(12) Ulllted States Patent
`Boyer et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,637,553 B2
`Jan. 28, 2014
`
`US008637553B2
`
`(54) FLUORO SUBSTITUTED
`OMEGA-CARBOXYARYL DIPHENYL UREA
`FOR THE TREATMENT AND PREVENTION
`0F DISEASES AND CONDITIONS
`
`(75) Inventors: Stephen Boyer, Hilden (DE); Jacques
`Dumas Bethany CT (US)- Bernd
`-
`’
`’
`.
`’
`-
`Rledl, Wuppertal (DE), Scott Wilhelm,
`Orange> CT (US)
`
`(73) Assignee: Bayer Healthcare LLC, TarrytoWn, NY
`(Us)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1812 days.
`
`(21) Appl. No.: 10/895,985
`
`(22) Filed?
`
`Jul- 22, 2004
`
`(65)
`
`Prior Publication Data
`Us 2005/0038080 A1
`Feb. 17, 2005
`
`CH
`CL
`
`9/1972 Schellenbaum et al.
`3,689,550 A
`grantiey
`2
`M974 Lgjgéfy
`3,823,161 A
`8/1974 Broad et al.
`3,828,001 A
`1/1975 NikaWitZ
`3,860,645 A
`3,990,879 A 11/1976 Soper
`4,001,256 A
`1/1977 Callahan et al.
`4,009,847 A
`3/1977 Aldrich et al.
`4,042,372 A
`8/l977 Harper
`4,062,861 A 12/1977 Yukinaga et al.
`4,071,524 A
`1/1978 Banitt
`4,103,022 A
`7/1978 Sirrenberg et al.
`4,111,680 A
`9/1978 Yukinaga et al.
`4,111,683 A
`9/1978 Singer
`2
`glil??lag?zzilzl
`431733638 A 11/1979 Nishgama et a1:
`4,183,854 A
`1/1980 Crossley
`4,212,981 A
`7/1980 Yukinaga et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`1 1/ 1969
`47/9557
`_ 6/1993
`38688
`(Contmued)
`OTHER PUBLICATIONS
`
`Related US. Application Data
`
`(60) Provisional application No. 60/489,102, ?led on Jul.
`23, 2003, provisional application NO_ 60/540,326,
`?led on Feb 2 2004'
`’
`
`(51) flngilglél/zulz
`
`(2006 01)
`
`'
`(200601)
`
`C0 7D 213/62
`(52) US. Cl.
`USPC ......................................... .. 514/350; 546/298
`(58) Field of Classi?cation Search
`USPC ......................................... .. 546/298: 514/350
`’
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`8/1893 Thoms
`502,504 A
`2/1931 Fitzky
`1,792,156 A
`7/1936 Goldstein et al.
`2,046,375 A
`9/1937 Coffey et al.
`2,093,265 A
`6/1942 Rohm et al.
`2,288,422 A
`8/1953 Martin
`2,649,476 A
`7/1954 Hill etal.
`2,683,082 A
`2,722,544 A 11/1955 Martin
`2,745,874 A
`5/1956 Schettyet a1.
`2,781,330 A
`2/1957 Downey
`2,797,214 A
`6/1957 Bossard
`2,867,659 A
`1/1959 Model et a1.
`2,877,268 A
`3/1959 Applegath et a1.
`2,960,488 A 11/1960 Tamblyn et al.
`2,973,386 A
`2/1961 Weldon
`3,151,023 A
`9/1964 Martin
`3,200,035 A
`8/1965 Martin etal.
`3,230,141 A
`1/1966 Fricket al.
`3,284,433 A 11/1966 Becker et a1.
`3,424,760 A
`1/1969 Helsley et al.
`3,424,761 A
`1/1969 Helsleyet al.
`3,424,762 A
`1/1969 Helsley et al.
`3,547,940 A 12/1970 Brantley
`3,639,668 A
`2/1972 Alles et al.
`3,646,059 A
`2/1972 Brantley
`3,668,222 A
`6/1972 Hauser
`
`_
`_
`_
`_
`Caplus 86:72448, Abstract JP 57053785, Pyr1d1ne der1vat1ves,
`Maeda RyoZo et al., Nov. 15, 1982.
`Caplus 84: 180049, Abstract JP 56029871, Hamada Yoshinori et al.,
`Jul. 10, 1981.
`Caplus 84:43857,Abstract JP 58021626, Maeda RyoZo et al., May 2,
`
`1983.
`Abstract of JP 55162772, Substituted acetic derivatives, Shionogi &
`(30., May 23, 1980.
`Abstract ofEP 0 202 538 A1, “Growth Promoting Agents,” Nov. 26,
`I985
`
`~
`d
`C t
`( on mue )
`
`Primary Examiner * Kamal Saeed
`Assistant Examiner * Janet L Coppins
`(74) Attorney, Agent, or Firm *Millen, White, Zelano &
`Branigan, PC.
`
`(57)
`ABSTRACT
`A compound of Formula (1):
`
`C113
`
`c1
`
`0
`
`N
`/
`
`i
`1
`1
`
`H
`
`H
`
`F
`
`0
`
`(1)
`
`CH3
`
`salts thereof, prodrugs thereof, metabolites thereof, pharma
`ceutical compositions containing such a compound, and use
`of such compound and compositions to treat diseases medi
`ated by raf, VEGFR, PDGFR, p38 and ?t-3.
`
`16 Claims, No Drawings
`
`FUSTIBAL Ex. 1001
`
`

`
`D>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
`
`12/1997
`1/1998
`2/1998
`3/1998
`5/1998
`6/1998
`7/1998
`7/1998
`7/1998
`7/1998
`7/1998
`9/1998
`9/1998
`9/1998
`9/1998
`2/1999
`2/1999
`3/1999
`4/1999
`6/1999
`7/1999
`7/1999
`9/1999
`10/1999
`12/1999
`12/1999
`1/2000
`1/2000
`2/2000
`2/2000
`2/2000
`3/2000
`3/2000
`3/2000
`6/2000
`7/2000
`8/2000
`9/2000
`10/2000
`10/2000
`10/2000
`11/2000
`11/2000
`11/2000
`11/2000
`1/2001
`1/2001
`1/2001
`1/2001
`1/2001
`2/2001
`2/2001
`3/2001
`4/2001
`4/2001
`5/2001
`5/2001
`6/2001
`7/2001
`8/2001
`9/2001
`10/2001
`10/2001
`11/2001
`11/2001
`12/2001
`12/2001
`1/2002
`2/2002
`3/2002
`3/2002
`3/2002
`3/2002
`4/2002
`4/2002
`4/2002
`5/2002
`5/2002
`5/2002
`
`Kleemann et al.
`Minami et al.
`Myers et al.
`Dodge et al.
`Schnur et al.
`Tang et al.
`Lee et al.
`Brent et al.
`Widdowson et al.
`Lee et al.
`Krongrad
`Armistead et al.
`Bold et al.
`Bell et al.
`Heinz et al.
`McDonnell
`Lee et al.
`Widdowson et al.
`Shiraishi et al.
`Doi et al.
`Monia et al.
`Widdowson et al.
`Lee et al.
`Petrie et al.
`Breu et al.
`Widdowson et al.
`Widdowson et al.
`Brent et al.
`Vacher et al.
`Mantlo et al.
`Peterson
`McDonnell et al.
`Yoshida et al.
`Widdowson et al.
`Regan et al.
`Salituro et al.
`Avruch et al.
`Monia et al.
`Thompson et al.
`Widdowson
`Foulkes et al.
`Kubo et al.
`Dent et al.
`Barbachyn et al.
`Hammock et al.
`Mantlo et al.
`Ullrich et al.
`Takebayashi et al.
`McMahon et al.
`Widdowson et al.
`Wood et al.
`Karin et al.
`Tang et al.
`Widdowson et al.
`Widdowson
`Regan et al.
`Larson et al.
`Breu et al.
`Widdowson et al.
`Widdowson
`Peterson
`Cirillo et al.
`Bottcher et al.
`Bishop et al.
`Cirillo et al.
`Cirillo et al.
`Mantlo et al.
`Kanno et al.
`Ranges et al.
`Astles et al.
`Guo et al.
`Breitfelder et al.
`Lee et al.
`Regan
`Baine et al.
`Marfat et al.
`Marshall et al.
`Pevarello et al.
`Petrie et al.
`
`US 8,637,553 B2
`Page 2
`
`5,698,581
`5,710,094
`5,721,237
`5,726,167
`5,747,498
`5,773,459
`5,777,097
`5,780,262
`5,780,483
`5,783,664
`5,786,362
`5,807,876
`5,807,891
`5,808,080
`5,814,646
`5,869,043
`5,871,934
`5,886,044
`5,891,895
`5,908,865
`5,919,773
`5,929,250
`5,955,366
`5,965,573
`6,004,965
`6,005,008
`6,015,908
`6,017,692
`6,020,345
`6,022,884
`6,025,151
`6,033,873
`6,040,339
`6,043,374
`6,080,763
`6,093,742
`6,103,692
`6,114,517
`6,130,053
`6,133,319
`6,136,779
`6,143,764
`6,147,107
`6,147,116
`6,150,415
`6,174,901
`6,177,401
`6,178,399
`6,180,631
`6,180,675
`6,187,799
`6,193,965
`6,204,267
`6,211,373
`6,218,539
`6,228,881
`6,235,764
`6,242,601
`6,262,113
`6,271,261
`6,294,350
`6,297,381
`6,310,068
`6,316,462
`6,319,921
`6,329,415
`6,333,341
`6,339,045
`6,344,476
`6,352,977
`6,358,525
`6,358,945
`6,361,773
`6,372,773
`6,372,933
`6,380,218
`6,383,734
`6,387,900
`6,391,917
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,240,820
`4,279,639
`4,358,596
`4,405,644
`4,410,697
`4,418,066
`4,437,878
`4,468,380
`4,473,579
`4,499,097
`4,511,571
`4,514,571
`4,526,997
`4,540,566
`4,546,191
`4,587,240
`4,623,662
`4,643,849
`4,677,111
`4,740,520
`4,760,063
`4,775,763
`4,808,588
`4,820,871
`4,835,180
`4,863,924
`4,898,886
`4,904,668
`4,973,675
`4,983,605
`4,985,449
`5,036,072
`5,059,614
`5,063,247
`5,098,907
`5,100,883
`5,118,677
`5,118,678
`5,120,842
`5,130,331
`5,151,344
`5,151,413
`5,162,360
`5,185,358
`5,254,582
`5,256,790
`5,258,389
`5,270,458
`5,283,354
`5,290,795
`5,312,820
`5,319,099
`5,378,725
`5,399,566
`5,423,905
`5,429,918
`5,432,468
`5,441,947
`5,447,957
`5,456,920
`5,468,773
`5,470,882
`5,480,906
`5,500,424
`5,504,103
`5,508,288
`5,547,966
`5,559,137
`5,596,001
`5,597,719
`5,624,937
`5,656,612
`5,658,903
`5,667,226
`5,696,138
`
`12/1980
`7/1981
`11/1982
`9/1983
`10/1983
`11/1983
`3/1984
`8/1984
`9/1984
`2/1985
`4/1985
`4/1985
`7/1985
`9/1985
`10/1985
`5/1986
`11/1986
`2/1987
`6/1987
`4/1988
`7/1988
`10/1988
`2/1989
`4/1989
`5/1989
`9/1989
`2/1990
`2/1990
`11/1990
`1/1991
`1/1991
`7/1991
`10/1991
`11/1991
`3/1992
`3/1992
`6/1992
`6/1992
`6/1992
`7/1992
`9/1992
`9/1992
`11/1992
`2/1993
`10/1993
`10/1993
`11/1993
`12/1993
`2/1994
`3/1994
`5/1994
`6/1994
`1/1995
`3/1995
`6/1995
`7/1995
`7/1995
`8/1995
`9/1995
`10/1995
`11/1995
`11/1995
`1/1996
`3/1996
`4/1996
`4/1996
`8/1996
`9/1996
`1/1997
`1/1997
`4/1997
`8/1997
`8/1997
`9/1997
`12/1997
`
`Dickore et al.
`Okamoto et al.
`Kriiger
`Kabbe et al.
`Torok et al.
`Boger et al.
`Acker et al.
`O’Doherty et al.
`Devries et al.
`Tomcufcik et al.
`Boger et al.
`Nakai et al.
`O’Doherty et al
`Davis et al.
`Nishiyama et al.
`Hider et al.
`DeVries
`Hirai et al.
`Haga et al.
`Hallenbach et al.
`Hallenbach et al.
`Dalton et al.
`King
`Kissener et al.
`Schlegel et al.
`Haga et al.
`Amat-LarraZ
`Kondo et al.
`Israel et al.
`Kondo et al.
`Haga et al.
`Nakajima et al.
`Lepage et al.
`Sekiya et al.
`Kondo et al.
`Schiehser
`Cau?eld
`Kao et al.
`Failli et al.
`Pascual
`Abe et al.
`Cau?eld et al.
`Creswell et al.
`Creswell et al.
`Boder et al.
`Nelson
`Goulet et al.
`Lemischka
`Lemischka
`Hansen
`Ashton et al.
`Kamata et al.
`Bonjouklian et al.
`Katano et al.
`Fringeli
`Seto et al.
`Moriyama et al.
`Dodge et al.
`Adams et al.
`Matoba et al.
`Dodge et al.
`DiXon et al.
`Creemer et al.
`Nagamine et al.
`Bonjouklian et al.
`Forbes et al.
`AtWal et al.
`Adams et al.
`Hamanaka
`Freed et al.
`Reel et al.
`Monia
`Adams et al.
`Mannesmann
`Olesen et al.
`
`

`
`(56)
`
`References Cited
`
`U_g_ PATENT DQCUMENTS
`
`6/2002 Hayakawa et a1.
`6,403,588 B1
`7/2002 Hogenkamp etal‘
`6,414,011 B1
`9/2002 Oremus et a1‘
`6 444 691 B1
`9000; Monia etal‘
`6’448’079 B1
`11/2002 As?es et a1‘
`634793519 B1
`12/2002 Breitfelder et a1.
`6,492,393 B1
`12/2002 Gelfand et a1‘
`6495 331 B1
`6’500’863 B1 @2002 Jin etal‘
`635113800 B1
`V2003 Singh
`6511997 Bl
`V2003 Minami et a1‘
`6’521’407 B1
`200% Wareniusetal,
`6’521’592 B2
`200% KO et a1‘
`6’524’832 B1
`200% Kufe et a1‘
`6’525’046 B1
`200% Cirillo etal‘
`635253065 B1
`200% Caldwell et a1‘
`6,525,091 B2
`2/2003 Robinson etal.
`6,583,282 B1
`6/2003 Zhang et a1‘
`6,608,052 B2
`8/2003 Breitfelderet a1.
`6,617,324 B1
`9/2003 Naraian et a1‘
`6,635,421 B1
`10/2003 Klagsbrun et a1‘
`6,653,320 B2 11/2003 Hayakawa et a1‘
`6656 963 B2 12/2003 Firestone et a1‘
`636733777 B1
`V2004 Tracey et a1‘
`6,689,560 B1
`2/2004 Rapp et a1‘
`6 797 823 B1
`9/2004 KaZuO et a1‘
`7’070’968 B2
`700% Kufe et a1‘
`7’235’576 B1
`@2007 Riedl et a1‘
`7’253’286 B2
`8/2007 Funahashietal,
`733073071 B2 12/2007 Lyons et a1‘
`7 329 670 B1
`2/2008 Dumas et a1‘
`733512834 B1
`4/2008 Riedl et a1‘
`7,371,736 B2
`5/2008 Shaughnessy et a1.
`7371763 B2
`5/2008 Dumas
`7’517’880 B2
`4/2009 Miller et a1‘
`7’528’255 B2
`5/2009 Riedl et a1‘
`7’557’129 B2
`7/2009 Scott et a1‘
`7’625’915 B2 @2009 Dumas et a1‘
`7’678’811 B2
`3/2010 Dumas et a1‘
`738383524 B2 “0010 Lee etal‘
`7,838,541 B2 11/2010 Dumas et a1.
`7897 623 B2
`3/2011 Riedlet a1‘
`7’928’239 B2
`400“ Dumas et a1‘
`7’928’277 B1
`400“ COX Jr,
`8’071’616 B2 12/2011 Dun’ms et a1‘
`8’076’488 B2 12/2011 Dumas et a1‘
`8’101’773 B2
`V2012 Smith etal,
`8’110’887 B2
`2001; Dumas et a1‘
`8’124’630 B2
`2001; Riedl et a1‘
`831242782 B2
`2001; Logers et a1‘
`8207166 B2
`6/2012 Lee et a1‘
`2001/b006’975 A1
`7/2001 Woodetal,
`2001/0011135 A1
`8/2001 Riedl et a1.
`mun/0011136 Al
`80001 Riedl et a1‘
`2001/0016659 A1
`8/2001 Riedl et a1.
`2001/0027202 A1 10/2001 Riedl et a1.
`2001/0034447 A1 100001 Riedl et a1‘
`2001/003gg42 A1 11/2001 Achen et a1‘
`2002/0037276 A1
`3/2002 Ptasznik et a1.
`2002/0042517 A1
`4/2002 Udayet a1‘
`2002/0062763 A1
`5/2002 Macholdt et a1.
`mun/0065283 A1
`5/2002 McMahon etal‘
`2002/0065296 A1
`5/2002 Dumas et a1.
`2002/0082255 A1
`6/2002 Eastwood
`mun/0085857 A1
`7/2002 Kim et a1‘
`2002/0085859 A1
`7/2002 Hashimoto etal.
`2002/0103253 A1
`g/ZOOZ Rangesetal‘
`2002/0128321 A1
`9/2002 Widdowson et a1.
`2002/0137774 A1
`9/2002 Riedl et a1.
`2002/0161014 A1 10/2002 Sadhu et a1.
`2002/0165275 A1 11/2002 Wu et a1.
`2002/0165349 A1 11/2002 Kirsch et a1.
`2002/0165394 A1 11/2002 Dumas et a1.
`2002/0173507 A1 11/2002 Santora et a1.
`2002/0188027 A1 12/2002 Robinson et a1.
`2003/0069284 A1
`4/2003 Keegan et a1.
`
`US 8,637,553 B2
`Page 3
`
`7/2003 Lyons et a1.
`2003/0125359 A1
`7/2003 Moss etal.
`2003/0130309 A1
`7/2003 Riedletal.
`2003/0139605 A1
`7/2003 Riedletal.
`2003/0144278 A1
`8/2003 Waksal
`2003/0157104 A1
`9/2003 Rledlet a1.
`2003/0181442 A1
`2003/0207870 A1 11/2003 Dumas et al.
`2003/0207872 A1 11/2003 Riedletal.
`2003/0207914 A1 11/2003 Dumas et a1.
`2003/0216446 A1 11/2003 Dumas er a1~
`2003/0232400 A1 12/2003 Radka et a1.
`2003/0232765 A1 12/2003 Calteretal.
`2004/0096855 A1
`5/2004 Stratton et al.
`2004/0147541 A1
`7/2004 Lane et al.
`2004/0192770 A1
`9/2004 Kozikowski et a1.
`2004/0197256 A1 10/2004 Rogers et a1.
`2004/0209905 A1 10/2004 Kubo et a1.
`2004/0229937 A1 11/2004 Dumas et a1.
`2004/0235829 A1 11/2004 Scott et a1.
`2005/0004533 A1
`1/2005 smlth
`2005/0032798 A1
`2/2005 Boyer et a1.
`2005/0038031 A1
`2/2005 Dumas 9t a1~
`2005/0038080 A1
`2/2005 Boyer et 211.
`2005/0059703 A1
`3/2005 Wilhelm et a1. ............ .. 514/338
`2005/0192304 A1
`9/2005 Nagarathnam et a1.
`2005/0209261 A1
`9/2005 Nagarathnam et a1.
`2005/0256174 A1 11/2005 Wood et a1.
`2005/0288286 A1 12/2005 Flynn et a1.
`2006/0058358 A1
`3/2006 Dumas et a1.
`2006/0078617 A1
`4/2006 Schueckler
`2006/0211738 A1
`9/2006 Mitchell et a1.
`2006/0234931 A1 10/2006 Biggsetal.
`2006/0247186 A1 11/2006 Calteretal.
`2007/0020704 A1
`1/2007 Wilhelm et 31.
`2007/0105142 A1
`5/2007 Wilhelm
`2007/0173514 A1
`7/2007 M988
`2007/0178494 A1
`8/2007 Elt1ngeta1.
`2007/0244120 A1 10/2007 Dumas et a1.
`2007/0265315 A1 11/2007 Dumas et a1.
`2008/0009527 A1
`1/2008 Dumas et a1.
`2008/0027061 A1
`1/2008 Riedletal.
`2008/0032979 A1
`2/2008 Riedletal.
`2008/0045546 A1
`2/2008 Bouchon etal.
`Zoos/0045589 A1
`2/2008 Kelley
`2008/0085902 A1
`4/2008 Bold et a1.
`2008/0108672 A1
`5/2008 Riedletal.
`2008/0153823 A1
`6/2008 Riedletal.
`2008/0194580 A1
`8/2008 Dumas et a1.
`2008/0214545 A1
`9/2008 Lee etal.
`2008/0227828 A1
`9/2008 Dumas et a1.
`2008/0242707 A1 10/2008 Schuckleretal.
`2008/0262236 A1 10/2008 Logers et a1.
`2008/0269265 A1 10/2008 Miller et al.
`2008/0300281 A1 12/2008 Dumas et al.
`2008/0311601 A1 12/2008 Elting et a1.
`2009/0068146 A1
`3/2009 w?helm
`2009/0093526 A1
`4/2009 M11leretal.
`2009/0118268 A1
`5/2009 Rledletal
`2009/0176791 A1
`7/2009 sandnefetal
`2009/0192127 A1
`7/2009 Scheunng etal.
`2009/0215833 A1
`55/2009 Grunenberg et a1.
`2009/0215835 A1
`8/2009 wllhelm
`2009/0221010 A1
`9/2009 Eltlng et a1.
`2009/0227637 A1
`9/2009 weberétal
`2009/0306020 A1 12/2009 Scheunng etal.
`low/0035888 A1
`2/2010 Sandneretal
`2010/0063088 A1
`3/2010 Woodetal.
`2010/0063112 A1
`3/2010 Grunenberg et a1.
`2010/0075971 A1
`3/2010 Dumas er 91
`2010/0081812 A1
`4/2010 Smithetal.
`2010/0113533 A1
`5/2010 Stiehl er a1.
`2010/0125139 A1
`5/2010 Bankston et a1.
`2010/0129321 A1
`5/2010 Weberetal.
`2010/0144749 A1
`6/2010 Wilhelm
`2010/0150863 A1
`6/2010 Smith et a1.
`2010/0160371 A1
`6/2010 Ranges etal.
`2010/0173953 A1
`7/2010 Grunenberg et a1.
`2010/0173954 A1
`7/2010 Wilhelm etal.
`2010/0249159 A1
`9/2010 Nagarathnam etal.
`
`

`
`US 8,637,553 B2
`Page 4
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2010/0267777 A1
`2011/0015195 A1
`2011/0136809 A1
`2011/0158942 A1
`2011/0178137 A1
`2011/0195110 A1
`2011/0257035 A1
`2012/0009150 A1
`2012/0040925 A1
`2012/0040986 A1
`2012/0046290 A1
`2012/0129893 A1
`2012/0142741 A1
`2012/0142742 A1
`
`10/2010 Wilhelm etal.
`1/2011 Dumas et al.
`6/2011 Lee etal.
`6/2011 Weberetal.
`7/2011 Albrecht-Kupperetal.
`8/2011 Smith etal.
`10/2011 Pena etal.
`1/2012 Weberetal.
`2/2012 Caner et al.
`2/2012 Riedlet al.
`2/2012 Miller etal.
`5/2012 Dumas et al.
`6/2012 Schueckler
`6/2012 Riedletal.
`
`FOREIGN PATENT DOCUMENTS
`0384-2004
`11/2004
`2744'2003
`2/2005
`1702'2004
`5/2005
`1805'2004
`9/2005
`2 145 707
`10/ 1995
`487014 C1
`11/1929
`511468 C1
`10/1930
`523 437 C1
`4/ 1931
`2435179 C2
`2/ 1975
`25 01548 A1
`7/1975
`2435179 A1
`10/1981
`3305866 A1
`8/1984
`35 29 247 A1
`2/1987
`3529247 A1
`2/1987
`35 40 377 A1
`5/1987
`253997 A1
`2/ 1988
`0016371 A1
`10/1980
`0107214 A2
`9/ 1983
`0115932 A1
`8/ 1984
`0192253 E1
`8/ 1985
`0202538 A1
`11/1986
`0230400 A2
`7/1987
`0233559 B1
`8/1987
`0242555 A1
`10/ 1987
`0254904 A2
`4/ 1988
`0314515 W
`5/ 1989
`0335155 A1
`10/1989
`0359148 A1
`3/ 1990
`0371876 A1
`6/1990
`0379915 A1
`8/1990
`0380048 A2
`8/ 1990
`0381987 A1
`8/1990
`0405233 A1
`1/1991
`0425443 A1
`5/1991
`0459887 A1
`12/1991
`0509795 A2
`10/ 1992
`0709225 A1
`5/ 1995
`0590344
`5/ 1995
`0575395 A2
`10/ 1995
`0 590 344 A1
`1/ 1995
`0709225 E1
`5/ 1995
`0850433 A1
`8/ 1998
`1199305 A1
`4/2002
`90323922103 R
`8/2002
`1256587 A1
`11/2002
`1275 385 A1
`1/2003
`1537075
`8/2005
`90559712515 R
`7/2008
`1457172 A
`9/1999
`771 333
`3/1957
`828 251
`19/1959
`828231
`2/1960
`921682
`3/1963
`1110099
`5/1955
`1 590 370
`5/1931
`1590870
`6/1981
`P0004437
`12/1998
`
`CL
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`CL
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`
`A
`
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`10-306078 A
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`6124
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`96/41807
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`W0 96/40675 A1
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`W0 97/17267 A1
`W0 97/17329 A1
`W0 97/29743 A1
`W0 97/30992 A1
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`W0 97/40028 A1
`97/40842 A1
`WO 97/45400 A1
`W0 97/49399 A1
`W0 97/49400 A1
`
`1/2000
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`
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`5/1995
`6/1995
`7/1995
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`12/1995
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`4/1996
`5/1996
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`12/1996
`12/1996
`12/1996
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`3/1997
`5/1997
`5/1997
`8/1997
`8/1997
`9/1997
`10/1997
`11/1997
`12/1997
`12/1997
`12/1997
`
`

`
`US 8,637,553 B2
`Page 5
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`4/1998
`98/17207 A1
`WO
`4/1998
`W0 98/17267 A1
`W0
`5/1998
`W0 98/20868
`W0
`5/1998
`W0 98/20868 A1
`W0
`5/1998
`W0 98/22103 A1
`W0
`5/1998
`W0 98/22432 A1
`W0
`7/1998
`W0 98/32439 A1
`W0
`8/1998
`W0 98/34929 A1
`W0
`8/1998
`W0 98/34947 A1
`W0
`10/1998
`98/45268 A1
`WO
`10/1998
`W0 98 45268 A1
`W0
`10/1998
`W0 98/45268 A1
`W0
`11/1998
`98/49150 A1
`WO
`98/52937 A2 11/1998
`WO
`98/52941 A1
`11/1998
`W0
`W0 98/52558 A1
`11/1998
`W0
`W0 98/52559 A1
`11/1998
`W0
`98/56377
`12/1998
`WO
`98/56377 A1
`12/1998
`W0
`WO 99/00357
`V1999
`W0
`WO 99/00370 A1
`1/1999
`W0
`99/206l7 A1
`4/1999
`W0
`W0 99/20617 A1
`4/1999
`W0
`99/24035
`5/1999
`WO
`W0 99/21835 A1
`5/1999
`W0
`W0 99/23091 A1
`5/1999
`W0
`WO 99/24398 A2
`5/1999
`W0
`WO 99/24635 A1
`5/1999
`W0
`99/26657 A1
`@1999
`WO
`WO 99/28305 Al
`6/l999
`W0
`99/32109
`7/1999
`WO
`99/35132
`7/1999
`WO
`W0 99/32106 A1
`7/1999
`W0
`W0 99/32110 A1
`7/1999
`W0
`WO 99/32111 A1
`7/1999
`W0
`WO 99/32436 Al
`7/l999
`W0
`W0 99/32437 A1
`7/1999
`W0
`WO 99/32455 A1
`7/1999
`W0
`WO 99/32463 Al
`7/l999
`W0
`WO 99/33458 Al
`7/l999
`W0
`WO 99/40673 A1
`8/1999
`W0
`99/58502 A1
`11/1999
`WO
`W0 99/62890 A1
`12/1999
`W0
`00/12497
`3/2000
`WO
`W0 00/17175 A1
`3/2000
`W0
`00/19205 A1
`4/2000
`W0
`00/274l4 A2
`5/2000
`W0
`W0 PCT/US00/00648 R
`5/2000
`W0 PCT/US00/00768 R
`5/2000
`W0
`WO 00/26203 Al
`5/2000
`WO
`00/31238 A2
`6/2000
`W0
`Q0/3430} A1
`6/2000
`WO
`00/35455 A1
`@2000
`WO
`00/39116
`6/2000
`W0
`WO 00/35454 A1
`6/2000
`W0
`WO_00/420l2
`6/2000
`WO
`00/39101
`7/2000
`W0
`W0 00/41698 A1
`7/2000
`W0
`WO 00/42012 A1
`7/2000
`W0
`W0 00/43366 A1
`7/2000
`W0
`WO 00/43384 A1
`7/2000
`W0
`WO 02/42012 A1
`7/2000
`W0
`WO 00/47577 Al
`8/2000
`W0
`WO 00/50425 A1
`8/2000
`W0
`WO 00/55139
`9/2000
`W0
`W0 ()0/55152 A1
`9/2000
`W0
`W0 00/56331 A1
`9/2000
`W0
`00/71506 A2 11/2000
`W0
`W0 00/71532 A1
`11/2000
`W0
`W0 01/04115 A2
`1/2001
`W0
`W0 01/07411 A1
`2/2001
`W0
`W0 01/09088 A1
`2/2001
`W0
`W0 01/12188
`2/2001
`W0
`W0 01/36403 A1
`5/2001
`W0
`01/04789 A1
`7/2001
`
`55/2001
`01/54723 A1
`WO
`8/2001
`01/54727 A1
`WO
`8/2001
`01/64303 A2
`WO
`8/2001
`W0 01/57008 A1
`W0
`9/2001
`01/66099
`WO
`9/2001
`01/66540 A1
`WO
`1/2002
`02/06382 A1
`WO
`V2002
`02/07008 A1
`WO
`V2002
`02/07772 A2
`WO
`1/2002
`WO 02/07747 A1
`W0
`V2002
`WO 02/07772
`W0
`2/2002
`WOW/10141 A1
`W0
`2/2002
`WO 02/14281 A1
`W0
`2/2002
`W0 02/14311 A2
`W0
`3/2002
`02/25286
`WO
`3/2002
`WOW/18346 A1
`W0
`3/2002
`W0 02/24635 A2
`W0
`4/2002
`WO 02/32872 Al
`W0
`5/2002
`02/40445 A1
`WO
`6/2002
`02/50091 A1
`WO
`6/2002
`WOW/44156 A2
`W0
`6/2002
`WO 02/44158 Al
`W0
`8/2002
`02/060900 A2
`W0
`8/2002
`W0 02/059081 A2
`W0
`8/2002
`W0 02/059102 A2
`W0
`8/2002
`W0 02/062763 A2
`W0
`9/2002
`02/070008
`W0
`02/076930 A2 10/2002
`WO
`02/076977
`10/2002
`W0
`02085857 A2 10/2002
`WO
`W0 02/083628 A1
`10/2002
`W0
`W0 02/083642 A1
`10/2002
`W0
`W0 02/085857 A2 10/2002
`W0
`W0 02/085859 A1
`10/2002
`W0
`02/088090 A2 ll/2002
`WO
`W0 02/092576 Al
`ll/2002
`W0
`03/004523
`1/2003
`W0
`03005999 A2
`V2003
`WO
`W0 03/043630 Al
`5/2003
`W0
`W0 03/099771 A2
`5/2003
`W0
`03/047579 A1
`6/2003
`W0
`W0 03/047523 Al
`6/2003
`W0
`W0 03/ 047523 A2
`6/2003
`W0
`W0 03/047579 Al
`6/2003
`W0
`W0 03/050455 Al
`6/2003
`W0
`03/056036 A2
`7/2003
`WO
`03/059373 A2
`7/2003
`W0
`03/060111 A2
`7/2003
`WO
`03/065995 A2
`8/2003
`W0
`03068223
`8/2003
`WO
`W0 03/068228 Al
`8/2003
`W0
`W0 03/068229 A1
`8/2003
`W0
`W0 03/068746 A1
`8/2003
`W0
`W0 WO 2003/094626 A
`9/2003
`W0
`W0 03/082272 A2 10/2003
`W0 WO 2004/019941 Al
`3/2004
`W0 W0 2004/037789 A2
`5/2004
`W0 W0 2004/037789 A2
`5/2004
`W0 WO 2004/043374 A2
`5/2004
`WO
`2004/045578
`6/2004
`WO
`2004/052880
`6/2004
`WO
`2004/078128
`9/2004
`WO
`2004/078747 Al
`9/2004
`WO
`2004/078748
`9/2004
`W0 WO 2004/078746 A2
`9/2004
`W0 WO 2004/078747 Al
`9/2004
`W0 WO 2004/085399 A1
`10/2004
`W0 WO 2004/085425 A1
`10/2004
`WO
`2004/108713 A1
`12/2004
`WO
`2004/108715 A1
`12/2004
`WO
`2004/113274
`12/2004
`W0 W0 2004/113274 A 12/2004
`W0
`2005/000284
`1/2005
`W0
`2005/005434 A1
`1/2005
`W0 W0 2005/000284 A2
`1/2005
`W0 W0 2005/002673 A1
`1/2005
`W0 W0 2005/004863 A1
`1/2005
`W0 W0 2005/004864 A1
`1/2005
`W0 W0 2005/005389 A2
`1/2005
`
`

`
`US 8,637,553 B2
`Page 6
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`1/2005
`W0 WO 2005/006899 A1
`1/2005
`W0 WO 2005/007649 A1
`2/2005
`WO
`2005/009961 A2
`2/2005
`WO
`2005/011700 A1
`2/2005
`WO
`2005/016252 A2
`2/2005
`WO
`2005009367 A2
`2/2005
`WO
`2005009961 A2
`2/2005
`W0 WO 2005/009367 A
`2/2005
`W0 WO 2005/009961 A
`3/2005
`W0 WO 2005/019192 A1
`4/2005
`W0 WO 2005/032548 A1
`4/2005
`W0 WO 2005/037273 A1
`4/2005
`W0 WO 2005/037285 A1
`4/2005
`W0 WO 2005/037829 A1
`5/2005
`W0 WO 2005/042520 A1
`5/2005
`W0 WO 2005/047283 A1
`6/2005
`W0 WO 2005/048948 A2
`6/2005
`W0 WO 2005/049603 A1
`6/2005
`W0 WO 2005/058832 A1
`8/2005
`WO
`95/33460
`8/2005
`WO
`2005075425 A2
`9/2005
`WO
`2005/089443 A2
`9/2005
`W0 WO 2005/089443 A
`W0 WO 2005/110994 A2 11/2005
`WO
`2006/026500
`3/2006
`WO
`2006/027346 A2
`3/2006
`W0 WO 2006/026501
`3/2006
`W0 WO 2006/034797 A
`4/2006
`WO
`2006105844 A1
`10/2006
`WO
`2006/125540 A1
`11/2006
`WO
`2007015947 A
`2/2007
`W0 WO 2007/015947 A
`2/2007
`W0 WO 2007/039404 A1
`4/2007
`WO
`2007/053573 A2
`5/2007
`WO
`2007/054215 A1
`5/2007
`WO
`2007/059094
`5/2007
`WO
`2007/059154
`5/2007
`WO
`2007/059155
`5/2007
`WO
`2007064872 A2
`6/2007
`WO
`2007/087575
`8/2007
`WO
`2007/123722
`11/2007
`WO
`2007/139930
`12/2007
`WO
`2008/055966 A1
`5/2008
`WO
`2008/079968
`7/2008
`WO
`2008/079972
`7/2008
`WO
`2008/089389
`7/2008
`WO
`WO2008089388
`7/2008
`WO
`WO2008089389
`7/2008
`W0 W0 2010/0048304
`4/2010
`W0 W0 2011/0146725
`11/2011
`W0 W0 2012 012404
`1/2012
`
`OTHER PUBLICATIONS
`Audia, James E., et al., “Potent, Selective Tetrahydro-B-carboline
`Abstract ofDE 3305866 a (EP equivalent 116,932), R.D. Acker et al.,
`Aug. 23, 1984.
`Abstract of EP 116,932, Aug. 29, 1984.
`Abstract of EP 16,371, Oct. 1, 1980.
`Abstract of EP 4931A (Equivalent 4,240,820), Dickore, K. et al.
`Abstract of EP 0405233A1, Tetsuo Sekiya et al.
`Abstract ofEP 0 676 395 (US. equivalent 5,698,581), Dec. 16, 1997.
`Abstract WO 9822103, Hedge May 28, 1998, Philip et al.
`Chemical Abstract, vol. 116, No. 21, May 25, 1992, (pp. 741-742) N
`1 16 :2 14456.
`TarZia, G. et al., “Synthesis and anit-in?ammatory properties of some
`pyrrolo(1H,3H) [3,4-d]pyrimidin-2-ones and pyrrolo(1H,6H)[3,4
`d]pyrimidin-2-ones,” Chemical Abstracts, vol. 91, 1979, 91:74558.
`XP-002918005, White, A. D., et al., “Heterocyclic Ureas: Inhibitors
`of
`Acyl-CoA:Cholesterol
`O-Acyltransferase
`as
`Hypochelesterolemic Agents,” J. Med. Chem. 1996, 39, pp. 43 82
`4395 . Antagonists of the Serotonin 2B (SHTZB) Contractile Receptor
`in the Rat Stomach Fundus,” J. Med. Chem. 1996, 39, pp. 2773-2780.
`
`XP-000941493, Forbes, Ian T., “N-(l-Methyl-5-indolyl)-N-(3
`methyl-5-isothiaZolyl)urea: A Novel, High-Af?nity S-HTZB Recep
`tor Antagonist,” Journal of Medicinal Chem. vol. 38, No. 6, Mar. 17,
`1995, pp. 855-857.
`XP-000943551, Boulton, A. J ., et al., “Heterocyclic Rearrangements.
`Part X.1 A Generalised Monocyclic Rearrangements,” J. Chem. Soc.
`(C), 1967, pp. 2005-2007.
`W. Kolch, et al., “Raf-1 protein kinase is required for growth of
`induced NIH/3T3 cells,” Letters to Nature, vol. 349, Jan. 31, 1991,
`pp. 426-428.
`M. Fridman, et al., “The Minimal Fragements of c-Raf-l and NF1
`That Can Suppress v-Ha-Ras-Induced Malignant Phenotype,” The
`Journal of Biological Chemistry, vol. 269, No. 48, Dec. 2, 1994, pp.
`30105-30108.
`G. L. Bolton, et al., Chapter 17. Ras Oncogene Directed Approaches
`in Cancer Chemotherapy, Annual Reports In Medicinal Chemistry,
`vol. 29, 1994, pp. 165-174.
`J. L. Bos, “ras Oncogenes in Human Cancer: A Review,” Cancer
`Research, vol. 49, Sep. 1, 1989, pp. 4682-4689.
`Michaelis, Justus, Liebigs Ann. Chem. (JLACBF) 397, 1913, p. 143.
`B. P. Monia, et al., “Antitumor activity of a phosphorothioate
`antisense oligodeoXynucleotide targeted against C-raf kinase,”
`Nature Medicine, vol. 2, No. 6, Jun. 1996, pp. 668-675.
`Lee, et al., “Bicyclic ImidaZoles as a Novel Class of Cytokine
`Biodynthesis Inhiibitors,” Annuals N.Y. Academy of Science, 1993,
`pp. 149-170.
`F. Lepage, et al., “New N-aryl isoXaZolecarboXamides and
`N-isoXaZolybenZamides as anticonvulsant agents,” Eur. J. Med.
`Chem., vol. 27, 1992, pp. 581-593.
`Ridley, et al., “Actions of IL-1 are Selectively Controlled by p38
`Mitogen-Activated Protein Kinase,” The American Association of
`Immunologists, 1997, p. 3165-73.
`N. S. Magnuson, et al., “The Raf-1 serine/threonine protein kinase,”
`Cancer Biology, vol. 5, 1994, pp. 247-253.
`G. Daum, et al., “The ins and outs of Raf Kinasesf’: TIBS 19, Nov.
`1994, pp. 474-480.
`al.: “Some Hypotensive
`XP-000944187, Grant, AM. et
`thiadiazoles,” J. Med. Chem. (1972), 15(10), p. 1082-4.
`XP-000943466, Russo, F. et al. “Synthesis of 2,6-substituted deriva
`tives of 5H-1,3,4-thiadiaZolo:3,2-a!-s triaZine-5,7-dione” Farmaco,
`Ed.Sci. (1978), 33(12), 972-83.
`Joseph T. Bruder et al., Journal of Virology, Jan. 1997, “Adenovirus
`Infection Stimulates the Raf/MAPK Signaling Pathway and Induces
`Interleukin-8 Expression,” May 17, 1996, pp. 398-404.
`XP-000943598,
`Foussard-Blanpin,
`Odette:
`“Comparative
`pharmacodynamic study of variously substituted carboXamides of
`the central nervous ststem” Ann. Pharm. Fr. (1982), 40 (4), pp.
`339-350.
`XP-000943800, Kubo, Hiroshi et al., vol. 18, No. 1, Jan-Feb. 1970
`“Herbicidal activity of 1,3,4-thiadiaZole derivatives” J. Agr. Food
`Chem. (1970), 18(1), pp. 60-65.
`Avruch et al., “Raf meets Ras: completing the framework of a signal
`transduction pathway,” TIBS 19; Jul. 1994; pp. 279-281.
`Caplus 113:106314, Abstract of JP 2022650, Silver halide color
`photographic material containing a cyan coupler of 2-ureido-phenol
`type to improve dye developability and remove lecuo cyan dye,
`Noboru MiZukura et al. Jan. 25, 1990.
`Caplus 113:142130, Abstract of JP 2023337, Silver halide photo
`graphic material containing phenolic cyan coupler a colorless cyan
`coupler, Toshihiko Yagi et al., Jan. 25, 1990.
`Caplus 87:62295, “The metabolism and toxicity of halogenated
`carbanilides. Biliary metabolites of 3,4,4‘-trichlorocarbanilide and
`3-tri?uoromethyl-4,4‘-dichlorocarbanilide in the rat,” Chemical Life
`Science, pp. 157-166, 1977.
`Caplus 127:293717, “Optical properties of segmented oligourethane
`with aZomethine terminal fragments,” National Academy of Science
`ofUkraine, M. V. Kurik et al., pp. 2038-2041, 1996.
`Caplus 127:273945, “Quantitative structure-biodegradability stud
`ies: an investigation of the MITI aromatic compound database,”
`School of Pharmacy and Chemistry, J. C. Dearden, Biodegradability
`Prediction Edited by Willie J .G.M. Peijnenburg et al., NATO ASI
`Series, 2. Environmentivol. 23, pp. 93-104, 1996.
`
`

`
`US 8,637,553 B2
`Page 7
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Caplus 1261166148, “Inhibitors of coenZyme A-independent
`transacylase induce apoptosis in human HL-60 cells,” James D.
`Winkler et al., J. Pharmacol. Exp. Ther. pp. 956-966, 1996.
`Caplus 98178152, Abstract of JP 57185219, “Antitumor
`benZophenone derivatives,” Nov. 15, 1982.
`Caplus 72179046, Abstract of CH 479557, “Tuberculostatic and
`cancerostatic polybasic ureas,” Dr. A. Wander, Oct. 15, 1969.
`Caplus 1251245169, “Production of murine monoclonal antibodies
`against sulcofuron and ?ucofuron by in vitro immunization,” G. A.
`BonWick et al., J. Immunol. Methods, pp. 163-173, 1996.
`Caplus 127134137f, “Preparation of quinoline an dquinaZoline
`derivatives inhibiting platelet-derived growth factor receptor
`autophosphorylation,” KaZuo Kubo et al., May 15, 1997.
`Caplus 131158658k, “Inhibition of raf kinase using symmetrical and
`unsymmetrical substituted diphenyl ureas,” Miller, Scott, Jul. 1,
`1999.
`Caplus 131187909y, “Inhibition of p38 kinase activity using substi
`tuted heterocyclic ureas,” Jacques Dumas, Jul. 1, 1999.
`Caplus 131173649b, “Preparation of pyraZolyl aryl ureas and related
`compounds as p3 8kinase inhibitor,” Jacques Dumas, Jul. 1, 1999.
`Joseph V. Simone, “Cecil Textbook of Medicine,” 20th Edition, vol.
`1, Feb. 3, 1997. pp. 1004-1010.
`XP-002205797, Cesar Raposo et al., “Catalysis of Nucleophilic
`Addition of Pyrrolidine to 2-(5H)-Furanone through Chromenone
`Cleft-Type Receptors,” vol. 37, No. 38, pp. 6947-6950, 1996.
`Jacqueline E. van Muijlwijk-Koezen et al., “Isoquinoline and
`QuinaZoline Urea Analogues as Antagonists for the Human
`Adenosine A3 Receptor,” J. Ed. Chem. 2000, 43, pp. 2227-2238, Jan.
`3, 2000.
`Jacques Dumas et al., “1-Phenyl-5-pyraZoly Ureas: Potent and Selec
`tive p38 Kinase Inhibitors,” Bioorganic & Medicinal Chemistry Let
`ters, pp. 2051-2054, May 2, 2000.
`Robert W. Carling et al., “1-(3 -Cyanobenxylpiperidin-4-yl)-5
`methyl-4-phenyl-1,3-dihydroimidaZol-2-one1 A Selective High-Af
`?nity Antagonist for the Human Dopanine D4 Receptor With Excel
`lent Selectivity over Ion Channels,” J. Med. Chem., 1999, 42, pp.
`2706-2715.
`Abstract WO 9822103, May 28, 1998, John Philip Hedge et al.
`Abstract of DE 3305866A1, Aug. 29, 1984, Dr. Acker Rolf-Dieter et
`al.
`Abstract ofEP 493 1(equivalent 4,240,820), K. Dickore et al. (1980).
`Dumas, J.. “CAS Substructure,” May 6, 1997, pp. 1-29.
`Scott, Bill, “Substructure (Patent Families),”Aug. 11, 1997, pp. 1- 19.
`Scott, Bill, “Substructure #2,” Nov. 25, 1997, pp. 1-3.
`“Beilstein number” Collection, 28 pages (1997).
`“Beilstein Collection,” 4 pages (1997).
`Scott, Bill, “Substructure Search,” Dec. 2, 1997, pp. 1-51.
`Substructure Search, pp. 1-30. (1997).
`DerWent World Patents Index Search, pp. 20-26. (1997).
`Abstract of EP 116,932 (1984).
`Abstract of EP 676,395 (1995).
`Abstract ofEP 0 202 538 (1986).
`Abstract of EP 16,371 (1980).
`A “Notice of References Cited” from the USPTO for US. Appl. No.
`08/995,749, ?led Dec. 2, 1998, Inhibition ofP38 Kinase Using Syrn
`metrical and Unsymmetrical Diphenyl Ureas.
`A “Notice of References Cited” from the USPTO for US. Appl. No.
`09/083,399, ?led Jan. 8, 2001, Inhibition of Raf Kinase Activity
`Using Aryl Ureas.
`A “Notice of References Cited” from the USPTO for US. Appl. No.
`09/425,228, ?led Sep. 10, 2001, Inhibition of Raf Kinase Using
`Symmetrical and Unsymmetrical Substituted Diphenyl Ureas.
`A “Notice of References Cited” from the USPTO for US. Appl. No.
`09/425,229, ?led Mar. 4, 2002, Omega-Ca