PCT PCT
`
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION WORLD INTELLECTUAL PROPERTY ORGANIZATION
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`International Bureau International Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(51) International Patent Classification 6 : (51) International Patent Classification 6 :
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`CO7D 401/04, A61K 31/44 CO7D 401/04, A61K 31/44
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`
`
`(11) International Publication Number: (cid:9)(11) International Publication Number: (cid:9)
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`
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`WO 98/52941 WO 98/52941
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`
`
`Al Al
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`
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`(43) International Publication Date: 26 November 1998 (26.11.98) (43) International Publication Date: 26 November 1998 (26.11.98)
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`
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`(21) International Application Number: (cid:9)(21) International Application Number: (cid:9)
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`
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`PCT/US98/11684 PCT/US98/11684
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`
`
`(22) International Filing Date: (cid:9)(22) International Filing Date: (cid:9)
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`
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`22 May 1998 (22.05.98) 22 May 1998 (22.05.98)
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`
`(30) Priority Data: (30) Priority Data:
`
`60/047,569 (cid:9)60/047,569 (cid:9)
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`
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`22 May 1997 (22.05.97) (cid:9)22 May 1997 (22.05.97) (cid:9)
`
`
`
`US US
`
`
`(71) Applicant (for all designated States except US): G.D. SEARLE (71) Applicant (for all designated States except US): G.D. SEARLE
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`AND CO. [US/US]; P.O. Box 5110, Chicago, IL 60680 AND CO. [US/US]; P.O. Box 5110, Chicago, IL 60680
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`(US), (US),
`
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR, (81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`
`GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`
`patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
`
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`
`CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG). CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`
`(72) Inventors; and (72) Inventors; and
`
`(75) Inventors/Applicants (for US only): HANSON, Gunnar, J. (75) Inventors/Applicants (for US only): HANSON, Gunnar, J.
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`[US/US]; 7410 Keystone Avenue, Skokie, IL 60076 (US). [US/US]; 7410 Keystone Avenue, Skokie, IL 60076 (US).
`
`LIAO, Shuyuan [CN/US]; 2N. 500 Diane Avenue, Glen LIAO, Shuyuan [CN/US]; 2N. 500 Diane Avenue, Glen
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`Ellyn, IL 60137 (US). Ellyn, IL 60137 (US).
`
`
`Published Published
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`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.
`
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`(74) Agents: ROEDEL, John, K., Jr. et al.; Senniger, Powers, (74) Agents: ROEDEL, John, K., Jr. et al.; Senniger, Powers,
`
`Leavitt & Roedel, 16th floor, One Metropolitan Square, St. Leavitt & Roedel, 16th floor, One Metropolitan Square, St.
`
`Louis, MO 63102 (US). Louis, MO 63102 (US).
`
`
`
`(54) Title: PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS (54) Title: PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS
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`
`
`(57) Abstract (57) Abstract
`
`
`A class of pyrazole derivatives is described for use in treating p38 A class of pyrazole derivatives is described for use in treating p38
`
`kinase mediated disorders. Compounds of particular interest are defined by kinase mediated disorders. Compounds of particular interest are defined by
`
`Formula (I) wherein Q, RI, R2, R3 and R4 are as described in the specification. Formula (I) wherein Q, RI, R2, R3 and R4 are as described in the specification.
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`
`
`( I ) ( I )
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`Ex. 1012 - Page 1
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`

`

`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
`RE
`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
`Cote d'Ivoire
`Cote d'lvoire
`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
`GH
`GH
`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
`UA
`UA
`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
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`Ex. 1012 - Page 2
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`
`
`PCT/US98/11684 PCT/US98/11684
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`
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`PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS PYRAZOLE DERIVATIVES AS p38 KINASE INHIBITORS
`
`
`
`5 (cid:9)5 (cid:9)
`
`
`Cross-Reference to Related Application Cross-Reference to Related Application
`
`This application claims priority from U.S. This application claims priority from U.S.
`
`Provisional Application Serial No. 60/047,569 filed May Provisional Application Serial No. 60/047,569 filed May
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`22, 1997. 22, 1997.
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`
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`10 (cid:9)10 (cid:9)
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`15 (cid:9)15 (cid:9)
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`20 (cid:9)20 (cid:9)
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`25 (cid:9)25 (cid:9)
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`30 (cid:9)30 (cid:9)
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`35 (cid:9)35 (cid:9)
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`Field of the Invention Field of the Invention
`
`This invention relates to a novel group of pyrazole This invention relates to a novel group of pyrazole
`
`compounds, compositions and methods for treating p38 compounds, compositions and methods for treating p38
`
`kinase mediated disorders. kinase mediated disorders.
`
`
`Background of the Invention Background of the Invention
`
`Mitogen-activated protein kinases (MAP) is a family Mitogen-activated protein kinases (MAP) is a family
`
`of proline-directed serine/threonine kinases that of proline-directed serine/threonine kinases that
`
`activate their substrates by dual phosphorylation. The activate their substrates by dual phosphorylation. The
`
`kinases are activated by a variety of signals including kinases are activated by a variety of signals including
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`nutritional and osmotic stress, UV light, growth factors, nutritional and osmotic stress, UV light, growth factors,
`
`endotoxin and inflammatory cytokines. The p38 MAP kinase endotoxin and inflammatory cytokines. The p38 MAP kinase
`
`group is a MAP family of various isoforms, including group is a MAP family of various isoforms, including
`
`p38a, p38g and p38y, and is responsible for p38a, p38g and p38y, and is responsible for
`
`phosphorylating and activating transcription factors phosphorylating and activating transcription factors
`
`(e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. ATF2, CHOP and MEF2C) as well as other kinases
`
`(e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are
`
`activated by bacterial lipopolysaccharide, physical and activated by bacterial lipopolysaccharide, physical and
`
`chemical stress and by pro-inflammatory cytokines, chemical stress and by pro-inflammatory cytokines,
`
`including tumor necrosis factor (TNF-a) and interleukin-1 including tumor necrosis factor (TNF-a) and interleukin-1
`
`(IL-1). The products of the p38 phosphorylation mediate (IL-1). The products of the p38 phosphorylation mediate
`
`the production of inflammatory cytokines, including TNF the production of inflammatory cytokines, including TNF
`
`and IL-1, and cyclooxygenase-2. and IL-1, and cyclooxygenase-2.
`
`TNF-ce is a cytokine produced primarily by activated TNF-ce is a cytokine produced primarily by activated
`
`monocytes and macrophages. Excessive or unregulated TNF monocytes and macrophages. Excessive or unregulated TNF
`
`production has been implicated in mediating a number of production has been implicated in mediating a number of
`
`diseases. Recent studies indicate that TNF has a diseases. Recent studies indicate that TNF has a
`
`causative role in the pathogenesis of rheumatoid causative role in the pathogenesis of rheumatoid
`
`arthritis. Additional studies demonstrate that arthritis. Additional studies demonstrate that
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`Ex. 1012 - Page 3
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`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`
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`PCT/US98/11684 PCT/US98/11684
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`
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`2 2
`
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`inhibition of TNF has broad application in the treatment inhibition of TNF has broad application in the treatment
`
`of inflammation, inflammatory bowel disease, multiple of inflammation, inflammatory bowel disease, multiple
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`sclerosis and asthma. sclerosis and asthma.
`
`TNF has also been implicated in viral infections, TNF has also been implicated in viral infections,
`
`such as HIV, influenza virus, and herpes virus including such as HIV, influenza virus, and herpes virus including
`
`herpes simplex virus type-1 (HSV-1), herpes simplex virus herpes simplex virus type-1 (HSV-1), herpes simplex virus
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`type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster
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`virus (VZV), Epstein-Barr virus, human herpesvirus-6 virus (VZV), Epstein-Barr virus, human herpesvirus-6
`
`(HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8
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`(HHV-8), pseudorabies and rhinotracheitis, among others. (HHV-8), pseudorabies and rhinotracheitis, among others.
`
`IL-8 is another pro-inflammatory cytokine, which is IL-8 is another pro-inflammatory cytokine, which is
`
`produced by mononuclear cells, fibroblasts, endothelial produced by mononuclear cells, fibroblasts, endothelial
`
`cells, and keratinocytes, and is associated with cells, and keratinocytes, and is associated with
`
`conditions including inflammation. conditions including inflammation.
`
`IL-1 is produced by activated monocytes and IL-1 is produced by activated monocytes and
`
`macrophages and is involved in the inflammatory response. macrophages and is involved in the inflammatory response.
`
`IL-1 plays a role in many pathophysiological responses IL-1 plays a role in many pathophysiological responses
`
`including rheumatoid arthritis, fever and reduction of including rheumatoid arthritis, fever and reduction of
`
`bone resorption. bone resorption.
`
`TNF, IL-1 and IL-8 affect a wide variety of cells TNF, IL-1 and IL-8 affect a wide variety of cells
`
`and tissues and are important inflammatory mediators of a and tissues and are important inflammatory mediators of a
`
`wide variety of disease states and conditions. The wide variety of disease states and conditions. The
`
`inhibition of these cytokines by inhibition of the p38 inhibition of these cytokines by inhibition of the p38
`
`kinase is of benefit in controlling, reducing and kinase is of benefit in controlling, reducing and
`
`alleviating many of these disease states. alleviating many of these disease states.
`
`Various pyrazoles have previously been described. Various pyrazoles have previously been described.
`
`U.S. Patent No. 4,000,281, to Beiler and Binon, describes U.S. Patent No. 4,000,281, to Beiler and Binon, describes
`
`4,5-aryl/heteroaryl substituted pyrazoles with antiviral 4,5-aryl/heteroaryl substituted pyrazoles with antiviral
`
`activity against both RNA and DNA viruses such as activity against both RNA and DNA viruses such as
`
`myxoviruses, adenoviruses, rhinoviruses, and various myxoviruses, adenoviruses, rhinoviruses, and various
`
`viruses of the herpes group. WO 92/19615, published viruses of the herpes group. WO 92/19615, published
`
`November 12, 1992, describes pyrazoles as novel November 12, 1992, describes pyrazoles as novel
`
`fungicides. U.S. Patent No. 3,984,431, to Cueremy and fungicides. U.S. Patent No. 3,984,431, to Cueremy and
`
`Renault, describes derivatives of pyrazole-5-acetic acid Renault, describes derivatives of pyrazole-5-acetic acid
`
`as having anti-inflammatory activity. Specifically, [1- as having anti-inflammatory activity. Specifically, [1-
`
`isobuty1-3,4-dipheny1-1H-pyrazol-5-yl]acetic acid is isobuty1-3,4-dipheny1-1H-pyrazol-5-yl]acetic acid is
`
`
`
`5 (cid:9)5 (cid:9)
`
`
`
`10 (cid:9)10 (cid:9)
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`
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`15 (cid:9)15 (cid:9)
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`20 (cid:9)20 (cid:9)
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`
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`25 (cid:9)25 (cid:9)
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`30 (cid:9)30 (cid:9)
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`35 (cid:9)35 (cid:9)
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`Ex. 1012 - Page 4
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`
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`
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`PCT/US98/11684 PCT/US98/11684
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`
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`3 3
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`
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`5 (cid:9)5 (cid:9)
`
`
`described. U. S. Patent No. 3,245,093 to Hinsgen et al, described. U. S. Patent No. 3,245,093 to Hinsgen et al,
`
`describes a process for preparing pyrazoles. WO describes a process for preparing pyrazoles. WO
`
`83/00330, published February 3, 1983, describes a new 83/00330, published February 3, 1983, describes a new
`
`process for the preparation of diphenyl-3,4-methyl-5- process for the preparation of diphenyl-3,4-methyl-5-
`
`pyrazole derivatives. WO 95/06036, published March 2, pyrazole derivatives. WO 95/06036, published March 2,
`
`1995, describes a process for preparing pyrazole 1995, describes a process for preparing pyrazole
`
`derivatives. U.S. patent 5,589,439, to T. Goto, et al., derivatives. U.S. patent 5,589,439, to T. Goto, et al.,
`
`describes tetrazole derivatives and their use as describes tetrazole derivatives and their use as
`
`herbicides. EP 515041 describes pyrimidyl substituted herbicides. EP 515041 describes pyrimidyl substituted
`
`pyrazole derivatives as novel agricultural fungicides. pyrazole derivatives as novel agricultural fungicides.
`
`Japanese Patent 4,145,081 describes pyrazolecarboxylic Japanese Patent 4,145,081 describes pyrazolecarboxylic
`
`acid derivatives as herbicides. Japanese Patent acid derivatives as herbicides. Japanese Patent
`
`5,345,772 describes novel pyrazole derivatives as 5,345,772 describes novel pyrazole derivatives as
`
`inhibiting acetylcholinesterase. inhibiting acetylcholinesterase.
`
`Pyrazoles have been described for use in the Pyrazoles have been described for use in the
`
`treatment of inflammation. Japanese Patent 5,017,470 treatment of inflammation. Japanese Patent 5,017,470
`
`describes synthesis of pyrazole derivatives as anti-describes synthesis of pyrazole derivatives as anti-
`
`inflammatory, anti-rheumatic, anti-bacterial and anti-inflammatory, anti-rheumatic, anti-bacterial and anti-
`
`viral drugs. EP 115640, published December 30, 1983, viral drugs. EP 115640, published December 30, 1983,
`
`describes 4-imidazolyl-pyrazole derivatives as inhibitors describes 4-imidazolyl-pyrazole derivatives as inhibitors
`
`of thromboxane synthesis. 3-(4-Isopropy1-1-of thromboxane synthesis. 3-(4-Isopropy1-1-
`
`methylcyclohex-1-y1)-4-(imidazol-1-y1)-1H-pyrazole is methylcyclohex-1-y1)-4-(imidazol-1-y1)-1H-pyrazole is
`
`specifically described. WO 97/01551, published January specifically described. WO 97/01551, published January
`
`16, 1997, describes pyrazole compounds as adenosine 16, 1997, describes pyrazole compounds as adenosine
`
`25 antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-25 antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-
`
`phenylpyrazole is specifically described. U.S. Patent phenylpyrazole is specifically described. U.S. Patent
`
`No. 5,134,142, to Matsuo et al. describes 1,5-diaryl No. 5,134,142, to Matsuo et al. describes 1,5-diaryl
`
`pyrazoles as having anti-inflammatory activity. pyrazoles as having anti-inflammatory activity.
`
`U.S. Patent No. 5,559,137 to Adams et al, describes U.S. Patent No. 5,559,137 to Adams et al, describes
`
`novel pyrazoles (1,3,4,-substituted) as inhibitors of novel pyrazoles (1,3,4,-substituted) as inhibitors of
`
`cytokines used in the treatment of cytokine diseases. cytokines used in the treatment of cytokine diseases.
`
`Specifically, 3-(4-fluoropheny1)-1-(4-Specifically, 3-(4-fluoropheny1)-1-(4-
`
`methylsulfinylpheny1)-4-(4-pyridy1)-5H-pyrazole is methylsulfinylpheny1)-4-(4-pyridy1)-5H-pyrazole is
`
`described. WO 96/03385, published February 8, 1996, described. WO 96/03385, published February 8, 1996,
`
`describes 3,4-substituted pyrazoles, as having anti- describes 3,4-substituted pyrazoles, as having anti-
`
`inflammatory activity. Specifically, 4-[1-ethy1-4-(4- inflammatory activity. Specifically, 4-[1-ethy1-4-(4-
`
`
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`10 (cid:9)10 (cid:9)
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`15 (cid:9)15 (cid:9)
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`20 (cid:9)20 (cid:9)
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`30 (cid:9)30 (cid:9)
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`35 (cid:9)35 (cid:9)
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`Ex. 1012 - Page 5
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`(cid:9)
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`PCT/US98/11684 PCT/US98/11684
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`4 4
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`pyridy1)-5-trifluoromethy1-1H-pyrazol-3-pyridy1)-5-trifluoromethy1-1H-pyrazol-3-
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`yl]benzenesulfonamide is described. yl]benzenesulfonamide is described.
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`The invention's pyrazolyl compounds are found to The invention's pyrazolyl compounds are found to
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`show usefulness as p38 kinase inhibitors. show usefulness as p38 kinase inhibitors.
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`5 5
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`Description of the Invention Description of the Invention
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`A class of substituted pyrazolyl compounds useful in A class of substituted pyrazolyl compounds useful in
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`treating p38 mediated disorders is defined by Formula I: treating p38 mediated disorders is defined by Formula I:
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`
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`(ID (ID
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`
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`10 10
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`wherein wherein
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`R1 is selected from hydrido, alkyl, cycloalkyl, R1 is selected from hydrido, alkyl, cycloalkyl,
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`alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl,
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`cycloalkylalkylene, cycloalkenylalkylene, haloalkyl, cycloalkylalkylene, cycloalkenylalkylene, haloalkyl,
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`15 hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, 15 hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl,
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`aralkenyl, aralkynyl, heterocyclylalkylene, alkoxyalkyl, aralkenyl, aralkynyl, heterocyclylalkylene, alkoxyalkyl,
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`aryloxyalkyl, heterocyclyloxyalkyl, mercaptoalkyl, aryloxyalkyl, heterocyclyloxyalkyl, mercaptoalkyl,
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`mercaptoaryl, mercaptoheterocyclyl, alkylthioalkylene, mercaptoaryl, mercaptoheterocyclyl, alkylthioalkylene,
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`arylthioalkylene, amino, alkylamino, arylamino, arylthioalkylene, amino, alkylamino, arylamino,
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`aminoalkyl, aminoaryl, alkylaminoalkylene, and aminoalkyl, aminoaryl, alkylaminoalkylene, and
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`heterocyclylalkylene; and heterocyclylalkylene; and
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`Q is selected from oxy, thio, alkylene, alkenylene, Q is selected from oxy, thio, alkylene, alkenylene,
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`alkynylene, sulfinyl, sulfonyl, alkynylene, sulfinyl, sulfonyl,
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`
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`20 (cid:9)20 (cid:9)
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`Ex. 1012 - Page 6
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`PCT/US98/11684 PCT/US98/11684
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`0 0
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`
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`OH OH
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`5 5
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`R s R s
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`
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`R 7 R R 7 R
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`0 0 0 0
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`
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`;and ;and
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`
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`10/ 10/
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`
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`p i2 p i2
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`
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`—N- —N-
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`
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`wherein wherein
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`5 5
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`
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`10 (cid:9)10 (cid:9)
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`
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`15 (cid:9)15 (cid:9)
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`represents a four to eight membered ring represents a four to eight membered ring
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`heterocyclylidenyl comprising one or more heteroatoms heterocyclylidenyl comprising one or more heteroatoms
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`selected from oxygen, sulfur and nitrogen; and selected from oxygen, sulfur and nitrogen; and
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`wherein n is an integer from 1 to 7; and wherein n is an integer from 1 to 7; and
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`R2 is aryl optionally substituted with one or more R2 is aryl optionally substituted with one or more
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`radicals independently selected from halo, alkyl, radicals independently selected from halo, alkyl,
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`alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, alkenoxy, alkenyl, alkynyl, aryl, heterocyclyl, alkoxy, alkenoxy,
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`alkynoxy, aryloxy, heterocyclyloxy, aralkoxy, alkylthio, alkynoxy, aryloxy, heterocyclyloxy, aralkoxy, alkylthio,
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`arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl,
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`arylsulfonyl, amino, alkylamino, alkenylamino, arylsulfonyl, amino, alkylamino, alkenylamino,
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`Ex. 1012 - Page 7
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`PCT/US98/11684 PCT/US98/11684
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`6 6
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`
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`5 (cid:9)5 (cid:9)
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`
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`10 (cid:9)10 (cid:9)
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`alkynylamino, arylamino, heterocyclylamino, aminoalkyl, alkynylamino, arylamino, heterocyclylamino, aminoalkyl,
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`aminocarbonyl, cyano, hydroxyl, hydroxyalkyl, aminocarbonyl, cyano, hydroxyl, hydroxyalkyl,
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`alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,
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`formyl, nitro, nitroalkyl, alkylcarbonylamino, formyl, nitro, nitroalkyl, alkylcarbonylamino,
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`arylcarbonylamino, haloalkylsulfinyl, haloalkylsulfonyl, arylcarbonylamino, haloalkylsulfinyl, haloalkylsulfonyl,
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`alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, and alkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, and
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`haloalkyl; and haloalkyl; and
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`R3 is heteroaryl optionally substituted with one or R3 is heteroaryl optionally substituted with one or
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`more radicals independently selected from halo, alkyl, more radicals independently selected from halo, alkyl,
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`alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino,
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`aminocarbonyl, cyano, hydroxyl, alkoxycarbonyl, formyl, aminocarbonyl, cyano, hydroxyl, alkoxycarbonyl, formyl,
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`aralkyl, aralkyloxy, aralkylthio, aralkylamino, aralkyl, aralkyloxy, aralkylthio, aralkylamino,
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`aminosulfonyl, alkylamino, nitro, arylamino, aminosulfonyl, alkylamino, nitro, arylamino,
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`alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl
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`and alkylcarbonyl; and and alkylcarbonyl; and
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`R4 is selected from hydrido, alkyl, aryl, haloalkyl, R4 is selected from hydrido, alkyl, aryl, haloalkyl,
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`heterocyclyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxy, heterocyclyl, cycloalkyl, alkenyl, cycloalkenyl, alkoxy,
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`alkylthio, arylthio, carboxy, alkoxycarbonyl, alkylthio, arylthio, carboxy, alkoxycarbonyl,
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`carboxyalkyl, alkoxycarbonylalkylene, heterocyclylalkyl, carboxyalkyl, alkoxycarbonylalkylene, heterocyclylalkyl,
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`amino, alkylamino, alkynylamino, arylamino, amino, alkylamino, alkynylamino, arylamino,
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`heterocyclylamino, heterocyclylalkylamino, heterocyclylamino, heterocyclylalkylamino,
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`heterocyclylaminoalkyl, and aminoheterocyclylamino; heterocyclylaminoalkyl, and aminoheterocyclylamino;
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`wherein the aryl, heterocyclyl, cycloalkyl, cycloalkenyl wherein the aryl, heterocyclyl, cycloalkyl, cycloalkenyl
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`groups are optionally substituted with one or more groups are optionally substituted with one or more
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`radicals independently selected from halo, amino, alkyl, radicals independently selected from halo, amino, alkyl,
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`alkenyl, alkynyl, alkoxy, aryloxy, aralkoxy, haloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, aralkoxy, haloalkyl,
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`and alkylamino; and wherein the amino radicals of the and alkylamino; and wherein the amino radicals of the
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`heterocylcylalkylamino and heterocylcylaminoalkyl group heterocylcylalkylamino and heterocylcylaminoalkyl group
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`are optionally substituted with one or more alkyl; and are optionally substituted with one or more alkyl; and
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`R6 is selected from hydrido, alkyl, alkenyl, and R6 is selected from hydrido, alkyl, alkenyl, and
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`alkynyl; and alkynyl; and
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`R' and R8 are independently selected from hydrido, R' and R8 are independently selected from hydrido,
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`alkyl, alkenyl, and alkynyl, or together form a alkyl, alkenyl, and alkynyl, or together form a
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`carbocyclic or heterocyclic ring having three to eight carbocyclic or heterocyclic ring having three to eight
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`35 members; and 35 members; and
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`15 (cid:9)15 (cid:9)
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`20 (cid:9)20 (cid:9)
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`25 (cid:9)25 (cid:9)
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`30 (cid:9)30 (cid:9)
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`Ex. 1012 - Page 8
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`PCT/US98/11684 PCT/US98/11684
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`7 7
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`R9 is selected from hydrido, alkyl, alkenyl, and R9 is selected from hydrido, alkyl, alkenyl, and
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`alkynyl; and alkynyl; and
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`R" is selected from hydrido, alkyl, alkenyl, and R" is selected from hydrido, alkyl, alkenyl, and
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`alkynyl; and alkynyl; and
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`Ril is selected from hydrido, alkyl, alkenyl, and Ril is selected from hydrido, alkyl, alkenyl, and
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`alkynyl; and alkynyl; and
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`RI' is selected from hydrido and alkyl; or RI' is selected from hydrido and alkyl; or
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`a pharmaceutically-acceptable salt or tautomer a pharmaceutically-acceptable salt or tautomer
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`thereof. thereof.
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`Compounds of Formula I would be useful for, but not Compounds of Formula I would be useful for, but not
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`limited to, the treatment of any disorder or disease limited to, the treatment of any disorder or disease
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`state in a human, or other mammal, which is exacerbated state in a human, or other mammal, which is exacerbated
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`or caused by excessive or unregulated TNF or p38 kinase or caused by excessive or unregulated TNF or p38 kinase
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`production by such mammal. Accordingly, the present production by such mammal. Accordingly, the present
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`invention provides a method of treating a cytokine-invention provides a method of treating a cytokine-
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`mediated disease which comprises administering an mediated disease which comprises administering an
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`effective cytokine-interfering amount of a compound of effective cytokine-interfering amount of a compound of
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`Formula I, or a pharmaceutically acceptable salt or Formula I, or a pharmaceutically acceptable salt or
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`tautomer thereof. tautomer thereof.
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`Compounds of Formula I would be useful for, but not Compounds of Formula I would be useful for, but not
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`limited to, the treatment of inflammation in a subject, limited to, the treatment of inflammation in a subject,
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`and for use as antipyretics for the treatment of fever. and for use as antipyretics for the treatment of fever.
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`Compounds of the invention would be useful to treat Compounds of the invention would be useful to treat
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`arthritis, including but not limited to, rheumatoid arthritis, including but not limited to, rheumatoid
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`arthritis, spondyloarthropathies, gouty arthritis, arthritis, spondyloarthropathies, gouty arthritis,
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`osteoarthritis, systemic lupus erythematosus and juvenile osteoarthritis, systemic lupus erythematosus and juvenile
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`arthritis, osteoarthritis, gouty arthritis and other arthritis, osteoarthritis, gouty arthritis and other
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`arthritic conditions. Such compounds would be useful for arthritic conditions. Such compounds would be useful for
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`the treatment of pulmonary disorders or lung the treatment of pulmonary disorders or lung
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`inflammation, including adult respiratory distress inflammation, including adult respiratory distress
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`syndrome, pulmonary sarcoidosis, asthma, silicosis, and syndrome, pulmonary sarcoidosis, asthma, silicosis, and
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`chronic pulmonary inflammatory disease. The compounds chronic pulmonary inflammatory disease. The compounds
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`are also useful for the treatment of viral and bacterial are also useful for the treatment of viral and bacterial
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`infections, including sepsis, septic shock, gram negative infections, including sepsis, septic shock, gram negative
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`sepsis, malaria, meningitis, cachexia secondary to sepsis, malaria, meningitis, cachexia secondary to
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`5 (cid:9)5 (cid:9)
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`10 10
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`15 (cid:9)15 (cid:9)
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`20 (cid:9)20 (cid:9)
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`25 (cid:9)25 (cid:9)
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`30 (cid:9)30 (cid:9)
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`35 (cid:9)35 (cid:9)
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`Ex. 1012 - Page 9
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`WO 98/52941 (cid:9)WO 98/52941 (cid:9)
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`PCT/US98/11684 PCT/US98/11684
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`8 8
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`infection or malignancy, cachexia secondary to acquired infection or malignancy, cachexia secondary to acquired
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`immune deficiency syndrome (AIDS), AIDS, ARC (AIDS immune deficiency syndrome (AIDS), AIDS, ARC (AIDS
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`related complex), pneumonia, and herpesvirus. The related complex), pneumonia, and herpesvirus. The
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`compounds are also useful for the treatment of bone compounds are also useful for the treatment of bone
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`resorption diseases, such as osteoporosis, endotoxic resorption diseases, such as osteoporosis, endotoxic
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`shock, toxic shock syndrome, reperfusion injury, shock, toxic shock syndrome, reperfusion injury,
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`autoimmune disease including graft vs. host reaction and autoimmune disease including graft vs. host reaction and
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`allograft rejections, cardiovascular diseases including allograft rejections, cardiovascular diseases including
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`atherosclerosis, thrombosis, congestive heart failure, atherosclerosis, thrombosis, congestive heart failure,
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`and cardiac reperfusion injury, renal reperfusion injury, and cardiac reperfusion injury, renal reperfusion injury,
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`liver disease and nephritis, and myalgias due to liver disease and nephritis, and myalgias due to
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`infection. The compounds are also useful for the infection. The compounds are also useful for the
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`treatment of influenza, multiple sclerosis, cancer, treatment of influenza, multiple sclerosis, cancer,
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`diabetes, systemic lupus erthrematosis (SLE), skin- diabetes, systemic lupus erthrematosis (SLE), skin-
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`related conditions such as psoriasis, eczema, burns, related conditions such as psoriasis, eczema, burns,
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`dermatitis, keloid formation, and scar tissue formation. dermatitis, keloid formation, and scar tissue formation.
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`Compounds of the invention also would be useful to treat Compounds of the invention also would be useful to treat
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`gastrointestinal conditions such as inflammatory bowel gastrointestinal conditions such as inflammatory bowel
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`disease, Crohn's disease, gastritis, irritable bowel disease, Crohn's disease, gastritis, irritable bowel
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`syndrome and ulcerative colitis. The compounds would syndrome and ulcerative colitis. The compounds would
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`also be useful in the treatment of ophthalmic diseases, also be useful in the treatment of ophthalmic diseases,
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`such as retinitis, retinopathies, uveitis, ocular such as retinitis, retinopathies, uveitis, ocular
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`photophobia, and of acute injury to the eye tissue. photophobia, and of acute injury to the eye tissue.
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`Compounds of the invention also would be useful for Compounds of the invention also would be useful for
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`