PCT PCT
`
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`International Bureau International Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(51) International Patent Classification 6 : (51) International Patent Classification 6 :
`
`CO7D 213/56, A61K 31/44, CO7D 213/75, Al CO7D 213/56, A61K 31/44, CO7D 213/75, Al
`
`213/74, 401/06, 213/73 213/74, 401/06, 213/73
`
`
`
`(11) International Publication Number: (cid:9)(11) International Publication Number: (cid:9)
`
`
`
`WO 99/58502 WO 99/58502
`
`
`
`(43) International Publication Date: (cid:9)(43) International Publication Date: (cid:9)
`
`
`
`18 November 1999 (18.11.99) 18 November 1999 (18.11.99)
`
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG, (81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB,
`
`GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
`
`KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI,
`
`SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA,
`
`ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ, ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ,
`
`UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD,
`
`RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK, RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK,
`
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR,
`
`NE, SN, TD, TG). NE, SN, TD, TG).
`
`
`Published Published
`
`With international search report. With international search report.
`
`Before the expiration of the time limit for amending the Before the expiration of the time limit for amending the
`
`claims and to be republished in the event of the receipt of claims and to be republished in the event of the receipt of
`
`amendments. amendments.
`
`
`
`(21) International Application Number: (cid:9)(21) International Application Number: (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`
`
`(22) International Filing Date: (cid:9)(22) International Filing Date: (cid:9)
`
`
`
`11 May 1999 (11.05.99) 11 May 1999 (11.05.99)
`
`
`(30) Priority Data: (30) Priority Data:
`
`60/085,053 60/085,053
`
`60/127,626 60/127,626
`
`60/129,099 60/129,099
`
`
`11 May 1998 (11.05.98) 11 May 1998 (11.05.98)
`
`1 April 1999 (01.04.99) 1 April 1999 (01.04.99)
`
`13 April 1999 (13.04.99) 13 April 1999 (13.04.99)
`
`
`US US
`
`US US
`
`US US
`
`
`(71) Applicant (for all designated States except US): VERTEX (71) Applicant (for all designated States except US): VERTEX
`
`PHARMACEUTICALS INCORPORATED [US/US]; 130 PHARMACEUTICALS INCORPORATED [US/US]; 130
`
`Waverly Street, Cambridge, MA 02139-4242 (US). Waverly Street, Cambridge, MA 02139-4242 (US).
`
`
`(72) Inventors; and (72) Inventors; and
`
`(75) Inventors/Applicants (for US only): SALITURO, Francesco (75) Inventors/Applicants (for US only): SALITURO, Francesco
`
`[US/US]; 25 Baker Drive, Marlborough, MA 01752 (US). [US/US]; 25 Baker Drive, Marlborough, MA 01752 (US).
`
`GALULLO, Vincent [US/US]; 18A Ayer Road, Harvard, GALULLO, Vincent [US/US]; 18A Ayer Road, Harvard,
`
`MA 01451 (US). BELLON, Steven [US/US]; 3 Hun-MA 01451 (US). BELLON, Steven [US/US]; 3 Hun-
`
`dreds Road, Wellesley, MA 02181 (US). BEMIS, Guy dreds Road, Wellesley, MA 02181 (US). BEMIS, Guy
`
`[US/US]; 256 Appleton Street, Arlington, MA 02476 (US). [US/US]; 256 Appleton Street, Arlington, MA 02476 (US).
`
`COCHRAN, John [US/US]; 700 Princeton Boulevard #18, COCHRAN, John [US/US]; 700 Princeton Boulevard #18,
`
`Lowell, MA 01851 (US). Lowell, MA 01851 (US).
`
`
`(74) Agents: HALEY, James, F., Jr.; Fish & Neave, 1251 Avenue (74) Agents: HALEY, James, F., Jr.; Fish & Neave, 1251 Avenue
`
`of the Americas, New York, NY 10020 (US) et al. of the Americas, New York, NY 10020 (US) et al.
`
`
`
`(54) Title: HETEROCYCLIC INHIBITORS OF P38 (54) Title: HETEROCYCLIC INHIBITORS OF P38
`
`
`
`(57) Abstract (57) Abstract
`
`
`The present invention relates to inhibitors of p38, a mammalian protein kinase involved in cell proliferation, cell death and response The present invention relates to inhibitors of p38, a mammalian protein kinase involved in cell proliferation, cell death and response
`
`to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical
`
`compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of
`
`various disorders. various disorders.
`
`Ex. 1013 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY FOR THE PURPOSES OF INFORMATION ONLY
`
`
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT. Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`
`AL AL
`
`AM AM
`
`AT AT
`
`AU AU
`
`AZ AZ
`
`BA BA
`
`BB BB
`
`BE BE
`
`BF BF
`
`BG BG
`
`BJ BJ
`
`BR BR
`
`BY BY
`
`CA CA
`
`CF CF
`
`CG CG
`
`CH CH
`
`CI CI
`
`CM CM
`
`CN CN
`
`CU CU
`
`CZ CZ
`
`DE DE
`
`DK DK
`
`EE EE
`
`
`Albania Albania
`
`Armenia Armenia
`
`Austria Austria
`
`Australia Australia
`
`Azerbaijan Azerbaijan
`
`Bosnia and Herzegovina Bosnia and Herzegovina
`
`Barbados Barbados
`
`Belgium Belgium
`
`Burkina Faso Burkina Faso
`
`Bulgaria Bulgaria
`
`Benin Benin
`
`Brazil Brazil
`
`Belarus Belarus
`
`Canada Canada
`
`Central African Republic Central African Republic
`
`Congo Congo
`
`Switzerland Switzerland
`
`C6te d'Ivoire C6te d'Ivoire
`
`Cameroon Cameroon
`
`China China
`
`Cuba Cuba
`
`Czech Republic Czech Republic
`
`Germany Germany
`
`Denmark Denmark
`
`Estonia Estonia
`
`
`ES ES
`
`FI FI
`
`FR FR
`
`GA GA
`
`GB GB
`
`GE GE
`
`Gil Gil
`
`GN GN
`
`GR GR
`
`HU HU
`
`IE IE
`
`IL IL
`
`IS IS
`
`IT IT
`
`JP JP
`
`KE KE
`
`KG KG
`
`KP KP
`
`
`KR KR
`
`KZ KZ
`
`LC LC
`
`LI LI
`
`LK LK
`
`LR LR
`
`
`Spain Spain
`
`Finland Finland
`
`France France
`
`Gabon Gabon
`
`United Kingdom United Kingdom
`
`Georgia Georgia
`
`Ghana Ghana
`
`Guinea Guinea
`
`Greece Greece
`
`Hungary Hungary
`
`Ireland Ireland
`
`Israel Israel
`
`Iceland Iceland
`
`Italy Italy
`
`Japan Japan
`
`Kenya Kenya
`
`Kyrgyzstan Kyrgyzstan
`
`Democratic People's Democratic People's
`
`Republic of Korea Republic of Korea
`
`Republic of Korea Republic of Korea
`
`Kazakstan Kazakstan
`
`Saint Lucia Saint Lucia
`
`Liechtenstein Liechtenstein
`
`Sri Lanka Sri Lanka
`
`Liberia Liberia
`
`
`LS LS
`
`LT LT
`
`LU LU
`
`LV LV
`
`MC MC
`
`MD MD
`
`MG MG
`
`MK MK
`
`
`ML ML
`
`MN MN
`
`MR MR
`
`MW MW
`
`MX MX
`
`NE NE
`
`NL NL
`
`NO NO
`
`NZ NZ
`
`PL PL
`
`PT PT
`
`RO RO
`
`RU RU
`
`SD SD
`
`SE SE
`
`SG SG
`
`
`Lesotho Lesotho
`
`Lithuania Lithuania
`
`Luxembourg Luxembourg
`
`Latvia Latvia
`
`Monaco Monaco
`
`Republic of Moldova Republic of Moldova
`
`Madagascar Madagascar
`
`The former Yugoslav The former Yugoslav
`
`Republic of Macedonia Republic of Macedonia
`
`Mali Mali
`
`Mongolia Mongolia
`
`Mauritania Mauritania
`
`Malawi Malawi
`
`Mexico Mexico
`
`Niger Niger
`
`Netherlands Netherlands
`
`Norway Norway
`
`New Zealand New Zealand
`
`Poland Poland
`
`Portugal Portugal
`
`Romania Romania
`
`Russian Federation Russian Federation
`
`Sudan Sudan
`
`Sweden Sweden
`
`Singapore Singapore
`
`
`SI SI
`
`SK SK
`
`SN SN
`
`SZ SZ
`
`TD TD
`
`TG TG
`
`TJ TJ
`
`TM TM
`
`TR TR
`
`TT TT
`
`UN UN
`
`UG UG
`
`US US
`
`UZ UZ
`
`VN VN
`
`YU YU
`
`ZW ZW
`
`
`Slovenia Slovenia
`
`Slovakia Slovakia
`
`Senegal Senegal
`
`Swaziland Swaziland
`
`Chad Chad
`
`Togo Togo
`
`Tajikistan Tajikistan
`
`Turkmenistan Turkmenistan
`
`Turkey Turkey
`
`Trinidad and Tobago Trinidad and Tobago
`
`Ukraine Ukraine
`
`Uganda Uganda
`
`United States of America United States of America
`
`Uzbekistan Uzbekistan
`
`Viet Nam Viet Nam
`
`Yugoslavia Yugoslavia
`
`Zimbabwe Zimbabwe
`
`Ex. 1013 - Page 2
`
`

`

`(cid:9) (cid:9)
`
`5 proliferation, cell death and response to extracellular
`5 proliferation, cell death and response to extracellular
`
`10 (cid:9)
`10 (cid:9)
`
`stimuli. The invention also relates to methods for
`stimuli. The invention also relates to methods for
`
`producing these inhibitors. The invention also provides
`producing these inhibitors. The invention also provides
`
`pharmaceutical compositions comprising the inhibitors of
`pharmaceutical compositions comprising the inhibitors of
`
`
`
`the invention and methods of utilizing those compositions the invention and methods of utilizing those compositions
`
`in the treatment and prevention of various disorders.
`in the treatment and prevention of various disorders.
`
`
`
`BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION
`
`Protein kinases are involved in various
`Protein kinases are involved in various
`
`cellular responses to extracellular signals. Recently, a
`cellular responses to extracellular signals. Recently, a
`
`
`
`family of mitogen-activated protein kinases (MAPK) has family of mitogen-activated protein kinases (MAPK) has
`
`15 been discovered. Members of this family are Ser/Thr
`15 been discovered. Members of this family are Ser/Thr
`
`
`
`kinases that activate their substrates by phosphorylation kinases that activate their substrates by phosphorylation
`
`[B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98
`[B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98
`
`(1996)]. MAPKs are themselves activated by a variety of
`(1996)]. MAPKs are themselves activated by a variety of
`
`signals including growth factors, cytokines, UV
`signals including growth factors, cytokines, UV
`
`20 radiation, and stress-inducing agents.
`20 radiation, and stress-inducing agents.
`
`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`
`
`HETEROCYCLIC INHIBITORS OF P38 HETEROCYCLIC INHIBITORS OF P38
`
`TECHNICAL FIELD OF INVENTION
`TECHNICAL FIELD OF INVENTION
`
`
`
`The present invention relates to inhibitors of The present invention relates to inhibitors of
`
`p38, a mammalian protein kinase involved in cell
`p38, a mammalian protein kinase involved in cell
`
`25
`25 (cid:9)
`
`One particularly interesting MAPK is p38. p38,
`One particularly interesting MAPK is p38. p38,
`
`also known as cytokine suppressive anti-inflammatory drug
`also known as cytokine suppressive anti-inflammatory drug
`
`binding protein (CSBP) and RK, was isolated from murine
`binding protein (CSBP) and RK, was isolated from murine
`
`
`
`pre-B cells that were transfected with the pre-B cells that were transfected with the
`
`lipopolysaccharide (LPS) receptor, CD14, and induced with
`lipopolysaccharide (LPS) receptor, CD14, and induced with
`
`
`
`LPS. p38 has since been isolated and sequenced, as has LPS. p38 has since been isolated and sequenced, as has
`
`the cDNA encoding it in humans and mouse. Activation of
`the cDNA encoding it in humans and mouse. Activation of
`
`p38 has been observed in cells stimulated by stress, such
`p38 has been observed in cells stimulated by stress, such
`
`
`
`as treatment of lipopolysaccharides (LPS), UV, as treatment of lipopolysaccharides (LPS), UV,
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 3
`
`

`

`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`-2-
`-2-
`
`
`
`anisomycin, or osmotic shock, and by cytokines, such as anisomycin, or osmotic shock, and by cytokines, such as
`
`
`
`IL-1 and TNF. IL-1 and TNF.
`
`Inhibition of p38 kinase leads to a blockade on
`Inhibition of p38 kinase leads to a blockade on
`
`
`
`the production of both IL-1 and TNF. IL-1 and TNF the production of both IL-1 and TNF. IL-1 and TNF
`
`5 (cid:9)
`
`
`5 stimulate the production of other proinflammatory stimulate the production of other proinflammatory
`
`
`
`cytokines such as IL-6 and IL-8 and have been implicated cytokines such as IL-6 and IL-8 and have been implicated
`
`in acute and chronic inflammatory diseases and in post-
`in acute and chronic inflammatory diseases and in post-
`
`menopausal osteoporosis [R. B. Kimble et al.,
`menopausal osteoporosis [R. B. Kimble et al.,
`
`
`
`Endocrinol., 136, pp. 3054-61 (1995)]. Endocrinol., 136, pp. 3054-61 (1995)].
`
`10 (cid:9)
`10 (cid:9)
`
`
`
`Based upon this finding, it is believed that Based upon this finding, it is believed that
`
`
`
`p38, along with other MAPKs, have a role in mediating p38, along with other MAPKs, have a role in mediating
`
`cellular response to inflammatory stimuli, such as
`cellular response to inflammatory stimuli, such as
`
`
`
`leukocyte accumulation, macrophage/monocyte activation, leukocyte accumulation, macrophage/monocyte activation,
`
`
`
`tissue resorption, fever, acute phase responses and tissue resorption, fever, acute phase responses and
`
`15 neutrophilia. In addition, MAPKs, such as p38, have been
`15 neutrophilia. In addition, MAPKs, such as p38, have been
`
`
`
`implicated in cancer, thrombin-induced platelet implicated in cancer, thrombin-induced platelet
`
`aggregation, immunodeficiency disorders, autoimmune
`aggregation, immunodeficiency disorders, autoimmune
`
`diseases, cell death, allergies, osteoporosis and
`diseases, cell death, allergies, osteoporosis and
`
`
`
`neurodegenerative disorders. Inhibitors of p38 have also neurodegenerative disorders. Inhibitors of p38 have also
`
`20 been implicated in the area of pain management through
`20 been implicated in the area of pain management through
`
`
`
`inhibition of prostaglandin endoperoxide synthase-2 inhibition of prostaglandin endoperoxide synthase-2
`
`induction. Other diseases associated with I1-1, IL-6,
`induction. Other diseases associated with I1-1, IL-6,
`
`
`
`IL-8 or TNF overproduction are set forth in WO 96/21654. IL-8 or TNF overproduction are set forth in WO 96/21654.
`
`Others have already begun trying to develop
`Others have already begun trying to develop
`
`25 drugs that specifically inhibit MAPKs. For example, PCT
`25 drugs that specifically inhibit MAPKs. For example, PCT
`
`publication WO 95/31451 describes pyrazole compounds that
`publication WO 95/31451 describes pyrazole compounds that
`
`inhibit MAPKs, and, in particular, p38. However, the
`inhibit MAPKs, and, in particular, p38. However, the
`
`
`
`efficacy of these inhibitors in vivo is still being efficacy of these inhibitors in vivo is still being
`
`investigated.
`investigated.
`
`30 (cid:9)
`30 (cid:9)
`
`
`
`Accordingly, there is still a great need to Accordingly, there is still a great need to
`
`
`
`develop other potent inhibitors of p38, including p38- develop other potent inhibitors of p38, including p38-
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`
`
`-3- -3-
`
`
`
`specific inhibitors, that are useful in treating various specific inhibitors, that are useful in treating various
`
`
`
`conditions associated with p38 activation. conditions associated with p38 activation.
`
`
`
`SUMMARY OF THE INVENTION SUMMARY OF THE INVENTION
`
`
`
`The present invention addresses this problem by The present invention addresses this problem by
`
`
`
`5 providing compounds that demonstrate strong inhibition of 5 providing compounds that demonstrate strong inhibition of
`
`
`
`p38. p38.
`
`
`
`These compounds have the general formula: These compounds have the general formula:
`
`
`
`91 F? 91 F?
`
`
`
`V (cid:9)V (cid:9)
`
`
`
`N N
`
`
`
`Y U Y U
`
`
`91 (cid:9)91 (cid:9)
`
`z (cid:9)z (cid:9)
`
`.. ,U (cid:9).. ,U (cid:9)
`
`V 1Y--"Y (cid:9)V 1Y--"Y (cid:9)
`
`N ,- N ,-
`
`
`
`Ws (cid:9)Ws (cid:9)
`
`
`
`Q2 Q2
`
`
`
`(Ia), (cid:9)(Ia), (cid:9)
`
`
`
`Qi (cid:9)Qi (cid:9)
`
`
`
`(Ib), (cid:9)(Ib), (cid:9)
`
`
`0 0
`
`Q1' N)( NH2 Q1' N)( NH2
`
`
`
`N N
`
`
`
`91 91
`1, 1,
`
`,Z Y-.. .0 ,Z Y-.. .0
`
`
`V V
`(cid:9) 'Y (cid:9) 'Y
`
`NN
`
`
`A A
`
`1 1
`
`B B
`
`
`
`Q2 Q2
`
`
`
`(Ic), (Ic),
`
`
`
`10 wherein each of Qi and Q2 are independently selected from 10 wherein each of Qi and Q2 are independently selected from
`
`
`
`a phenyl or 5-6 membered aromatic heterocyclic ring a phenyl or 5-6 membered aromatic heterocyclic ring
`
`
`
`system, or a 8-10 membered bicyclic ring system system, or a 8-10 membered bicyclic ring system
`
`
`
`comprising aromatic carbocyclic rings, aromatic comprising aromatic carbocyclic rings, aromatic
`
`
`
`heterocyclic rings or a combination of an aromatic heterocyclic rings or a combination of an aromatic
`
`
`
`15 carbocyclic ring and an aromatic heterocyclic ring. 15 carbocyclic ring and an aromatic heterocyclic ring.
`
`
`
`A heterocyclic ring system or a heterocyclic A heterocyclic ring system or a heterocyclic
`
`
`
`ring contains 1 to 4 heteroatoms, which are independently ring contains 1 to 4 heteroatoms, which are independently
`
`
`
`selected from N, 0, S, SO and SO2. selected from N, 0, S, SO and SO2.
`
`
`
`The rings that make up Qi are substituted with The rings that make up Qi are substituted with
`
`
`
`20 (cid:9)20 (cid:9)
`
`
`
`1 to 4 substituents, each of which is independently 1 to 4 substituents, each of which is independently
`
`
`
`selected from halo; C1-C3 alkyl optionally substituted selected from halo; C1-C3 alkyl optionally substituted
`
`
`
`with NR'2, OR', CO2R' or CONR'2; 0-(C1-C3)-alkyl with NR'2, OR', CO2R' or CONR'2; 0-(C1-C3)-alkyl
`
`
`
`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 5
`
`

`

`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`
`
`-4- -4-
`
`
`
`optionally substituted with NR'2, OR', CO2R' or CONR'2; optionally substituted with NR'2, OR', CO2R' or CONR'2;
`
`
`
`NR'2 ; OCF3 ; CF3; NO2; CO2R'; CONR'; SR'; S(02)N(R')2; SCF3 ; NR'2 ; OCF3 ; CF3; NO2; CO2R'; CONR'; SR'; S(02)N(R')2; SCF3 ;
`
`
`
`CN; N(R')C(0)R4; N(R')C(0)0R4; N(R')C(0)C(0)R4; CN; N(R')C(0)R4; N(R')C(0)0R4; N(R')C(0)C(0)R4;
`
`
`
`N(R')S(02)R4; N(R')R4; N(R4)2; OR4; OC(0)R4; OP(0)3H2; or N(R')S(02)R4; N(R')R4; N(R4)2; OR4; OC(0)R4; OP(0)3H2; or
`
`
`
`5 (cid:9)5 (cid:9)
`
`
`
`N-C-N (R' ) 2. N-C-N (R' ) 2.
`
`
`
`The rings that make up Q2 are optionally The rings that make up Q2 are optionally
`
`
`
`substituted with up to 4 substituents, each of which is substituted with up to 4 substituents, each of which is
`
`
`
`independently selected from halo; C1-C3 straight or independently selected from halo; C1-C3 straight or
`
`
`
`branched alkyl optionally substituted with NR'2, OR', branched alkyl optionally substituted with NR'2, OR',
`
`
`
`10 (cid:9)10 (cid:9)
`
`
`
`CO2R', S(02)N(R')2, N=C-N(R')2, R3, or CONR'2; 0-(Cl-C3)- CO2R', S(02)N(R')2, N=C-N(R')2, R3, or CONR'2; 0-(Cl-C3)-
`
`
`
`alkyl; 0-(C1-C3) -alkyl optionally substituted with NR'2. alkyl; 0-(C1-C3) -alkyl optionally substituted with NR'2.
`
`
`
`OR', CO2R', S(02)N(R')2, N=C-N(R')2, R3, or CONR'2; NR'2; OR', CO2R', S(02)N(R')2, N=C-N(R')2, R3, or CONR'2; NR'2;
`
`
`
`OCF3; CF3; NO2; CO2R'; CONR' ; R3; OR3; NR3; SR3; C(0)R3 ; OCF3; CF3; NO2; CO2R'; CONR' ; R3; OR3; NR3; SR3; C(0)R3 ;
`
`
`
`C(0)N(R')R3; C(0)0R3; SR'; S(02)N(R')2; SCF3; N=C-N(R')2; C(0)N(R')R3; C(0)0R3; SR'; S(02)N(R')2; SCF3; N=C-N(R')2;
`
`
`
`15 or CN. 15 or CN.
`
`
`
`Q2' is selected from phenyl or a 5-6 member Q2' is selected from phenyl or a 5-6 member
`
`
`
`aromatic heterocyclic ring optionally substituted with 1-aromatic heterocyclic ring optionally substituted with 1-
`
`
`
`3 substituents, each of which is independently selected 3 substituents, each of which is independently selected
`
`
`
`from halogen; C1-03 alkyl optionally substituted with from halogen; C1-03 alkyl optionally substituted with
`
`
`
`20 20
`
`
`
`NR'2, OR', CO2R', CONR'2, or 0-P(03)H2; 0-(C2 -C3) -alkyl NR'2, OR', CO2R', CONR'2, or 0-P(03)H2; 0-(C2 -C3) -alkyl
`
`
`
`optionally substituted with NR'2, OR', CO2R', CONR'2, or optionally substituted with NR'2, OR', CO2R', CONR'2, or
`
`
`
`OP(03)H2; OCF3; CF3; OR4; 0-0O2R4; 0-P(03)H2; CO2R'; CONR'; OP(03)H2; OCF3; CF3; OR4; 0-0O2R4; 0-P(03)H2; CO2R'; CONR';
`
`
`
`SR'; S(02)N(R')2; SCF3; CN; N(R')C(0)R4; N(R')C(0)0R4 ; SR'; S(02)N(R')2; SCF3; CN; N(R')C(0)R4; N(R')C(0)0R4 ;
`
`
`
`N(R')C(0)C(0)R4; N(R')S(02)R4; N(R')R4; N(R4)2; OR4 ; N(R')C(0)C(0)R4; N(R')S(02)R4; N(R')R4; N(R4)2; OR4 ;
`
`
`
`25 (cid:9)25 (cid:9)
`
`
`
`OC(0)R4; OP(0)3H2; or N=C-N(R')2; provided that Q2' is not OC(0)R4; OP(0)3H2; or N=C-N(R')2; provided that Q2' is not
`
`
`
`phenyl optionally substituted 1 to 3 substituents phenyl optionally substituted 1 to 3 substituents
`
`
`
`independently selected from halo, methoxy, cyano, nitro, independently selected from halo, methoxy, cyano, nitro,
`
`
`
`amino, hydroxy, methyl or ethyl. amino, hydroxy, methyl or ethyl.
`
`
`
`R' is selected from hydrogen; (C1-C3) -alkyl; R' is selected from hydrogen; (C1-C3) -alkyl;
`
`
`
`30 (cid:9)30 (cid:9)
`
`
`
`(02-C3)-alkenyl or alkynyl; phenyl or phenyl substituted (02-C3)-alkenyl or alkynyl; phenyl or phenyl substituted
`
`
`
`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 99/58502 (cid:9)
`WO 99/58502 (cid:9)
`
`PCT/US99/10291
`PCT/US99/10291
`
`-5-
`-5-
`
`with 1 to 3 substituents independently selected from
`with 1 to 3 substituents independently selected from
`
`halo, methoxy, cyano, nitro, amino, hydroxy, methyl or
`halo, methoxy, cyano, nitro, amino, hydroxy, methyl or
`
`ethyl; or a 5-6 membered heterocyclic ring system
`ethyl; or a 5-6 membered heterocyclic ring system
`
`
`
`optionally substituted with 1 to 3 substituents optionally substituted with 1 to 3 substituents
`
`5 (cid:9)
`5 (cid:9)
`
`independently selected from halo, methoxy, cyano, nitro,
`independently selected from halo, methoxy, cyano, nitro,
`
`amino, hydroxy, methyl or ethyl.
`amino, hydroxy, methyl or ethyl.
`
`3 .
`R3
`is selected from 5-8 membered aromatic or
`R is selected from 5-8 membered aromatic or
`
`non-aromatic carbocyclic or heterocyclic ring systems
`non-aromatic carbocyclic or heterocyclic ring systems
`
`
`
`each optionally substituted with R', R4, -C(0)R', -C(0)R4, each optionally substituted with R', R4, -C(0)R', -C(0)R4,
`
`10 (cid:9)
`10 (cid:9)
`
`-C(0)0R4 or -J; or an 8-10 membered bicyclic ring system
`-C(0)0R4 or -J; or an 8-10 membered bicyclic ring system
`
`comprising aromatic carbocyclic rings, aromatic
`comprising aromatic carbocyclic rings, aromatic
`
`heterocyclic rings or a combination of an aromatic
`heterocyclic rings or a combination of an aromatic
`
`carbocyclic ring and an aromatic heterocyclic ring each
`carbocyclic ring and an aromatic heterocyclic ring each
`
`optionally substituted with R', R4, -C(0)R', -C(0)R4, -
`optionally substituted with R', R4, -C(0)R', -C(0)R4, -
`
`15 (cid:9)
`15 (cid:9)
`
`C(0)0R4 or -J.
`C(0)0R4 or -J.
`
`R4 is (C1-C4)-straight or branched alkyl
`R4 is (C1-C4)-straight or branched alkyl
`
`optionally substituted with N(R')2, OR', CO2R', CON(R')2,
`optionally substituted with N(R')2, OR', CO2R', CON(R')2,
`
`
`
`or SO2N(R2)2; or a 5-6 membered carbocyclic or or SO2N(R2)2; or a 5-6 membered carbocyclic or
`
`heterocyclic ring system optionally substituted with
`heterocyclic ring system optionally substituted with
`
`20 (cid:9)
`20 (cid:9)
`
`
`N(R') , OR', CO2R', CON(R')2, or SO2N(R2)2. N(R') , OR', CO2R', CON(R')2, or SO2N(R2)2.
`R5 is selected from hydrogen; (C1-C3)-alkyl
`R5 is selected from hydrogen; (C1-C3)-alkyl
`
`optionally substituted with R3; (C2-C3)-alkenyl or alkynyl
`optionally substituted with R3; (C2-C3)-alkenyl or alkynyl
`
`each optionally substituted with R3; phenyl or phenyl
`each optionally substituted with R3; phenyl or phenyl
`
`substituted with 1 to 3 substituents independently
`substituted with 1 to 3 substituents independently
`
`25 (cid:9)
`25 (cid:9)
`
`
`
`selected from halo, methoxy, cyano, nitro, amino, selected from halo, methoxy, cyano, nitro, amino,
`
`hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic
`hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic
`
`ring system optionally substituted with 1 to 3
`ring system optionally substituted with 1 to 3
`
`
`
`substituents independently selected from halo, methoxy, substituents independently selected from halo, methoxy,
`
`cyano, nitro, amino, hydroxy, methyl or ethyl.
`cyano, nitro, amino, hydroxy, methyl or ethyl.
`
`30 (cid:9)
`30 (cid:9)
`
`W is selected from N(R2)S02-N(R2)2; N(R2)S02-
`W is selected from N(R2)S02-N(R2)2; N(R2)S02-
`N(R-) (R3); N(R2)C(0)-0R2; N(R2)C(0)-N(R2)2; N(R2)C(0)-
`N(R-) (R3); N(R2)C(0)-0R2; N(R2)C(0)-N(R2)2; N(R2)C(0)-
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`
`
`PCT/US99/10291 PCT/US99/10291
`
`
`
`N(R2) (R3); N(R2)C(0)-R2; N(R2)2; C(0)-R2; CH(OH)-R2; C(0)- N(R2) (R3); N(R2)C(0)-R2; N(R2)2; C(0)-R2; CH(OH)-R2; C(0)-
`
`
`
`-6- -6-
`
`
`
`N(R2) (cid:9)N(R2) (cid:9)
`
`C(0)-0R2; J; or (C1-C4) straight or branched alkyl C(0)-0R2; J; or (C1-C4) straight or branched alkyl
`
`
`optionally substituted with N(R')2, OR', CO2R', CON(R')2, optionally substituted with N(R')2, OR', CO2R', CON(R')2,
`
`
`
`R3, SO2N(R2)2, OC(0)R2, OC(0)R', OC(0)N(R2)2, -N(R4 ) (R5), - R3, SO2N(R2)2, OC(0)R2, OC(0)R', OC(0)N(R2)2, -N(R4 ) (R5), -
`
`
`
`5 (cid:9)5 (cid:9)
`
`C(0)N(R5) (R2) , -C(0)R5, -N(R2)C(0)N(R2) (R5), -NC(0)0R5 , - C(0)N(R5) (R2) , -C(0)R5, -N(R2)C(0)N(R2) (R5), -NC(0)0R5 , -
`
`
`OC(0)N(R2) (R5), or -J; a 5-6 membered carbocyclic or OC(0)N(R2) (R5), or -J; a 5-6 membered carbocyclic or
`
`
`
`heterocyclic ring system optionally substituted with heterocyclic ring system optionally substituted with
`
`
`
`N(R')2, OR', CO2R', CON(R')2, or SO2N(R2)2; or a 8-10 N(R')2, OR', CO2R', CON(R')2, or SO2N(R2)2; or a 8-10
`
`
`
`membered carbocyclic or heterocyclic ring system membered carbocyclic or heterocyclic ring system
`
`
`
`10 (cid:9)10 (cid:9)
`
`
`
`optionally substituted with N(R')2, OR', CO2R', CON(R')2, optionally substituted with N(R')2, OR', CO2R', CON(R')2,
`
`
`
`or SO2N(R2)2; provided that W is not an R3 substituted C1 or SO2N(R2)2; provided that W is not an R3 substituted C1
`
`
`
`alkyl. alkyl.
`
`
`
`W' is selected from N(R2)-S02-Q2; N (R2) -0O2-Q2; W' is selected from N(R2)-S02-Q2; N (R2) -0O2-Q2;
`
`
`N(R')-C(0)-Q2; N(R2) (42); C(0)-Q2; CO2-Q2; C(0)N(R2) (Q2); N(R')-C(0)-Q2; N(R2) (42); C(0)-Q2; CO2-Q2; C(0)N(R2) (Q2);
`
`2 n 2 n
`
`1 1
`
`r- PIR r- PIR
`
`,,2 • ,,2 •
`
`
`
`15 (cid:9)15 (cid:9)
`
`
`
`-R2, -N(R2-R2, -N(R2
`
`
`Each R is independently selected from hydrogen, Each R is independently selected from hydrogen,
`
`, SR2, SR2
`
`) 2, -OR2) 2, -OR2
`
`
`
`, -C (0) -N (R2 ) 2/ -S (02) -1\T (R2 ) 2f , -C (0) -N (R2 ) 2/ -S (02) -1\T (R2 ) 2f
`
`
`
`-C(0)-0R2 or -C(0)R2 wherein two adjacent R are optionally -C(0)-0R2 or -C(0)R2 wherein two adjacent R are optionally
`
`
`
`bound to one another and, together with each Y to which bound to one another and, together with each Y to which
`
`
`
`20 (cid:9)20 (cid:9)
`
`
`
`they are respectively bound, form a 4-8 membered they are respectively bound, form a 4-8 membered
`
`
`
`carbocyclic or heterocyclic ring. carbocyclic or heterocyclic ring.
`
`
`
`R2 is selected from hydrogen, (C1-C3)-alkyl, or R2 is selected from hydrogen, (C1-C3)-alkyl, or
`
`
`
`(C1-C3)-alkenyl; each optionally substituted with -N(R')2, (C1-C3)-alkenyl; each optionally substituted with -N(R')2,
`
`
`
`-OR', SR', -C(0)-N(R')2, -S(02)-N(R')2, -C(0)-OR', -OR', SR', -C(0)-N(R')2, -S(02)-N(R')2, -C(0)-OR',
`
`
`
`25 (cid:9)25 (cid:9)
`
`
`
`-NSO2R4 , -NSO2R3, -C (0)N (R' ) (R3) , -NC (0) R4, -N (R') (R3 ) -NSO2R4 , -NSO2R3, -C (0)N (R' ) (R3) , -NC (0) R4, -N (R') (R3 )
`
`
`
`-N(R') (R4), -C(0)R3, -C(0)N(R') (R4), -N(R4)2, -N(R') (R4), -C(0)R3, -C(0)N(R') (R4), -N(R4)2,
`
`
`
`-C (0) N=C (NH) 2 or R3. -C (0) N=C (NH) 2 or R3.
`
`
`
`Y is N or C. Y is N or C.
`
`
`
`Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or
`
`
`
`30 (cid:9)30 (cid:9)
`
`
`
`C(F). C(F).
`
`
`
`SUBSTITUTE SHEET (RULE 26) SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`
`
`WO 99/58502 (cid:9)WO 99/58502 (cid:9)
`
`PCT/US99/10291
`PCT/US99/10291
`
`-7-
`- 7 -
`
`U is selected from R or W.
`U is selected from R or W.
`
`
`
`3 is selected from -C(0)NH2, -P(0) (NH2)2, or 3 is selected from -C(0)NH2, -P(0) (NH2)2, or
`
`-SO2NH2.
`- S 02 NH2 .
`
`A,B, and C are independently selected from -0-,
`A,B, and C are independently selected from -0-,
`
`
`
`-CHR'-, -CHR4-, -NR'-, -NR4- or -S-. 5 -CHR'-, -CHR4-, -NR'-, -NR4- or -S-.
`5 (cid:9)
`
`J is a (C1-C4) straight chain or branched alkyl
`J is a (Ci-C4) straight chain or branched alkyl
`
`
`
`derivative substituted with 1-3 substituents selected derivative substituted with 1-3 substituents selected
`
`from D, from D, -T-C(0)R', or -0P03H2.
`
`
`
`-T-C(0)R', or -0P03H2.
`
`D is selected from the group
`D is selected from the group
`
`10
`10
`
`0
`0
`
`NH2
`
`O
`
`or
`or
`
`T is either 0 or NH.
`T is either 0 or NH.
`
`
`
`G is either NH2 or OH. G is either NH2 or OH.
`
`15 (cid:9)
`15 (cid:9)
`
`In another embodiment, the invention provides
`In another embodiment, the invention provides
`
`pharmaceutical compositions comprising the p38 inhibitors
`pharmaceutical compositions comprising the p38 inhibitors
`
`
`
`of this invention. These compositions may be utilized in of this invention. These compositions may be utilized in
`
`
`
`methods for treating or preventing a variety of methods for treating or preventing a variety of
`
`disorders, such as cancer, inflammatory diseases,
`disorders, such as cancer, inflammatory diseases,
`
`20 autoimmune diseases, destructive bone disorders,
`20 autoimmune diseases, destructive bone disorders,
`
`proliferative disorders, infectious diseases, viral
`proliferative disorders, infectious diseases, viral
`
`diseases and neurodegenerative diseases. These
`diseases and neurodegenerative diseases. These
`
`compositions are also useful in methods for preventing
`compositions are also useful in methods for preventing
`
`cell death and hyperplasia and therefore may be used to
`cell death and hyperplasia and therefore may be used to
`
`25 treat or prevent reperfusion/ischemia in stroke, heart
`25 treat or prevent reperfusion/ischemia in stroke, heart
`
`attacks, and organ hypoxia. The compositions are also
`attacks, and organ hypoxia. The compositions are also
`
`useful in methods for preventing thrombin-induced
`useful in methods for preventing thrombin-induced
`
`platelet aggregation. Each of these above-described
`platelet aggregation. Each of these above-described
`
`methods is also part of the present invention.
`methods is also part of the present invention.
`
`SUBSTITUTE SHEET (RULE 26)
`SUBSTITUTE SHEET (RULE 26)
`
`Ex. 1013 - Page 9
`
`

`

`WO 99/58502 (cid:9)
`WO 99/58502
`
`PCT/US99/10291
`PCT/US99/10291
`
`-8-
`-8-
`
`DETAILED DESCRIPTION OF THE INVENTION
`DETAILED DESCRIPTION OF THE INVENTION
`
`These compounds have the general formula:
`These compounds have the general formula:
`
`, Z Y„U (cid:9)
`Z, (cid:9)
`Y, ,U (cid:9)
`'Y (cid:9)
`V
`V
`II (cid:9)
`
`W
`VV
`
`
`Z Y, ,U ,Z Y„U
`v-
`- Y
`v (cid:9)
`II
`N
`N
`
`W'
`
`Q2 (cid:9)
`Q2 (cid:9)
`
`(Ia.)/
`(Ia)
`
`9, R
`91 R
`Z
`U
`V ,Zy'Y
`V (cid:9)
`Y
`11
`N
`
`A
`B
`Q2 ,13
`Q2
`
`NH2
`
`Q2
`
`
`
`(Id) and (Id) and
`
`N
`
`
`
`wherein each of Ql and Q2 are independently selected from wherein each of Ql and Q2 are independently selected from
`
`5 a phenyl or 5-6 membered aromatic heterocyclic ring
`5 a phenyl or 5-6 membered aromatic heterocyclic ring
`
`system, or a 8-10 membered bicyclic ring system
`system, or a 8-10 membered bicyclic ring system
`
`comprising aromatic carbocyclic rings, aromatic
`comprising aromatic carbocyclic rings, aromatic
`
`
`
`heterocyclic rings or a combination of an aromatic heterocyclic rings or a combination of an aromatic
`
`carbocyclic ring and an aromatic heterocyclic ring.
`carbocyclic ring and an aromatic heterocyclic ring.
`
`10 (cid:9)
`10 (cid:9)
`
`
`
`The rings that make up Ql are substituted with The rings that make up Qi are substituted with
`
`1 to 4 substituents, each of which is independently
`1 to 4 substituents, each of which is independently
`
`selected from halo; C1-C3 alkyl optionally substituted
`selected from halo; C1-C3 alkyl optionally substituted
`
`with NR'2, OR', CO2R' or CONR'2; 0-(C1-C3)-alkyl
`with NR'2, OR', CO2R' or CONR'2; 0-(C1-C3)-alkyl
`
`optiona