 99% (FAB) --a. O N EtOAc 15 0 232-0.54 100% 490 A8 C2d NH 235 EtOAc (M+H) + -Me (FAB) 0 OMe 16 210-0. 29 5% $75 A5 Me NH 213 MeOH (M+H) + B1 Clc jMe/45% (HPLC 0 N EtOAc ES-MS) -el N pet ether 17 0 187-0.17 50% 495 A6 NH 188 EtOAc (M+H) + B1 Cla \ + Me/50% (HPLC 0 N pet ES-MS) ether 18 0 0.48 100% 475 A2 step Me NH2 EtOAc (M+H) + 4, (HPLC B1 Cla ES-MS) ON 19 O 194-0. 31 5% 475 A2 NH 196 MeOH (M+H) + BI Cla A Et/45% (HPLC 0 N EtOAc ES-MS) 0 pet ether 20 0 214-0.25 5% 495 A2 C 1 a Cl SNH 216 MeOH (M+H) + -Me/45% (HPLC 0 N EtOAc ES-MS) //50% pet ether 21 0 208-0.30 50% 481 A 19 C2a 0 S : z 0 210 EtOAc (M+H) + Me/50% (HPLC hexane ES-MS) 22 O 188-030 70% 447 A 15, NH2 190 EtOAc (M+H) + step 4, /50% (HPLC Cla hexane ES-MS) 23 0. 50 70% 472 A3 z % \/EtOAc (M+H) + BI Cla NH/30% NH/30% (FAB) hexane 0 24 O Me 203-0.13 100% 479 A2 BI N 205 EtOAc (M+H) + Cla . Me (HPLC e ES-MS) / 25 0 0. 09 75% 458 A12 -0-0 EtOAc (M+H) + C2d nu (HPLC hexane ES-MS 26 Meq 169-0.67 50% 474 A 13 N 171 EtOAc (M+H) + stepl, /50% (HPLC A13 step Me pet ES-MS) 4, ether A 16, BI Cla 27 O 218-0.40 50% 477 A2 step NH 219 EtOAc (M+H) + 3b, -Me (HPLC A2 step s N pet ES-MS) 4, ether ether B1, Cla 28 212-0.30 40% A9 214 EtOAc BI Cla NM/60% \NMe 0 hexane O 29 0 0.33 50% 474 A2 step NH EtOAc (M+H) + 3b, Me/50% (HPLC A2 step w S N pet ES-MS) 4, ether B 1, Cla 30 O 210-A2 NH 211 BI pur-i Cla -C°' 31 O 210-0.43 10% A14 NH 204 MeOH Bl --a 0 N CH2CI D4 Hz O 32 O 247-0.57 10% A 14 NH 249 MeOH BI 0 CH2CI D4 N 2 33 0 217-0.07 10% A14 NH 219 MeOH Bl 0 90<x/) N-M CH2CI D4 N Me 2 34 _ _ _ 0.11 70% All N H EtOAc B 1 /30°/a Clf --a 0 N hexane Dic 35 0.38 70% A11 EtOAc B 1 /30% calf hexane D 1 c NF N --ao-eo O 36 0. 77 70% All F-ANH EtOAc B I \=) =O/30% Clf -hexane D 1 c -au 37 Me n 0.70% All t Bl Me \=/) =0/30% Clf hexane D 1 c 38 NR 0.58 70% All Me0 y-NHEtOAc Bl O/30% Clf hexane D 1 c O 39 0. 17 70% All O NH EtOAc B1 0/30% =0/30% Clf -hexane D 1 c O 40 N--1 0.21 70% All N N NH EtOAc B1 U p/30% Clf hexane duc zozo Table 4. 3-(Trifluoromethyl)-4-chlorophenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (°C) (min.) Rf System [Source] Method 7 41 7 Or 163-0.08 50% 464 A13 NH 165 EtOAc/ (M+H) + C3 -Me 50% pet (HPLC --ao ether ES-MS) 42 O 215 0.06 50% 465 A2 NH EtOAc/ (M+H) + Cla -Me 50% pet 0 N ether ES-MS) 43 0 0.10 50% 451 A2 NH2 EtOAc/ (M+H) Cla 50% pet (HPLC ether N ether ES-MS) 44 0 0.25 30% 451 A2 NH2 EtOAc/ (M+H) + Cla \= pet (HPLC ether ES-MS) ON 45 n O 0.31 30% 465 A2 N H EtOAc/ (M+H) + Cla -Q-'me 70% pet ether ES-MS) \. 46 23 40%6'3 179 179 EtOAc/ (M+H) + Cla NH 60% (FAB) hexane O 47 O 0.29 5% 478 A5 Me NH MeOH/ (M+H) + Clc Me (HPLC (/-0- NEtOAc/ES-MS) ether ether 48 O 206-A 15 tANH 209 Cla Me PO 49 O 147-0.22 50% 499 A6 Cl NH 151 EtOAc/ (M+H) + Cla -Me 50% pet +/\904, N ether ES-MS) / 50/\ O 0.54 100% 479 A2 Me NH EtOAc (MtH) + Cta Me (HPLC ES-MS) O N 51 0 187-0.33 5% 479 A2 N H 189 MeOH/ (M+H) + Cla -Et Et 45% (HPLC 404s N EtOAc/ES-MS) 50% pet ether 52 0 219 0.18 5% 499 A2 Cl NH MeOH/ (M+H) + Cla 45°/a (HPLC 0 N EtOAc/ES-MS) 50% pet ether 53 0 246-0.30 50% 485 A19, Cla 0 o 248 EtOAc/ (M+H) + 50% (HPLC hexane ES-MS) 54 0 196-0.30 70% 502 A15 0 5 :--0 200 EtOAc/ (M+H) + Cla \=/'u'NH NH 30% (HPLC Me hexane) ES-MS) 55 O 228-0.30 30% 466 9 230 EtOAc/ (M+H) + -me (HPLC - (/\\-0- N CH2C12 ES-MS) 56 N 0 238- O 245 Nu Me 57 0 221-0.75 80% 492 Cld q 222 EtOAc/ (M+H) + Dia _ H < (FAB) texane 58 247 0.35 100% Cld SNH EtOAc Dla Me D2 ZON 1 1 590Me198-0.09 100% 479 A2 200 EtOAc (M+H) + Cla - N ES-MS) 60 MeO 158-0.64 50% N 160 EtOAc/ 50% peu mye ether 6l O 195-0. 39 10% A13 NH 197 MeOH/Cla . H2C1 o-e N 2 0 62 0 170-0.52 10% A13 NH 172 MeOH/Cla -CH2C1 . o 63 °\ 168- 0.39 10% A 13 NH 0 171 MeOH/Cla --C CH2CI 64 O Et 176-0.35 10% A13 NH N 177 MeOH/Cla CH2C1 2 65 0 130-487 A2 NH 133 >NH 133 (M+H) + B1 -Me (HPLC Cla zut N ES-MS) 66 O 155 A2 NH Cla -Pr-i -0-0 N 67 0 225-0.23 100% Cle NH 229 EtOAc D3 Me Dlb zon 68 234-0.29 40% A9 236 EtOAc/C I a nome 60% hexane _ O 69 O, 0.48 50% 481 NH EtOAc/ (M+H) + w me 50% pet (HPLC S N ether ES-MS) N 70 O 0.46 5% 564 A 10 NH MeOH/ (M+H) + Cla fi5/= 95% (HPLC N CH2CI2 ES-MS) 71 O 199-0.50 10% A14 NH 201 MeOH/Cla CH2CI D4 0 N 2 N 0 72 O 235-0.55 10% A14 NH 237 MeOH/Cla CH2C1 D4 -p 2 N 2 73 O 200-0.21 50% A14 NH 201 MeOH/Cla CH2Cl D4 N N-Me 2 zon Me 74 O 145- NH 148 /\ o- w0Y/# OSi (Pr-i) 3 N 75 N 0.12 70% 527 All 527 A11 (/XNH EtOAc/ (M+H) + Clf 0 30% (HPLC D 1 c hexane ES-MS) 76 O 0.18 70% All Me EtOAc/Clf -30% Dlc hexane 0 N 0-60 77 0.74 70% All F--NH EtOAc/Clf 30% Dlc -hexane 0 78 Me 0.58 70% All NH NH EtOAc/Clf Me O 30% Dlc hexane zozo 79 0 0.47 70% 569 All NH EtOAc/ (M+H) + Clf 30% (HPLC Dic 0 NH hexane ES-MS) 80 0. 18 70% 508 All NH EtOAc/ (M+H) + Clf 30% 30% (HPLC Dlc oye hexane ES-MS) 8. NR 0. 58 70% 557 Al l 81 MeO NH EtOAc/ (M+H) + Clf \=/\=030% (HPLC Die hexane ES-MS) 0-I I 82/\ <\ 0.37 70% 611 All O EtOAc/ (M+H) + Clf O 30% (HPLC Dlc hexane ES-MS) 83 0.19 70% All N EtOAc/C 1 f 30% Dlc hexane o0X° L °- O 84 0 179-A2 NH 183 A17 cula Dus O N OH Table 5. 3-(Trifluoromethyl)-4-bromophenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. En R (°C) (min.) Rf System [Source] Method 85 0 186-0.13 50% 509 A2 NH 187 EtOAc/ (M+H) + Bl -Me 50% pet (HPLC ES-Cla ether MS) ON 86 O 150-0. 31 50% 545 A6 NH 152 EtOAc/ (M+H) + Bl 9 50% pet (HPLC ES-Cla 0 N ether MS) 87 O 217-0.16 50% 545 A2 Cl _eN. 2 219 EtOAc/ (M+H) + B1 Me 50% pet (HPLC ES-Cla ether MS) \=/\U 88 O 183-0.31 50% 525 A2 NH 184 EtOAc/ (M+H) + B1 . Et 50% pet (HPLC ES-Cla 0 N ether MS) 89 00.21 50% 511 A2 NH EtOAc/ (M+H) (M+H) Bl 50% pet (HPLC ES-Cla 0 N ether MS) N 90 n O 0. 28 50% 525 A2 Me NH EtOAc/ (M+H) + B1 me 50% pet (HPLC ES-Cla O N ether MS) U 91 O Me 214-0.28 50% 522 A2 N 216 EtOAc/ (M+H) + B1 -Me 50% pet (HPLC ES-Cla 0 N ether MS) 92 O 0.47 50% 527 A2 step NH EtOAc/ (M+H) + 3b, _ jg 50% pet (HPLC ES-A2 step s-jel N ether MS) 4, Cla Cla 93/-\ 00.46 50% 527 A2 step NH EtOAc/ (M+H) + 3b. -Me 50% pet (HPLC ES-A2 step ether MS) V-Bt. Cla 94 O 145-0.41 5% A10 NH 150 MeOH/BI 95% cl oxo N N-. CH2CI2 O Table 6.5- 4-chloro-2-methoxyphenyl Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry R (°C) (min. Rf System [Source] Method 95 O 140-0.29 5% 495 A2 NH 144 MeOH/ (M+H) + A7 0 N EtOAc/ES-MS) Cla 50% pet ether 96 O 244-0. 39 5% 529 A6 NH 245 MeOH/ (M+H) + A7 -Me 45% (HPLC B 1 0 N EtOAc/ES-MS) Cla 50% pet ether 97 O 220-0.25 5% 529 A2 ci NH 221 MeOH/ (M+H) + A7 -Me 45% (HPLC B1 0 N EtOAc/ES-MS) Cla 50% pet ether 98/-\ 0 0.27 5% 495 A2 NH MeOH/ (M+H) + A7 -Me 45% (HPLC B 1 0 N EtOAc/ES-MS) Cla 50% pet ether '99 O 180-0.52 5% 509 A2 NH 181 MeOH/ (M+H) + A7 Et Et 45% (HPLC B 1 0 N EtOAc/ES-MS) Cla 50% pet ether 100 O 162-. A2 NH 165 A7 Pr-i BI ON Cla Table 7. Additional Ureas TLC Mass mp HPLC TLC Solvent Spec. Synth. Entry (°C) (min.) Rf System [Sourcel Method 101 0 162-Al 0 165 A2 NH C3 te N nua 102 0.10 50% 442 A2 EtOAc/ (M+H) + A4 0 50% (HPLC C2d N N ; N Me hexane ES-MS) H H H H Me N Me 103 0 125-0.24 40% 512 A2 130 EtOAc/ (M+H) + C2b HN NH 60% (FAB) hexane A Aw w 0H qo NH-Me Me-NH

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

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.