OA12981A - Substituted pyrazoles as p38 kinase inhibitors. - Google Patents

Substituted pyrazoles as p38 kinase inhibitors. Download PDF

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OA12981A
OA12981A OA9900252A OA9900252A OA12981A OA 12981 A OA12981 A OA 12981A OA 9900252 A OA9900252 A OA 9900252A OA 9900252 A OA9900252 A OA 9900252A OA 12981 A OA12981 A OA 12981A
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pyrazol
alkyl
methyl
aryl
heterocyclyl
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OA9900252A
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Ashok Anantanarayan
Michael Clare
Paul W Collins
Joyce Zuowu Crich
Rajesh Devraj
Daniel L Flynn
Lifeng Geng
Gunnar J Hanson
Francis J Koszyk
Shuyuan Liao
Richard A Partis
Shashidhar N Rao
Shaun Raj Selness
Michael S South
Michael A Stealey
Richard M Weier
Xiangdong Xu
Ish K Kanna
Yi Yu
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Searle & Co
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Abstract

A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula (I) wherein R<1>, R<2>, R<3> and R<4> are as described in the specification.

Description

G1 29 8 1
Cross-Referen.ee to Related Application
This application daims priority from U. S.
Provisional Application Serial No. 60/047,570 filed May 22, 1997.
Field of the Invention
This invention relates to a novel group of pyrazolecompounds, compositions and methods for treating p38kinase mediated disorders.
Backqround of the Invention
Mitogen-activated protein kinases (MAP) is a familyof proline-directed serme/threonine kinases thatactivate their substrates by dual phosphorylation. Thekinases are acti'-ated by a variety of signais includingnutritional and osmot.'.c stress, UV light, growth factors,endotoxin and inflammatory cytokines The p3 8 MAP kinasegroup is a MAP family of various isoforms, includingρ38α, ρ38β and p38-y, and is responsable forphosphorylâting and activating transcription factors(e.g. ATF2, CHOP and MEF2C) as well as other kinases(e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms areactivated by bacterial lipopolysaccharide, physical andChemical stress and by pro-inflammatory cytokines,including tumor necrosis factor (TNF-α) and interleukin-1(IL-1). The products of the p38 phosphorylation médiatethe production of inflammatory cytokines, including TNFand IL-1, and cyclooxygenase-2. TNF-a is a cytokine produced primarily by activatedmonocytes and macrophages. Excessive or unregulated TNFproduction has been implicated in mediating a number ofdiseases. Recent studies indicate that TNF has acausative rôle in the pathogenesis of rheumatoid 01298 1 2 arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma. TNF has also been implicated in viral infections,such as HIV, influenza virus, and herpes virus includingherpes simplex virus type-1 (HSV-1), herpes simplex virustype-2 (HSV-2), cytomégalovirus (CMV), varicella-zostervirus (VZV), Epstein-Barr virus, human herpesvirus-6(HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8(HHV-8), pseudorabies and rhinotracheitis, among others. IL-8 is another pro-inflammatory cytokine, which isproduced by mononuclear cells, fibroblasts, endothélialcells, and kératinocytes, and is associated withconditions including inflammation. IL-1 is produced by activated monocytes andmacrophages and is involved in the inflammatory response.IL-1 plays a rôle in many pathophysiological responsesincluding rheumatoid arthritis, fever and réduction ofbone résorption. TNF, IL-1 and IL-8 affect a wide variety of cellsand tissues and are important inflammatory mediators of awide variety of disease States and conditions. Theinhibition of these cytokines by inhibition of the p38kinase is of benefit in controlling, reducing andalleviating many of these disease States.
Various pyrazoles hâve previously been described. U.S. Patent No. 4,000,281, to Beiler and Binon, describes 4,5-aryl/heteroaryl substituted pyrazoles with antiviralactivity against both RNA and DNA viruses such asmyxoviruses, adenoviruses, rhinoviruses, and variousviruses of the herpes group. WO 92/19615, publishedNovember 12, 1992, describes pyrazoles as novel fungicides. U. S. Patent No. 3,984,431, to Cueremy andRenault, describes dérivatives of pyrazole-5-acetic acidas having anti-inflammatory activity. Specifically, [1- 01298 1- 3 isobutyl-3,4-diphenyl-lH-pyrazol-5-yl]acetic acid isdescribed. U. S. Patent No. 3,245,093 to Hinsgen et al,describes a process for preparing pyrazoles. WO83/00330, published February 3, 1983, describes a newprocess for the préparation of diphenyl-3,4-methyl-5-pyrazole dérivatives. WO 95/06036, published March 2,1995, describes a process for preparing pyrazoledérivatives. US patent 5,589,439, to T. Goto, et al.,describes tetrazole dérivatives and their use asherbicides. EP 515,041 describes pyrimidyl substitutedpyrazole dérivatives as novel agricultural fungicides.Japanese Patent 4,145,081 describes pyrazolecarboxylicacid dérivatives as herbicides. Japanese Patent5,345,772 describes novel pyrazole dérivatives asinhibiting acetylcholinesterase.
Pyrazoles hâve been described for use in thetreatment of inflammation. Japanese Patent 5,017,470describes synthesis of pyrazole dérivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec 30, 1983,describes 4-imidazolyl-pyrazole dérivatives as inhibitorsof thromboxane synthesis. 3-(4-Isopropyl-l- methylcyclohex-l-yl)-4-(imidazol-l-yl)-ΙΗ-pyrazole isspecifically described. WO 97/01551, published Jan 16,1997, describes pyrazole compounds as adenosineantagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specifically described. U.S. PatentNo. 5,134,142, to Matsuo et al. describes 1,5-diarylpyrazoles as having anti-inflammatory activity. U.S. Patent No. 5,559,137 to Adams et al, describesnovel pyrazoles (1,3,4,-substituted) as inhibitors ofcytokines used in the treatment of cytokine diseases.Specifically, 3-(4-fluorophenyl)-l-(4- methylsuifinylphenyl)-4-(4-pyridyl)-5H-pyrazole isdescribed. WO 96/03385, published February 8, 1996,describes 3,4-substituted pyrazoles, as having anti- 01298 1 4 inflammatory activity. Specifically, 4-[l-ethyl-4-(4- pyr idy 1 ) - 5 - tri f luoromethyl - 1H -pyra zol - 3 - yl)benzenesulfonamide is described.
The invention's pyrazolyl compounds are found to 5 show usefulness as p38 kinase inhibitors.
Description of the Invention A class of substituted pyrazolyl compounds useful in10 treating p38 mediated disorders is defined by Formula I:
H
(I) wherein R1 is selected from hydrido, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, 15 cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl,haloalkynyl, hydroxyalkyl, hydroxyalkenyl,hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl,arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, 20 alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl,alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino,alkenylamino, alkynylamino, arylamino, heterocyclylamino, 25 alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl,alkenylsuifonyl, alkynylsulfonyl, arylsulfonyl,heterocyclylsuifonyl, alkylaminoalkylene, 01298 î 5 alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, hèterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene,arylcarbonylarylene, heterocyclylcarbonylarylene,alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene,heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene,arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; orR1 has the formula (II) from 0 to 9;
H wherein: i is an integer R25 is selected from hydrogen, alkyl, aralkyl,heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylaminoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkylalkylene, aralkyl,alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl,aryl, heterocyclyl, aralkyl, cycloalkylalkylene,cycloalkenylalkylene, cycloalkylarylene, cycloalkylcyeloalkyl, heterocyclylalkylene, alkylarylene,alkylaralkyl, aralkylarylene, alkylheterocyclyl,alkylheterocyclylalkylene, alkylheterocyclylarylene,aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene,alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene,aryloxyarylene, aralkoxyarylene, 01 298 1 6 alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene,arylaminocarbonylalkylene, alkylaminocarbonylalkylene,arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene,arylcarbonylarylene, alkylarylcarbonylarylene,alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene,cycloalkylthioalkylene, alkylthioarylene,aralkylthioarylene, heterocyclylthioarylene,arylthioalklylarylene, arylsulfonylaminoalkylene,alkylsulfonylarylene, alkylaminosulfonylarylene; whereinsaid alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl,heterocyclylalkylene, alkylheterocyclylarylene,alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene,aryloxycarbonylarylene, arylcarbonylarylene,alkylthioarylene, heterocyclylthioarylene,arylthioalklylarylene, and alkylsulfonylarylene groupsare optionally substituted with one or more radicalsindependently selected from alkyl, halo, haloalkyl,alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29is selected from aralkyl, aralkoxyalkylene,heterocyclylalkylene, alkylheterocyclylalkylene,alkoxycarbonylalkylene, alkylthioalkylene, andaralkylthioalkylene; wherein said aralkyl andheterocylcyl groups are optionally substituted with oneor more radicals independently selected from alkyl andnitro; or R26 and R27 together with the nitrogen atom to whichthey are attached form a heterocycle, wherein saidheterocycle is optionally substituted with one or more 01298-1 7 radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl,alkoxycarbonyl, aralkoxycarbonyl, alkylamino andalkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals areoptionally substituted with one or more radicalsindependently selected from halogen, alkyl and alkoxy;and B2 is selected from hydrido, halogen, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl,aralkyl, alkylheterocyclyl, heterocyclylalkyl,alkylamino, alkenylamino, alkynylamino, arylamino,heterocyclylamino, heterocyclylalkylamino, aralkylamino,aminoalky1, aminoaryl,.aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene,alkylaminoarylene, alkylaminoalkylamino, cycloalkyl,cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,arylthio, heterocyclylthio, carboxy, carboxyalkyl,carboxycycloalkyl, carboxycycloâlkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl,alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl,alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino,alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;wherein the aryl, heterocyclyl, heterocyclylalkyl,cycloalkyl and cycloalkenyl groups are optionallysubstituted with one or more radicals independentlyselected from halo, keto, amino, alkyl, alkenyl, alkynyl,aryl, heterocyclyl, aralkyl, heterocyclylalkyl,epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy,aralkoxy, haloalkyl, alkylamino, alkynylamino,alkylaminoalkylamino, heterocyclylalkylamino,alkylcarbonyl, alkoxycarbonyl, alkylsuifonyl,arylsulfonyl, and aralkylsulfonyl; or R2 has the formula: 01298 1 8
-C — CCHjPj- R3·· (III) wherein: j is an integer from 0 to 8 ; andm is 0 or 1 ; and R30 and R31 are independently selected from hydrogen,alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl,heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylaminoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; R33 is selected from hydrogen, alkyl, -C(O)R35,-C(O)OR35, -SO2R36, -C(O)NR37R30, and -SO2NR39R40, wherein R35,R36, R37, R30, R39 and R40 are independently selected fromhydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl,alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl,quinolinyl, purinyl, c
; and (IV) (V) 9 wherein R43 is selected from hydrogen, alkyl,aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl andpurinyl groups are optionally substituted with one ormore radicals independently selected from halo, alkyl,aralkyl, aralkenyl, arylheterocyclyl, carboxy,carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,aralkoxy, heterocyclylalkoxy, amino, alkylamino,alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl,aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino,aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl,alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R4S wherein R44 is alkylcarbonyl oramino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, whereinR4 is optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, alkylthio, arylthio,alkylthioalkylene, arylthioalkylene, alkylsulfinyl,alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene,arylsuifonylalkylene, alkoxy, aryloxy, aralkoxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,nitro, alkylamino, arylamino, alkylaminoalkylene,arylaminoalkylene, aminoalkylamino, and hydroxy; provided R3 is not 2-pyridinyl when R4 is a phenyl 012981 10 ring containing a 2-hydroxy substituent and when R1 ishydrido; further provided R2 is selected from aryl,heterocyclyl, unsubstituted cycloalkyl and cycloalkenylwhen R4 is hydrido; and further provided R4 is notmethylsulfonylphenyl; or a pharmaceutically-acceptable sait or tautomerthereof,
Compounds of Formula I would be useful for, but notlimited to, the treatment of any disorder or diseaseState in a human, or other mammal, which is excacerbatedor caused by excessive or unregulated TNF or p38 kinaseproduction by such mammal. Accordingly, the présentinvention provides a method of treating a cytokine-mediated disease which comprises administering aneffective cytokine-interfering amount of a compound ofFormula I or a pharmaceutically acceptable sait thereof.
Compounds of Formula I would be useful for, but notlimited to, the treatment of inflammation in a subject,and for use as antipyretics for the treatment of fever.Compounds of the invention would be useful to treatarthritis, including but not limited to, rheumatoidarthritis, spondyloarthropathies, gouty arthritis,osteoarthritis, systemic lupus erythematosus and juvénilearthritis, osteoarthritis, gouty arthritis and otherarthritic conditions. Such compounds would be useful forthe treatment of pulmonary disorders or lung inflammation, including adult respiratory distresssyndrome, pulmonary sarcoisosis, asthma, silicosis, andchronic pulmonary inflammatory disease. The compoundsare also useful for the treatment of viral and bacterialinfections, including sepsis, septic shock, gram négativesepsis, malaria, meningitis, cachexia secondary toinfection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated çomplex), pneumonia, and herpesvirus. The 012981 11 compounds are also useful for the treatment of bonerésorption diseases, such as osteoporosis, endotoxicshock, toxic shock syndrome, reperfusion injury,autoimmune disease inclüding graft vs. host reaction and 5 allograft rejections, cardiovascular diseases inclüdingathéroscléroses, thrombosis, congestive heart failure,and cardiac reperfusion injury, rénal reperfusion injury,liver disease and nephritis, and myalgias due toinfection. The compounds are also useful for the 10 treatment of influenza, multiple sclérosés, cancer,diabètes, systemic lupus erthrematosis (SLE), skin-related conditions such as psoriasis, eczema, burns,dermatitis, keloid formation, scar tissue formation, andangiogenic disorders. Compounds of the invention also 15 would be useful to treat gastrointestinal conditions suchas inflammatory bowel disease, Crohn's disease,gastritis, irritable bowel syndrome and ulcérâtivecolitis. The compounds would also be useful in thetreatment of ophthalmic diseases, such as retinitis, 20 rétinopathies, uveitis, ocular photophobia, and of acuteinjury to the eye tissue. Compounds of the inventionalso would be useful for treatment of angiogenesis,inclüding neoplasia; metastasis; ophthalmologicalconditions such as corneal graft rejection, ocular 25 neovascularization, retinal neovascularization inclüdingneovascularization following injury or infection,diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; ulceràtive diseases such as gastriculcer; pathological, but non-malignant, conditions such 30 as hemaginomas, inclüding invantile hemaginomas, angiofibroma of the nasopharynx and avascular nécrosés ofbone; diabetic nephropathy and cardiomyopathy; anddisorders of the female reproductive System such asendometriosis. The compounds of the invention may also 35 be useful for preventing the production ofcyclooxygenase-2. 0 1298 1 12
Besides being useful for human treatment, thesecompounds are also useful for veterinary treatment ofcompanion animais, exotic animais and farm animais,including mammals, rodents, and the like. More preferredanimais include horses, dogs, and cats.
The présent compounds may also be used in co-therapies, partially or completely, in place of otherconventional anti-inflammatories, such as together withsteroids, cyclooxygenase-2 inhibitors, DMARD's,immunosuppressive agents, NSAIDs, 5-lipoxygenaseinhibitors, LTB4 antagonists and LTA4 hydrolaseinhibitors.
As used herein, the term "TNF médiated disorder"refers to any and ail disorders and disease States inwhich TNF plays a rôle, either by control of TNF itself,or by TNF causing another monokine to be relêased, suchas but not limited to IL-1, IL-6 or IL-8. A disease Statein which, for instance, IL-1 is a major component, andwhose production or action, is exacerbâted or secreted inresponse to TNF, would therefore be considered a disordermediated by TNF.
As used herein, the term "p38 mediated disorder"refers to any and ail disorders and disease States inwhich p38 plays a rôle, either by control of p38 itself,or by p38 causing another factor to be released, such asbut not limited to IL-1, IL-6 or IL-8. A disease Statein which, for instance, IL-1 is a major component, andwhose production or action, is exacerbated or secreted inresponse to p38, would therefore be considered a disordermediated by p3 8.
As TNF-β has close structural homology with TNF-a(also known as cachectin) and since each induces similarbiologie responses and binds to the same cellularreceptor, the synthesis of both TNF-α and TNF-/? areinhibited by the compounds of the présent invention andthus are herein referred to collectively as "TNF" unless 01298 î o y '
- C_N ,26 ,27 (II) 13 specifically delineated otherwise. A preferred class of compounds consista of those compounds of Formula I wherein R1 is selected from hydrido, lower alkyl, lower 5 cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl,lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl,lower mercaptoalkyl, lower alkylthioalkylene, amino,lower alkylamino, lower arylamino, lower 10 alkylaminoalkylene, and lower heterocyclylalkylene; orR1 has the formulaR25
-f-CCHPiH wherein: i is 0, 1 or 2 ; and 15 R25 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, loweralkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl,lower alkylaminoalkyl, lower phenoxyaminoalkyl, loweralkylcarbonylalkylene, lower phenoxycarbonylalkylene, and 20 lower heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lowerphenylalkyl, lower alkoxycarbonylalkylene, and loweralkylaminoalkyl; and 25 R27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl andnaphthyl, lower heterocyclyl, lower phenylalkyl, lowercycloalkylalkylene, lower cycloalkenylalkylene, lowercycloalkylarylene, lower cycloalkylcycloalkyl, lower 30 heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, loweralkylheterocyclyl, lower alkylheterocyclylalkylene, lower 012981 14 alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, loweralkoxyphenylene, lower alkoxyphenylalkyl, loweralkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lowerphenoxyphenylene, lower phenylalkoxyphenylene, loweralkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene,lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, loweralkoxyphenylaminocarbonylalkylene, loweraminocarbonylalkylene, arylaminocarbonylalkylene, loweralkylaminocarbonylalkylene, lower phenylcarbonylalkylene,lower alkoxycarbonylphenylene, lowerphenoxycarbonylphenylene, loweralkylphenoxycarbonylphenylene, lowerphenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, loweralkoxycarbonylheterocyclylphenylene, loweralkoxycarbonylalkoxylphenylene, lowerheterocyclylcarbonylalkylphenylene, loweralkylthioalkylene, cycloalkylthioalkylene, loweralkylthiophenylene, lower phenylalkylthiophenylene, lowerheterocyclylthiophenylene, lower phenylthioalklylphenylene, lowerphenylsulfonylaminoalkylene, loweralkylsulfonylphenylene, lower alkylaminosulfonylphenylene; wherein said lower alkyl,lower cycloalkyl, aryl selected from phenyl, biphenyl andnaphthyl, lower heterocyclyl, lower phenylalkyl, lowerheterocyclylalkylene, lower alkylheterocyclylphenylene,lower alkoxyphenylene, lower phenoxyphenylene, lowerphenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene,lower alkylthiophenylene, lower- 0.1298 1 15 heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene groupa are optionally substitutedwith one or more radicals independently selected fromlower alkyl, halo, lower haloalkyl, lower alkoxy, keto,amino, nitro, and cyano; or R27 is -CHR46R47 wherein R46 is lower alkoxycarbonyl,and R47 is selected from lower phenylalkyl, lowerphenylalkoxyalkylene, lower heterocyclylalkylene, loweralkylheterocyclylalkylene, lower alkoxycarbonylalkylene,lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl andheterocylcyl groupa are optionally substituted with oneor more radicals independently selected from lower alkyland nitro; or R26 and R27 together with the nitrogen atom to whichthey are attached form a 4-8 membered ring heterocycle,wherein said heterocycle is optionally substituted withone or more radicals independently selected from loweralkyl, aryl selected from phenyl, biphenyl and naphthyl,heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, loweralkoxyphenylene, lower alkylphenoxyalkylene, loweralkylcarbonyl, lower alkoxycarbonyl, lowerphenylalkoxycarbonyl, lower alkylamino and loweralkoxycarbonylamino; wherein said aryl selected fromphenyl, biphenyl and naphthyl, lower heterocyclylalkyleneand lower phenoxyalkylene radicals are optionallysubstituted with one or more radicals independentlyselected from halogen, lower alkyl and lower alkoxy; and R2 is selected from hydrido, halogen, lower alkyl,aryl selected from phenyl, biphenyl, and naphthyl, lowerhaloalkyl, lower hydroxyalkyl, 5- or 6-membered heterocyclyl, lower alkylheterocyclyl, lowerheterocyclylalkyl, lower alkylamino, lower alkynylamino,phenylamino, lower heterocyclylamino, lower 01298 1 16 heterocyclylalkylami.no, lower phenylalkylami.no, loweraminoalkyl, lower aminoalkylami.no, loweralkylaminoalkylamino, lower cycloalkyl, lower alkenyl,lower alkoxycarbonylalkyl, lower cycloalkenyl, lowercarboxyalkylamino, lower alkoxycarbonyl, lowerheterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl,lower alkoxycarbonylheterocyclylcarbonyl,alkoxycarbonylalkyl, lower alkoxyalkylamino, loweralkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lowerheterocyclylthio; wherein the aryl, heterocylyl,heterocyclylalkyl, cycloalkyl, and cycloalkenyl groupaare optionally substituted with one or more radicaleindependently selected from halo, keto, lower alkyl,lower alkynyl, phenyl, 5- or 6-membered heterocyclyl,lower phenylalkyl, lower heterocyclylalkyl, lowerepoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lowerphenylalkoxy, lower haloalkyl, lower alkylamino, loweralkylaminoalkylamino, lower alkynylamino, loweramino(hydroxyalkyl), lower heterocyclylalkylamino, loweralkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl,lower phenylalkylsulfonyl, R2 has the formula : R30
I -c—CCH-Pj- R3"1 wherein: j is 0, 1 or 2; andm is 0; R30 and R31 are independently selected from hydrogen,alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl,alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, and phenylsu1fonyl; or ,33 ,3-1 (III) Ο 1 298.1 17 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoaïkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and 5 R33 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40; wherein R35 is selected from alkyl, cycloalkyl,haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl,arylcycloalkyl, cyçloalkenylalkylene, 10 heterocyclylalkylene, alkylarylene, alkylheterocyclyl,arylarylene, arylheterocyclyl, alkoxy, alkenoxy,alkoxyalkylene, alkoxyaralkyl, alkoxyarylene,aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene,alkoxycarbonyl, heterocyclylcarbonyl, 15 alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene,alkoxycarbonylalkylene, alkoxycarbonylarylene,aralkoxyôarbonylheterocyclyl, alkylcarbonylheterocyclyl,arylcarbonyloxyalkylarylene, and alkylthioalkylene;wherein said aryl, heterocyclyl, aralkyl, alkylarylene, 20 _ arylheterocyclyl, alkoxyarylene, aryloxyalkylene,cycloalkoxyalkylene, alkoxycarbonylalkylene, andalkylcarbonylheterocyclyl groupe are optionallysubstituted with one or more radicals independentlyselected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, 25 keto, amino, nitro, and cyano; or R35 is CHR48R49 wherein R48 is arylsulfonylamino or alkylarylsulfonylamino, and R49 is selected from aralkyl,amino, alkylamino, and aralkylamino; or R35 is -NR50R51 wherein R50 is alkyl, and R51 is aryl ; 30 and wherein R36 is selected from alkyl, haloalkyl, aryl,heterocyclyl, cycloalkylalkylene, alkylarylene,alkenylarylene, arylarylene, aralkyl, aralkenyl,heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, 35 alkoxycarbonylarylene, alkylcarbonylaminoarylene,alkylcarbonylaminoheterocyclyl, 01298 1 18 arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene,alkylamino, alkylaminoarylene, alkylsulfonylarylene,alkylsulfonylaralkyl, and arylsulfonylheterocyclyl;wherein said aryl, heterocyclyl, cycloalkylalkylene,aralkyl, alkylcarbonylaminoheterocyclyl, andalkylsulfonylarylene groups are optionally substitutedwith one or more radicals independently selected fromalkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy,keto, amino, nitro, and cyano; and wherein R37 is selected from hydrogen and alkyl; andwherein R38 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene,arylcycloalkyl, arylarylene, cycloalkylalkylene,heterocyclylalkylene, alkylheterocyclylalkylene,aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene,aryloxyarylene, arylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkylene, alkoxycarbonylarylene,alkylcarbonylcarbonylalkylene, alkylaminoalkylene,alkylaminoaralkyl, alkylcarbonylaminoalkylene,alkylthioarylene, alkylsulfonylaralkyl, andaminosulfonylaralkyl; wherein said aryl, heterocyclyl,aralkyl, and heterocyclylalkylene groups are optionallysubstituted with one or more radicals independentlyselected from alkyl, halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, keto, amino, nitro, and cyano; or R38 is -CRS2R53 wherein R52 is alkoxycarbonyl, and R53is alkylthioalkylene; or R37 and R38 together with the nitrogen atom to whichthey are attached form a heterocycle; and R39 and R40 hâve the same définition as R26 and R27 inclaim 1; or R2 is -CR54R55 wherein R54 is phenyl and R55 is hydroxy;or R2 is selected from the group consisting of .01298Ί
CCH2)k _ (VI) (VII) (VIII) wherein k is an integer from 0 to 3 ; and R56 is hydrogen or lower alkyl; and R57 is hydrogen or lower alkyl; or R56 and R57 fortn a lower alkylene bridge; and
Rse is selected f rom hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl,alkylsulfonyl, aralkylsulfonyl, arylsulf onyl, -C(O)R59,-SO2R60, and -C(O)NHR61; wherein R59 is selected from alkyl, haloalkyl,cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl,alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy,alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; whereinsaid aryl, heterocyclyl, and aralkyl groups areoptionally substituted with one or more radicalsindependently selected from alkyl, halo, hydroxy,haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, andcyano; and wherein R60 is selected from alkyl, aryl,heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl,heterocyclylheterocyclyl, alkoxyarylene, alkylamino,alkylaminoarylene, alkylsuifonylarylene, and arylsulfonylheterocyclyl; wherein said aryl,heterocyclyl, and aralkyl groups are optionallysubstituted with one or more radicals independentlyselected from alkyl, halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, keto, amino, nitro, and cyano; and 01298 1 20 wherein R®1 is selected from alkyl, aryl,alkylarylene, and alkoxyarylene; wherein said aryl groupis optionally substituted with one or more radicaleindependently selected from alkyl, halo, hydroxy,haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, andcyano; and R3 is selected from pyridinyl, pyrimidinyl,quinolinyl, purinyl, and (IV) wherein R43 is selected from hydrogen, lower alkyl,lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyland lower aryloxyalkyl; and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl andpurinyl groups are optionally substituted with one ormore radicale independently selected from loweralkylthio, lower alkylsulfonyl, aminosulfonyl, halo,lower alkyl, lower aralkyl, lower phenylalkenyl, lowerphenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano,lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, loweralkoxy, amino, lower cycloalkylamino, lower alkylamino,lower alkenylamino, lower alkynylamino, lower aminoalkyl,arylamino, lower aralkylamino, nitro, halosulfonyl, loweralkylcarbonyl, lower alkoxycarbonylamino, loweralkoxyphenylalkylamino, lower alkylaminoalkylamino, lowerhydroxyalkylamino, lower heterocyclylamino, lowerheterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl,lower alkoxyphenylalkylamino, hydrazinyl, loweralkylhydrazinyl, or -NR62R63 wherein R52 is loweralkylcarbonyl or amino, and R63 is lower alkyl or lower 01298 1 21 phenylalkyl; and R4 is selected from hydrido, lower cycloalkyl, lowercycloalkenyl, aryl selected from phenyl, biphenyl, andnaphthyl, and 5- or 6- membered heterocyclyl; wherein thelower cycloalkyl, lower cycloalkenyl, aryl and 5-10membered heterocyclyl groups of R4 are optionallysubstitüted with one or more radicals independentlyselected from lower alkylthio, lower alkylsulfonyl, loweralkylsulfinyl, halo, lower alkyl, lower alkynyl, loweralkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, loweralkylami.no, and hydroxy; or a pharmaceutically-acceptable sait or tautomerthereof. A class of compounds of particular interest consistsof these compounds of Formula I wherein
Rx is selected from hydrido, methyl, ethyl, propyl,isopropyl, tert-butyl, isobutyl, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloroethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl,dichloroethyl, dichloropropyl, ethenyl, propenyl,ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl,piperazinyl, morpholinyl, benzyl, phenylethyl,morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl,piperazinylraethyl, piperidinylmethyl, pyridinylmethyl,thienylmethyl, methoxymethyl, ethoxymethyl, amino,methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl,dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl,cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,hydroxymethyl, hydroxyethyl, mercaptomethyl, andmethylthiomethyl; and R2 is selected from hydrido, chloro, fluoro, bromo, 0 1298 1 22 methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl,phenyl, biphenyl, fluoromethyl, dif luoromethyl,trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl,dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl,isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl,pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl,benzimidazolyl, furyl, pyrazinyl, piperidinyl,piperazinyl, morpholinyl, N-methylpiperazinyl,methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino,Ν,Ν-dimethylamino, N-ethylamino, Ν,Ν-diethylamino, N-n-propylamino, Ν,Ν-dimethylamino, N-methyl-N-phenylamino,N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl,aminoethylamino, aminopropylamino, N,N-dimethylaminoethylamino, N,N-dimethylaminopropylamino,morpholinylethylamino, morpholinylpropylamino,carboxymethylamino, methoxyethylamino, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1- dimethylethoxycarbonylaminoethylamino, 1,1-dimethylethoxycarbonylaminopropylamino,piperazinylcarbonyl, and 1,1- dimethylethoxycarbonylpiperazinylcarbonyl; wherein thearyl, heteroaryl, cycloalkyl and cycloalkenyl groupa areoptionally substituted with one or more radicalsindependently selected from fluoro, chloro, bromo, keto,methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl,carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl,dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1-dimethylethylcarbonyl; or 0 1-29 a 1 23 R2 is -CRS4R55 wherein R54 is phenyl and R55 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, andpurinyl; wherein R3 is optionally substituted with one ormore radicals independently selected from methylthio,methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl,isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylcarbonylamino, trifluoromethyl,difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl,fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy,methoxy, ethoxy, propyloxy, n-butoxy, methylamino,ethylamino, dimethylamino, diethylamino, 2- methylbutylamino, propargylamino, aminomethyl,aminoethyl, N-methyl-N-phenylamino, phenylamino,diphenylamino, benzylamino, phenethylamino,cyclopropylamino, nitro, chlorosulfonyl, amino,methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino,hydroxyethylamino, imidazolylethylamino,morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino,piperidinylamino, pyridinylmethylamino,phenylmethylpiperidinylamino, phenylmethylamino,fluorophenylmethylamino, fluorophenylethylamino,methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl,methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, or -NR62R63 wherein R{J is methylcarbonyl oramino, and R63 is methyl, ethyl or phenylmethyl; and R4 is selected from hydrido, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, 01298 1 24 biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridiriyl, thienyl, isothiazôlyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, 5 pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl,benzofuryl, dihydrobenzofuryl, and benzodioxolyl; whereinthe cycloalkyl, cycloalkenyl, aryl and heterocyclylgroups of R4 are optionally substituted with one or more 10 radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl,methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl,fluoromethyl, difluoromethyl, amino, cyano, nitro, 15 dimethylamino, and hydroxy; or a pharmaceutically-acceptable sait or tautomer thereof.
Another class of compounds of particular interest 20 consists of these compounds of Formula I whereinR1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl ormorpholinylethyl; R2 is selected from hydrido, methyl, ethyl, propyl, 25 phenyl, trifluoromethyl, methoxycarbonylethyl, N,N- dimethylamino, N-phenylamino, piperidinyl, piperazinyl,pyridinyl, N-methylpiperazinyl, and piperazinylamino;wherein the phenyl, piperidinyl, and pyridinyl groups areoptionally substituted with one or more radicals 30 independently selected from fluoro, chloro, bromo,methyl, ethyl, and trifluoromethyl; R3 is selected from pyridinyl, pyrimidinyl orquinolinyl; wherein R3 is optionally substituted with oneor more radicals independently selected from fluoro, 35 bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl,benzyl, phenethyl, acetyl, hydroxyl, methoxy, 01298 1 25 dimethylamino, benzylamino, phenethylamino, aminomethyl,amino, hydroxy, and methylcarbonyl; R4 is selected from phenyl, quinolyl, biphenyl,pyridinyl, „ thienyl, f uryl, dihydropyranyl, benzofuryl,dihydrobenzofuryl, and benzodioxolyl; wherein thecycloalkyl, cycloalkenyl, aryl and heterocyclyl groupa ofR4 are optionally substituted with one or more radicalsindependently selected from methylthio, fluoro, chloro,bromo, methyl, ethyl, methoxy, ethoxy, phenoxy,benzyloxy, trifluoromethyl, nitro, dimethylamino, andhydroxy; or a pharmaceutically-acceptable sait or tautomerthereof. A class of compounds of spécifie interest consisteof those compounds of Formula I wherein R1 is hydrido or methyl; R2 is selected from hydrido, methyl or ethyl; R3 is selected from pyridinyl, pyrimidinyl orquinolinyl; wherein R3 is optionally substituted with oneor more radicals independently selected from fluoro,bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl,benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl,amino, hydroxy, and methylcarbonyl; R4 is selected from phenyl which is optionallysubstituted with one or more radicals independentlyselected from methylthio, fluoro, chloro, bromo, methyl,ethyl, methoxy, ethoxy, phenoxy, benzyloxy,trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable sait or tautomerthereof.
Still another class of compounds of particularinterest consists of those compounds of Formula I wherein R1 is selected from hydrido, methyl, ethyl, propyl,
26 isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl,dichloroethyl, dichloropropyl, ethenyl, propenyl,ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl,piperazinyl, morpholinyl, benzyl, phenylethyl,morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl,piperazinylmethyl, piperidinylmethyl, pyridinylmethyl,thienylmethyl, methoxymethyl, ethoxymethyl, amino,methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl,dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl,cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,hydroxymethyl, hydroxyethyl, mercaptomethyl, andmethylthiomethyl; and R2 has the formula: R30 Γ H η R32
I I Z
-C — (CH,) C -N wherein: j is 0, 1 or 2 ; andm is 0 ; and R30 and R31 are independently selected from hydrogenand lower alkyl; R32 is selected from hydrogen, lower alkyl, lowerphenylalkyl, lower heterocyclylalkyl, loweralkoxyalkylene, aryloxyalkylene, aminoalkyl, loweralkylaminoalkyl, lower phenylaminoalkyl, loweralkylcarbonylalkylene, lower phenylcarbonylalkylene, andlower heterocyclylcarbonylaminoalkylene; R33 is selected from hydrogen, lower alkyl, -C(O)R35,-C(O)OR35, -SO2R36, -C (0) NR37R38, and -SO2NR39R40; 04298 ί 27 wherein R35 is selected from lower alkyl, lowercycloalkyl, lower haloalkyl, lower alkenyl, aryl selectedfrom phenyl, biphenyl and naphthyl, lower heterocyclyl,lower phenylalkyl, lower phenylcycloalkyl, lowercycloalkenylalkylene, lower heterocyclylalkylene, loweralkylphenylene, lower alkylheterocyclyl, phenylphenylene,lower phenylheterocyclyl, lower alkoxy, lower alkenoxy,lower alkoxyalkylene, lower alkoxyphenylalkyl, loweralkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, loweralkoxycarbonyl, lower heterocyclylcarbonyl, loweralkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene,lower alkoxycarbonylphenylene, lowerphenylalkoxycarbonylheterocyclyl, loweralkylcarbonylheterocyclyl, lowerphenylcarbonyloxyalkylphenylene, and loweralkylthioalkylene; wherein said aryl selected fromphenyl, biphenyl and naphthyl, lower heterocyclyl, lowerphenylalkyl, lower alkylphenylene, lowerphenylheterocyclyl, lower alkoxyphenylene, lowerphenoxyalkylene, lower cycloalkoxyalkylene, loweralkoxycarbonylalkylene, and loweralkylcarbonylheterocyclyl groups are optionallysubstituted with one or more radicale independentlyselected from lower alkyl, halo, lower haloalkyl, loweralkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or R3S is CHR48R49 wherein R48 is phenylsulfonylamino orlower alkylphenylsulfonylamino, and R49 is selected fromlower phenylalkyl, amino, lower alkylamino, and lowerphenylalkylamino; or R35 is -NR50R51 wherein R58 is lower alkyl, and RS1 isaryl selected from phenyl, biphenyl and naphthyl; and wherein R36 is selected from lower alkyl, lowerhaloalkyl, aryl selected from phenyl, biphenyl and
01298J 28 naphthyl, lower heterocyclyl, lower cycloalkylalkylene,lover alkylphenylene, lover alkenylphenylene,phenylphenylene, lover phenylalkyl, lover phenylalkenyl,lover heterocyclylheterocyclyl, carboxyphenylene, loveralkoxyphenylene, lover alkoxycarbonylphenylene, loveralkylcarbonylarainophenylene, lover alkylcarbonylaminoheterocyclyl, lover phenylcarbonylaminoalkylheterocyclyl, lover alkylaminophenylene, lover alkylamino, lover alkylaminophenylene, lover alkylsulfonylphenylene, loveralkylsulfonylphenylalkyl, and lover phenylsulfonylheterocyclyl; vherein said aryl selectedfrom phenyl, biphenyl and naphthyl, lover heterocyclyl,lover cycloalkylalkylene, lover phenylalkyl, loveralkylcarbonylaminoheterocyclyl, and lover alkylsulfonylphenylene groupa are optionally substitutedvith one or more radicals independently selected fromlover alkyl, halo, hydroxy, lover haloalkyl, loveralkoxy, lover haloalkoxy, keto, amino, nitro, and cyano;and vherein R37 is selected from hydrogen and loveralkyl; and vherein R38 is selected from hydrogen, lover alkyl,lover alkenyl, aryl selected from phenyl, biphenyl andnaphthyl, lover heterocyclyl, lover phenylalkyl, loveralkylphenylene, lover phenylcycloalkyl, phenylphenylene,lover cycloalkylalkylene, lover heterocyclylalkylene,lover alkylheterocyclylalkylene, lover phenylalkylheterocyclyl, lover alkoxyalkylene, loveralkoxyphenylene, lover phenoxyphenylene, phenylcarbonyl,lover alkoxycarbonyl, lover alkoxycarbonylalkylene, loveralkoxycarbonylphenylene, lover alkylcarbonylcarbonylalkylene, lover alkylaminoalkylene,lover alkylaminophenylalkyl, lover alkylcarbonylaminoalkylene, lover alkylthiophenylene,lover alkylsulfonylphenylalkyl, and lover 01298 î 29 aminosulfonylphenylalkyl; wherein said aryl selected fromphenyl, biphenyl and naphthyl, lower heterocyclyl, lowerphenylalkyl, and lower heterocyclylalkylene groupa areoptionally substituted with one or more radicalsindependently selected from lower alkyl, halo, hydroxy,lower haloalkyl, lower alkoxy, lower haloalkoxy, keto,amino, nitro, and cyano; or R38 is -CRS2R53 wherein RS2 is lower alkoxycarbonyl,and R53 is lower alkylthioalkylene ; or R37 and R38 together with the nitrogen atom to whichthey are attached form a 4-8 membered ring heterocycle; R39 and R40 hâve the same définition as R26 and R27 inclaim 2 ; or R2 is selected from the group consisting of
I (VI) (VII) (VIII) wherein k is an integer from 0 to 2; and R56 is hydrogen or lower alkyl ; and R57 is hydrogen or lower alkyl; and R58 is selected from hydrogen, lower alkyl, lowerphenylalkyl, aryl selected from phenyl, biphenyl andnaphthyl, lower heterocyclyl, lower heterocyclylalkyl,lower alkoxycarbonyl, lower alkylsulfonyl, lowerphenylalkylsulfonyl, lower phenylsulfonyl, -C(O)RS9,-SOjR60, and -C(O)NHR61; wherein R59 is selected from lower alkyl, lowerhaloalkyl, lower cycloalkyl, aryl selected from phenyl,biphenyl and naphthyl, lower heterocyclyl, lower 01 298 1 30 alkylphenylene, lower phenylalkyl, lower alkylhetërocyclyl, lower alkoxy, lower alkenoxy, loewrphenylalkoxy, lower alkoxyalkylene, loweralkoxyphenylene, lower alkoxyphenylalkyl; wherein saidaryl selected from phenyl, biphenyl and naphthyl, lowerheterocyclyl, and lower phenylalkyl groupa are optionallysubstituted with one or more radicals independentlyselected from lower alkyl, halo, hydroxy, lowerhaloalkyl, lower alkoxy, lower haloalkoxy, keto, amino,nitro, and cyano; and wherein R60 is selected from lower alkyl, arylselected from phenyl, biphenyl and naphthyl, lowerheterocyclyl, lower alkylphenylene, lower alkylhetërocyclyl, lower phenylalkyl, lowerheterocyclylheterocyclyl, lower alkoxyphenylene, loweralkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl selectedfrom phenyl, biphenyl and naphthyl, lower heterocyclyl,and lower phenylalkyl groupe are optionally substitutedwith one or more radicals independently selected fromlower alkyl, halo, hydroxy, lower haloalkyl, loweralkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;and wherein R61 is selected from lower alkyl, arylselected from phenyl, biphenyl and napthyl, loweralkylphenylene, and lower alkoxyphenylene; wherein saidaryl group is optionally substituted with one or moreradicals independently selected from lower alkyl, halo,hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy,keto, amino, nitro, and cyano; and R3 is selected from pyridinyl, pyrimidinyl, andpurinyl; wherein R3 is optionally substituted with one ormore radicals independently selected from methylthio,methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, 01 298 1 31 isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl,atninocarbonyl, methylcarbonylamino, trifluoromethyl,difluoromethyl, fluoromethyl, trichloromethyl,dichloromethyl, chloromethyl, hydroxy, 5 fluorophenylmethyl, fluorophenylethyl,chlorophenylmethyl, chlorophenylethyl,fluorophenylethenyl, chlorophenylethenyl,fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy,methoxy, ethoxy, propyloxy, n-butoxy, methylamino, 10 ethylamino, dimethylamino, diethylamino, 2- methylbutylamino, propargylamino, aminomethyl,aminoethyl, N-methyl-N-phenylamino, phenylamino,diphenylamino, benzylamino, phenethylamino,cyclopropylamino, nitro, chlorosulfonyl, amino, 15 methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino,hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, {1-ethyl-2-hydroxy)ethylamino, 20 piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino,fluorophenylmethylamino, fluoropheny1e t hy1ami no,methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl,methoxyphenylmethylamino, hydrazinyl, 1-methyl- 25 hydrazinyl, or -NR62R63 wherein R62 is methylcarbonyl oramino, and R63 is methyl, ethyl or phenylmethyl; and R4 is selected from hydrido, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, 30 biphenyl, morpholinyl, pyrrolidinyl, piperazinyl,piperidinyl, pyridinyl, thienyl, isothiazolyl,isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl,isoquinolinyl, imidazolyl, benzimidazolyl, furyl,pyrazinyl, dihydropyranyl, dihydropyridinyl, 35 dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein 012981 32 the cycloalkyl, cycloalkenyl, aryl and heterocyclylgroups of R4 are optionally substitutëd with one or moreradicals independently selected from methylthio,methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo,methyl, ethyl, isopropyl, tert-butÿl, isobutyl, ethynyl,methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl,fluoromethyl, difluoromethyl, amino, cyano, nitro,dimethylamino, and hydroxy; or a pharmaceutically-acceptable sait or tautomerthereof.
Still another class of compounds of particularinterest consists of those compounds of Formula I wherein R1 is hydrido, methyl, ethyl, propargyl,hydroxyethyl, dimethylaminoethyl, diethylaminoethyl ormorpholinylethyl; R2 has the formula: R30
I • C—CCH.,) J-η3Ί
H
I c hL R' ,32
-N (III) wherein: j is 0, 1 or 2 ; and m is 0 ; and R30 is hydrogen; and R31 is selected from hydrogen and lower alkyl; andR32 is selected from hydrogen and lower alkyl ; andR33 is selected from lower alkyl, -C(O)R35, -C(O)OR35, -SO2R3€, -C(O)NR37R38, and -SO2NR39R40; wherein R35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, loweralkoxyalkylene, lower phenoxyalkylene, and lowerphenylalkoxyalkylene; wherein said phenyl and lowerphenoxyalkylene groups are optionally substitutëd with
01298J 33 one or more radicale independently selected frotn lower alkyl, halo, and lowèr haloalkyl; and wherein R36 is selected from lower alkyl, phenyl,lower heterocyclyl, lower alkylphenylene,phenylphenylene, lower phenylalkyl, loweralkylheterocyclyl, lower heterocyclylheterocyclyl, loweralkoxyphenylene, and lower alkylamino; wherein saidphenyl and lower heterocyclyl groups are optionallysubstituted with one or more radicals independentlyselected from lower alkyl, halo, hydroxy, lowerhaloalkyl, lower alkoxy, lower haloalkoxy, keto, amino,nitro, and cyano; and wherein R37 is hydrogen; and wherein R38 is selected from lower alkyl, phenyl, andlower alkylphenylene; wherein R39 and R40 hâve the same définition as R26 andR27 in claim 2; or R2 is selected from the group consisting of
CCH2)k _ (VI) (VII) (VIII) wherein k is an integer from 0 or 1 ; andR56 is hydrogen; andR57 is hydrogen; and R5e is selected from -C(0)R59 and -SO2R60;wherein Rs9 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and loweralkoxyalkylene; wherein said phenyl group is optionallysubstituted with one or more radicals independently 01298 1 34 selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R60 is selected from lower alkyl; and R3 is selected from pyridinyl, pyrimidinyl orquinolinyl; wherein R3 is optionally substituted with oneor more radicale independently selected from fluoro,bromo, methyl, cyano, methoxycarbonyl,. aminocarbonyl,benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl,amino, -hydroxy, and methylcarbonyl; and R4 is selected from phenyl, quinolyl, biphenyl,pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl,dihydrobenzofuryl, and benzodioxolyl; wherein thecycloalkyl, cycloalkenyl, aryl and heterocyclyl groupe ofR4 are optionally substituted with one or more radicalsindependently selected from methylthio, fluoro, chloro,bromo, methyl, ethyl, methoxy, ethoxy, phenoxy,benzyloxy, trifluoromethyl, nitro, dimethylamino, andhydroxy; or a pharmaceutically-acceptable sait or tautomerthereof.
Still another class of compounds of spécifieinterest consiste of those compounds of Formula I wherein R1 is hydrido or methyl; and R3 is selected from pyridinyl, pyrimidinyl orquinolinyl; wherein R3 is optionally substituted with oneor more radicals independently selected from fluoro,bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl,benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl,amino, hydroxy, and methylcarbonyl; and R4 is selected from phenyl which is optionallysubstituted with one or more radicals independentlyselected from methylthio, fluoro, chloro, bromo, methyl, 01298 1 35 ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; ora pharmaceuticaliy-acceptable sait or tautomer thereof.
In one embodiment of the présent invention, thecompounds of Formula I satisfy one or more of thefollowing conditions: R1 is hydrido or lower alkyl ; more preferably, R1 ishydrido or methyl; and still more preferably, R1 ishydrido; R2 is hydrido or lower alkyl; more preferably, R2 ishydrido or methyl; and still more preferably, R2 ishydrido; R3 is substituted or unsubstituted pyridinyl; andpreferably, the pyridinyl is a 4-pyridinyl; or R4 is substituted or unsubstituted phenyl; andpreferably, R4 is phenyl substituted with halo.
In addition, where R3 is substituted pyrimidinyl,preferably at least one R3 substitutent is attached to thecarbon atom positioned between two nitrogen atoms of thepyrimidinyl ring. A family of spécifie compounds of particularinterest within Formula I consists of compounds,tautomers and pharmaceuticaliy-acceptable saits thereofas follows: 4- [5- (3-fluoro-4-methoxyphenyl) - 3-methyl-lH-pyrazol-4-yl]pyridine; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyridine; 4- [5-methyl-3- (2-methylphenyl) -lH-pyrazol-4-yl]pyridine;4- [3- (4-f luorophenyl) -5-methyl-lH-pyrazol-4-yl]pyridine;4- [5-methyl-3- (4-methylphenyl) - IH-pyrazol-4-yl] pyridine ;4- [5-methyl-3-[4-(methylthio)phenyl] -lH-pyrazol-4-yl]pyridine; 4- [3- (4-chlorohpenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 36 4-[3-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4-[5-(2, 5-dimethylphenyl)-3-methyl-lH-pyrazol-4 yl]pyridine; 4-[5-(1,3-benzodioxol-5-yl)-3-methyl-lH-pyrazol-4- yl]pyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -lH-pyrazol-4-yl]pyridine;4- [5- [ (1,1 '-biphenyl)-4-yl]-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[3-methyl-5-[3-(phenoxyphenyl)-lH-pyrazol-4-~yl]Pyridine; 4-[3-methyl-5- [3-(phenylmethoxy)phenyl]-lH-pyrazol-4-yl]pyridine; 4- [3-methyl-5-[2-(phenylmethoxy)phenyl]-lH-pyrazol-4-yl]pyridine; 2- [3-methyl-4-(4-pyridinyl)-lH-pyrazol-4-yl]phénol; 3- [3-methyl-4-(4-pyridinyl)-ΙΗ-pyrazol-4-yl]phénol ; l-hydroxy-4-(3-methyl-5-phenyl-lH-pyrazol-4- yl]pyridinium; 5- (4-fluorophenyl)-N, N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3 -amine ; 5-(4-fluorophenyl)-N-phenyl-4-(4-pyridinyl)-lH-pyrazol-3-amine; 4-[5-(4-fluorophenyl)-3-phenyl-lH-pyrazol-4-yl]pyridine; 4- [5-(3-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-4-yl]pyridine;4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]pyridine; 4-(5-cyclohexyl)-3-methyl-ΙΗ-pyrazol-4-yl)pyridine; 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(3-methylphenyl)-3-propyl-lH-pyrazol-4-yl]pyridine;4-[(3-methyl-5-phenyl-lH-pyrazol-4-yl)methyl]pyridine; 4-[3,5-bis(3-methylphenyl)-ΙΗ-pyrazol-4-yl]pyridine; 4-[4-methyl-2-(2-trifluorophenyl)-lH-pyrazol-4-yl]pyridine; 4-[3-(2-chlorophenyl)- 5-methyl-ΙΗ-pyrazol-4-yl]pyridine;4-[5-methyl-3-(2,4-dimethylphenyl)-lH-pyrazol-4- 01298 î 37 yllpyridine; 4- [5- (4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4- yl]pyridine; 4- [3- (3-fluoro-2-methylphenyl)-5-methyl-lH-pyrazol-4- yl]pyridine; 4- [3-(3,5-dimethylphenyl)-5-methyl-lH-pyrazol-4- yl]pyridine? 4-[3-(3,5-dimethoxyphenyl)-5-methyl-lH-pyrazol-4~ yllpyridine; 4- [5-methyl-3-(3-nitrophenyl)-lH-pyrazol-4-yl]pyridine?N,N-dimethyl-4- [5-met.hyl-4- (4-pyridinyl) -lH-pyrazol-3yl]benzenamine; 4- [3-(2,3-dihydrobenzofuran-5-yl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4- [3- (4-bromophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3- (2-fluorophenyl) -5-methyl-lH-pyrazol-4-yl]pyridine;4-[3-(3-fluorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine;4- (3-methyl-5- [3-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl]pyridine; 4-(3-ethyl-4-phenyl-lH-pyrazol-4-yl)pyridine; 4- (5-(3-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl}pyridine;4- [3-ethyl-5- (3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4- [5- (3,4-difluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4- [5- (3-ethoxyphenyl) -3-methyl-lH-pyrazol-4-yllpyridine;4- [3-methyl-5-(4-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl]pyridine; 4- [3-methyl-5-(3-thienyl)-lH-pyrazol-4-yllpyridine; 4-[5-(2,4-dichlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4- [5- (3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine;4- [5-(3-chloro-4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; ethyl 3-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazole-5-propanoate; 4- [3-(4-fluorophenyl)-1-methyl-pyrazol-4-yl]pyridine; 01298 1 38 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl] pyrimidin- 2-amine ; 5-[3-methyl-5-(3-methylphenyl) -lH-pyrazol-4-yl]pyrimidin- 2-amine; 5-[3-methyl-5-(2-methylphenyl)-lH-pyrazol-4-yl]pyrimidin- 2-amine; ' 5-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyrimidin- 2-amine ; 5-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyrimidin- 2-amine ; 5-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol-4- yl]pyrimidin-2 -amine ; 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine; 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine? 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine ; 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine; 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine; 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2-amine; 4- [5-(4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl)pyridin- 2-amine ; 5- [5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]-2-methoxypyridine; 2-methoxy-5-(3-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 2-methoxy-5-[5- (4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine? 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]-2-methoxypyridine ; 2-methoxy-4-[3-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; - 01298 1 39 2-methoxy-4- [3-methyl-5- (2-methylphenyl) -lH-pyrazol-4-yl]pyridine; 4- [5-(4-chlorophenyl)-3-methyl-lH-pyrazol-4-yl] -2-methoxypyridine; 5 4- [5- (4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]-2- methoxypyridine; 2-methoxy-4- [3-methyl-5- (4-methylphenyl) -lH-pyrazol-4-yl]pyridine; 5- [5- (3-chlorophenyl) -3 -methyl-lH-pyrazol-4-yl] pyridin-2-10 ol; 4- [5- (3-chlorophenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-ol; 4- [5- (3-methylphenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-ol ; 15 4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2- ol ; 4- [5- (4-chlorophenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-ol; 4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-20 ol ; 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-ol? 5- [5- (3-chlorophenyl) -3-methyl-lH-pyrazol-4-yl]pyridine-2-methanamine; 25 4- [5- (3-chlorophenyl) -3-methyl-lH-pyrazol-4-yl]pyridine- 2-methanamine; 4- [5- (3-methylphenyl) -3-methyl-lH-pyrazol-4-yl]pyridine-2-methanamine; 4- [5- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yl]pyridine-30 2-methanamine; 4- [5- (4-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2-methanamine; 4- (5- (4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2-methanamine; 35 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl]pyridine- 2-methanamine; 01298Ί 40 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine- 2-carboxamide; 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine- 2 -carboxamide ? 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2 -carboxamide; 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2 -carboxamide; 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine- 2-carboxamide; 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2-carboxamide; 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine-2-carboxamide; 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(benzofuran-6-yl)-3-methyl-lH-pyrazol-4-yl]pyridine;4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine? 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(1-cyclohexyen-l-yl)-3-methyl-lH-pyrazol-4-yl]pyridine? 4-[5-(1,3-cyclohexadien-l-yl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-lH-pyrazol-4-yl]pyridine; 4 -(5-cycloheXy1-3-methyl-ΙΗ-pyrazol-4-yl)pyridine ? 4-[5-(4-methoxy-3-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine; 41 4- [5- (3-methoxy-4-methylphenyl) -3-methyl-lH-pyrazol-4- yl]pyridine; 4- [5- (3-methoxy-5-methylphenyl) -3-methyl·-lH-pyrazol-4- yl]pyridine; 4- [5- (3-furyl) -3-methyl-lH-pyrazol-4-yl]pyridine; 2 -methyl-4 - (3-methyl -5-phenyl- 1H-pyrazol-4-yl) pyridine ; 2 -methoxy-4 - ( 3 - methyl - 5 -phenyl - ΙΗ-pyrazol - 4 -y 1 ) pyr idine ;methyl 4- (3-methyl-5-phenyl-lH-pyrazol~4-yl)pyri-dine-2-carboxylate; 4-(3-methyl-5-phenyl-ΙΗ-pyrazol-4-yl)pyridine-2- carboxamide; 1- [4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-2-yl]ethanone; N,N-dimethyl-4-(3-methyl- 5-phenyl-ΙΗ-pyrazol-2 - yl)pyridin-2-amine; 3-methyl-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyridine; 3- methoxy-4- (3-methyl-5-phenyl-lH-pyrazol- 4-yl)pyridine;methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4yl)pyridine-3-carboxylate ; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyridine-3 -carboxamide; 1- [4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-3-yl]ethanone; 3- bromo-4 - ( 3 -methyl - 5- phenyl - 1H-pyrazol-4 - yl) pyridine ; N,N-dimethyl-4-(3-methyl-5-phenyl-lH-pyrazol-2- yl)pyridin-3-amine; 2- methyl-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyrimidine ? 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine ; 2- methoxy-4 -(3-methyl-5-phenyl-ΙΗ-pyrazol-4 -yl)pyrimidine; 4 - (3-methyl-5-phenyl-ΙΗ-pyrazol-4 -yl ) pyrimidin-2 -amine ;N,N-dimethyl-4-(3-methyl-5-phenyl-lH-pyrazol-4 -yl)pyrimidin-2-amine; 4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5-phenyl-1H-pyrazole; 3- methyl-5-phenyl-4-(3-thienyl)-lH-pyrazole; 42 01298 1 4-(3-furyl)-3-methyl-5-phenyl-ΙΗ-pyrazole? 3- methyl-5-phenyl-4- (2-thienyl) -lH-pyrazole? 4- (2-furyl)-3-methyl-5-phenyl-lH-pyrazole; 4-(3-isothiazolyl)-3-methyl-5-phenyl-lH-pyrazole 4-(3-isoxazolyl)-3-methyl-5-phenyl-lH-pyrazole? 4-(5-isothiazolyl)-3-methyl-5-phenyl-lH-pyrazole; 4-(5-isoxazolyl)-3-methyl-5-phenyl-ΙΗ-pyrazole? 3-methyl-5-phenyl-4,- (5-thiazolyl) -lH-pyrazole? 3- methyl-4-(5-oxazolyl)-5-phenyl-lH-pyrazole; 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine; 2-methyl-4-[3-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4-(l-methyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4-(3-phenyl-lH-pyrazol-4-yl)pyridine; 2-methyl-4 -(3-phenyl-lH-pyrazol-4-yl)pyridine; 4-[3-(3-chlorophenyl)-l-methyl-pyrazol-4-yl]pyridine? 4-[3-(4-chlorophenyl)-l-methyl-pyrazol-4-yl]pyridine? 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] pyridine; 4-[3-(4-chlorophenyl)-lH-pyrazol-4-yl]pyridine; 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl) -2-methylpyridine;4-[3-(3-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine;4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyridine? 4- [3-(3-chlorophenyl)-l-methyl-pyrazol-4-yl]-2-methylpyridine; 5- (4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-lH-pyrazol-3-amine; 5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-lH-pyrazol-3-amine ? 5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine dihydrate; 5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3 -amine ? N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3 -amine ? N-methyl-5-(3-methylphenyl)-4-(4-pyridinyl)-lH-pyrazol-3-amine ? N-ethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-lH-pyrazol-3- . 01 298 1 43 amine ; N,N-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl)- N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3 -amine ; 4- [5- (4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]morpholine; 5- (4-chlorophenyl) -N-propyl-4- (4-pyridinyl) -lH-pyrazol-3-amine; 5- (4-chlorophenyl) -N- (phenylmethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine hydrate (2:1); 5- (4-chlorophenyl) -N- (2-methoxyethyl) -4- (4-pyridinyl) -1H-pyrazol-3 -amine monohydrate ; 1,1-dimethylethyl 4- [5- (4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-1-piperazinecarboxylate; 1- [5- (4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]piperazine trihydrochloride; 1- [5- (4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-methylpiperazine; 1,1-dimethylethyl 4- [5- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-1-piperazinecarboxylate ; 1- [5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]piperazine trihydrochloride; 1- [5- (4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-ÿl]piperazine; N- [5-(4-chlorophenyl)-4-[2-(phenylmethyl)amino] -4-pyridinyl]-lH-pyrazol-3-yl]-1,3-propanediamine,trihydrochloride; 1- [5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-(phenylmethy1)piperazine; 4- [3-(4-fluorophenyl)-5-(1-piperazinyl)-lH-pyrazol-4-yl]pyrimidine, dihydrochloride; 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4- (4-pyridinyl)-lH-pyrazol-3-yl)amino]propyl]carbamate; N- [5- [4-chlorophenyl)-4-(4-pyridinyl) -lH-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate ; 01298 1 44 1,l-dimethylethyl [2-[[5-(4-chlorophenyl)-4-(4- pyridinyl)-lH-pyrazol-3-yl)amino]ethyl]carbamate; 1,l-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2- hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-1- piperazinecarboxylate; 1,l-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4- pyrimidinyl)-lH-pyrazol-3-yl]-1-piperazinecarboxylate; 1.1- dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-lH-pyrazol-3-yl]amino]propyl]carbamate; 1-(5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-ethylpiperazine; N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]- 1.2- ethanediamine; 4-[3-(2,6-difluorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4-[3-(3-ethylphenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4-[3-(3-chlorophenyl)-5-ethyl-lH-pyrazol-4-yl]pyridine; 4-[3-ethyl-5-(3-ethylphenyl)-lH-pyrazol-4-yl]pyridine; 4-[3-(4-chlorophenyl)-5-(1-methylethyl)-lH-pyrazol-4-yl]pyridine; 4-[3-cyclopropyl-5-(4-fluorophenyl)-lH-pyrazol-4-yl)pyridine; 4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-lH-pyrazol-4-yl)pyridine; 4- [5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-lH-pyrazol-4-y1]pyridine; 5- cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-éthanol; 3- (4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-IH-pyrazole-l-ethanol; 4- [3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]-2(1H)-pyridinone; l-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]-2(1H)-pyridinone;
Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylate; 01298 1 45 2- [3 - (4-fluorophenyl) -1- (2-hydroxyethyl) - 4- (4-pyridinyl) -lH-pyrazol-5-yl]cyclopropanecarboxylic acid; 3- (4-fluorophenyl)-5-(4-imidazolyl) -4 -(4-pyridinyl)-1H-pyrazole-1-éthanol; 4- [3- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yl]pyridine 5- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3- carboxylic acid; 5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3- me thanol; 1- ( [5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]carbonyl]piperazine; 1,1-dimethylethyl 4- [ [5- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate; 4- (1,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (1,3-dimethyl-5-phenyl-lH-pyrazol-4-yl]pyridine; 4- (3- (4-chlorophenyl)-1,5-dimethyl-lH-pyrazol-4-yl]pyridine; 4- [5- (4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4-yl]pyridine; 4- [5-ethÿl-l-methyl-3-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4- [3-ethyl-l-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4- [3- (4-chlorophenyl)-l-ethyl-5-methyl-lH-pyrazol-4-yl]pyridine; 4- [3- (4-chlorophenyl)-2-ethyl-5-methyl-lH-pyrazol-4-y1]pyridine; 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine; 4- [3- (2-chlorophenyl)-lH-pyrazol-4-yl]pyridine; 3- (4-fluorophenyl)-4-(4-pyridinyl) -ΙΗ-pyrazole-l-ethanol; 3- (4-fluorophenyl)-4-(4-pyrimidinyl)-lH-pyrazole-1-ethanol; 4- [3-(4-fluorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine; 2-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl] arrtino] -1 -butanol ; 4- [5-bromo-3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4- 012981 46 yllpyridine? 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2- pyridinecarbonitrile? 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-1-yl]ethyl]morpholine ? 3- (4-fluorophenyl)-l-methyl-a-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol? N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-morpholineethanamine? 4- [3-(3-chlorophenyl)-lH-pyrazol-4-yl] -2(1H)-pyridinonehydrazone; 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] -N-(phenylmethyl)- 2-pyridinamine; 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine? 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2-pyridinamine? 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxamide;
Methyl 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylate? 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2-pyridinecarboxylic acid? 4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyridine; 4-[3-(1,3-benzodioxol-5-yl)-lH-pyrazol-4-yl]pyridine4- [3-(3 -fluorophenyl)-1-methyl-1H-pyrazol-4-y1]pyr idîne ; 4-(3-(4-chlorophenyl)-lH-pyrazol-4-yl] pyridine; 4-[3-(1,3-benzodioxol-5-y)-l-methyl-lH-pyrazol-4-yl]pyridine ; 4-[3-(4-chlorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine?4-[3-(3-chlorophenyl)-l-methyl-lH-pyrazol-4-yl]-2-methylpyridine? 4-[5-(3-chlorophenyl)-l-methyl-lH-pyrazol-4-yl] -2-methylpyridine? 4 -[3-(3-chlorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine; 01298 1 47 4- [5- (3-chlorophenyl) -l-methyl-lH-pyrazol-4-yl]pyridine? 2-methyl-4- [l-methyl-3- (3-methylphenyl) -lH-pyrazol-4-yl]pyridine; 2-methyl-4- [l-methyl-5- (3-methylphenyl) -lH-pyrazol-4-yllpyridine? 4 -(3 -phenyl-1H-pyrazol-4-y1)pyridine;
4- [3- [3-(trifluoromethyl)phenyl] -lH-pyrazol-4-yl]pyridineZ 4- [l-methyl-3- [3- (trifluoromethyl)phenyl] -lH-pyrazol-4-yl]pyridine; 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine; 4- [3- (4-chlorophenyl)-lH-pyrazol-4-yl] -2-fluoropyridine; 4- [3- (4-bromophenyl) -lH-pyrazol-4yl] pyridine 4- [3-(3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yl]pyridine ; 4- [3- (4-bromophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine; (E) -4 - [3- (4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-phenylethenyl)pyridine; (S) -4- [3- (4-chlorophenyl) -lH-pyrazol-4-yl] -N- (2-methylbutyl)- 2-pyridinamine; 4- [3-(4-chlorophenyl)-1H-pyrazol-4-yl] -N-[(4-methoxy-phenyl)methy1]- 2-pyridinamine; N- [4- [3- (4-chlorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]- 2-pyridinemethanamine; N- [4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]- 2-pyridinemethanamine; 2-fluoro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine;4- [3-(4-iodophenyl)-lH-pyrazol-4-yl]pyridine; 4- [3-(4-iodophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine; 4- [l-methyl-3- [4- (trifluoromethyl)phenyl] - 1H-pyrazol-4-yl]pyridine; N- [1- (4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinamine; N- [ (3-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinamine; 4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2- (1- 01298 1 48 methylhydrazino)pyridine; 2- fluoro-4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine; 4-[3-(3,4-difluorophenyl)-lH-pyrazol-4-yl]-2-fluoro-pyridine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-3-methylpyridine; 4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-3-methyl-pyridine ; 4-[3-(3,4-difluorophenyl)-l-methyl-lHr-pyrazol-4-yl]-2-fluoropyridine; 3- (4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-lH-pyrazole-1-ethanamine; 2- [2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-Ι-ώβ thyl -lH-pyrazol-4-yl]pyridine; 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-(1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine; N' -(4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2-pyridinyl]-N,N-dimethyl~l,2-ethanediamine; 2,4-bis[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine; N-[4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine; 3- (4-fluorophenyl)-4-(2-fluoro-4-pyridinÿl)-lH-pyrazole-1-éthanol ; 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl) -N-[2-(IH-imidazol-1-yl)ethyl]-2-pyridinamine; 4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-l-yl]ethyl]morpholine ; (E) -3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethenyl]-4-pyridinyl]-lH-pyrazole-1-éthanol; 3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-ΙΗ-pyrazole-l-ethanamine; 3- (4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-ΙΗ-pyrazole-l-éthanol ; 4- [1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethy1-2-pyridinamine ; 4-(1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H- 01298 7 49 pyrazol-4-yl] -N- [ (4-f luorophenyl) methyl] -2-pyridinamine; 3- (4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-py r i di ny1]-N,N-dime thy 1 - 1H - py r a zole-l-et hanami ne ; N- t (4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-Ι- Ε [2-(4-morpholinyl)ethyl]-lH-pyrazol-4-yl]-2-pyri d i nami ne ; 4- [3- (4-fluorophenyl)-lH-pyrazol-4-yl] -N-4-piperadinyl-2-pyridinamine; N,N-diethyl-3 -(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-lH-pyrazole-Ι-ethanamine; 4- [1- [2-(diethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine; 2- t [4- [3-(4-(fluorophenyl)-lH-pyrazol-4-yl]-2- pyridinyl]amino]éthanol ; 2- [[4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2-pyridinyl]amino]éthanol; 3- [ [4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol; 3- (4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]- 4- pyridinyl]-ΙΗ-pyrazole-l-ethanol; 5- (4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]- 4-pyridinyl]-lH-pyrazole-l-ethanol; N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine; N- [ (4-fluorophenyl)methyl] -4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-lH-pyrazol-4-yl) -2-pyridinamine; N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-morpholinepropanamine; N'- [5- (4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazol-3-yl]-N,N-dimethyl-l,3-propanediamine; 5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine; 3- (4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl)amino]- 4- pyridinyl]-lH-pyrazole-Ι-éthanol ; 5- (4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino] -4-pyridinyl]-ΙΗ-pyrazole-l-ethanol; 01298 1 50 4-[3-[(4-fluorophenyl)-lH-pyrazol-4-yl]quinoline; N-[5-(4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazol-3-yl]glycine methyl ester; N- [5- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]glycine; 4-[3-(4-fluorophenyl)-1-(2-propynyl) -lH-pyrazol-4-yl]pyridine; 4-[5-(4-fluorophenyl)-1-(2-propynyl)-lH-pyrazol-4-yl]pyridine; 4,4'-(ΙΗ-pyrazole-3,4-diyl)bis[pyridine]; 4-[3-(3,4-dichlorophenyl)-lH-pyrazol-4-yl]pyridine; N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-piperidinamine; 2-Chloro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2(1H)-pyrimidinonehydrazone; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine; 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl] -N-methyl-2-pyrimidinamine; 4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl] -N-(phenylmethyl)-2-pyrimidinamine; N-cyclopropyl-4- (3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinamine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N- [ (4-methoxyphenyl)methyl]-2-pyrimidinamine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinamine;N-(4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide;
Ethyl [4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl]carbamate; 4-[3-(3-methylphenyl)-lH-pyrazol-4-yl]pyrimidine; 4-[3-(4-chlorophenyl)-lH-pyrazol-4-yl] pyrimidine; 4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine? and4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] pyrimidine. 01298 1 51
Within Formula I there is another subclass ofcompounds of high interest represented by Formula IX:
N (IX) wherein 5 Z représente a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, loweraralkyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl 10 selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl,piperazinyl, imidazolyl, pyridinyl and morpholinyl, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl,lower alkylamino, lower alkylaminoalkyl, phenylamino, 15 lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, loweraminoalkylamino, lower alkynylamino, lowerheterocyclylamino, lower heterocyclylalkyl, lowerheterocyclylalkylamino, lower alkylheterocyclyl, lower 20 carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino,lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and 01 298 1 52 heteroaryl groups are optionally substituted with one ormore radicals independently selected from halo, loweralkyl, keto, aralkyl, carboxy, lower alkylatninoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and loweralkoxycarbonyl; or R2 is -CR54R5S wherein R54 is phenyl and R55 is hydroxy; and R4 is selected from hydrido, lower cycloalkyl, lowercycloalkenyl, lower cycloalkyldienyl, 5- or 6-memberedheterocyclyl, and aryl selected from phenyl, biphenyl,naphthyl; wherein R4 is optionally substituted at asubstitutable position with one or more radicalsindependently selected from halo, lower alkyl, loweralkoxy, aryloxy, lower aralkoxy, lower haloalkyl, loweralkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano,aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, loweraminoalkyl, lower aralkyl, lower aralkyloxy, loweraralkylamino, lower alkoxycarbonyl, lower alkylamino,lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, loweralkoxycarbonylamino, lower alkoxyaralkylamino, loweralkylaminoalkylamino, lower heterocyclylamino, lowerheterocyclylalkylamino, lower aralkylheterocyclylamino,lower alkylaminocarbonyl, lower alkylcarbonyl, loweralkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR62R63 wherein R62 is loweralkylcarbonyl or amino, and R63 is lower alkyl or lowerphenylalkyl; or a pharmaceutically-acceptable sait or tautomerthereof.
A preferred class of compounds consists of thosecompounds of Formula IX R1 is selected from hydrido, methyl, ethyl, 01298 1 53 hydroxyethyl and propargyl; and R2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino,5 Ν,Ν-dimethylamino, N-ethylamino, Ν,Ν-diethylamino, N- propylamino, N-phenylamino, aminomethyl, aminoethyl,aminoethylamino, aminopropylamino, propargylamino,benzylanjino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, 10 piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1- dimethyl)ethylcarbonylaminopropylamino, (1,1- dimethyl)ethylcarbonylaminoethylamino, 15 piperazinylcarbonyl, 1,1-dimethyl- ethylpiperazinylcarbonyl; wherein the phenyl,piperidinyl, piperazinyl, imidazolyl, morpholinyl, andpyridinyl groupe are optionally substituted with one ormore radicals independently selected from fluoro, chloro, 20 bromo, keto, methyl, ethyl, trifluoromethyl, benzyl,methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and R4 is selected from cyclohexyl, cyclohexenyl,cyclohexadienyl, phenyl, quinolyl,. biphenyl, pyridinyl, 25 thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl ,· wherein R4 isoptionally substituted with one or more radicalsindependently selected from methylthio, fluoro, chloro,bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, 30 benzyloxy, trifluoromethyl, nitro, dimethylamino, andhydroxy; and R5 is selected from fluoro, chloro, bromo, methyl,fluorophenylethyl, fluorophenylethenyl,fluorophenylpyrazolyl, cyano, methoxycarbonyl, 35 aminocarbonyl, acetyl, hydroxy, carboxy, methoxy,methylamino, dimethylamino, 2-methylbutylamino, 01298 1 54 ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, 5 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl,ethoxycarbonylamino, methoxyphenylmethylamino,phenylmethylamino, fluorophenylmethylamino,fluorophenylethylamino, methylaminocarbonyl, 10 methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR62R63 wherein R62 is methylcarbonyl or amino, and R63 ismethyl or benzyl; or a pharmaceutically-acceptable sait or tautomerthereof. 15
Within Formula I there is another subclass ofcompounds of high interest represented by Formula X: R5
wherein 20 Z represents a carbon atom or a nitrogen atom; and R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and loweralkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl 01298 1 55 selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl,piperazinyl, imidazolyl, pyridinyl and morpholinyl, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl,lower alkylamino, lower alkylaminoalkyl, phenylamino,lower aralkyl, lower aralkylamino, loweralkylaminoalkylamino, lower aminoalkyl, loweraminoalkylamino, lower alkynylamino, lowerheterocyclylamino, lower heterocyclylalkyl, lowerheterocyclylalkylamino, lower alkylheterocyclyl, lowercarboxycycloalkyl, lower carboxyalkylamino, loweralkoxyalkylamino, lower alkoxycarbonylaminoalkylamino,lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl andheteroaryl groups are optionally substituted with one ormore radicale independently selected from halo, loweralkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lowerheterocyclylalkylamino, lower alkylcarbonyl and loweralkoxycarbonyl; or R2 is -CR54R55 wherein R54 is phenyl and R55 is hydroxy; and R4 is selected from 5- or 6-membered heteroaryl, andaryl selected from phenyl, biphenyl, and naphthyl;wherein R4 is optionally substituted with one or moreradicale independently selected from halo, lower alkyl,lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl,lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano,aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, loweraminoalkyl, lower aralkyl, lower aralkyloxy, loweraralkylamino, lower alkoxycarbonyl, lower alkylamino,lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, loweralkoxycarbonylamino, lower alkoxyaralkylamino, lower z 01298 1 56 alkylaminoalkylamino, lower heterocyclylamino, lower hetërocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower 5 alkylhydrazinyl, or -NR62R63 wherein R62 is lower alkylcarbonyl or amïno, and R63 is lower alkyl or lowerphenylalkyl; or a pharmaceutically-acceptable sait or tautomerthereof. 10
A preferred class of compounds consiste of thosecompounds of Formula X R1 is selected from methyl, ethyl, hydroxyethyl andpropargyl; and 15 R2 is selected from methyl, ethyl, propyl, phenyl, trifluorométhyl, hydroxyethyl, methoxycarbonylethyl,ethoxycarbonylethyl, N-methylamino, Ν,Ν-dimethylamino, N-ethylamino, Ν,Ν-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, 20 aminopropylamino, propargylamino, benzylamino,piperadinylamino, dimethylaminoethylamino,dimethylaminopropylamino, morpholinylpropylamino,morpholinylethylamino, piperidinyl, piperazinyl,imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, 25 carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl,(1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1- dimethyl)ethylcarbonylaminoethylamino,piperazinylcarbonyl, and 1,1-dimethyl- 30 ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, andpyridinyl groups are optionally substituted with one ormore radicale independently selected from fluoro, chloro,bromo, keto, methyl, ethyl, trifluorométhyl, benzyl, 35 methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and 01298 1 57 R4 is selected from phenyl, quinolyl, biphenyl,pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl,dihydrobenzofuryl, and benzodioxolyl; wherein R4 isoptionally substituted with one or more radicalsindependently selected from methylthio, fluoro, chloro,bromo, methyl, ethyl, methoxy, ethoxy, phenoxy,benzyloxy, trifluoromethyl, nitro, dimethylamino, andhydroxy; and R5 is selected from fluoro, chloro, bromo, methyl,fluorophenylethyl, fluorophenylethenyl,fluorophenylpyrazolyl, cyano, methoxycarbonyl,aminocarbonyl, acetyl, hydroxy, carboxy, methoxy,methylamino, dimethylamino, 2-methylbutylamino,ethylamino, dimethylaminoethylamino, hydroxypropylamino,hydroxyethylamino, propargylamino, imidazolylamino,morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino,piperidinylamino, pyridinylmethylamino,phenylmethylpiperidinylamino, aminomethyl,cyclopropylamino, amino, hydroxy, methylcarbonyl,ethoxycarbonylamino, methoxyphenylmethylamino,phenylmethylamino, fluorophenylmethylamino,fluorophenylethylamino, methylaminocarbonyl,methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -Nr62r«3 wherein R62 is methylcarbonyl or amino, and R63 ismethyl or benzyl; or a pharmaceutically-acceptable sait or tautomerthereof.
Within Formula I there is another subclass ofcompounds of high interest represented by Formula XI : 58
(XI) wherein Z représente a carbon atom or a nitrogen atom; andR1 is selected from lower alkyl, lower hydroxyalkyl, 5 lower alkynyl, lower aminoalkyl and loweralkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, arylselected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, 10 piperazinyl, imidazolyl, pyridinyl and morpholinyl, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxycarboriyl,lower alkylamino, lower alkylaminoalkyl, phenylamino,lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower 15 aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lowerheterocyclylalkylamino, lower alkylheterocyclyl, lowercarboxycycloalkyl, lower carboxyalkylamino, loweralkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, 20 lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl andheteroaryl groups are optionally substituted with one ormore radicals independently selected from halo, lower 0 1 29Έ 1 59 alkyl, keto, aralkyl, carboxy, lower alkylatninoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CR54R55 wherein R54 is phenyl and Rss is hydroxy; and R4 is selected frora 5- or 6-membered heteroaryl, andaryl selected from phenyl, biphenyl, and naphthyl;wherein R4 is optionally substituted with one or moreradicals independently selected from halo, lower alkyl,lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl,lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano,aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, loweraminoalkyl, lower aralkyl, lower aralkyloxy, loweraralkylamino, lower alkoxycarbonyl, lower alkylamino,lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, loweralkoxycarbonylamino, lower alkoxyaralkylamino, loweralkylaminoalkylamino, lower heterocyclylamino, lowerheterocyclylalkylamino, lower aralkylheterocyclylamino,lower alkylaminocarbonyl, lower alkylcarbonyl, loweralkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR62R63 wherein R62 is loweralkylcarbonyl or amino, and R63 is lower alkyl or lowerphenylalkyl; or a pharmaceutically-acceptable sait or tautomerthereof.
A preferred class of compounds consists of thosecompounds of Formula XI R1 is selected from methyl, ethyl, hydroxyethyl andpropargyl; and R2 is selected from methyl, ethyl, propyl, phenyl,trifluoromethyl, hydroxyethyl, méthoxycarbonylethyl,ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N- 01298 1 60 ethylamino, Ν,Ν-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino,aminopropylamino, propargylamino, benzylamino,dimethylaminopropylamino, morpholinylpropylamino, 5 morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino,methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1- dimethyl)ethylcarbonylaminopropylamino, (1,1- dimethyl}ethylcarbonylaminoethylamino, 10 piperazinylcarbonyl, 1,1-dimethyl- ethylpiperazinylcarbonyl; wherein the phenyl,piperidinyl, piperazinyl, imidazolyl, morpholinyl, andpyridinyl groupe are optionally substituted with one ormore radicale independently selected from fluoro, chloro, 15 bromo, keto, methyl, ethyl, trifluorornethyl, benzyl,methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; R4 is selected from phenyl, quinolyl, biphenyl,pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, 20 dihydrobenzofuryl, and benzodioxolyl ; wherein R4 is optionally substituted with one or more radicaleindependently selected from methylthio, fluoro, chloro,bromo, methyl, ethyl, methoxy, ethoxy, phenoxy,benzyloxy, trifluoromethyl, nitro, dimethylamino, and 25 hydroxy; and R5 is selected from fluoro, chloro, bromo, methyl,fluorophenylethyl, fluorophenylethenyl,fluorophenylpyrazolyl, cyano, methoxycarbonyl,aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, 30 methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino,hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino,piperidinylamino, pyridinylmethylamino, 35 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, 012981 61 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or - 5 NR62R63 wherein R62 is methylcarbonyl or amino, and Re3 is methyl or benzyl; or a pharmaceutically-acceptable sait or tautomerthereof. 10 A preferred class of compounds consiste of those compounds of Formula IX wherein Z représenta a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower 15 hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, arylselected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, 20 piperazinyl, imidazolyl, pyridinyl and morpholinyl, lowerhaloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl,lower alkylamino, lower alkylaminoalkyl, phenylamino,lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower 25 aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lowerheterocyclylalkylamino, lower alkylheterocyclyl, lowercarboxycycloalkyl, lower carboxyalkylamino, loweralkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, 30 lowêr heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl andheteroaryl groups are optionally substituted with one ormore radicals independently selected from halo, lower 35 alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower 01298 1 62 heterocyclylalkylamino, lower alkylcarbonyl and loweralkoxycarbonyl; or R2 is -CR54R55 wherein R54 is phenyl and Rss is hydroxy; and R4 is phenyl that is optionally substituted with oneor more radicals independently selected from halo, loweralkyl, lower alkoxy, aryloxy, lower aralkoxy, lowerhaloalkyl, lower alkylthio, lower alkylamino, nitro,hydroxy; and
Rs is selected from halo, amino, cyano,aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, loweraminoalkyl, lower aralkyl, lower aralkyloxy, loweraralkylamino, lower alkoxycarbonyl, lower alkylamino,lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, loweralkoxycarbonylamino, lower alkoxyaralkylamino, loweralkylaminoalkylamino, lower heterocyclylamino, lowerheterocyclylalkylamino, lower aralkylheterocyclylamino,lower alkylaminocarbonyl, lower alkylcarbonyl, loweralkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR62R63 wherein R62 is loweralkylcarbonyl or amino, and R63 is lower alkyl or lowerphenylalkyl; or a pharmaceutically-acceptable sait or tautomerthereof. A class of compounds of spécifie interest consistsof those compounds of Formula IX wherein R1 is selected from hydrido, methyl, ethyl,hydroxyethyl and propargyl; R2 is selected from methyl, ethyl, propyl, phenyl,trifluoromethyl, hydroxyethyl, methoxycarbonylethyl,ethoxycarbonylethyl, N-methylamino, Ν,Ν-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino,aminopropylamino, propargylamino, benzylamino, 01 298 1 63 dîme thylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino,methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1- dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl- ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, andpyridinyl groupe are optionally substituted with one ormore radicale independently eelected from fluoro, chloro,bromo, keto, methyl, ethyl, trifluoromethyl, benzyl,methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; R4 ie phenyl that ie optionally eubetituted with oneor more radicale independently eelected from methylthio,fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy,phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
Rs ie selected from fluoro, chloro, bromo, methyl,fluorophenylethyl, fluorophenylethenyl,fluorophenylpyrazolyl, cyano, methoxycarbonyl,aminocarbonyl, acetyl, hydroxy, carboxy, methoxy,methylamino, dimethylamino, 2-methylbutylamino,ethylamino, dimethylaminoethylamino, hydroxypropylamino,hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino,piperidinylamino pyridinylmethylamino,phenylmethylpiperidinylamino, aminomethyl,cyclopropylamino, amino, hydroxy, methylcarbonyl,ethoxycarbonylamino, methoxyphenylmethylamino,phenylmethylamino, fluorophenylmethylamino,fluorophenylethylamino, methylaminocarbonyl,methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -Nr62r63 wherein R62 ie methylcarbonyl or amino, and R63 iemethyl or benzyl; or 01298 1 64 a pharmaceutically-acceptable sait or tautomerthereof.
Another class of compounds of spécifie interestconsists of those compounds of Formula IX wherein Z représente a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lowerhydroxyalkyl and lower alkynyl; and R2 is selected from hydrido and lower alkyl; andR4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more haloradicals; and R5 is selected from hydrido, halo andalkylhydrazinyl? or a pharmaceutically-acceptable sait or tautomerthereof.
Still another class of compounds of spécifieinterest consists of those compounds of Formula IXwherein Z représenta a carbon atom; and R1 is selected from hydrido, methyl, hydroxyethyl,propargyl; and R2 is hydrido; and R4 is selected from phenyl and benzodioxolyl; whereinphenyl is optionally substituted with one or moreradicals independently selected from chloro, fluoro andbromo; and R5 is selected from hydrido, fluoro, and 1-methylhydrazinyl; or a pharmaceutically-acceptable sait or tautomerthereof. A preferred class of compounds of spécifie interestconsists of those compounds of Formula IX wherein 01298 1 65 Z représenta a carbon atom; and R1 is selected from hydrido and methyl; and R2 is hydrido; and R4 is selected from phenyl that is optionally5 substituted with one or more radicale independently selected from chloro, fluoro and bromo; and
Rsis selected from hydrido and fluoro; ora pharmaceutically-acceptable sait or tautomer thereof. 10
The term ''hydrido" dénotés a single hydrogen atom (H) . This hydrido radical may be attached, for example,to an oxygen atom to form a hydroxyl radical or twohydrido radicale may be attached to a carbon atom to form15 a methylene (-CH2-) radical. Where used, either alone orwithin other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", "cyanoalkyl" and"mercaptoalkyl", the term "alkyl" embraces linear orbranched radicale having one to about twenty carbon atoms20 or, preferably, one to about twelve carbon atoms. Morepreferred alkyl radicals are "lower alkyl" radicalehaving one to about ten carbon atoms. Most preferred arelower alkyl radicals having one to about six carbonatoms. Examples of such radicals include methyl, ethyl, 25 n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term"alkenyl" embraces linear or branched radicals having atleast one carbon-carbon double bond of two to abouttwenty carbon atoms or, preferably, two to about twelve30 carbon atoms. More preferred alkenyl radicals are "loweralkenyl" radicals having two to about six carbon atoms.Examples of alkenyl radicals include ethenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms"alkenyl" and "lower alkenyl", embrace radicals having"cis" and "trans" orientations, or alternatively, "E" and"Z" orientations. The term "alkynyl" embraces linear or 35 01298 1 66 branched radicals having at least one carbon-carbontriple bond of two to about twenty carbon atoms or,preferably, two to about twelve carbon atoms. Morepreferred alkynyl radicals are "lower alkynyl" radicalshaving two to about six carbon atoms. Examples ofalkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butenyl and 1-pentynyl. The term"cycloalkyl" embraces saturated carbocyclic radicalshaving three to about twelve carbon atoms. The term"cycloalkyl" embraces saturated carbocyclic radicalshaving three to about twelve carbon atoms. Morepreferred cycloalkyl radicals are "lower cycloalkyl"radicals having three to about eight carbon atoms.Examples of such radicals include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkylene" embraces alkyl radicals substitutedwith a cycloalkyl radical. More preferredcycloalkylalkylene radicals are "lowercycloalkylalkylene" which embrace lower alkyl radicalssubstituted with a lower cycloalkyl radical as definedabove. Examples of such radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyland cyclohexylmethyl. The term "cycloalkenyl" embracespartially unsaturated carbocyclic radicals having threeto twelve carbon atoms. Cycloalkenyl radicals that arepartially unsaturated carbocyclic radicals that containtwo double bonds (that may or may not be conjugated) canbe called "cycloalkyldienyl". More preferredcycloalkenyl radicals are "lower cycloalkenyl" radicalshaving four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl andcyclohexenyl. The term "halo" means halogens such asfluorine, chlorine, bromine or iodine. The term"haloalkyl" embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo asdefined above. Specifically embraced are monohaloalkyl, 298 67 dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may hâve either an iodo, bromo,chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may hâve two or more of the saniehalo atoms or a combination of different halo radicals."Lower haloalkyl" embraces radicals having one to sixcarbon atoms. Examples of haloalkyl radicals includefluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. The term "hydroxyalkyl" embraces linearor branched alkyl radicals having one to about ten carbonatoms any one of which may be substituted with one ormore hydroxyl radicals. More preferred hydroxyalkylradicals are "lower hydroxyalkyl" radicals having one tosix carbon atoms and one or more hydroxyl radicals.Examples of such radicals include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. The terms "alkoxy" and "alkyloxy" embracelinear or branched oxy-containing radicals each havingalkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tert-butoxy.The term "alkoxyalkyl" embraces alkyl radicals having oneor more alkoxy radicals attached to the alkyl radical,that is, to form monoalkoxyalkyl and dialkoxyalkylradicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro,chloro or bromo, to provide haloalkoxy radicals. The term"aryl", alone or in combination, means a carbocyclicaromatic System containing one, two or three ringswherein such rings may be attached together in a pendentmanner or may be fused. The term "aryl" embraces 01 298 1 68 aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moietiesmay also be substituted at a substitutable position withone or more substituents selected independently fromhalo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl,alkylthio, arylthio, alkylthioalkylene, arylthioalkylene,alkylsulfinyl, alkylsulfinyialkylene, arylsuifinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy,aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkyl, amino, cyano, nitro, alkylamino, arylamino,alkylaminoalkylene, arylaminoalkylene, aminoalkylamino,hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkylene, acyl, carboxy, and aralkoxycarbonyl. The term "heterocyclyl" embracessaturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which canalso be called "heterocyclyl", "heterocycloalkenyl" and"heteroaryl" correspondingly, where the heteroatoms maybe selected from nitrogen, sulfur and oxygen. Examplesof saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl,piperidino, piperazinyl, etc.); saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms (e.g.,thiazolidinyl, etc.). Examples of partially unsaturatedheterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dlhydrothiazole.
Heterocyclyl radicals may include a pentavalent nitrogen, such as in tétrazolium and pyridinium radicals. The term "heteroaryl" embraces unsaturated heterocyclyl radicals.
Examples of heteroaryl radicals include unsaturated 3 to
i Π O Q
i d O 69 6 membered heteromonocyclic group containing 1 to 4nitrogen atoms, for example, pyrrolyl, pyrrolinyl,imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl(e.g. ΙΗ-tetrazolyl, 2H-tetrazolyl, etc.), etc.;unsaturated condensed heterocyclyl group containing 1 to5 nitrogen atoms, for example, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3to 6-membered heteromonocyclic group containing an oxygenatom, for example, pyranyl, furyl, etc.; unsaturated 3 to6-membered heteromonocyclic group containing a sulfuratom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturatedcondensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl,benzoxadiazolyl, etc.); unsaturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturatedcondensed heterocyclyl group containing 1 to 2 sulfuratoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl,benzothiadiazolyl, etc.) and the like. The term"heterocycle" also embraces radicale where heterocyclylradicale are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals includebenzofuran, benzothiophene, and the like. Said"heterocyclyl group" may hâve 1 to 3 substituents such asalkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio andalkylamino. The term "heterocyclylalkylene" embraces 01298 1 70 heterocyclyl-substituted alkyl radicale. More preferredheterocyclylalkylene radicale are "lowerheterocyclylalkylene" radicale having one to six carbonatome and a heterocyclyl radicale. The term "alkylthio"embracee radicale containing a linear or branched alkylradical, of one to about ten carbon atome attached to adivalent sulfur atom. More preferred alkylthio radicaleare "lower alkylthio" radicale having alkyl radicale ofoneto six carbon atoms. Examples of such loweralkylthio radicals are methylthio, ethylthio, propylthio,butylthio and hexylthio. The term "alkylthioalkylene"embraces radicals containing an alkylthio radicalattached through the divalent sulfur atom to an alkylradical of one to about ten carbon atoms. More preferredalkylthioalkylene radicals are "lower alkylthioalkylene"radicals having alkyl radicals of one to six carbonatoms. Examples of such lower alkylthioalkylene radicalsinclude methylthiomethyl. The term "alkylsulfinyl"embraces radicals containing a linear or branched alkylradical, of one to about ten carbon atoms, attached to adivalent -S(=O)- radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkylradicals of one to six carbon atoms. Examples of suchlower alkylsulfinyl radicals include methylsulfinyl,ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term"sulfonyl", whether used alone or linked to other termesuch as "alkylsulfonyl", "halosulfonyl" dénotés adivalent radical, -SO2-. "Alkylsulfonyl" embraces alkylradicals attached to a sulfonyl radical, where alkyl isdefined as above. More preferred alkylsulfonyl radicalsare "lower alkylsulfonyl" radicals having one to sixcarbon atoms. Examples of such lower alkylsulfonylradicals include methylsulfonyl, ethylsulfonyl andpropylsuifonyl. The "alkylsulfonyl" radicals may befurther substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide haloalkylsulfonyl 71 radicale. The term "halosulfonyl" embraces halo radicaleattached to a sulfonyl radical. Exatnples of suchhalosulfonyl radicale include chlorosulfonyl, andbromosulfonyl. The terme "sulfamyl", "aminosulfonyl" and"sulfonamidyl" dénoté NH2O2S-. The term "acyl" dénotés aradical provided by the residue after removal of hydroxylfrom an organic acid. Examples of such acyl radicaleinclude alkanoyl and ar.oyl radicale. Examples of suchalkanoyl radicale include formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, and radicale formed from succinic, glycolic,gluconic, lactic, malic, tartaric, citrie, ascorbic,glucuronic, maleic, fumaric, pyruvic, mandelic,pantothenic, β-hydroxybutyric, galactaric andgalacturonic acids. The term "carbonyl", whether usedalone or with other terms, such as "alkoxycarbonyl",dénotés -(C=0)-. The terms "carboxy" or "carboxyl",whether used alone or with other terms, such as"carboxyalkyl", dénotés -CO2H. The term "carboxyalkyl"embraces alkyl radicals substituted with a carboxyradical. More preferred are "lower carboxyalkyl" whichembrace lower alkyl radicals as defined above, and may beadditionally substituted on the alkyl radical with halo.Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term"alkoxycarbonyl" means a radical containing an alkoxyradical, as defined above, attached via an oxygen atom toa carbonyl radical. More preferred are "loweralkoxycarbonyl" radicals with alkyl portions having oneto six carbons. Examples of such lower alkoxycarbonyl(ester) radicals include substituted or unsubstitutedmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,butoxycarbonyl and hexyloxycarbonyl. The term"alkoxycarbonylalkyl" embraces alkyl radicals substitutedwith a alkoxycarbonyl radical as defined above. Morepreferred are "lower alkoxycarbonylalkyl" radicals«with 0129.8 1 72 alkyl portions having one to six carbone. Examples ofsuch lower alkoxycafbonylalkyl radicale inc.ludesubstituted or unsubstituted methoxycarbonylmethyl,ethoxycarbonylmethyl, methoxycarbonyl-ethyl andethoxycarbonylethyl. The term "alkylcarbonyl",· includesradicale having alkyl, hydroxylalkyl, radicals, asdefined herein, attached to a carbonyl radical. Examplesof such radicals include substituted or unsubstitutedmethylcarbonyl, ethylcarbonyl, propylcarbonyl,butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl,hydroxyethylcarbonyl. The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl,diphenylmethyl, triphenylmethyl, phenylethyl, anddiphenylethyl. The aryl in said aralkyl may beadditionally substituted with one or more substituentsselected independently from halo, alkyl, alkoxy,halkoalkyl, haloalkoxy, amino and nitro. The termsbenzyl and phenylmethyl are interchangeable. The term "heterocyclylalkylene" embraces saturated and partiallyunsaturated heterocyclyl-substituted alkyl radicals (alsocan be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly), such aspyrrolidinylmethyl, and heteroaryl-substituted alkylradicals (also can be called heteroarylalkylene), such aspyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl,and quinolylethyl. The heteroaryl in said heteroaralkylmay be additionally substituted with halo, alkyl, alkoxy,halkoalkyl and haloalkoxy. The term "aryloxy" embracesaryl radicals attached through an oxygen atom to otherradicals. The term ”aralkoxy'’ embraces aralkyl radicalsattached through an oxygen atom to other radicals. Theterm "aminoalkyl" embraces alkyl radicals substitutedwith amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term "alkylamino" dénotés amino groupe which are substituted 01298 1 73 with one or two alkyl radicals, Preferred are "loweralkylamino" radicals having alkyl portions having one tosix carbon atoms. Suitable lower alkylamino may bemonosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term"arylamino" dénotés amino groups which are substitutedwith one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted onthe aryl ring portion of the radical. The term " aminocarboriyl " dénotés an amide group of the formula -C(=O)NH2- The term "alkylaminocarbonyl" dénotés anaminocarbonyl group which has been substituted with oneor two alkyl radicals on the amino nitrogen atom.
Preferred are "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" radicals. More preferred are"lower N-alkylaminocarbonyl" and "lower N,N-dialkylaminocarbonyl" radicals with lower alkyl portionsas defined above. The term "alkylcarbonylamino" embracesamino groups which are substituted with one alkylcarbonylradicals. More preferred alkylcarbonylamino radicals are"lower alkylcarbonylamino" having lower alkylcarbonylradicals as defined above attached to amino radicals.
The term "alkylaminoalkylene" embraces radicals havingone or more alkyl radicals attached to an aminoalkylradical.
The "hydrocarbon" moieties described herein areorganic compounds or radicals consisting exclusively ofthe éléments carbon and hydrogen. These moieties includealkyl, alkenyl, alkynyl, and aryl moieties. Thesemoieties also include alkyl, .alkenyl, alkynyl, and arylmoieties substituted with other aliphatic or cyclichydrocarbon groups, such as alkaryl, alkenaryl andalkynaryl. Preferably, these moieties comprise 1 to 20carbon atoms.
The heterosubstituted hydrocarbon moieties described 01298 1 74 herein are hydrocarbon moieties which are substitutedwith at least one atom other than carbon, includingmoieties in which a carbon chain atom is substituted witha hetero atom such as nitrogen, oxygen, sulfur, or a 5 halogen atom. These substituents include lower alkoxysuch as methoxy, ethoxy, butoxy; halogen such as chloroor fluoro; ethers; acetals; ketals; esters; heterocyclylsuch as furyl or thienyl; alkanoxy; hydroxy; protectedhydroxy; acyl; acyloxy; nitro; cyano; âmino; and amido. 10 The additional terms used to describe the substituents of the pyrazole ring and not specificallydefined herein are defined in a similar manner to thatillustrated in the above définitions. As above, morepreferred substituents are those containing "lower" 15 radicals. Unless otherwise defined to contrary, the term"lower" as used in this application means that each alkylradical of a pyrazole ring substituent comprising one ormore alkyl radicals has one to about six carbon atoms;each alkenyl radical of a pyrazole ring substituent 20 comprising one or more alkenyl radicals has two to aboutsix carbon atoms; each alkynyl radical of a pyrazole ringsubstituent comprising one or more alkynyl radicals hastwo to about six carbon atoms; each cycloalkyl orcycloalkenyl radical of a pyrazole ring substituent 25 comprising one or more cycloalkyl and/or cycloalkenylradicals is a 3 to 8 membered ring cycloalkyl orcycloalkenyl radical, respectively; each aryl radical ofa pyrazole ring substituent comprising one or more arylradicals is a monocyclic aryl radical; and each 30 heterocyclyl radical of a pyrazole ring substituent comprising one or more heterocyclyl radicals is a 4-8membered ring heterocyclyl.
The présent invention comprises the tautomeric formsof compounds of Formulas I and IX. As illustrated below, 35 the pyrazoles of Formula I and 1' are magnetically andstructurally équivalent because of the prototropic 01298 1 75 tautomeric nature of the hydrogen:
The présent invention also comprises compounds ofFormula I, IX, X and XI having one or more asymmetriccarbons. It is known to those skilled in the art thatthose pyrazoles of the présent invention havingasymmetric carbon atoms may exist in diastereomeric,racemic, or optically active forms. Ail of these formsare contemplated within the scope of this invention.
More specifically, the présent invention includésenantiomers, diastereomers, racemic mixtures, and othermixtures thereof.
The présent invention comprises a pharmaceuticalcomposition for the treatment of a TNF mediated disorder,a P38 kinase mediated disorder, inflammation, and/orarthritis, comprising a therapeutically-effective amountof a compound of Formula I, or a therapeutically-acceptable sait or tautomer thereof, in association withat least one pharmaceutically-acceptable carrier,adjuvant or diluent.
The présent invention further encompassessubstituted pyrazoles that specifically bind to the ATPbinding site of p38 kinase. Without being held to aparticular theory, applicants hypothesize that thesesubstituted pyrazoles interact with p3 8 kinase as setforth below. As the substituent at the 3-position of thepyrazole ring approaches the ATP binding site of p38 01298 1 76 kinase, a hydrophobie cavity in the p38 kinase formsaround the 3-position substitutent at the binding site.This hydrophobie cavity is believed to form as the 3-position substituent binds to a spécifie peptide sequenceof the enzyme. In particular, it is believed to bind tothe sidechains of Lys52, Glu69, Leu73, Ile82, Leu84, Leu101and the methyl group of the Thr103 sidechain of p38 kinaseat the ATP binding site (wherein the numbering schemecorresponds to the numbering scheme conventionally usedfor ERK-2). Where the 3-position substituent is aryl orheteroaryl, such aryl or heteroaryl may be furthersubstituted. It is hypothesized that such ringsubstituents may be bénéficiai in preventing hydroxylation or further metabolism of the ring.
The substituent at the 4-position of the pyrazolering is one that is a partial mimic of the adenine ringof ATP, although it may be further elaborated.
Preferably, it is a planar substituent terminated by asuitable hydrogen bond acceptor functionality. It ishypothesized that this acceptor hydrogen bonds to thebackbone N-H of the Met106 residue while one edge of thissubstituent is in contact with bulk solvent.
Substitution at the 5-position of the pyrazole ringis well tolerated and can provide increased potency andselectivity. It is hypothesized that such substituentsextend out in the direction of the bulk solvent and thatsuitable polar functionality placed at its terminus caninteract with the sidechain of Asp109, leading toincreased potency and selectivity.
Similarly, substitution on the nitrogen atom at the1~ or 2-position of the pyrazole ring is well toleratedand can provide increased potency. It is hypothesizedthat a hydrogen substituent attached to one of the ringnitrogen atoms is hydrogen bonded to Asp165. Preferably,the nitrogen atom at the 2-position is double bonded tothe carbon atom at the 3-position of the pyrazole while 01298 1 77 the nitrogen atom at. the 1-position of the pyrazole isavailable for substitution with hydrogen or othersubstituents,
The 5-position substitutent and the 1- or 2-positionsubstituent of the pyrazole can be selected so as toimprove the physical characteristics, especially aqueoussolubility and drug delivery performance, of thesubstituted pyrazole. Preferably, however, thesesubstituents each hâve a molecular weight less than about360 atomic mass units. More preferably, thesesubstituents each hâve a molecular weight less than aboutless than about 250 atomic mass units. Still morepreferably, these substituents hâve a combined molecularweight less than about 360 atomic mass units. A class of substituted pyrazoles of particularinterest consists of those compounds having the formula:
wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical having a molecular weight less thanabout 360 atomic mass units; and R2 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical that binds with p38 kinase at saidATP binding site of p38 kinase; and R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and 01298 1 78 R4 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical having a molecular weight less thanabout 360 atomic mass units? provided R3 is not 2-pyridinyl when Riis a phenylring containing a 2-hydroxy substituent and when R1 ishydrido; further provided R2 is selected from aryl,heterocyclyl, unsubstituted cycloalkyl and cycloalkenylwhen R4 is hydrido; and further provided R4 is notmethylsulfonylphenyl; or a pharmaceutically-acceptable sait or tautomerthereof. A class of substituted pyrazoles of particularinterest consists of those compounds of Formula XIwherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical having a molecular weight less thanabout 360 atomic mass units; and R3 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical wherein said radical binds withLys52, G1u69, Leu73, IleB2, Leu84, Leu101, and Thr103 sidechainsat said ATP binding site of p38 kinase, said radicalbeing substantially disposed within a hydrophobie cavityformed during said binding by p38 kinase at the ATPbinding site; and R3 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical having a hydrogen bond acceptorfunctionality that hydrogen bonds with the N-H backboneof Met106 of p38 kinase; and R4 is a hydrocarbyl, heterosubstituted hydrocarbyl orheterocyclyl radical having a molecular weight less thanabout 360 atomic mass units.
The présent invention also comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having 01 298 1 79
or susceptible to such disorder or condition with atherapeutically-effective amount of a compound o£ FormulaI
wherein R1 is selected from hydrido, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl,cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl,alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl,heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl,alkylthioalkylene, alkenylthioalkylene,alkylthioalkenylene, amino, aminoalkyl, alkylamino,alkenylamino, alkynylamino, arylamino, heterocyclylamino,alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl,arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl,heterocyclylsulfonyl, alkylaminoalkylene,alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene,heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene,aryloxycarbonylarylene, heterocyclyloxycarbonylarylene,alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, 01298 1 80 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene,heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene,arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; orR1 has the formula wherein: i is an integer from 0 to 9; R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylaminoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkylalkylene, aralkyl,alkoxycarbonylalkylene, and alkylaminoalkyl; andR27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene,alkylaralkyl, aralkylarylène, alkylheterocyclyl,alkylheterocyclylalkylene, alkylheterocyclylarylene,aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene,alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene,aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene,alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl,alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl,alkylaminoalkylene, arylaminocarbonylalkylene,alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene,arylaminocarbonylalkylene, alkylaminocarbonylalkylene,arylcarbonylalkylene, alkoxycarbonylarylene, 01298 Ί 81 aryloxycarbonylarylene, alkylaryloxycarbonylarylene,arylcarbonyïarylene, alkylarylcarbonylarylene,alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene,cycloalkylthioalkylene, alkylthioarylene,aralkylthioarylene, heterocyclylthioarylene,àrylthioalklylarylene, arylsulfonylaminoalkylene,alkylsulfonylarylene, alkylaminosulfonylarylene; whereinsaid alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl,heterocyclylalkylene, alkylheterocyclylarylene,alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene,aryloxycarbonylarylene, arylcarbonyïarylene,alkylthioarylene, heterocyclylthioarylene,arylthioalklylarylene, and alkylsulfonylarylene groupeare optionally substituted with one or more radicalsindependently selected from alkyl, halo, haloalkyl,alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR2®R29 wherein R26 is alkoxycarbonyl, and R29is selected from aralkyl, aralkoxyalkylene,heterocyclylalkylene, alkylheterocyclylalkylene,alkoxycarbonylalkylene, alkylthioalkylene, andaralkylthioalkylene; wherein said aralkyl andheterocylcyl groups are optionally substituted with oneor more radicals independently selected from alkyl andnitro; or R26 and R27 together with the nitrogen atom to whichthey are attached form a heterocycle, wherein saidheterocycle is optionally substituted with one or moreradicals independently selected from alkyl, aryl,heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are Ο 1298 1 82 optionally substituted with one or more radicaleindependently selected from halogen, alkyl and alkoxy;and R2 is selected from hydrido, halogen, alkyl, alkenyl, 5 alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl,aralkyl, alkylheterocyclyl, heterocyclylalkyl,alkylamino, alkenylamino, alkynylamino, arylamino,heterocyclylamino, heterocyclylalkylamino, aralkylamino,aminoalkyl, aminoaryl, aminoalkylamino, 10 arylaminoalkylene, alkylaminoalkylene, arylaminoarylene,alkylaminoarylene, alkylaminoalkylamino, cycloalkyl,cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,arylthio, heterocyclylthio, carboxy, carboxyalkyl,carboxycycloalkyl, carboxycycloalkenyl, 15 carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl,alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino,alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;wherein the aryl, heterocyclyl, heterocyclylalkyl, 20 cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independentlyselected from halo, keto, amino, alkyl, alkenyl, alkynyl,aryl, heterocyclyl, aralkyl, heterocyclylalkyl,epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, 25 aralkoxy, haloalkyl, alkylamino, alkynylamino,alkylaminoalkylamino, heterocyclylalkylamino,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,arylsulfonyl, and aralkylsulfonyl; or R2 has the formula: 30 R30
I •C—CCH-Pj- R3^
H
I c
I
L R
-N ,33 (III) wherein: j is an integer from 0 to 8; and 0 1298 1 83 m is 0 or 1; and R30 and R31 are independently selected from hydrogen,alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl,heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylaminoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; R33 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R3S, R36, R37, R38, R39 and R40 are independentlyselected from hydrocarbon, heterosubstitutedhydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl,alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl,quinolinyl, purinyl,
(IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groupe are optionally substituted with one or more radicale independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, 01298 1 84 carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl,aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino,aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl,alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl oramino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, whereinR4 is optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, alkylthio, arylthio,alkylthioalkylene, arylthioalkylene, alkylsulfinyl,alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene,arylsuifonylalkylene, alkoxy, aryloxy, aralkoxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,nitro, alkylamino, arylamino, alkylaminoalkylene,arylaminoalkylene, aminoalkylamino, and hydroxy; provided R3 is not 2-pyridinyl when R4 is a phenylring containing a 2-hydroxy substituent and when R1 ishydrido; further provided R2 is selected from aryl,heterocyclyl, unsubstituted cycloalkyl and cycloalkenylwhen R4 is hydrido; and further provided R4 is notmethylsulfonylphenyl; or a pharmaceutically-acceptable sait or tautomer thereof. 0 1298 1 85
Also included in the family of compounds of FormulaI are the pharmaceutically-acceptable salts thereof. Theterm "pharmaceutically-acceptable salts" embraces saltscommonly used to form alkali métal salts and to formaddition salts of free acids or free bases. The natureof the sait is not critical, provided. that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula Imay be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, nitric, carbonic, sulfuric andphosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclyl, carboxylic and sulfonicclasses of organic acids, example of which are formic,acetic, propionic, succinic, glycolic, gluconic, lactic,malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic,pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acid.
Suitable pharmaceutically-acceptable base addition saltsof compounds of Formula I include metallic salts andorganic salts. More preferred metallic salts include,but are not limited to appropriate alkali métal (groupla) salts, alkaline earth métal (group lia) salts andother physiological acceptable metals. Such salts can bemade from aluminum, calcium, lithium, magnésium,potassium, sodium and zinc. Preferred organic salts canbe made from tertiary amines and quaternary ammoniumsalts, including in part, tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- 0 1 298 1 86 methylglucamine) and procaine. Ail of these salts may beprepared by conventional means from the correspondingcompound of Formulas I-III by reacting, for example, theappropriate acid or base with the compound of Formulas I- 5 III.
General Svnthetic Procedures
The compounds of the invention can be preparedaccording to the following procedures of Schemes I-XVIII 10 wherein R1, R2, R3, R4, R5 and Ar1 are as previously definedfor the compounds of Formula I, IX, X and XI except whereexpressly noted.
SCHEME I
5 6 15
Scheme I shows the synthesis of pyrazole 5 by two 01298 ί 87 routes. Condensation of the pyridylmethyl ketone 1 withaldéhyde 2 in the présence of a base, such as piperidine,in a solvent, such as toluene or benzene, either in theabsence or the presence of acetic acid at reflux, 5 provides the a,β-unsaturated ketone 3. In route 1,ketone 3 is first converted to epoxide 4, such as bytreatment with hydrogen peroxide solution at roomtempérature, in the presence of base such as sodiumhydroxide. Treatment of epoxide 4 with hydrazine in10 éthanol or other suitable solvent at a température ranging up to reflux, yields pyrazole 5. In route 2,ketone 3 is condensed directly with tosyl hydrazide inthe presence of an acid such as acetic acid, at reflux,to provide pyrazole 5. Alternatively, the intermediatetosyl hydrazone 6 may be isolated, conversion of it topyrazole 5 is effected by treatment with a base, such aspotassium hydroxide, in a suitable solvent, such asethylene glycol, at a température ranging from 25 °C upto 150 °C. 15 01-298 1 88
SCHEME II
12
Scheme II shows the synthesis of pyrazole 12 of the 5 présent invention. The treatment of pyridine dérivative7 with ester 8 in the presence of a base, such as sodiumbis(trimethylsilyl)amide, in a suitable solvent, such astetrahydrofuran, gives ketone 9. Treatment of ketone 9or a hydrohalide sait of ketone 9 with a halogenating 10 agent, such as bromine, N-bromosuccinimide or N- chlorosuccinimide, in suitable solvents, such as aceticacid, methylene chloride, methanol, or combinationsthereof, forms the α-halogenated ketone 10 (wherein X ishalo). Examples of suitable hydrohalide salts include 15 the hydrochloride and hydrobromide salts. Reaction ofhaloketone 10 with thiosemicarbazide 11 (where R6 and R7can be hyrido, lower alkyl, phenyl, heterocyclyl and thelike or where R6 and R7 form a heterocyclyl ringoptionally containing an additional heteroatom) provides 20 pyrazole 12. Examples of suitable solvents for this 01298 1 89 reaction are éthanol and dimethylformamide. The reactionmay be carried out in the présence or absence of base oracid at températures ranging from room température to100 °C.
Thiosemicarbazides which are not commerciallyavailable may be conveniently prepared by one skilled inthe art by first reacting an appropriate amine withcarbon disulfide in the presence of a base, followed bytreatment with an alkylating agent such as methyl iodide.Treatment of the résultant alkyl dithiocarbamate withhydrazine results in the desired thiosemicarbazide. Thischemistry is further described in E. Lieber and R.C.Orlowski, J. Org. Chem., Vol. 22, p. 88 (1957). Analternative approach is to add hydrazine to appropriatelysubstituted thiocyanates as described by Y. Nomoto etal-, Chem, Pharm. Bull., Vol. 39, p.86 (1991). TheLieber and Nomoto publications are incorporated herein byreference.
19 01298 1 90
Scheme III shows the synthesis of pyrazole 19 inmore general form by three routes. In Route 1, ketone 13is condensed with hydrazine 14 to give the substitutedhydrazide 16, which is then reacted with acyl halide oranhydride 17 at low température to provide acyl hydrazone18. Upon heating at a température up to 200°C, acylhydrazone 18 is converted to pyrazole 19. In Route 2,acyl hydrazone 18 is formed directly by reaction ofketone 13 with acyl hydrazide 15, formed by reaction ofhydrazine with a carboxylic acid ester, at room température. Heating acyl hydrazone 18 as above thenprovides pyrazole 19. In Route 3, ketone 13 is treatedwith acyl hydrazide 15 at a suitable température, rangingfrom room température to about 200 °C, to give pyrazole19 directly. Alternatively, this condensation may becarried out in an acidic solvent, such as acetic acid, orin a solvent containing acetic acid.
SCHEME IV
1 9 91
Synthetic Scheme IV describes the préparation ofpyrazole 19.
SCHEME V
NaHMDS/THFR4COOMe or R^COOEt
X = halyl, alkyl
R1 = Me, CH2CH2OH R-1 = cyclopropyl, 4-pyridyl, 4-imidazolyl 5
Scheme V shows the two step synthesis of the 3-substituted 4-pyridyl-5-arylpyrazoles 33 of the présentinvention by cyclization of hydrazone dianions withcarboxylates. In step 1, the reaction of substituted 10 pyridylmethyl ketones 31 (prepared, for example, as laterdescribed in Scheme IX) with hydrazines in the presenceof solvents such as éthanol gives ketohydrazones 32.Examples of suitable hydrazines include, but are notlimited to, phenylhydrazine and p-methoxyphenylhydrazine. 15 In step 2, the hydrazones 32 are treated with twoéquivalents of a base such as sodium bis(trimethylsilyl)amide in a suitable solvent such astetrahydrofuran to generate dianions. This reaction maybe carried out at températures of about 0 °C or lower. 01298 1 92
In the same step, the dianions then are condensed withesters such as methyl isonicotinate, methylcyclopropanecarboxylate, to give the desired pyrazoles33. It may be necessary to treat the product from this 5 step with a dehydrating agent, such as a minerai acid, toproduce the target pyrazole in some instances. 01298 1 93
CE τ cc σι cr )-ο >x ΕΞ —+-1 (0φ 4-1 LU Ε Φ
tr> m : l Φ (fl (0 η Ο
ΌΌ φ— Φ +_,>χ ·*-< 3(— 3 4_J (0 +J —Ο - 4_- +-< ω(Λ £)-Û 3 3 ιη ιη c
3II φ +-> φ ΕΞ >s(_ - (0 >χ \_ UZ ο (Ο —>> I- Cφ φ5 ΔΖΟ —~ <0 cr
II m rt (X cr
(D m
X 94
Scheme VI shows an alternative method forsynthesizing pyrazoles which are unsubstituted at the 5position of the ring. In accordance with this method, aheteroarylmethyl ketone 34 is synthesized by firsttreating a.heteroarylmethane with a strong base such aslithium hexamethyldisilazide or lithium diisopropylamide.Examples of suitable heteroarylmethanes are 4- methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine,2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridineand 2-fluoro-4-methylpyridine. The resuitingheteroarylmethyl lithium species is then reacted with asubstituted benzoate ester to produce ketone 34.
Examples of suitable benzoate esters are methyl and ethylp-fluorobenzoate and ethyl and methyl p-chlorobenzoate.Ketone 34 is converted to the aminomethylene dérivative35 by reaction with an aminomethylenating agent such asdimethylformamide dimethyl acetal or tert- butoxybis(dimethylamino)methane. Ketone 35 is convertedto pyrazole 36 by treatment with hydrazine. A modification of this synthetic route serves toregioselectively synthesize pyrazole 38 which contains asubstituted nitrogen at position 1 of the ring. Ketone34 is first converted to hydrazone 37 by reaction withthe appropriate substituted hydrazine. Examples ofsuitable hydrazines are N-methylhydrazine and N-(2-hydroxyethyl)hydrazine. Reaction of hydrazone 37 with anaminomethylenating agent produces pyrazole 38. Examplesof suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tert-butoxybis(dimethylamino)methane.
In cases where the R3 substituent of pyrazoles 36 and38 bears a leaving group such as a displaceable halogen,subséquent treatment with an amine produces an amino-substituted heteroaromatic dérivative. Examples of suchamines include benzylamine, cyclopropylamine and ammonia. 01 298 1 95
The leaving group may also be replaced with othernucleophiles such as mercaptides and alkoxides. Examplesof substitutable R3 groups include, but are not limitedto, 2-chloropyridinyl and 2-bromopyridinyl groups. 5 .01298 ΐ
ιη 0 1 298 1 97
Scheme VII describes the préparation of dérivativesfrom pyrazole 5 (prepared in accordance with Scheme I)when R2 = CH3. Oxidation of pyrazole 5 gives carboxylicacid 39, which is then reduced to hydroxymethyl compound 5 40, or coupled with amine NR1OR1X (wherein R10 and R11 are independently selected, for example, from hydrogen, alkyland aryl, or together with the nitrogen, atom to whichthey are attached form a 4-8 membered ring that maycontain one or more additional heteroatoms selected from 10 oxygen, nitrogen or sulfur) to form amide 41 followed byréduction to generate amine dérivative 42.
SCHEME VIII R3, R2
NH Λ 3
Scheme VIII illustrâtes the synthesis of pyrazoles44 and 45 from pyrazole 43. The alkylation of the ringnitrogen atoms of pyrazole 43 can be accomplished using 20 conventional techniques. Treatment of pyrazole 43 withan appropriate base (for example, sodium hydride)followed by treatment with an alkyl halide (for example,CH3I) yields a mixture of isomers 44 and 45. 01298 1 98
SCHEME IX
48 desoxybenzolη" d i me t hy I f o r ma m I de dlmethyl acetalÇ 4 fο I d excess)tetrahydrofuran C1 volume)
RT
A 9 50 01298 1 99
Scheme IX illustrâtes the synthesis of 3-aryl-4-pyridyl-pyrazoles of the présent invention. Benzoate 46is reacted with pyridine 47 in the presence of a strongbase, such as an alkali métal hexamethyldisilazide(preferably sodium hexamethyldisilazide or lithiumhexamethyldisilazide), in a suitable solvent, such astetrahydrofuran, to give desoxybenzoin 48. Desoxybenzoin48 is then converted to ketone 49 by treatment with anexcess of dimethylformamide dimethyl acetal. Ketone 49is then reacted with hydrazine hydrate in a suitablesolvent such as éthanol to yield pyrazole 50. In SchemeIX, R12 représente one or more radicals independentlyselected from the optional substituents previouslydefined for R4’. Preferably, R12 is hydrogen, alkyl, halo,trifluoromethyl, methoxy or cyano, or représentemethylenedioxy.
The 3-aryl-4-pyrimidinyl-pyrazoles of the présentinvention can be synthesized in the manner of Scheme IXby replacing pyridine 47 with the correspondingpyrimidine. In a similar manner, Schemes X through XVIIcan be employed to synthesize 3-aryl-4-pyrimidinyl-pyrimidines corresponding to the 3-aryl-4-pyrimidinyl-pyrazoles shown in those schemes. 01298 1 100
SCHEME X
52
Scheme X illustrâtes one variation of Scheme IX that5 can be used to synthesize 3-aryl-4-pyridyl-pyrazoles that are further substituted on the nitrogen atom at position1 of the pyrazole ring. If desoxybenzoin 48 (prepared inaccordance with Scheme IX) instead is first converted tohydrazone 51 by treatment with hydrazine and hydrazone 51 10 is then treated with dimethylformamide dimethyl acetal,then the resulting product is pyrazole 52.
Schemes XI through XVIII illustrate furthermodifications that can be made to Scheme IX to synthesizeother 3-aryl-4-pyridyl-pyrazoles having alternative 15 substituents. 101
SCHEME XX
55 56
In Scheme XII, X is chloro, fluoro or bromo; R13 isfor example, hydrogen, alkyl, phenyl, aralkyl,heteroarylalkyl, amino or alkylamino; and R20 is, for 10 example, hydrogen or alkyl. 01298 1 102
SCHEME XIII
59 01298 1 103
SCHEME XV
10
In Scheme XV, n is 1, 2, 3, 4 or 5; and R14 and R15are independently selected from, for example, hydrogen,alkyl or aryl, or together with the nitrogen atom towhich they are attached form a 4-7 membered ring that maycontain one or more additional heteroatoms selected fromoxygen, nitrogen or sulfur.
SCHEME XVI
57 64 01298 1 104
In Scheme XVI, R16 is selected, for example, fromhydrogen, alkyl and phenyl.
SCHEME XVII
4B N-chI orosuceinlmlde dimethylformamide
HN-R 1 7 h2n
I H Y'
In Scheme XVII, R11 is selected, for example, fromalkyl, phenylalkyl and heterocyclylalkyl. 66 10 Ο 1298 1 105
SCHEME XVIXI
72 71
Compounds wherein the 2-position of the pyridinering is substituted by a carboxyl group or a carboxyldérivative may be synthesized according to the proceduresoutline in Scheme XVIII. The starting pyridyl pyrazole67 is converted to the 2-cyano dérivative 68 by first 5 01 298 1 106 conversion to its pyridine N-oxide by réaction with anoxidizing agent such as m-chloroperoxybenzoic acid.Treatment of the pyridine N-oxide with trimethylsilylcyanide followed by dimethylcarbamoyl chloride producesthe 2-cyano compound 68. Compound 68 is converted to itscarboxamide 69 by reaction with hydrogen peroxide in thepresence of a suitable base. Examples of suitable basesinclude potassium carbonate and potassium bicarbonate.Carboxamide 69 is converted to its methyl ester 70 byreaction with dimethylformamide dimethyl acetal inmethanol.· The ester 70 is converted to its carboxylicacid 71 by saponification. Typical saponificationconditions include reaction with a base such as sodiumhydroxide or potassium hydroxide in a suitable solventsuch as éthanol or éthanol and water or methanol andwater or the like. Ester 70 is also convertible tosubstituted amide 72 by treatment with a desired amine,such as methylamine at a suitable température.
Températures may range from room température to 180°C.
In Scheme XVIII, R18 and R19 are independently selected,for example, from hydrogen, alkyl and aryl, or togetherwith the nitrogen atom to which they are attached form a4-8 membered ring that may contain one or more additionalheteroatoms selected from oxygen, nitrogen or sulfur.
The following examples contain detailed descriptionsof the methods of préparation of compounds of Formulas I,XI, X and XI. These detailed descriptions fall within thescope, and serve to exemplify, the above describedGeneral Synthetic Procedures which form part of theinvention. These detailed descriptions are presented forillustrative purposes only and are not intended as arestriction on the scope of the invention. Ail parts areby weight and températures are in Degrees centigradeunless otherwise indicated. Ail compounds showed NMRspectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by 01 298 1 107 nuclear Overhauser effect (NOE) experiments.
The following abbreviations are used: HCl - hydrochloric acid
MgS04 - magnésium sulfate
Na2SC>4 - sodium sulfate
NaIO4 - sodium periodate
NaHSC>3 - sodium bisulfite
NaOH - sodium hydroxide KOH - potassium hydroxide P2°5 ~ phosphorus pentoxide
Me - methyl
Et - ethyl
MeOH - methanol
EtOH - éthanol HOAc (or AcOH) - acetic acid
EtOAc - ethyl acetateH2O - water H2O2 - hydrogen peroxide CH2CI2 - methylene chloride K2CO3 - potassium carbonate KMnO4 - potassium permanganate
NaHMDS - sodium hexamethyldisilazide DMF - dimethylformamide EDC - 1-(3-dimethylaminopropyl)3-ethylcarbodiimindehydrochloride HOBT - 1-hydroxybenzotriazolemCPBA - 3-chloroperoxybenzoic acidTs - tosyl TMSCN - trimethylsilyl cyanideMe2NCOCl - Ν,Ν-dimethylcarbamoyl chlorideSEM-Cl - 2-(trimethylsilyl)ethoxymethyl chlorideh - hour hr - hour min - minutes THF - tetrahydrofuran TLC - thin layer chromatography - 01298 1 108 DSC - differential scanning calorimetry b.p. - boiling point m.p. - melting point eq - équivalent RT - room température
Exemple A-l
4 - [ 5 - C 3-.f I υθΓθ-Ί-methoxypheny I ) - 3-methyI-1H-pyrazol- 4 - y I]pyr idine
Step 1: Préparation of 4-(3-fluoro-4-methoxvlphenvl)-3- pyridyl-3-butene-2-one A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldéhyde (1.25 g, 8.1 mmol), and piperidine(0.13 g, 1,5 mmol) in toluene (50 ml) was heated toreflux. After 18 hours, the reaction was cooled to roomtempérature and the solvent was removed under reducedpressure. The crude product (3.0 g) was purified bycolumn chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4 -(3-fluoro-4-methoxylphenyl)-3 -pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%) .
Step 2: Préparation of 4-[5-(3-fluoro-4-methoxvphenvl)-3- methvl-lH-Pvrazol-4-vn pyridine
To a solution of 3-pyridyl-4-(3-fluoro-4- methoxylphenyl)-3-butene-2-one (step 1) (0.99 g, 3.65
mmol) in acetic acid (25 ml), p-toluenesulfonyl hydrazide(0.68 g, 3.65 mol) was added. The reaction solution washeated to reflux for 6 hours. Acetic acid was removed bydistillation from the reaction solution. The resultingresidue was diluted with CH2CI2 (150 ml), washed with H2O 01 298 1 109 (2x100 ml) , dried (Na2SC>4) , filtered, and concentrated.The crude product (1.5 g) was purified by chromâtography(silica gel, ethyl acetate) to give 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl) pyridine as apale yellow solid (213 mg, 20.7%): Anal. Calc'd forC16H14N3OF.O.I H2O: C, 67.41; H, 5.02; N, 14.74. Found:C, 67.37; H, 4.88? N, 14.35.
Exemple A-2
4-C3-methy I -5-phenyI -1H-pyrazot- 4-y 1)pyridine
Step 1: Préparation of 4-pyridylacetone 4-Pyridylacetone was prepared according to the method of Ippolito et al, U.S. Patent 4,681,944.
Step 2: Préparation of 4-phenyl-3-(4-pyridyl)-3-butene- 2-one
Using the procedure of Example A-l, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL)containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78 %) wasobtained as a crystalline solid: m. p. 101-103 °C. Anal.Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Step 3: Préparation of 4-phenyl-3-(4-pyridyl)-3,4- epoxv-2 -butanone
Using the procedure of Example A-l, step 2, a solution of 4-phenyl-3-(4-pyridyl)- 3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated 01298 1 110 with 30% aqueous hydrogen peroxide (1 ml) in the presenceof sodium hydroxide (230 mg, 5.7 mmol). The crudeproduct was purified by chromâtography (silica gel, 1:1ethyl acetate/hexane) to give 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (270 mg, 20%).
Step 4: Préparation of 4-(3~methyl-5-phenvl-lH-pyrazol- 4-vl)pyridine
Using the procedure of Example A-l, step 3, asolution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone(step 3) (250 mg, 1 mmol) in éthanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated toreflux for 4 hours. The crude product was purified bychromatography (silica gel, 1:1 acetone/hexane). Theproduct was recrystallized from ethyl acetate and hexaneto give 4-(3-methyl~5-phenyl-lH-pyrazol-4-yl)pyridine(81 mg, 35%) as a crystalline solid: m. p. 212-214 °C.Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57;N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.
Example A-3
4 - [5-methyI -3-C2-methyIphenyI J-1H-pyrazol-4-y1]pyridine
Step 1: Préparation of 4-(2-methvlphenyl)-3-(4-pyridyl)- 3-butene-2-one A solution of 4-pyrridylacetone (Example A-5, step1) (0.75 g, 5.56 mmol), o-tolualdehyde (0.73 g, 5.56 mmol) and piperidine (100 mg) in toluene (50 ml) washeated to reflux. Water generated during the reactionwas removed by a Dean-Stark trap. After heating at 01298 1 111 reflux for 5 hours, the reaction mixture was stirred atroom température for 15 hours. The mixture wasconcentrated to an orange color oily residue. The crudeketone was purified by chromatography to give 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one: Anal. Calc'dfor C16H15NO (237.30): C, 80.98; H, 6.37; N, 5.90. Found:C, 80.78; H, 6.61; N, 5.85.
Step 2: Préparation of 4-(2-methylphenvl)-3-(4-pyridyl)- 3,4-epoxy-2-butanone
To a solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one (step 1) (1.0g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H2O2 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4ml) was added. The reaction was stirred at roomtempérature for 70 hours. After methyl alcohol wasremoved, water (25 ml) and ethyl acetate (100 ml) wereadded and the two phase mixture was stirred for 30minutes. The layers were separated, and the aqueouslayer was washed with ethyl acetate (100 ml) . Thecombined organic layer was dried with Na2SC>4, filteredand concentrated to give an oil. 4-(2-Methylphenyl)-3- (4-pyridyl)-3,4-epoxy-2-butanone was isolated from theoil residue by chromatography.
Step 3: Préparation of 4-[5-methyl-3-(2-methylphenyl)1H- pyrazol-4-yl]pyridine A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol(50 ml) was heated at reflux for 20 hours. The solventwas removed and the resuiting residue was purified bychromatography to give 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N3(249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84. 01298 1 112
Example A-4
4 - [5-methyI - 3-Ç 4-fIuoropheny I 3-1H-py r a z o I - 4- y l ] py r idi ne
By following the method of Example A-3 and5 substituting p-fluorobenzaldéhyde for o-tolualdehyde, the titled compound was prepared: Anal. Calc'd for C15H12N3F+ 0.1 H2O: (249.32): C, 70.63; H, 4.82; N, 16.47. Found:C, 70.63; H, 4.78; N, 16.40. 10 Exemple A-5
4 - [ 5-methy I. - 3-C4~methy Ipheny I } - 1H-pyrazo l-4-y1]pyridi ne
By following the method of Example A-3 (with oneminor modification: in Step 2, the préparation of the 15 intermediate epoxide was accomplished at 0-10 °C for 1 hour, and the reaction was quenched by being partitioned 01298 1 113 between water, containing 2 eq. sodium bisulfite, andethyl acetate) and substituting p-tolualdehyde for o-tolualdehyde, the titled product was isolated: Anal.Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 5 16.85. Found: C, 76.97; H, 6.09; N, 16.90.
4-[5-methyl-3-[4-£methylthlo}phenyIJ-'lH-pyrazol-4-y'1]pyr idi ne 10 By following the method of Example A-5 and substituting 4-(methylthio)benzaldehyde for p-tolualdehyde, the titled product was prepared: Anal.Calc'd for C16H15N3S (281.38): C, 68.30; H, 5.37; N,14.93. Found: C, 68.34; H, 5.09; N, 14.78. 01298 1 114
Example A-7
4 - [3-Ç 4 -c hloropheny! 5-5 - methyI -1H-pyrazol-4-yl]pyri dine 5 By following the method of Example A-5 and substitutingp-chlorobenzaldehyde for p-tolualdehyde, the titledproduct was obtained. Anal. Calc'd for C15H12N3CI(269.77): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.43;H, 4.44; N, 15.78.
4 - [3-methyI-5-C3-methyIphenyI1H-pyrazol-4-y1]pyr idine
By following the method of Example A-5 and substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C16H15N3 + 0.2H2Û: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, 15 01 298 1 115 6.05; N, 16.38.
Exemple A-9
4 - [ 5-C2, 5-dlmethy Ipheny Q-3-methy I -IH-pyrazol- 4-y 1]pyridi ne
By following the method of Example A-5 andsubstituting 2,5-dimethylbenzaldehyde for p-tolualdehyde,the titled product was obtained: Anal. Calc'd for 10 C17H17N3 + O.IH2O: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51.
Example A-10
4-[5-C1,3-benzodIoxoI-5-y 4)-3-methyI -1H-pyrazol-4-y1]pyr idi ne 4-Pyridylacetone (1.5 g, 12 mmol), piperonal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene 15 01298 1 116 (30 mL) and heated for 2 hours at reflux in a flaskequipped with a Dean-Stark trap. The solution was cooledto room température, and ethyl acétate was added toprecipitate a solid, which was collected on a filterplate (1.25 g). A sample (500 mg) of this solid washeated with p-toluensulfonyl hydrazide (348 mg, 1.81mmol) in acetic acid (5 mL) at 80 °C for 1 hour. Thereaction was heated to reflux for 1 hour. The reactionwas cooled to room température and the solvent wasevaporated. The residue was dissolved in ethyl acetate,washed with 5% aqueous potassium carbonate, and water.
The organic layer was dried (MgSC>4) , filtered andevaporated to.obtain a yellow solid. This solid wastriturated with methylene chloride, yielding 4-(5-(1,3-benzodioxol-5-yl)-3-methyl-lH-pyrazol-4-yl]pyridine whichwas collected on a filter plate (220 mg, 42% yield).
Anal. Calc'd for C16H13N3O2: C, 68.81; H, 4.69; N, 15.04.Found: C, 68.02; H, 4.54; N, 14.76. MS (M+H); 280 (basepeak).
4 - [3-methyl-5-(4-phenoxyphenyl ) -1H-pyrazol-4-y-l]pyr idine 4-Pyridylacetone (1.5 g, 12 mmol), 4-phenoxybenzoldehyde 92.1 g, 10.6 mmol), acetic acid (110mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) weredissolved in toluène (30 mL) and heated for 2 hours at - 0129Ô1 117 reflux in. a flask equipped with a Dean-Stark trap. Thesolution was cooled to room température and ethyl acetatewas added to precipitate a solid, which was collected ona filter plate. A sample (223 mg) of this solid was 5 heated with p-toluensulfonyl hydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium hydroxide (77 mg)at 110 °C for 0.5 hour. The work up procedure was thesame as that in Example A-10. 4-[3-Methyl-5-(4- phenoxyphenyl)-lH-pyrazol-4-yl]pyridine was obtained (100 10 mg, 66% yield): Anal. Calc'd for C21H17N3O + 0.1 H2O: C, 76.62; H, 5.·27; N, 12.76. Found: C, 76.37; H, 5.19; N,12.64. MS (M+H): 328 (base peak).
Example A-12
4 - [5-[ [ 1, 1 -bipheny I ]-4-y1]-3-methy I1H-pyrazol-4-y1]pyridine
The same procedure as for the préparation of ExampleA-10 was used, substituting 4-formylbiphenyl in place ofpiperonal, to give 4-[5-[(1,1' -biphenyl)-4-yl]-3-methyl- 20 ΙΗ-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 312 (base peak).
4 - [3-methyI -5 - [3-Cphenoxypbenyl3 -1H-p y r a z ο I - 4 - y13 p y ri d i ne 01 298 1 118
The same procedure for the préparation of Example A-10 was used, substituting 3-phenoxybenzaldehyde in placeof piperonal, to give 4-[3-methyl-5-[3-(phenoxyphenyl)-lH-pyrazol-4-yl]pyridine as a white solid.
Exemple A-14
4 -[3-methyI - 5-[3-CPhenyI me thoxy)phenyI J -1H-pyrazol-4-y1]pyr dîne
The same procedure for the préparation of Example A-10 was used, substituting 3-benzyloxybenzaldehyde in 10 place of piperonal, to give 4-[3-methyl-5-[3- (phenylmethoxy)phenyl]-lH-pyrazol-4-yl] pyridine as awhite solid: MS (M+H): 342 (base peak).
Exemple A-15
4-[3-methy l-5-[2-fphenyImethoxyJ-pheny l]-1H-pyrazol-4-y 1]pyr idi ne
The same procedure for the préparation of Example A-10 was used, substituting 2-benzyloxybenzaldehyde inplace of piperonal, to give 4-[3-methyl-5-[2- 01298 1 119 (phenylmethyloxy)phenyl] -lH-pyrazol-4-yl] pyridine. MS(M+H): 342 (base peak). 5 Example A-16
3-methyl-4-C4-pyrIdinypyrazoI - 4-y 4]pheno I
The same procedure for the préparation of Example A-10 was used, substituting 2-hydroxybenzaldehyde in placeof piperonal, to give 2-[3-methyl-4-(4-pyridinyl)-1H- 10 pyrazol-4-yl]phénol : MS (M+H): 252 (base peak).
3-[ 3-methyl-4-Ç4-pyr i d i nyI)- 1H-pyrazo l-4-y1]phenoI
The same procedure for the préparation of Example A-15 10 was used, substituting 3-hydroxybenzaldehyde in place of piperonal, to give 3-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phénol : MS (M+H): 252 (base peak). 01298 1 120
Example A-18
1-hydroxy-4-[3-methyI -5-phenyI - 1H-pyrazo,-4-y1]pyridinium
To a solution of 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine (Example A-2) (2.06 g, 8.76 mmol) in a 5 mixture of CH2CI2 (10 mL) and MeOH (20 mL), was added 3-chloroperoxybenzoic acid (57-86%) (2.65 g, 8.76 mmol).
The reaction was stirred at room température for 2h,quenched with K2CO3 solution (25%, 15 mL), andconcentrated. The resulting residue was partitioned 10 between EtOAc (2.0 L) and H2O (500 mL). The organic layer was separated, washed with H2O (500 mL), dried overMgSC>4, filtered and concentrated to give l-hydroxy-4-[3-methyl-5-phenyl-lH-pyrazol-4-yl]pyridinium (1.12 g,54.5%); MS (M+H): 252 (base peak). 15
Example A-19
5 - C 4 - fIuorophenyl}-N,N-dimethyl - 4 - C 4 -pyr idi ny l}-1l-l-pyrazol-3~ami ne 01298 1 121
Step 1: Préparation of 1-fluoro-4-(4'- pyridvlacetyl)benzene
To a solution of sodium bis(trimethylsilyl)amide(200 mL, 1.0 M in THF) at 0 °C was added a solution of 4-picoline (18.6 g, 0.20 mol) in dry THF (200 mL) over 30minutes. The reaction mixture was stirred at 0-10 °C foranother 30 minutes, then was added to a solution of ethyl4-fluorobenzoate (16.8 g, 0.10 mol) in dry THF (200 mL)at such a rate that the internai température didn'texceed 15 °C. After the addition, the resulting yellowsuspension was stirred at room température for 3 hours.Water (600 mL) was added and the aqueous phase wasextracted with ethyl acetate (3 X 200 mL). The comhinedorganic layers were washed with brine, dried overmagnésium sulfate and filtered. The filtrate wasconcentrated in vacuo to give l-fluoro-4-(4'- pyridylacetyl)benzene (19.9 g, 92 %) as an oil whichsolidified upon standing: m.p.: 90-91 °C; Anal. Calc'dfor C13H10FNO: C, 72.55; H, 4.68; N, 6.51. Found: C,72.07; H, 4.66; N, 6.62.
Step 2: Préparation of l-fluoro-4-(4'- pyridylbromoacetyl)benzene
To a solution of 1-fluoro-4-(4'- pyridylacetyl)benzene (step 1) (10.0 g, 0.046 mol) in acetic acid (200 mL) was added a solution of bromine (8.2g, 0.052 mol) in acetic acid (20 mL) dropwise. Thereaction mixture was stirred at room températureovernight. After the solvent was removed, the residuewas triturated with ethyl acetate. A yellow solidformed, which was filtered and air-dried to give 1-fluoro-4-(4'-pyridylbromoacetyl)benzene (14.5 g). Thecompound was used in next step without further purification.
122
Step 3: Préparation of 5-(4-fluorophenvl)-N, N-dimethyl- 4-(4-pyridinvl)-lH-pyrazol-3-amine A mixture of l-fluoro-4-(4'-pyridylbromoacetyl)- benzene (step 2) (3.8 g, 0.01 mol) and 4,4-dimethylamino- 5 3-thiosemicarbazide (1.2 g, 0.01 mol) in éthanol (10 mL)was heated at reflux for 30 minutes. The dark greensolution was cooled and poured into water (100 mL). Theaqueous phase was extracted with methylene chloride (100mL). The combined organic layers were washed with brine, 10 dried over magnésium sulfate, filtered, and concentrated.The resulting residue was purified by chromâtography(silica gel, ethyl acetate) to give 0.3 g 5-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridinyl)-lH-pyrazol-3-amine (0.3 g, 11 %) as a light yellow solid: m.p.: 245- 15 247 °C. Anal. Calc'd for C16H15FN4: C, 68.07; H, 5.36; N, 19.84. Found; C, 68.00; H, 5.37; N, 19.61.
Exemple A-20
H N— Ph 5-C 4-fIuorophenyI)-N-phenyI-4-(4-pyridinyl)-1H-pyrazol-3-aniin« 5-(4-Fluorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine was prepared by the same procedure asdescribed for Example A-19: m.p. 218-219 °C. Anal.Calc'd for C20H15FN4 + 0.1 H2O: C, 72.33; H, 4.61; N,16.87. Found: C, 72.16; H, 4.56; N, 16.77. 20 01298 1 - 123
Exemple A-21
4-[5-C4-fluorophenyl3-3-phenyl-1H-pyrazol-4-y1]pyridine
Step 1: Préparation of l-fluoro-4-(40- pyridylacetyl) benzene N-benzoylhvdrazone
To a solution of benzoic hydrazide (1.36 g, 0.01mol) in THF (20 mL) was added 1-fluoro-4-(4'-pyridylacetyl)benzene (2.15 g, 0.011 mol) in one portionfollowed by a drop of conc. HCl. The reaction mixturewas stirred at room température overnight. There waswhite precipitate formed, which was filtered, washed withether and air-dried to give l-fluoro-4-(4'-pyridylacetyl)benzene N-benzoylhydrazone (2.90 g, 79 %)as a mixture of cis and trans (ratio, 1:9) isomers.
Step 2: Préparation of 4-[5-(4-fluorophenvl)-3-phenyl- lH-pyrazol-4-νΙΊ pvridine l-Fluoro-4-(4'-pyridylacetyl)benzene N-benzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180 °C under N2 for 15 minutes, then cooled. Theresulting solid was purified by chromâtography (silicagel, 1:1 ethyl acetate/hexane) to give 4-[5-(4-fluorophenyl)-3-phenyl-lH-pyrazol-4-yl]pyridine (0.25 g,53 %) as a pale yellow solid: m.p.: 265-267 °C. Anal.Calc'd for C20H14FN3 + 0.25 H2O: C, 75.10; H, 4.57; N,13.14. Found: C, 74.98; H, 4.49; N, 12.87. 01 298 1 124
Example A-22
4 -[5-C3-methyIphenyI ) - 3 - C t ri f Iuoromethy I)-1 H-pyrazο I - 4- y 1Jpyr idine
Step 1: Préparation of 3-(4'-pyridylacetyl)toluene 3-(4'-Pyridylacetyl)toluene was prepared by the sanie5 method as described for Example A-19, step 1 in 70% yield.
Step 2: Préparation of trifluoroacetvl hvdrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.1010 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in éthanol (25 mL) was heated at reflux for 6 hours. Solvent wasremoved and the resulting residue was dried in vacuum togive trifluoroacetyl hydrazide (12.3 g, 96 %) as a clearoil which solidified upon standing. 15
Step 3: Préparation of 4-[5-(3-methvlphenvl)-3- (trifluoromethyl)-lH-pyrazol-4-vllpvridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 20 0.01 mol) was heated at 200 °C under N2 for 15 minutes.
The crude residue was purified by chromâtography (silicagel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-4-yllpyridine (0.56 g) as a white solid: m.p. 237-239 ’C. 25 Anal. Calc'd for C3.6H12F3N3: C, 63.36; H, 3.99; N, 13.85. 01298 1 125
Found: C, 63.6; H, 4.00; N, 13.70.
Example A-23
4 - [ 3- C 4 - f I uor op he'ny 1 }-4~C4-pyr ldi ny I ) -1H-pyrazol-5-y1]pyr i d i ne A mixture of 1-fluoro-4-(4'-pyridylacetyl)benzene(1.0g, 4.6 mmol) and isonicotinic hydrazide (0.63 g, 4.6mmol) in THF (25 mL) was heated to dissolution and thenevaporated to dryness. The resulting solid was heated 10 first to 140 °C, which caused a phase change, and subsequently melted on further heating until 180 °Cwhereupon a solid crystallized out. The reaction wasimmediately cooled, diluted with 10 % HCl (50 mL) andwashed with chloroform. The aqueous layer was 15 neutralized with bicarbonate and a tan colored solid wasprecipitated out. The solid was purified by treatmentwith activated carbon (Darco®) in boiling MeOH (100 mL) ,followed by filtraticn and concentration, to give 4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]pyridine 20 (1.05 g, 69 %) as a shiny tan solid: m, .p. 304 °C (DSC). Mass (MH+) 137 (100%) . Anal. Calc'd for C19H13N4F. ,1/4H2O C, 71 .13; H, 4 .24; N, 17.46. Found: C, 70.88; H, 3.87; N, 17.38. 012984 126
Exemple A-24
4 - C5-cyc I o h 8 x y I }-3-methy I - 1 H-p y r a z ο I - 4 - y 1 )p y r id ine
Step 1: Préparation of 4-cyclohexyl-3-pyridyl-3-butene- 2-one 5 4-Cyclohexyl-3-pyridyl-3-butene-2-one was prepared by the method of Example A-l, step 1 by replacing of 3-fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde.
Step 2: Préparation of 4-(5-cyclohexyl)-3-methyl-lH- 10 pyrazol-4-vl)pyridine 4-(5-Cyclohexyl)-3-methyl-lH-pyrazol-4-yl)pyridine was prepared by the method for Example A-l, step 2, byreplacing 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one with 4-cyclohexyl-3-pyridyl-3-butene-2-one 15 (Step 1): Thial. Calc'd for C15H19N3: C, 73.56; H, 7.98;N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98.
4 - [ 5 - Ç 3-fIuoro-5-methoxypheny I}-3-methyl-1H-pyrazol-4-y1]pyr i d i ne 20 01298 1 127 4-{5-(3-Fluoro-5-methoxyphenyl)-3-methyl-3-methyl-lH-pyrazol-4-ylJpyridine was prepared by the method ofExample A-l, steps 1 and 2 by replacing 3-fluoro-p-anisaldehyde with 3-fluoro-m-anisaldéhyde : Anal. Calc'd 5 for C16H14N3OF: C, 67.83; H, 4.98; N, 14.83. Found: C,67.68, H, 4.92; N, 14.92.
The following examples (No 26-55) listed in Table 1were prepared by the procedures described above: 01298 1 128
Anal.Calc'd 1 Anal. Calo'd (oalod/found)
Formula
No 26 R1 R2 R3 R4 m.p. orDSC(°Ç 27 28
29 H 31 •|ch3 33 35 36 37 38 39 40 41 42 43 H2 ^Cc>ch3 -Ha.
•*CH3 | 'zÛn I 185-186 142-144 c«h19n3
Ci6H15N3 77.95/ 77.51 75.71/ 75.69 6.90/ 6.93 6.16/ 6.11 15.15/ 14.73 16.55/ 16.49
'P P
F-.C •{ch3 •1ch3 4ch3 4ch3 1ch3 4ch3 “ET“ •vQ JCH3c
Hs» •ICH3 240-242
c22h19n3.0.25HjO 80.09/ 79.74 5.96/ 5.90 12.74/ 13.01 •1 ch3 228.8 C«H12N3F3 63.36/ 63.28 3.99/ 3.73 13.85/ 13.69 P 1 11896 c15h12n3c
0.15H-)Q 66.13/ 65.98 4.55/ 4.31 15.42/ 15.74 p- P | zÇlc, y. 171.6 88.6 188.8 215.7 Y* !© P. N , NQ. '?CL-
l^N
Ç©''· P 210.7 252.5 •1ch3 •|ch3 |-CH2CH3 •|ch3 196.3 •|ch3 252.8 •|ch3 198.5 c17h17n3
.0.2H,O C16H14N3C1 c16h14n3f
Ci7H17N3
C17H17N3O2.0.25H2O
c15h12n4oJ
0.25H2Q c17h18n4
C17Hl5N3O
Ci5H12N3F 76.49/ 76.69 67.72/ 67.35 71.89/ 71.72 77.54/ 77.24 68.10/ 67.92 63.26/ 63.59 73.35/ 72.61 73.63/ 73.43 57.34/ 57.09 6.57/ 6.53 4.97/ 5.29 5.28/ 5.45 6.51/ 6.80 5.88/ 5.65 4.42/ 4.39 6.52/ 6.79 5.45/ 5.46 3.85/ 3.79 4.78/ 5.01 15.74/ 15.61 14.81/ 15.02 15.72/ 15.77 15.96/ 15.71 14.01/ 13.65 19.67/ 19.31 20.13/ 19.59 15.15/ 15.19 13.37/ 13.06 16.59/ 16.76 P -p -p ÇFj 225.6 219.5
Ci5H12N3F: C16H12F3N,
b, N 227.7 Ci«Hi}N3 .0. lH.jp 71.13/ 70.74 4.78/ 4.66 16.59/ 16.44 63.36/ 63.19 76.53/ 76.53 3.99/ 4.07 6.10/ 6.20 13.85/ 13.38 16.73/ 16.49 71.13/ 71.23 01298 1 129 R1 R3 R3 R4 m.p. orDSC(°C AnaLCalc'd Formula Anal. Calc'd (calcd/found) C H N H •1-CHj Vb <^,N 175.6 c16h15n3o .0.15H2O 71.70/ 71.92 5.75/ 5.76 15.68/ 15.29 H •Vch2ch: Vh 1<,N -iQ — C17H19N3 77.54/ 77.13 6.51/ 6.28 15.96/ 15.69 H •Vch3 i<^F 412.1 c15hun3f2 66.42/ 66.12 4.09/ 3.86 15.49/ 15.25 H •i-CH3 <^,N 168.5 C17H17N3O .O.lSHjO 72.40/ 72.39 6.18/ 5.87 14.90/ 14.50 H 4>ch3 k>,N ^CF, 211.2 C16H12N3F3 •0.2H-)O 62.62/ 62.64 4.07/ 4.06 13.69/ 13.35 H •Vch3 1<,N X_ — C13HuN3S 64.71/ 64.44 4.59/ 4.58 17.41/ 17.27 H •Vch3 Vh C^C, 189.2 Ci5HuN3C12 59.23/ 59.22 3.65/ 3.24 13.81/ 13.81 H •Vch3 ’<,N lCrcl 211.7 c15h12n3ci ,0.15H2O 66.13/ 66.33 4.55/ 4.62 15.42/ 15.05 > H •Vch3 »5^N 219.8 Ci«H14N3C1 64.11/ 63.85 4.717 4.69 14.02/ 13.93 H -•^o-s »5>N 163.4 Οΐ9Η17Ν3θ2α 64.32/ 63.98 4.83/ 5.08 11.84/ 11.80 * -VcHj '"©F H — c15h12n3f ,0.2H2O 70.15/ 70.18 4.86/ 4.60 16.35/ 16.47 5 H <<zN H — c14h10n3f 70.28/ 69.97 4.21/ 3.84 17.56/ 17.53 0 125 8 Ί 130
The following pyrazoles could be prepared by theprocedures described above:
Example A-56 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl] pyrimidin-2-amine;
Example A-57 5-[3-methyl-5-(3-methylphenyl)-lH-pyrazol- 4-yl]pyrimidin-2-amine;
Example A-58 5-[3-methyl-5-(2-methylphenyl)-lH-pyrazol- 4-yl]pyrimidin-2-amine ;
Example A-59 5-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyrimidin-2-amine ;
Example A-60 5-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyrimidin-2-amine ;
Example A-61 5-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol- 4-yl]pyrimidin-2-amine ;
Example A-62 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine;
Example A-63 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine;
Example A-64 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine ;
Example A-65 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine ;
Example A-66 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine;
Example A-67 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol-4-yl]pyridin-2 -amine ;
Example A-68 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-amine;
Example A-69 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]-2-methoxypyridine;
Example A-70 2-methoxy-5-[3-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine;
Example A-71 2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine;
Example A-72 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- on g ,.· '· ή. π "'-G V»·/ 131 4-yl]-2-methoxypyridine;
Example A-73 2-methoxy-4-[3-methyl-5-(3-methylphenyl)-ΙΗ-pyrazol-4-yl]pyridine;
Example A-74 2-methoxy-4-[3-methyl-5-(2-methylphenyl)-lH-pyrazol-4-yl]pyridine;
Example A-75 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]-2-methoxypyridine;
Example A-76 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol- 4-yl]-2-methoxypyridine;
Example A-77 2-methoxy-4-[3-methyl-5-(4-methylphenyl)-ΙΗ-pyrazol-4-yl]pyridine;
Example A-78 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-ol;
Example A-79 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-ol;
Example A-80 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-ol;
Example A-81 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-ol;
Example A-82 4-[5-(4-chlorophenyl)-3-methyl-IH-pyrazol- 4-yl]pyridin-2-ol;
Example A-83 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol- 4-yl)pyridin-2-ol;
Example A-84 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridin-2-ol;
Example A-85 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-methanamine;
Example A-86 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-y1]pyridine-2-methanamine;
Example A-87 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-methanamine;
Example A-88 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-methanamine;
Example A-89 4-[5-(4-chlorophenyl) -3-methyl-lH-pyrazol- 4-yl]pyridine-2-methanamine;
Example A-90 4-[5-(4-fluorophenyl) -3-methyl-lH-pyrazol- 01298 1 132 4-yl]pyridine-2-methanamine;
Example A-91 4-[5- (4-methoxyphenyl) -3-methyl-lH-pyrazol- 4-yl]pyridine-2-methanamine;
Example A-92 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-93 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-94 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-95 4-[5-(2-methylphertyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-96 4-[5-(4-chlorophenyl) -3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-97 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2 -carboxamide;
Example A-98 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol- 4-yl]pyridine-2-carboxamide;
Example A-99 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl- ΙΗ-pyrazol-4-yl]pyridine;
Example A-100 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl- lH-pyrazol-4-yl]pyridine;
Example A-101 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl- lH-pyrazol-4-yl]pyridine;
Example A-102 4-[5-(2,3-dihydrobenzofuran-6-yl)-3- methy1-lH-pyrazol-4-yl]pyridine;
Example A-103 4-[5-(benzofuran-6-yl)-3-methyl-lH- pyrazol-4-yl]pyridine;
Example A-104 4- [5-(3-fluoro-5-methoxyphenyl)-3-methyl- lH-pyrazol-4-yl]pyridine;
Example A-105 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl- lH-pyrazol-4-yl]pyridine;
Example A-106 4-[5-(l-cyclohexyen-l-yl)-3-methyl-lH- pyrazol-4-yl]pyridine;
Example A-107 4-[5-(1,3-cyclohexadien-l-yl)-3-methyl-lH- pyrazol-4-yl]pyridine;
Example A-108 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl- 01298 1 133 2-methyl-4- (3-methyl-5-phenyl-ΙΗ-pyrazol- 2-methoxy-4-(3-methyl-5-phenyl-ΙΗ-pyrazol- lH-pyrazol-4-yl]pyridine;
Example A-109 4-(5-cyclohexyl-3-methyl-lH-pyrazol-4- yl)pyridine;
Example A-110 4-[5-(4-methoxy-3-methylphenyl)-3-methyl- lH-pyrazol-4-yl]pyridine;
Example A-lll 4-[5-(3-methoxy-4-methylphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine;
Example A-112 4-[5-(3-methoxy-5-methylphenyl)-3-methyl· IH-pyrazol-4-yl]pyridine;
Example A-113 4-[5-(3-furanyl)-3-methyl-lH-pyrazol-4- yl]pyridine;
Example A-1144-yl)pyridine;
Example A-1154-yl)pyridine;
Example A-116 methyl 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-2-carboxylate;
Example A-117 4-(3-methyl-5-phenyl-IH-pyrazol-4- yl)pyridine-2 -carboxamide;
Example A-118 1-[4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyridin-2-yl]ethanone;
Example A-119 N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-2-amine;
Example A-120 3-methyl-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine;
Example A-1.214-yl)pyridine;
Example A-122 methyl 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-3 -carboxylate;
Example A-123 4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyridine-3-carboxamide;
Example A-124 1-(4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyridin-3-yl]ethanone;
Example A-125 3-bromo-4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyridine;
Example A-126 N,N-dimethyl-4-(3-methyl-5-phenyl-lH- 3-methoxy-4-(3-methyl-5-phenyl-IH-pyrazol- 01298 1 134 pyrazol-2-yl)pyridin-3-amine;
Example A-127 2-methyl-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidine;
Example A-128 4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyrimidine;
Example A-129 2-methoxy-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidine;
Example A-130 4-(3-methyl-5-phenyl-lH-pyrazol-4- yl)pyrimidin-2 -amine ;
Example A-131 N,N-dimethyl-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidin-2-amine ;
Example A-132 4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5- phenyl-ΙΗ-pyrazole;
Example A-133 3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazole;
Example A-134 4-(3-furanyl)-3-methyl-5-phenyl-lH- pyrazole;
Example A-135 3-methyl-5-phenyl-4-(2-thienyl)-1H-pyrazole;
Example A-136 4-(2-furanyl)-3-methyl-5-phenyl-lH- pyrazole;
Example A-137 4-(3-isothiazolyl)-3-methyl-5-phenyl-1H- pyrazole;
Example A-138 4-(3-isoxazolyl)-3-methyl-5-phenyl-lH- pyrazole;
Example A-139 4-(5-isothiazolyl)-3-methyl-5-phenyl-lH- pyrazole;
Example A-140 4-(5-isoxazolyl)-3-methyl-5-phenyl-lH- pyrazole;
Example A-141 3-methyl-5-phenyl-4-(5-thiazolyl)-1H- pyrazole;
Example A-142 3-methyl-4-(5-oxazolyl)-5-phenyl-lH-pyrazole;
Example A-143 2-methyl-4-[3-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine;
Example A-144 4-(1-methyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 01298 1 135 10 15
Example A-145 4-(3-phenyl-lH-pyrazol-4-yl)pyridine;
Example A-146 2-methyl-4-(3-phenyl-lH-pyrazol-4-yl)pyridine;
Example A-147 4-[3-(3-chlorophenyl)-l-methyl-pyrazol-4- yl]pyridine;
Example A-148 4- [3-(4-chlorophenyl)-l-methyl-pyrazol-4- yl]pyridine;
Example A-149 4-[3-(3-chlorophenyl)-lH-pyrazol-4- yl]pyridine;
Example A-150 4-(3-(4-chlorophenyl)-lH-pyrazol-4- yl]pyridine;
Example A-151 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-2- methylpyridine;
Example A-152 4-[3-(3-fluorophenyl)-1-methyl-lH-pyrazol- 4-yl]pyridine;
Example A-153 4-[3 -(3-fluorophenyl)-IH-pyrazol-4- yl)pyridine; and
Example A-154 4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4- yl]-2-methylpyridine. 20 25
The compounds of Examples A-155 through A-172 weresynthesized in accordance with the chemistry describedabove (particularly Scheme II) and illustrated by many ofthe previously disclosed Examples by sélection of thecorresponding starting reagents :
5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-1H- 01 298 1 136 pyrazol-3-amine: DSC 261 °C. Anal. Calc'd for C2OH15C1N4+ 0,25 H2O (MW 351.32): C, 68.38, H, 4.30, N, 15.95.Found: C, 68.25, H, 4.41, N, 15.74.
5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-lH-pyrazol-3- amine : (MW 287 DSC 260 °C. 62 . Anal. .77, H, Cale'd for C1SH13C1N4 + 0.125 H2O . 00) : C, 4.57, N, 19. .52 . Found: C, 10 62.78, H, 4 .33, N, 19.22.
5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine dihydrate: DSC 230 °C. Anal. Calc'd forC16H1SC1N4 + 2 H2O (MW 334.81): C, 57.40, H, 4.52, N, 16.73.Found: C, 57.72, H, 4.85, N, 16.54. 15 01298 1 137
Exemple λ-158
5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 227 °C. Anal. Calc'd for C16H15FN4 + 5 0.125 H2O (MW 284.57): C, 67.53, H, 5.31, N, 19.69.
Found: C, 67.60, H, 5.20, N, 19.84.
N, N-dimethyl-5-(3-methylphenyl) -4-(4-pyridinyl)-1H-pyrazol-3-amine : DSC 222 °C. Anal. Calc'd for C17H1BN4 + O. 25 H20 (MW 282.86): C, 72.19, H, 6.41, N, 19.81. Found:C, 71.99, H, 6.46, N, 19.90. 10 138
N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -lH-pyrazol-3amine: DSC 226 °C. Anal. Calc'd for C16H16N4 + 0.125 H2O 5 (MW 266.58): C, 72.09, H, 6.05, N, 21.02. Found: C,72.12, H, 6.12, N, 20.83.
10 N-ethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -lH-pyrazol-3-amine: DSC 227 °C. Anal. Calc'd for C17H18N4 + 0.125 H2O (MW 280.61): C, 72.77, H, 6.47, N, 19.97. Found: C,72.63, H, 6.40, N, 19.73. 0 1298 1 139
N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 234 °C. Anal. Calc'd for C19H22N4 5 (MW 306.41): C, 74.48, H, 7.24, N, 18.29. Found: C,74.12, H, 7.18, N, 18.13.
10 5-(4-chlorophenyl)- N,N-diethyl-4-(4-pyridinyl)-1H- pyrazol-3-amine : m.p. 260-261°C. Anal. Calc'd forC18H19C1N4 (MW 326.83): C, 66.15, H, 5.86, N, 17.14.Found: C, 66.03, H, 5.72, N, 17.23.A[ 01 298 1 140
4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3- yl]morpholine : DSC 279 °C. Anal. Calc'd for C18H17C1N4O + 5 0.25 H2O (MW 345.32): C, 62.61, H, 4.96, N, 16.23. Found: C, 62.52, H, 4.77, N, 16.52.
10 5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl)-lH-pyrazol-3- amine : DSC 244 °C. Anal, , Calc'd for C17H17C1N4 + 0.125 H20 (MW 315 .06): C, 64. 81, H, 5.44, N, 17.78. Found: C, 64.94, H, 5.43, N, 17.78. 01298 1 141
Isolated as 5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl)-lH-pyrazol-3-amine hydrate (2:1): DSC 237 °C. 5 Anal. Calc'd for C21H17C1N4 + 0. 5 H2O (MW 369.86): C, 68.20, H, 4.63, N, 15.15. Found: C, 68.09, H, 4.55, N,15.15.
Isolated as 5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4-pyridinyl)-lH-pyrazol-3-amine monohydrate: DSC 223 °C.Anal. Calc'd for C17H17C1N4O + H2O (MW 346.82): C, 58.87, H,4.94, N, 16.15. Found: C, 58.59, H, 4.79, N, 16.02.
01 298 T 142
1,1-dimethylethyl 4-[5-(4-chlorophenyl)-45 lH-pyrazol-3-yl]-1-piperazinecarboxylate:
Anal. Calc'd for C23H26C1N5O (MW 439.95): C,5.96, N, 15.92. Found: C, 62.40, H, 5.82, (4-pyridinyl)-DSC 251 °C.62.79, H, N, 15.82.
Isolated as 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H- pyrazol-3-yl]piperazine trihydrochloride: DSC 99 °C. 01298 1 143
Anal. Calc'd for C18H18ClN4 + 3 HCl (MW 449.21): C, 48.13,H, 4.71, N, 15.59. Found: C, 47.76, H, 5.07, N, 15.51.
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-methylpiperazine ·. m.p. 247-249 °C. Anal. Calc'd forC19H2oC1N5 + 0.75 H2O (MW 367.33): C, 62.12, H, 5.49, N,19.06. Found: C, 62.45, H, 5.86, N, 19.32.
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)- lH-pyrazol-3-yl]-1-piperazinecarboxylate: m.p. 243-244 0 1298 1 144 °C. Anal. Calc'd for C23H26FN5O2 + 0.5 CH3CH2CO2CH2CH3 (MW467.55): C, 64.22, H, 6.47, N, 14.98. Found: C, 63.90,H, 6.61, N, 14.88.
1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]piperazine trihydrochloride: m.p. 204-206 °C. Anal. 10 Calc'd for C18H18Fn5 + 3 HCl + 0.5 H20 (MW 441.77): C, 48.94, H, 4.79, N, 15.85. Found: C, 48.66, H, 4.88, N,15.50. 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3- 15 yl]piperazine: m.p. 264-265 °C. Anal. Calc'd for C18H18C1N5 + 0.125 H2O (MW 342.08): C, 63.20, H, 5.30, N,20.47. Found: C, 63.04, H, 5.36, N, 20.33.
Additional compounds that vzere synthesized in 20 accordance with the chemistry described in Scheme II bysélection of the corresponding starting reagents furtherinclude the compounds disclosed in Table 2. 01298 1 145 TABLE 2 DSC υ M •8 182 259 S L217 J 220 232 220 N.D. O CS P CS o es -g 00 s© s ^r ΡΠ r- xf- s© r* en Ό m m 00 Z rr v© ô <N <© r-4 *a 'C <r 19. SA w c-' cale Ό o es CS O A* en 00 m en 00 r* *<r Os en ¥•4 t-* V© Z o CS s© a S£> »»< 19. SA oô »—4 ’S <s 8 s© »A 4.86 .04 a- 00 00 a es es A A S s K SA sa S© A 'O V© A «A ’T •3 63 § H cale 4.96 5.60 4.56 6.12 4.65 <3 A A H s© 5.81 5.65 00 A 4.53 s 1 00 SA en en .45 sa s© Os A s© Ό 00 00 OS r* Os r- m υ O <n Os Ό 00 «f S© 3 § v—4 Ό '09 00 A CS Ό A •St cale 1.63 X 3 .75 a 00 ♦M Ό S S S© es 00 O\ ’SJ· υ SA Os s© oo s· \o s S s S 59. 62. A «’f O o Formula a SA § en i »A o a A fS 6 i § o a «n CS i r·^ a (S O A 1 i o ? s en g Q 00 a s ê B s 25H3O C1N5O3 § A <? ! a 2H25 C1FN5O2 O a »A r- o • A CM S H19C14N5-3HC1 ffi δ O n S s© 55 Pi o O ♦M s? Fs Q »-4 ♦H kj U 0 U υ U υ υ u b <9 b a •o a a a a a a a a a a a S Φ Ü 8 S £ Sch. Sch. Sch. Sch. a Sch. Sch. Sch. Sch. Sch. φ ί ¢9 -173 -174 -175 -176 •177 178 179 180 T—4 00 CS 00 m 00 M W < < « « < « « < < < i 4 < 0-1298 1 146
N-[5-(4-chlorophenyl)-4-[2-(phenylmethyl)amino]-4-5 pyridinyl]-lH-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3- yl]-4-(phenylmethyl)piperazine 10 01298 1 147
Isolated as 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride
1,1-dimethylethyl [3-[ [5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]amino]propyl]carbamate 01298 1 148
Isolated as N- [5-[4-chlorophenyl)-4-(4-pyridinyl)-1H-5 pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate
10 1,1-dimethylethyl [2-[ [5-(4-chlorophenyl)-4-(4- pyridinyl)-lH-pyrazol-3-yl]amino]ethyl] carbamate 01298 $ 149
1,1-dimethylethyl 4- [5-(4-chlorophenyl)-1- (2-5 hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-1- piperazinecarboxylate
1,1-dimethylethyl 4- [5-(4-fluorophenyl)-4- (4-pyrimidinyl)-lH-pyrazol-3-yl]-1-piperazinecarboxylate 10 01 298 1 150
1,1-dimethylethyl [3- [ [5- (4-chlorophenyl)-4-(2-fluoro-4-5 pyridinyl)-lH-pyrazol-3-yl]amino]propyl]carbamate
1-[5-(4-chlorophenyl)-4- (4-pyridinyl)-lH-pyrazol-3-yl]-4-10 ethylpiperazine ο 1298 1 151
5 N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]- 1,2-ethanediamine
The compounds of Examples A-184 through A-189 weresynthesized in accordance with the chemistry described 10 above (particularly in Schemes I and IV) and illustratedby the previously disclosed Examples by sélection of thecorresponding starting reagents :
4 -[3 -(2,6-difluorophenyl)-5-methyl-lH~pyrazol-4- yllpyridine: Anal. Calc'd for C^H^F^: C, 66.42; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; m.p. 01298 1 152 236.67 °C.
5 4-[3-(3-ethylphenyl)-5-methyl-lH-pyrazol-4-yl]pyridine:
Anal. Calc'd for C17H17N3 : C, 77.54; H, 6.51; N, 15.96.Found; C, 77.16; H, 6.27; N, 15.69. m.p. (DSC): 189.25°C. 10 Exemple A-186
4- [3-(3-chlorophenyl)-5-ethyl-lH-pyrazol-4-yl]pyridine:Anal Calc'd for C16H14ClN3«0.1 mole H2O: C, 67.15; H, 4.91;N, 14.33. Found: C, 66.95; H, 5.00; N, 14.36. DSC: 15 176.18 "C. 01298 1 153
4-[3-ethyl-5-(3-ethylphenyl)-lH-pyrazol-4-yl]pyridine: 5 Anal. Calc'd for C18H19N3*0.1 mole H2O: C, 77.44; H, 6.93; N, 15.05. Found: C, 77.39; H, 6.94; N, 14.93. m.p.(DSC): 192.66 «C.
4-[3-(4-chlorophenyl)-5- (1-methylethyl)-lH-pyrazol-4-yl] pyridine: Anal. Calc'd for C17H16ClN2«0.4M EtOAc: C,67.08; H, 5.81; N, 12.62. Found: C, 67.40; H, 6.15; N,12.34. 01298 1 154
5 4- [3-cyclopropyl-5-(4-fluorophenyl)-lH-pyrazol-4- yl]pyridine: Anal. Calc'd for C17H14FN3 : C, 73.1; H, 5.05; N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63; m.p.: 239-240 °C. 10 The compound of Example A-190 was synthesized in accordance with the chemistry described above(particularly in Scheme III) and illustrated by thepreviously disclosed Examples by sélection of thecorresponding starting reagents :
This compound was prepared by the same procedure as 4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-lH-pyrazol-4- yl]pyridine 20 01298 1 155 described for Example A-22 by replacing 3-(4'-pyridylacetyl)toluene with 1-fluoro-4-(4'-pyridylacetyl)benzene (prepared as set forth in Example A-19). 5 Anal. Calc'd for C1SH9F4N3 : C, 58.64; H, 2.95; N, 13.68. Found: C, 58.57; H, 3.07; N, 13.31. m.p. (DSC):281.94 °C.
The compounds of Examples A-191 through A-198 were10 synthesized in accordance with the chemistry described above (particularly in Scheme V) by sélection of thecorresponding starting reagents:
4- [5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine
Step 1: Préparation of 1-(4-fluorophenyl)-2-(4- 20 pyridinvl)ethanone methvlhvdrazone
luoropheny l)-2-Ç4-pyr idi ny l)ethanone methy Ihydrazone 01298 1 156 Το a solution of 4-fluorobenzoyl-4'-pyridinylmethane (8.60 g, 0.04 mol) and methyl hydrazine (2.14 g,0.044 mol) in 50 mL of éthanol was added two drops ofconcentrated sulfurie acid. The reaction mixture wasstirred at room température overnight. After the removalof solvent, the residue was partitioned between ethylacetate and water. The organic layer was washed withsaturated sodium carbonate solution, washed with brine,and dried over magnésium sulfate. The filtrate wasconcentrated and the crude product was recrystallizedfrom diethyl ether and hexane to afford 7.5 g of a yellowsolid product (77% yield), 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone methylhydrazone.
Step 2; Préparation of 4-Î5-(cvclopropvl-3-(4- (fluorophenvl)-1-methyl-lH-pyrazol-4-vil pyridine
To a solution of sodium hexamethyldisilazide (5.5 mL·, 1.0 M in THF) at 0 °C was added a solution of thecompound prepared in step 1 (0.67 g, 0.0028 mol) in 10 mLof dry THF dropwise. The dark brown solution was stirredat this température for 30 minutes. Then a solution ofmethyl cyclopropanecarboxylate (0.34 g, 0.0034 mol) in 5mL of dry THF was added. The reaction mixture wasallowed to warm up to room température and stirred for 3hours. Water was added and the aqueous phase wasextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane/acetone, 10:9:1) to give 0.45 g ofproduct, 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine, as a light yellow solid (55% yield), mp : 129-130 °C; lH NMR (CDCL3) : δ 8.53 (m, 2H), 7.32 (m, 2H) , 7.14 (m, 2H) , 6.97 (m, 2H), 4.00 (s, 3H), 1.83 (m, , 1H) , 0.95 (m, 2H) , 0.36 (m, 2H); Anal. Calc'd For CieH: l6FN3 : C, 73.70; H, 5 .50; N, 14.32. Found: C, 01298 1 157 73.63; H, 5.57; N, 14.08.
5 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H- pyra zole-1-éthanol
Step 1: Préparation of 1-(4-fluorophenyl)-2-(4- pyridinvl)ethanone (2-hydroxyethyl)hydrazone
1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-hydroxyethyI)hydrazone
To a flask containing hydroxyethyl hydrazine (3.4 g,0.04 mol) at 80 °C was added 4-fluorobenzoyl-4'-pyridinylmethane (8.6g, 0.04 mol) portionwise. The yellow oïlwas stirred at this température overnight. The cooled 15 reaction mixture was dissolved with hot ethyl acetate andthen triturated with hexane to give 8.9 g of product, 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2- hydroxyethyl)hydrazone, as a yellow crystal (81%), mp:122-123 °C. 012981 158
Step 2: Préparation of 1-(4-fluorophenyl)-2-(4- pyridinvl)ethanone F 2-[[(1,1- dimethylethvl)dimethylsilyl]oxy]ethyl] hydrazone
1-(4-f luorophenyI)-2-(4-pyr Id I nyI)ethanone C 2-[ £ C 1. 1-di methylethyI)dimethyI s i ly I]oxy]ethyI]hydrazone
To a solution of the 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-hydroxyethyl)hydrazone prepared instep 1 (2.73 g, 0.01 mol) and (1,Ι- ΙΟ dimethylethyl)dimethylsilyl chloride (1.5 g, 0.01 mol) in25 mL of DMF was added imidazole portionwise. Thereaction mixture was stirred at room températureovernight. Water was added and extracted with ethylacetate, the organic layer was washed with water, washed 15 with brine, dried over magnésium sulfate and filtered.
The filtrate was concentrated to give 3.8 g of crudeproduct, 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone [2-ί[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]hydrazone,as a yellow oil that was used in the next step without 20 further purification. 01298 1 159
Step 3: 5-cyclopropyl-l-Î2-[f(1,1-dimethylethvl) dimethylsilylloxyl ethyl]-3,4-diphenvl-lH-pyrazole
5-cyclopropyl-l-[Z-[[Cl,1-Olmethylethyl5 almet hy I s l lyl3oxy]ethyl]-3,4-dlphenyt--lH-pyrazole
To a solution of sodium hexamethyldisilazide (4.2 5 mL, 1.0 M in THF) at 0 °C was added a solution of the compound prepared in step 2 (0.78 g, 0.002 mol) in 10 mLof dry THF dropwise. The dark brown solution was stirredat this température for 30 minutes. Then a solution ofmethyl cyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 10 mL of dry THF was added. The reaction mixture was allowed to warm up to room température and stirred for 3hours. Water was added and the aqueous phase wasextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate and
15 filtered. The filtrate was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane, 3:7)to give 0.30 g of product, 5-cyclopropyl-l-[2-[[(1,1-dimethylethyl) dimethylsilylloxylethyl] -3,4-diphenyl-lH-pyrazole, as a light yellow oil (35% yield), *H NMR 20 (CDCLj) : δ 8.53 (m, 2H) , 7.32 (m, 2H) , 7.14 (d, J- 5.6
Hz, 2H), 6.97 (m, 2H), 4.47 (t, J= 4.8 Hz, 2H), 4.14 (t,J = 4.8 Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H) , 0.41(m, 2H) ; Anal. Cale'd For C2SH32FN3OSi: C, 68.61;H, 7.37; N, 9.60. Found: C, 68.39? H, 7.81; N, 9.23. 01298 1 160
Step 4: Préparation of 5-cvclopropvl-3-(4-fluorophenvl)- 4-(4-pvridinvl)-lH-pvrazole-l-ethanol
To a solution of the compound prepared in step 3 (0.27 g, 0.00062 mol) in 5 mL of THF was added
tetrabutylammonium fluoride (1.9 mL of 1.0 M THF solution) at room température. After 1 hour, water wasadded and extracted with ethyl acetate. The organiclayer was washed with brine, dried over magnésium sulfateand filtered. The filtrate was concentrated and purifiedby chromatography on silica gel (ethyl acetate/hexane, 9:1) to give 0.16 g of product, 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-l-ethanol, as apale yellow solid, mp: 155-157 °C; XH NMR (CDCL3) : δ 8.53(br s, 2H), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97(m, 2H), 4.42 (t, J = 4.8 Hz, 2H), 4.14 (t, J = 4.8 Hz,2H), 1.83 (m, TH), 0.93 (m, 2H), 0.35(m, 2H); Anal.
Calc'd For C19H18FN3O: C, 70.57; H, 5.61; N, 12.99. Found:C, 70.46; H, 5.87; N, 12.84.
3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-ΙΗ-pyrazole-1-éthanol
To a solution of sodium hexamethyldisilazide (7.4 mL, 1.0 M in THF) at 0 °C was added a solution of the ο 1298 1 161 compound prepared in step 2 of Example A-192 (1,25 g,0.0034 mol) in 15 mL of dry THF dropwise. The dark brownsolution was stirred at this température for 30 minutes.Then a solution of methyl 4-(2-
methoxy) pyridinecarboxyl.ate (0.0.59 g, 0.0035 mol) in 5mL of dry THF was added. The reaction mixture wasallowed to warm up to room température and stirred for 3hours. Water was added and the aqueous phase wasextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane, 1:1)to give 0.28 g of product, 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-IH-pyrazole-l-ethanol, as a yellow solid, mp: 168-169 °C; XH NMR (CDCL3) : δ 8.42 (m, 2H), 8.20 (dd, J - 0.7, 5.2 Hz, 1H) ,7.37 (m, 2H), 7.02 (m, 2H) , 6.95 (m, 2H) , 6.71 (dd, J = 1.4, 5.2Hz, 1H), 6.66 (t, J » 0.7 Hz, 1H), 4.20 (m, 2H),4.14 (m, 2H) , 3.95 (s, 3H) ; Anal. Calc'd for C22H19FN4O2: C,67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N,14.03.
4-[1-[2- [ [(1,1-dimethylethyl)dimethylsilyl]- oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-lH-pyrazol- 5-yl]-2-methoxypyridine 01298 1 162 A second compound, 4-[1-[2-[[(1,1-dimethylethyl)dimethylsilyl] oxy]ethyl]-3-(4-fluorophenyl-4- (4-pyridinyl)-lH-pyrazol-5-yl]-2-methoxypyridine also wasisolated from the above reaction as a yellow oil by chromatography . *H NMR (CDCL3) : δ 8.45 (m, 2H), 8.20 (m, 1H) , 7.40 (m, 2H) , 7.04 (m, 2H), 6.93 (m, 2H), 6.81 (m, 2H), 4.24 (m, 2H) , 4.14 (m, 2H) , 3.98 (s, 3H), 0.83 (s, 9H) , 0.02 (s, 6H) .
4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]-2(1H)-pyridinone
To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-lH-pyrazole-1-éthanol (0.28 g,0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48%hydrobromic acid. The reaction mixture was heated atreflux for 3 hour. The cooled mixture was then treatedwith water, basified with ammonium hydroxide andextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and purified bychromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1)to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]-2(1H)- 01298 1 163 pyridinone, as a yellow solid (32% yield), mp; 250-251°C; ‘H NMR (DMSO-d6) : δ 11.74 (s, 1H) , 8.45 (d, 5.0
Hz, 2H) , 7.35 (m, 3H), 7.16 (m, 2H) , 7.03 ( d, J = 5.0Hz, 2H), 6.37 (s, 1H), 6.05 (d, J= 5.2 Hz, 1H), 5.0 (m, 5 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2*0.2 H2O: C, 66.06; H, 4.65; N, 14.67. Found: C,66.31; H, 4.49; N, 14.27.
l-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]-2(1H) -pyridinone l-acetyl-4-[3-(4-fluorophenyl) -1-(2-hydroxyethyl)-4-15 (4-pyridinyl)-lH-pyrazol-5-yl]-2(1H)-pyridinone was obtained as a byproduct of the reaction of Example A-194in the form of a yellow solid (38% yield), mp: 220-221°C; ’HNMR (CDC13) s δ 8.50 (m, 2H) , 7.39 (m, 3H) , 7.02 (m,4H) , 6.59 (m, 1H) 6.08 (dd, J - 1.4, 5.2 Hz, 1H) , 4.52(t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 2.04(s,3H); Anal. Calc'd for C23H19FN4O3«0.3' H2O: C, 65.46; H,4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99. 20 01298 1 164
Ethyl 2- [3- (4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylate
To a solution of sodium hexamethyldisilazide (17.0mL, 1.0 M in THF) at 0 °C was added a solution of thecompound prepared in step 1 of Example A-192 (1.37 g, 0.005 mol) in 20 mL of dry THF dropwise. The dark brownsolution was stirred at this température for 30 minutes.Then a solution of diethyl 1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 mL of dry THF was added. Thereaction mixture was allowed to warm up to roomtempérature and stirred for 2 hours. Water was added andthe aqueous phase was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over magnésiumsulfate and filtered. The filtrate was concentrated andpurified by chromatography on silica gel (ethylacetate/hexane, 8:2) to give 0.18 g of product, ethyl 2- [3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yllcyclopropanecarboxylate, as a lightyellow oil (35% yield) , XH NMR (CDCL3) : δ 8.55 (m, 2H) ,7.32 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H), 4.38 (m,2H),4.16 (m, 4H) , 2.47 (m, 1H), 1.53 (m, 2H), 1.26 (t, J=7.0Hz, 3H), (m, 2H), 0.90 (m, 2H); Anal. Calc'd for C22H22FN3O3*0.25 H2O: C, 66.07; H, 5.67; N, 10.51 Found: C, 01298 1 165 65.89; H, 5.80; N, 9.95.
2- [3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylic acid
To a solution of ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylate prepared in accordance withExample A-196 (0.21 g, 0.00045 mol) in 10 mL of methanolwas added a solution of sodium hydroxide (0.09 g, 0.0022mol) in 2 mL of water. The reaction mixture was stirredat reflux for 6 hours. After the solvent was removed,the residue was dissolved with 10 mL of IN HCl andstirred for 30 minutes. The pH was then adjusted to 5-6by addition of IN sodium hydroxide solution and thenextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium and filtered.
The filtrate was concentrated and the crude was purifiedby recrystallization from éthanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylicacid, as a white solid (60% yield), mp: 253-255 °C; XH NMR(CD3OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04(m, 2H), 4.39 (t, J = 5.0 Hz, 2H) , 4.03 (m, 2H), 2.60 (m,1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For 01298 1 166 C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92;H, 4.77; N, 11.20.
3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-éthanol
Step 1: Préparation of methvl 1-[(2-(trimethylsilvl) 10 ethoxvl methvll-lH-pyrrole-3-carboxvlateCO,Ue methyl 1-[[2-(trimethylsilyl)ethoxy]methyl]-lH-pyrrole-3-carboxylate
To a suspension of sodium hydride (1.0 g, 0.025 mol) 15 in 50 mL of DMF was added methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room température. Themixture was stirred at room température for 0.5 hours.Then SEM-C1 (4.17 g, 0.025 mol) was added dropwise over 5minutes. The reaction mixture was stirred for 4 hours 20 and quenched by adding water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnésium sulfate and filtered. The filtrate was concentrated and the crude 0129α1 167 was purified by chromatography on silica gel (ethylacetate/hexane, 8:2) to give 4.0 g of the majorregioisomer as a clear oil. 5 Steo 2: Préparation of 4-fl-Î2-ΓΓ(1,1-dimethvlethyl) dimethylsilyl]oxvl ethyl] -3- (4-fluorophenvl-5- fl-[[(2- trimethvsilvl) ethoxy]methyl-lH-imidizol-4-yll -lH-pyrazol-
TMS 10 4-[1- [2[[(1,1-dimethylethyl)dimethylsilyl]- oxy]ethyl]-3-(4-fluorophenyl)-5-[1-[[2-trimethylsilyl)ethoxy]methyl]-lH-ïmidazol-4-yl]-1H-pyrazol-4-yl]pyridine
To a solution of sodium hexamethyldisilazide (4.5 15 mL, 1.0 M in THF) at 0 °C under Ar was added a solution of the compound prepared in step 2 of Example A-192 (0. 8g, 0.002 mol) in 10 mL of dry THF dropwise. The darkbrown solution was stirred at this température for 30minutes. Then a solution of the compound prepared in 20 step 1 of the présent Example (0.54 g, 0.0021 mol) in 5mL of dry THF was added. The reaction mixture wasallowed to warm up to room température and stirred for 1hour. Water was added and the aqueous phase wasextracted with ethyl acetate. The organic layer was 01298 1 168 washed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and purified bychromatography on silica gel (ethyl acetate/hexane, 8:2)to give 0.98 g of product as a light yellow oil whichsolidified upon standing (91% yield), mp: 79-80 °C; lH NMR(CDCL3) : δ 8.48 (d, J = 6.0 Hz, 2H) , 7.68 (d, J » 1.3 Hz, 1H), 7.38 (d, J = 6.0 Hz, 2H), 7.10 (m, 2H), 7.00 (m, 2H), 6.93 (d, J = 1.3 Hz , 1H), 5.25 (s, 2H), 4.53 (t, J= 6.0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H) , 3.84 (t, J = 8.0
Hz, 2H), 0.92 (t, J = 8.0 Hz, 2H) , 0.84 (s, 9H) , 0.021 (s, 18H) ; Anal. Calc'd For C31H44FN5O2Si2 : C, 62.70; H, 7.47; N, 11.79. Found: C, 62.98; H, 7.74; N, 11.88.
Step 3: Préparation of 3- (4-fluorophenvl)-5-(4- imidazolyl)-4-(4-pyridinvl)-lH-pyrazole-l-ethanol
To a solution of the compound prepared in step 2 of the présent Example (0.54 g, 0.001 mol) in 10 mL of THFwas added a solution of tetrabutylammonium fluoride (1.0M in THF). After the mixture was heated at reflux for 3hours, the solvent was removed and the residue waspartitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnésium sulfateand filtered. The filtrate was concentrated and thecrude product was purified on silica gel (methylenechloride/methanol, 95:5) to give 0.22 g of the product, 3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-éthanol, as a white solid (63% yield), mp:227-228 °C; Ή NMR (DMSO-d6) : δ 8.45 (m, 2H) , 7.83 (s, 1H), 7.35 (m, 2H), 7.15 (m, 4H), 7.09 (s, 1H), 5.20 (brs, 1H), 4.32 (s, 2H), 3.81 (m, 2H); Anal. Calc'd ForC19HX6FN5O : C, 65.32; H, 4.62; N, 20.05. Found: C, 64.98;H, 4.55; N, 19.79.
The compound of Example A-199 was synthesized in accordance with the chemistry described above (particularly in Scheme VI) by sélection of the Ο 1298 1 169 corresponding starting reagents:
5 4- [3- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yl] pyridine
Anal. Calc'd for C1SH12N3C1 (269.74): C, 66.79; H, 4.48; N,15.58. Found: C, 66.57; H, 4.15; N, 15.54. m.p. (DSC):198.17 °C. .0
The compounds of Examples A-200 through A-202 weresynthesized in accordance with the chemistry describedabove (particularly in Scheme VII) by sélection of thecorresponding starting reagents :
5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-carboxylic acid 01298 1 170 A mixture of 4- [3- (4-fluorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine prepared as set forth in Example A-4 (5.83 g, 24.0909 mmol) and potassium permanganate(7.6916 g, 48.1818 mmol) in water (7.5 ml) and tert-butanol (10 ml) was heated at reflux for 6 hours (oruntil ail the potassium permanganate was consumed). Themixture was then stirred at room température overnightand then diluted with water (150 ml) . Manganèse dioxidewas removed from the mixture by filtration. The filtratewas extracted with ethyl acetate to remove unreactedstarting material. The aqueous layer was acidified withIN HCl to increase the pH to about 6. A white precipitate formed, was collected by filtration, washedwith water, and dried in a vacuum oven to give 5- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-carboxylicacid (isolated as the monohydrate sait) (2.9777 g, 43.7%) . Anal. Calc'd for C15H10N3FO2.H2O (283 + 18): C, 59.80;
H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH*) : 284 (base peak) .
5-(4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazole-3-methanol
To a suspension of 5- (4-fluorophenyl)-4- (4-pyridinyl)-lH-pyrazole-3-carboxylic acid, monohydrateprepared in accordance with Example A-200 (0.526 g, 2.0mmol) in dry THF (15 ml) at reflux under nitrogen, asolution of IN lithium aluminum hydride in THF (4.0 ml, 01298 1 . 171
4.0 mmol) was added dropwise over 15 minutes. A
precipitate formed. The mixture was boiled for anadditional hour. Excess lithium aluminum hydride wasthen decomposed by cautiously adding a solution of 4Npotassium hydroxide in water (0.5 ml). Upon hydrolysis,a white sait precipitated. After the addition wascomplété, the mixture was heated at reflux for 15minutes. The hot solution was filtered by suctionthrough a Buchner funnel, and remaining product wasextracted from the precipitate by refluxing with THF (15ml) for 1 hour, followed again by suction filtration. Thecombined filtrâtes were concentrated under reducedpressure. The resulting residue was taken into ethylacetate, washed with water and brine, dried over MgSO4 togive a crude product (0.45 g). Recrystallization of thecrude product from methanol gave 5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-methanol (0.2808 g, 56.5%). DSC:260.26 °C; Anal. Calc'd for C15H12N3FO (269): C, 66.91; H,4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20. MS (MH+) : 270 (base peak) .
1- I [5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3- yl]carbonyl]piperazine 01298 1 172
Step 1; Préparation of 1,1-dimethylethvl 4-[[5-(4-fluorophenvl)-4-(4-pyridinvl)-lH-pyrazol-3-vllcarbonvll- 1-pÎperazinecarboxvlate
To a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-carboxylic acid, monohydrate prepared inaccordance with Example A-200 (0.9905 g, 3.5 mmol) and 1-hydroxybenzotriazole (0.4824 g, 3.57 mmol) in DMF (20 ml)at 0 °C under nitrogen, 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride (0.6984 g, 3.57 mmol,Aldrich Chemical Co.) was added. The solution wasstirred at 0 °C under nitrogen for 1 hour then 1-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) was addedfollowed by N-methylmorpholine (0.40 ml, 3.6 mmol). Thereaction was stirred from 0 °C to room températureovemight. After 19 hours, the solvent was removed underreduced pressure, and resulting residue was diluted withethyl acetate, washed with saturated NaHC03 solution,water and brine, and dried over MgSO4. After filtration,the solvent was removed under reduced pressure to give acrude product (1.7595 g). 1,1-Dimethylethyl 4-[ [5-(4- fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]carbonyl]- 1-piperazinecarboxylate (1.2372 g, 78.4%) was obtained bychromatography. Anal. Calc'd for C24H26N5O3F. (451): C,63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N,15.16. MS (MH+) : 452 (base peak) . 01298 1 173
Step 2: Préparation of 1-[ (5-(4-fluorophenvl)-4-(4- pyridinvl)-lH-pvrazol-3-vl] carbonvl]pjperazine bis(trifluoroacetate), monohvdrate A solution of the compound prepared in step 1(0.1804 g, 0.4 mmol) in methylene chloride (1.0 ml) andTFA ( 0.3 ml) was stirred at room température undernitrogen for 2 hours. The solvent was removed underreduced pressure and TFA was chased by methylene chlorideand methanol. The resulting colorless oily residue wasdried in a vacuum oven overnight to give l-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3- yl]carbonyl]piperazine (isolated as the bis(trifluoroacetate), monohydrate sait) (0.2400g, 100%)as a white solid. Anal. Calc'd for C19H18Ns0F.2CF3COOH.H2O (351 + 228 + 18): C, 46.24; H, 3.71;N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH+) :352 (base peak).
The compounds of Examples A-203 through A-206 weresynthesized in accordance with the chemistry describedabove (particularly in Scheme VIII) by sélection of thecorresponding starting reagents:
4 -(1,5-dimethy1-3-phenyl-ΙΗ-pyrazol-4-yl)pyridine 0 1 298 1 174
4-(1,3-dimethyl-5-phenyl-lH-pyrazol-4-yl]pyridine A 60% dispersion of sodium hydride (41 mg, 0.00172moles) (prewashed with hexane) in minerai oil (69 mg) wasadded with 5 ml of dioxane to a stirred solution of 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine (200 mg, 0.00086moles) (prepared as set forth in Example A-2) in 50 ml ofdioxane. After 3 hours a solution of CH3I (122 mg, 0.00086 mole) in 10 ml dioxane was added and the mixturewas stirred at room température for 20 hours. Themixture was concentrated to a solid. The products werepartitioned between water (15 ml) and ethyl acetate (50ml). The organic layer was dried over Na2SO4, filteredand concentrated to a solid. The products were purifiedand separated by radial chromâtography. NMR (NOEexpérimente) showed that the first component off thecolumn (the minor component) was 4-(1,3-dimethyl-5-pheny1-1H-pyrazol-4-yl]pyridine, and the second material off the column was 4-(1,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine.
Major isomer (4-(1,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine): m.p.: 94-99 °C. Anal, calc'd for C16H15N3»0.1MH2O: C, 77.08; H, 6.06; N, 16.85. Found: C, 76.59; H, 5.70; N, 16.62 01298 1 175
4-[3-(4-chlorophenyl)-1,5-dimethyl-lH-pyrazol-4-yl]pyridine
4- [5-(4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4-yllpyridine (the compound of Example A-32) 10 4- [3- (4-chlorophenyl) -1,5-dimethyl-lH-pyrazol-4- yl]pyridine and 4-[5-(4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4-yl]pyridine were prepared by the same procedureas described for Example A-203 by replacing 4-(3-methyl- 5- phenyl-lH-pyrazol-4-yl)pyridine with 4-(3-(4- 15 chloropheny1)-5-methyl-lH-pyrazol-4-yl)pyridine (prepared as set forth in Example A-7).
Major Isomer (4- [3-(4-chlorophenyl)-1,5-dimethyl-lH-pyrazol-4-yl]pyridine); Anal, calc'd for C16H14N3C1 20 (283.76): C, 67.72; H, 4.97; N, 14.81; Found: C, 67.45; H, 4.71; N, 14.63. m.p. (DSC): 190.67 °C. 01298 1 176
Minor Isomer (4-[5-(4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4-yl]pyridine): m.p.: 82-88 °C. Anal, calc'dfor C16H14N3C1 : C, 67.72; H, 4.97; N, 14.81; Found: C,67.56; H, 4.96; N, 14.73.
4-[5-ethyl-l-methyl-3-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine
4-[3-ethyl-l-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine 4-[5-ethyl-l-methyl-3-(3-methylphenyl)-lH-pyrazol-4-15 yl]pyridine and 4-[3-ethyl-l-methyl-5-(3-methylphenyl)- lH-pyrazol-4-yl]pyridine were prepared by the same procedure as described for Example A-203 by replacing 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine with 4-(3-(4- methylphenyl)-5-ethyl-lH-pyrazol-4-yl)pyridine (prepared 01298 1 177 as set forth in Example A-45).
Major Isomer (4-[5-ethyl-l-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine): Anal. Calc'd for CieH19N03«0.45 5 MHjO: C, 75.73; H, 7.03; N, 14.77. Found: C, 76.03; H,6.87 N, 14.28.
Minor Isomer (4-[3-ethyl-l-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine): Anal. Calc'd for 10 Cl8H19N03«0.30MH20 : C, 76.46; H, 6.99; N, 14.86. Found: C, 76.58; H, 6.98; N, 14.63.
15 4- [3- (4-chlorophenyl)-l-ethyl-5-methyl-lH-pyrazol-4- yllpyridine: Anal. Calc'd for C17HieN3Cl (297.79): C, 68.57; H, 5.42; N, 14.11. Found: C, 68.33; H, 5.27; N,14.08; m.p. (DSC) 164.36 °C. 20 Exemple A-207
C I 01298 1 178 4-(3-(4-chlorophenyl)-2-ethyl-5-methyl-lH-pyrazol-4-yljpyridine: Anal. Calc'd for C17H16N3Cl (297.79): C, 68.57; H, 5.42; N, 14.11. Found: C, 68.25; H, 5.36; N,13.74; m.p. (DSC) 153.46 °C.
The compounds of Examples A-208 and A-209 wereprepared in accordance with the chemistry described above(particularly in Scheme IX):
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] pyridine
Step 1: Préparation of 4-fluorobenzoyl-4f-pyridyl methane
To a mixture of 4-picoline (32.6 g, 0.35 moles) andethyl-4-fluorobenzoate (50.45g, 0.3 moles), maintained at20 °C, was added lithium bis(trimethylsilylamide) (600 mL(IM)) in a steady but rapid stream so as to maintainambient température. The initial yellow solution turnedinto a suspension which was then stirred for an additional 2 hours. Toluene (250 mL) was added and themixture cooled to 0 °C. The reaction mixture wasquenched with concentrated HCl at 0 °C to lower the pH toabout 7. The organic layer was separated and the aqueouslayer re-extracted with of toluene (100 mL). The organiclayer was dried (sodium sulfate) and concentrated, tofurnish a yellow solid which on trituration with hexanes (200 mL) provided the pure desoxybenzoin, 4- 01298 1 179 fluorobenzoyl-4'-pyridyl methane, in 90% yield (58g). 1HNMR was consistent with the proposed structure.
Step 2 :
To a suspension of the desoxybenzoin prepared instep 1 (30g, 0.14 moles) in tetrahydrofuran (50 mL) wasadded dimethylformamide dimethyl acetal (50 mL) and themixture stirred at ambient température for two days. Thesolution was then concentrated to dryness and the solidpaste obtained was triturated with hexanes (150 mL) tofurnish a yellow solid which was of sufficient purity (asdetermined by NMR) and was used for the next step withoutadditional purification. Yield: 33.9 g (90%) . *H NMR wasconsistent with the proposed structure.
Step 3 :
The vinyl amine prepared in step 2 (33.9g, 0.1255moles) was dissolved in 125 mL of éthanol and cooled to 0°C. Hydrazine hydrate (8.0g of anhydrous or 16.0g. ofhydrate, 0.25 moles) was then added in one portion. Themixture was stirred well and allowed to warm up toambient température for a total reaction time of 3 hours.The mixture was concentrated and taken up in 200 mL ofchloroform. After washing with water (100 mL), theorganic layer was extracted with 150 mL of 10% HCl. Thewater layer was then treated with 0.5 g of activatedcharcoal at 70 °C for 10 minutes, filtered through celiteand neutralized cautiously to pH 7 - 8 with vigorousstirring and cooling (20% sodium hydroxide was used). The fine off-white precipitate was filtered and dried to give4- (3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine. Yield:27.3g. (91%). Mass spectrum: m/z = 240. 1H NMR wasconsistent with the proposed structure. Anal, calc'd forC14H10FN3 : C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H,4.33; N, 17.61. 01298 1 180
4-[3-(2-chlorophenyl)-lH-pyrazol-4-yl]pyridine 5 This compound was prepared by the same procedure described for Example A-208 using the correspondingstarting reagents.
Anal. Calc'd for C14H10ClN3 : C, 65.76; H, 3.94; N, 16.43. 10 Found: C, 65.22; H, 3.91; N, 16.50. m.p. (DSC): 208.46°C.
The compounds of Examples A-3W.0 and A-211 illustrate 15 were prepared in accordance with the chemistry describedabove (particularly in Scheme X) :
20 3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-1-éthanol 01298 1 181
The desoxybenzoin prepared in step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridyl methane, (12.7g, 0.059moles) was mixed with 90% hydroxyethyl hydrazine (5.3g,0.062 moles) in 30 mL of éthanol containing 0,5 mL ofacetic acid in a 500 mL Erlenmeyer flask. After gentleboiling (1 hour), a small sample was evacuated at highvacuum and examined by lH NMR to confirm completion ofhydrazone formation. On cooling to ambient température,the reaction mass solidified to a yellow cake. DMFdimethylacetal (36 mL, 0.27 moles) was then added and themixture heated to 80C for 10min, at which point ail thesolids dissolved and a clear yellow viscous solution wasobtained. The reaction mixture was immediately allowed tocool slowly to 25 °C, and water (20 mL) was addeddropwise with stirring, at which point a cloudy yellowoily suspension was obtained. The solution was nowwarmed to approximately 50-60 °C, whereupon the solutionturned clear yellow. Slow cooling to ambient températurewith stirring (a crystal seed if available speeds up theprocess) results in a copious formation of crystals.Suction filtration followed by washing with 10% éthanol-water (50 mL) , followed by drying, fumishes 3- (4- fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-1-éthanol as alight yellow crystalline solid. Re-heating the filtrateto clarity as before, followed by cooling, yieldsadditional product. The third and fourth recovery fromthe mother liquor on standing overnight furnishes theremaining 3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole- 1-éthanol. Total yield: {12.3 + 3.3 + 0.4 + 0.4} = 16.4g. (97.6%). Mass spectrum, m/z = 284. Ή NMR wasconsistent with the proposed structure. Anal, calc'd forC16H14FN3O + H20 : C, 63.78? H, 5.35; N, 13.95. Found: C,63.55; H,.5.07; N, 13.69. 01298 1 182
3-(4-fluorophenyl)-4-(4-pyrimidinyl)-lH-pyrazole-1-ethanol
This compound was prepared by the same procedure asdescribed for Example A-210 except that the 4-picolineused to synthesize the desoxybenzoin was replaced with 4-methyl-pyrimidine.
The compound of Example A-212 was prepared inaccordance with the chemistry of Scheme XI :
4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine
The vinyl amine prepared in Step 2 of Example A-208(5.0g, 0.0185 moles) was taken up in éthanol (75mL) andcooled to 0 °C. Methyl hydrazine (1.7g, 0.037 moles) inéthanol (75mL) was added in one portion while maintainingthe température at 0 to 10 °C. After 3 hours at ambienttempérature the solvent was removed and the residue takenup in methylene chloride (150 mL) and water (100 mL). Theorganic layer was separated, dried and concentrated toprôvide the crude regio-isomeric mixture as a light tancolored solid (80:20 by NMR in favor of the titlecompound). The crude isomeric mixture was taken up in10% HCl (100 mL) and washed with methylene chloride (100 01298 1 183 mL) and the water layer treated with activated charcoal(0.5g). After filtration through Celite, the solutionwas neutralized with sodium hydroxide (20%) to pH 8 withgood stirring and cooling. The cream colored precipitate 5 was filtered, washed with water and dried. The solid (5 g) was dissolved in hot 10% heptane/toluene (70 mL) andallowed to cool slowly, first to ambient température andthen to 15 °C. Scratching the sides of the flask startsthe crystallization process. After 2 hours of standing, 10 the solids formed were filtered, washed with cold 50%toluene/heptane (25 mL) followed by hexane (25 mL) anddried to yield the pure title compound. lH NMR confirmedthe structure (including regiochemistry using NOEexpérimenta). Yield: 2.1g. (45%). Mass spectrum, m/z = 15 254 (base peak) . Anal, calc'd for C1SH12FN3 + 0.2 H20 : C, 70.15; H, 4.86; N, 16.4. Pound: C, 70.18; H, 4.6; N, 16.47. 20
The compound of Example A-213 was prepared inaccordance with the chemistry of Scheme XII:
Exemple A-213
N-H HN.
OH 2-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]amino]-1-butanol 01298 î 184
An intimate mixture of 2-fluoro-pyridinyl pyrazole(0.2g, (prepared by the same procedure as described forExample A-210 except that the 4-picoline used tosynthesize the desoxybenzoin was replaced with 2-fluoro-4-methylpyridine) and (R,S)-2-amino-l-butanol (4 foldmolar excess) was heated to 210-220 °C in a sealed vialfor 1.5 hours. After cooling to 100 °C the vial wascautiously opened and 5 mL of toluène and 5 mL of waterwere added and stirred well for 1 hour. The solidobtained, 2-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]amino]-1-butanol, was suction-filtered andwashed with an additional 5 mL of water followed bytoluene and dried. Yield: 190mg. (71%). Mass spectrum,m/z = 343. *H NMR was consistent with the proposedstructure.
The compound of Example A-214 was prepared inaccordance with the chemistry of Scheme XIII ·.
4-[5-bromo-3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine
To a solution of 4-[3-(4-fluorophenyl)-1-methyl-lH- pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80 °C overnight. TLC indicated 01 298 1 185 that the reaction was complété. The mixture was quenchedslowly with K2CO3 (25g). When pH was about 5, aprecipitate was formed. The precipitate was washed withwater (50mL x 5) to give 4-[5-bromo-3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine (1.24g, 35%) : mp 174.38°C;Mass spectrum m/z = 332, 334; lH NMR was consistent withthe proposed structure. Anal. Calc'd for C15HuN3FBr· 0.2H20: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
The compound of Example A-215 was prepared inaccordance with the chemistry of Scheme XIV:
4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2- pyridinecarbonitrile
Step 1 :
To a solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yllpyridine (4.3g, 17.97 mmol) (prepared in accordancewith Example A-208) in methanol (100 mL) was added 3-chloroperoxybenzoic acid (5.44 g in 57 % purity, 17.97mmol). The solution was stirred at 25 °C for overnight.The mixture was concentrated. K2CO3 (10%, 100 mL) wasadded to the residue. A precipitate was formed, filteredand washed with water (30 mL x 3) to give the 01 298 1 186 corresponding N-oxide (3.764g, 81.66%}.
Step 2 :
To a suspension of the N-oxide prepared in step 1(0.40 g, 1.567 mmol) in DMF (5 mL) was addedtrimethysilyl cyanide (0.3 mL, 2.25 mmol). The mixturewas stirred for 15 minutes at 25 °C. Dimethylcarbamylchloride (0.8 mL, 8.69 mmol) was added. The mixture wasstirred at 25 °C for 2 hours. TLC indicated that thestarting materials were gone. The mixture waspartitioned into ethyl acetate:water (100 mL:20 mL). Theorganic layer was washed with K2CO3 (10%, 20 mL), water(50 mL) , brine (50 mL) , dried over MgSO4, f iltered andconcentrated to give 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2-pyridinecarbonitrile (0.23 g, 56 % yield): mp209.22 °C ; Mass speçtrum (chemical ionization): m/z =265; lH NMR was consistent with the proposed structure.Anal. Calc'd for C15H9N4F*0.2 H2O: C, 67.26; H, 3.54; N,20.92. Found: C, 67.44; H, 3.40; N, 20.69.
The compound of Example A-216 was prepared inaccordance with the chemistry of Scheme XV:
Example A-216
4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-1- yl]ethyl]morpholine 01298 1 187
Step 1 : 3-(4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazole-1-ethanol (prepared in accordance with Example A-210) (10.0 g, 0.0353 moles) was suspended in pyridine (100 mL) andcooled to 0 °C. Methane sulfonyl chloride (4.4 g, 0.0388moles) was added slowly while maintaining the températureat 0 °C. After stirring overnight at 10 °C, chilledwater (100 mL) and methylene chloride (150 mL) was addedand the two layers separated. The water layer was re-extracted with 100 mL of methylene chloride and theorganic layer dried and concentrated to a paste. Afterdrying at high vacuum, a light tan colored cake wasobtained which was triturated with ether (75 mL),filtered and dried to furnish a cream colored solid in79% yield (10.1g) . XH NMR was consistent with the proposedstructure. The compound was used as such for step 2.
Step 2 ;
The mesylate prepared in step 1 (5.0g, 0.0138moles) was dissolved in an eight fold excess ofmorpholine (9.6g, 0.11 moles) in methanol (50 mL) andheated at reflux for 3 to 4 hours. After an NMR sampleconfirmed completion, the mixture was concentrated andtaken up in methylene chloride (150 mL) and washed withwater (100 mL) and then with 75 mL of 5% HCl. The waterlayer was neutralized to pH 8 and extracted withmethylene chloride (100 mL). On drying and concentrationa light yellow pasty solid was obtained which wastriturated with 25 mL of ether to furnish a solid. Re-crystallization from toluene/hexane provided 4-[2-[3-(4- fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-1-yl]ethyl]morpholine as a solid. Yield: 4.5g (86%). Massspectrum, m/z = 353. XH NMR was consistent with theproposed structure. Anal, calc'd for C20H21FN4O: C, 68.16;H, 6.01; N, 15.90. Found: C, 68.20; H, 6.21; N, 15.80. Ο 1298 1 188
The compound of Example A-217 was prepared inaccordance with the chemistry of Scheme XVI :
Example A-217
3-(4-fluorophenyl)-l-methyl-a-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol
To solid magnésium (60 mg, 5 mmol) under nitrogen 10 was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol)(prepared in accordance with Example A-214) intetrahydrofuran (7 mL). The mixture was heated at 40 °Cfor 2 hours. Benzaldehyde (1 mL) was added. The mixture 15 was heated to 45 °C for 2 hours. It was quenched with HCl(10 mL, IN) and washed with ethyl acetate. The aqueousacid layer was basified and extracted with ethyl acetate.The organic layer was washed with water, brine, driedover MgSO4, filtered and concentrated to give a residue. 20 The residue was purified with a silica gel column to givethe title compound (59 mg, 12% yield). MS: m/z = 360(M+l); XH NMR was consistent with the proposed structure.Anal. Calc'd for C22H18N2OF»0.6EtOAC: C, 71.1; H, 5.6; N,10.2; Found: C, 70.9; H, 5.47; N, 10.2. 0 1298 1 189
The compound of Example A-218 was prepared inaccordance with the chemistry described above(particularly Scheme XVII):
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-morpholineethanamine
The starting desoxybenzoin prepared in step 1 ofExample A-208, 4-fluorobenzoyl-4'-pyridyl methane, (1.0g, 0.0046 moles) was dissolved in 10 mL of DMF and cooledto -10 °C (dry ice-aqueous isopropanol). N- chlorosuccinimide (0.62 g, 0.0046 moles) was added in oneportion while maintaining the température at -10 °C.
After 5 minutes the thiosemicarbazide (0.0046 moles) wasadded in one portion at 0 °C and allowed to warm toambrent température slowly over 1 hour. After stirringovernight, the solvent was removed at high vacuum andwater and toluene (25 mL each) added and stirred well.
The toluene layer was separated and the water layer (starting pH of 5.5) treated with bicarbonate to pH 8.
The fine precipitate formed was filtered and washed with water, toluene and ether. A final trituration with ether (25 mL) furnished an off white solid, N-[5-(4- fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4- morpholineethanamine, which was re-filtered and dried. 01298 1 190
Yield: 0.95g. (56%). Mass Spec. m/z: 368 (base peak).Anal. Calc'd for C20H22FN5O. C, 65.38; H, 6.04; N, 19.06.Found: C, 64.90; H, 5.92; N, 18.67.
4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] -2(1H)-pyridinonehydrazone 10 Step 1: Préparation of (E)-2-(2-bromo-4-pvridinvl)-N.N- dimethvlethenamine NMez
4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t-butoxybis(dimethylamino)methane (5 ml) were heated to 150 15 °C for 16 hours. 4-Methyl-2-bromopyridine was preparedas set forth in B. Adger et al., J. Chem, Soc.. PerkinTrans. 1, pp. 2791-2796 (1988), which is incorporatedherein by reference. The contents were evaporated andthe residue dissolved in ethyl acetate and washed with 20 water. The organic layer was dried over magnésium sulfate and solvent removed in vacuo to give 1.0 g of(E)-2-(2-bromo-4-pyridinyl)-N,N-dimethylethenamine as an 01298 1 191 oïl suitable for use in step 2.
Step 2: Préparation of (Z)-2-(2-bromo-4-pvridinvl)-1-(3- chlorophenvl)-3-(dimethvlamino)-2-propen-l-one O NMe2
The product from step 1 (1.0 g, 4.4 mmol) wasdissolved in methylene chloride (15 ml). Triethylamine(900 mg, 8.8 mmol) was added at O °C, followed by theaddition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol). 10 The mixture was stirred under nitrogen for 16 hours.Solvent was evaporated in vacuo and the residue wasdissolved in ether (25 ml), stirred with magnésiumsulfate (500 mg) and silica gel (500mg), and filtered.Ether was evaporated and the residue was chromatographed 15 on silica gel using mixtures of acetone and methylene chloride as eluents to give 670 mg of the product, (Z)-2-(2-bromo-4-pyridinyl)-1-(3-chlorophenyl)-3- (dimethylamino)-2-propen-l-one, as a glass which was usedin step 3 without further purification. 20
Step 3: Préparation of 2-bromo-4-Î3-(3-chlorophenvl)-1H-
Pvrazol-4-vllpyridine
Br
N
C I
H 01298 1 192 A solution of the product from step 2 (650 mg, 1.8mmol) and hydrazine monohydrate (100 mg) in éthanol (10ml) was refluxed for 24 hours. Solvent was evaporatedand the residue was chromatographed on silica gel usingmixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]pyridine(190 mg, 31%) as an oil : Anal. Calc'd for C14H9BrClN3 : C,50.25? H, 2.71? N, 12.56. Found: C, 50.10; H, 2.60; N,12.40.
Continued elution with mixtures of ethyl acetate andmethanol gave 4- [3-(3-chlorophenyl)-lH-pyrazol-4-yl]-2(1H)-pyridinone hydrazone (190 mg, 36%) as a crystallinesolid: m.p. 163-164 °C.? MS (M+H) = 286. Anal. Calc'dfor Cx4H12N5Cl: C, 58.85; H, 4.23; N, 24.51. Found: C,58.53; H, 4.28; N, 24.87.
4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl)- 2-pyridinamine A solution of the bromopyridine compound prepared instep 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine(5 ml) was heated at 175 °C for six hours. Aftercooling, excess benzylamine was removed by high vacuumdistillation and ethyl acetate added to the residue.
After washing the organic phase with water and drying over magnésium sulfate, the solvent was removed in vacuo 01298 1 193 and the residue chromatographed on silica gel usingmixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] -N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 °C.
Anal. Calc'd For C21H17C1N4: C, 69.90; H, 4.75; N, 15.53.Found: C, 69.69; H, 4.81; N, 15.11.
4- [3- (3-chlorophenyl)-lH-pyrazol-4-yl] -N-(phenylethyl)-2-pyridinamine A solution of the bromopyridine compound prepared instep 3 of Example A-219 (250 mg, 0.75 mmol) inphenethylamine (5 ml) was heated at 175 °C for six hoursunder a nitrogen atmosphère. The excess amine wasdistilled off under high vacuum and the residue wasdissolved in ethyl acetate and washed with water. Afterdrying over magnésium sulfate and removal of solvent, theresidue was chromatographed on silica gel with mixturesof ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine (230 mg, 81%) as a solid, m.p. 185-186 °C.
Anal. Calc'd For C22H19C1N4: C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66. 01 298 1 194
4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] -N-ethyl-2-pyridinamine 5 A solution of the bromopyridine compound prepared instep 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine(3.5 ml) and éthanol (5 ml) as heated at 150 °C in asealed tube for 9 hours. The solvent was removed in 10 vacuo and the residue chromatographed on silica gel with70 ethyl acetate/30 toluene to give 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2-pyridinamine(125 mg, 46%) as a solid, m.p. 186-187 °C. 15 Anal. Calc'd For C16HlsClN4: C, 64.32; H, 7.06; N, 18.75.Found: C, 64.42; H, 7.01; N, 18.45.
The compounds of Examples A-223 through A-226 weresynthesized in accordance with the chemistry described 20 above (particularly in Scheme XVIII) by sélection of thecorresponding starting reagents; 01298 1 195
Example A-223
4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyr idi ne c arboxami de 5
Step 1 :
To a suspension of 4-[3-(4-fluorophenyl)-IH-pyrazol-4-yl]pyridine (prepared as set forth in Example A-208) (8.8 g, 0.037 mol) in methylene chloride was added m- 10 chloroperoxybenzoic acid ('mCPBA) in one portion at roomtempérature. After stirring for 16 hours, solvent wasremoved and the residue was treated with saturated sodiumbicarbonate solution. The precipitate was filtered, air-dried to give 8.2 g of a product as a white solid (87%), 15 mp: 207-209°C.
Step 2: Préparation of 4-(3-(4-fluorophenyl)-lH-pyrazol- 4-vil-2-pvridinecarbonitrile
To a solution of the product of step 1 (5.1g, 0.02 20 mol) in 20 mL of DMF was added trimethylsilyl cyanide(2.5 g, 0.025 mol), followed by a solution of N, N-dimethylcarbamoyl chloride (2.7 g, 0.025 mol) in 5 mL ofDMF at room température. After stirring overnight, the 01298 1 196 reaction mixture was basified by 200 mL of 10% potassiumcarbonate water solution. The aqueous phase wasextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and the crudewas triturated with hexane and filtered to give 4.3 g of4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2-pyridinecarbonitrile (90%) as a pale yellow solid, mp:238-239°C.
Step 3: Préparation of 4-Γ3-(4-fluorophenyl)-ΙΗ-pvrazol- 4-vl] -2-pvridinecarboxamide:
To a solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4- yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017mol) in 10 mL of DMSO was added hydrogen peroxide (0.24mL of 30% aqueous solution, 1.7 mmol) and potassiumcarbonate (0.04 g, 0.4 mmol) at 0°C. The mixture wasstirred for 1 hour while allowing it to warm to roomtempérature. Water was added and the precipitate wascollected by filtration and air-dried to give 0.32 g of4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2- pyridinecarboxamide as a white solid (67% yield), mp:230-231 °C. Anal. Calc'd for C^H^F^O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Exemple A-224
197
Methyl 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2- pyridinecarboxylate
To a suspension of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth inExample A-223 (2.9 g, 0.01 mol) in 50 mL of methanol wasadded Ν,Ν-dimethylformamide dimethyl acetal (3.67 g, 0.03mol) dropwise. The reaction mixture was stirred at roomtempérature overnight and heated at reflux for 4hours.After cooling, the precipitate was collected byfiltration and air-dried to give 2.0 g of methyl 4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylate as awhite solid (69% yield), mp: 239-241°C. Anal. Calc'd forC16H12FN3O2 : C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide A mixture of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forthin Example A-224 (0.45 g, 1.5 mmol) and 20 mL ofmethylamine (40% aqueous solution) was heated at 120°C ina sealed tube for 16 hours. After cooling, water was 01298 1 198 added and the aqueous phase was extracted with ethylacetate. The organic layer was washed with brine, driedover magnésium sulfate and filtered. The filtrate wasconcentrated to afford 0.4 g of 4-[3-(4-fluorophenyl)-1H- 5 pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a whitesolid, mp: 88-89°C. Anal. Calc'd for C16H13FN4O + 0.4 H2O:C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N,18.35.
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylic acid 15 To a solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4- ylî-2-pyridinecarboxylate prepared as set forth inExample A-224 (0.90 g, 0.003 mol) in 10 mL of éthanol wasadded a solution of sodium hydroxide (0.24 g, 0.006 mol)in 5 mL of water. The reaction mixture was heated at 20 reflux for 10 hours. After the removal of solvent, theresidue was dissolved in water and acidified with citricacid solution to pH 5. Then the aqueous phase wasextracted with ethyl acetate and the organic phase wasdried over magnésium sulfate and concentrated. The crude 25 was purified by treating with ether to give 0.62 g of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylic Û1298 1 199 acid as a white solid (73% yield), mp: 245°C(dec). AnalCalc'd for ClsH10FN3O + 0.2 H20: C, 62.80; H, 3.65; N,14.65. Found: C, 62.77; H, 3.42; N, 14,58. 5 Additional compounds of the présent invention which were prepared according to one or more of above reactionschemes (particularly Schemes IX through XVIII) aredisclosed in Table 3. The spécifie synthesis scheme orschemes as well as the mass spectroscopy and elementalanalysis résulte for each compound also are disclosed inTable 3. 10 01298 1 200 TABLE 3 0 § « | added |[ Microanalysïs <3 •U S |added | 0.25 1 θ·1 0.2 CS O H O 0.1 0.25 0.6 1 0 m » | 16.8 | 14.98 | 16.3 16.52 13.90 15.32 14.9 | 15.4 15·7 i <n μ 14.32 i 13.83 16.31 in en rH 14.01 | 15.32 | 13.27 | 12.05 | 15.82 N cale | 17.2 15.32 in V© H | 16.43 | 13.86 15.58 KO ’φ rM 15.4 15.8 18.84 14.35 in CO en rH 16.33 J in m in H O O r-H 15.49 1 13.37 J 12.31 J 15.93 H found 4.6 4.33 in 3.78 4.31 4.24 m AO 6.5 5.1 3.51 3.91 3.52 3.01 | KO cq en O œ KO Γ0 H in 4« 6.17 H cale ro J 4.41 4.8 3.94 1 4.39 | 4.48 LO KO m KO KO O in 3.58 ! 3.99 3.53 3.31 KO en CO 4.09 3.85 4.81 KO Γ0 Ό 1 Ή a en ko σι KO m KO KO O 65.48 63.95 66.79 oo KO KO KO m KO 0- \c θ' 75.44 61.67 00 OJ Γ9 KO 65.39 61.14 | 55.99 | 66.41 57.22 { 76.16 in vo xl< Ό u «S ü U σ> KO en KO Lf» Ko 1 70.6 65.76 64.18 66.79 σι i© i© σι w Ό 77 75.38 ) 61.52 ' 63.36 65.37 61.44 J 56.02 | 03 KO KO 57.34 f 76.39 | 64.89 MS rH a O M* 03 v© vo 03 254 256 1 280 271 00 03 270 Ό 03 221 290 <*< O ω 258 274 | 300 272 314 03 XC m 341 General V « O 0 n Λ «L 1 IX rxi IX XI IX H π i XI XI IX 1 xi LZ*î IX | IX « IX IX IIX | Example | A-227 | A-228 | A-229 | A-230 | A-231 | A-232 1 A-233 | A-234 | A-235 vo ro 03 1 C | A-237 00 (*) 0, 1 <i 1 A-239 J o Ί« 03 1 4 I A-241 I A-242 1 | A-243 | | A-244 { A-245 ο 1298 1 201 rd O rH O o 0.6 h 0.2 0.25 0.1 0.25 m r-- o 0.75 | rd H 0.4 | 0.75 tH 0.25 | 0.5 | 0.2 CJ 12.01 11.54 13.81 14.34 14.6 20.7 23.32 14.78 14.73 15.84 14.51 ] 17.89 10.99 15.08 20.45 Π 15.83 17.56 J 13.53 1 22.5 14.17 10.15 1 16.8 | 9.89 J 18.7 | 14 12.1 11.63 | 13.85 | 14.47 | 14.73 | 20.9 | 23.55 J 15.49 | 15.02 1 15.72 | r> in rd 17.95 11.06 I 15.88 1 20.66 16.78 18.17 C" ω 22.7 14.42 10.3 17.1 J 10.14 19.1 14.4 2.82 3.51 KD σ\ m | 4.71 4.31 3.4 5.41 4.26 | 3.18 5.24 3.48 6.25 4.98 tn M* ko Ok o kO 4.23 | 6.5 1 4.8 j 5.24 [ r-t kO <# 5,6) 5.28 | 9'9 5.8 2.9 3.35 1 3.99 LO r- r- sP 3.5 1 5.42 1 4.09 | 3.06 00 CN tn 00 6.2 5.17 6.28 6.39 | 4.1 6.28 J 4.47 J 5.2 | 5.71 j 4.82 1 tn tn 5.35 1 en kO 6.3 48.07 49.89 Γ 63.34 (68.17 <N r-l ko KO 1 67.4 ko ko CO tn ko kO | 60.4 71.63 62.41 69.2 72.5 1 70.59 63.76 1 66.77 62.38 62.85 63.2 61.84 70.7 65.3 1 70.13 67.2 63.1 |48.44 49.88 1 63.36 | 68.24 , 66.31 | 67.3 | 64.63 J 66.42 60.11 00 rd 62.28 69.26 72.71 ' 70.81 | 63.79 J 66.18 62.32 , ko KO (N KO 62.9 J 61.85 1 70.66 | 65.8 | 69.95 j 66.9 1 KD ΓΟ KD GO sf* ro 362 304 377 363 265 298 OJ r- KO Γ'· 254 268 o <n tN 311 376 CO tN kO CJ m 400 | 368 302 349 371 404 | 329 406 354 434 XI XI ™ 1 H H X H H X | XIV J XII l· ™ - Xi H X H 1 xi X X, XV XI XII XII IX XII IX XII > X H X XI, XV > X H X H X XI 1 H H H X >xi *. H X 1 A-250 1 A-251 | A-252 | A-253 | A-254 I A-215 | A-255 1 A-256 I A-257 GO in 0« 1 I A-259 J A-260 j rd kO CJ 1 4 I A-262 fn to nj 1 1 A-264 1 I A-265 J I A-266 I A-267 00 ko nj 1 tn ko <s 1 1 A-270 1 H OJ 1 «C I A-272 I 1 A-273 1 A-274 01298 1 202 0.5 in o 0.6 0.5 r4 0.6 | 0.9 Cl O σι o in ci o 0.25 2.25 w r- ,n 0.1 H 0.4 1-s 1 1-3 1 12.05 13.6 16.61 | 14.8 13.7 , 17.21 17.48 J 17.38 Cl σι H 16.2 13.6 j 16.65 17.27 19.09 13.5 | Cl H 14.5 | 16.97 | 16.37 15 13.7 in Cl 14.5 12.64 13.3 18.75 15 13.6 17.86 17.73 | 17.73 kO m H 16.3 14.7 16.6 17.21 tn o en tH 13.8 13 14.5 00 ko r4 16.25 15.2 iH Cl in Cl 14.5 J 6.3 6.1 en m kO ko 6.2 | 5.11 5.63 | 5.43 5.2 en kO 6.2 ko in kO r4 kO 4.5 | 4.9 J 4.2 4.53 | 4.02 4.2 4.3 | c- σι Cl 6.18 6.1 6.48 6.5 6.7 5.37 | 5.55 5.55 tn 6.9 5.7 6.81 7.31 4.52 in 5.3 | 4.2 c- 4.85 | "ί< 4.9 | m 'φ 3.1 C" o c- 66.2 J 63.02 | 63.8 rH kO | 61.47 | 64.94 64.81 r* u> 70.3 68.5 59.69 vo N <0 in 69.4 | 67.5 64.5 | 74.9 61.46 00 en in tn 73.2 | c- c· VD o c- 57.7 | 70.44 65.9 rH rH kO | 64.2 67.4 | 61.27 σι ko ko | 64.63 Cl c- U) 70 68.2 | 59.77 o ko in o σ u> oo ko ko c· r- 61.22 55.75 | 73.6 | σι c- σι o c- 57.9 J 433 U3 l·' 338 357 462 σι σι Cl 313 313 407 339 476 1 382 340 m <01 ci 407 407 290 326 313 278 278 M X XI, XII,XV M K X | XI, XV XI, XII,XV H H X | XII | xii J XI, XII XI, XV j H H H X XVII H H £ XVII H M X M X XI, XII | K l XVII XVII XI xi 1 X M IX L A-275 A-276 J A-277 J A-278 A-279 | A-280 A-281 | A-282 I A-283 A-284 j A-285 | A-286 I A-287 00 00 Ci 1 *< O1 00 Cl «! A-290 | A-291 f | A-292 j A-293 | σι c 1 in σι CJ 1 u> σι Cl 1 «U C' σι Cl 1 -01298 1 203
Exemple A-227
4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyridine 5 Example A-228
4-[3-(1,3-benzodioxol-5-yl)-lH-pyrazol-4-yl]pyridine
Exemple A-229
F
a 10 01298 1 204 4-[3-(3-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine
5 4-[3-(4-chlorophenyl)-lH-pyrazol-4-yl]pyridine
Exemple A-231
4-[3-(1,3-benzodioxol-5-y)-l-methyl-lH-pyrazol-4-yl]pyrid10 ine
3 01298 1 205 4- [3-(4-chlorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine
Exemple A-233
5 4-[3-(3-chlorophenyl)-l-methyl-lH-pyrazol-4-yl]-2-methylp yridine and 4-[5-(3-chlorophenyl)-1-methyl-lH-pyrazol-4-yl]-2-methylpyridine 10 Example A-234
4-[3-(3-chlorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridineand 4-(5-(3-chlorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine 01 298 1 206
2-methyl-4-[l-methyl-3 (or 5) -(3-methylphenyl)-lH-pyrazol-4 -yl]pyridine 5 Example A-236
4-(3-phenyl-lH-pyrazol-4-yl)pyridine
Example A-237
10 4-[3-[3-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl]pyridine 01298 1 207
4- [l-methyl-3-[3-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl] pyridine
Example A-239
4-[3-(3,4-difluorophenyl)-lH-pyrazol-4-yl]pyridine 01298 1 208
4- [3-(4-chlorophenyl)-lH-pyrazol-4-yl] -2-fluoropyridine
4-[3-(4-bromophenyl)-lH-pyrazol-4yl]pyridine
Exemple A-242 10
4-[3-(3,4-difluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridi 01298 1 209 ne
5 4- [3- (4-bromophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine
(E)-4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-(2-phenylethenyl)pyridine 10 Ο 1 298 1 210
(S)-4-[3-(4-chlorophenyl)-lH-pyrazol-4-yl] -N-(2-methylbutyl)- 2-pyridinamine
4-[3-(4-chlorophenyl)-lH-pyrazol-4-yl] -N-[(4-methoxy-phenyl)methyl]- 2-pyridinamine - ο 1298 ΐ 211
Ν- [4- [3-(4-chlorophényl)-lH-pyrazol-4-yl]-2-pyridinyl]-2 -pyr idinemethanamine
N-[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]- 2-pyridinemethanamine
Anal CalC'd: C, 41.12; H, 3.58; N, 9.22. Found: C,41.74; H, 5.05 ; N, 11.11. ο 1298 1 212
2-fluoro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine
4-[3-(4-iodophenyl)-lH-pyrazol-4-yl] pyridine
4-[3-(4-iodophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine 01298 1 213
4-[l-methyl-3-[4-(trifluoromethyl)phenyl]-lH-pyrazol-4-yl]pyridine
Exemple A-253
N-[1-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]- 2-pyridinamine 01298 1 214
N- [ (3-fluorophenyl)methyl] -4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl]- 2-pyridinamine
4-[3-(4-fluorophenyl)-1-methyl-lH-pyrazol-4-yl]-2-Ci-me thylhydr a zino) pyridine 01298 1 215
2-fluoro-4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine
Example A-257
4-[3-(3,4-difluorophenyl)-lH-pyrazol-4-yl]-2-fluoro-pyridine Ο 1298 1 216
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -3-methylpyridine
4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl] -3-methylpyridine
Example A-260
01298 1 217 4- (3-(3,4-difluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2-fluoropyridine
3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-lH-pyrazole-l-ethanamine
2-[2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1-tne thyl - 1H -pyrazol - 4 -yl ] pyr idine Ο 1298 1 218
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine
N'-[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]- N,N-dimethyl-1,2-ethanediamine 01298 1 219
2,4-bis[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine
N-[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine Ο 1298 1 220
5 3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-lH-pyrazole- 1-éthanol
10 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-[2-(lH-imidazol- 1-yl)ethyl]-2-pyridinamine v=/ 01298 1 221
5 4- [2- [3- (4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H- pyrazol-1-yl]ethyl]morpholine
10 (E)-3-(4-fluorophenyl)-4-[2-(2-(4-fluorophenyl)ethenyl]- 4-pyridinyl]-ΙΗ-pyrazole-1-éthanol 01298 1 222
Example A-271
3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -N,N-dimethyl-lH-pyrazole-l-ethanamine
3 -(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4- pyridinyl]-lH-pyrazole-1-éthanol 01298 1 223
4- [1- (2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine
4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-10 pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine ο 1298 1 224
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl] -Ν,Ν-dimethyl-lH-pyrazole-l-ethanaTnine 5 Example λ-27 6
N-[(4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-1- [[2-(4-morpholinyl)ethyl]-lH-pyrazol-4-yl]-2-pyridinamine 01298 1
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -N-4-piperadinyl-2-pyridinamine
N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine ο 1298 1 226
Exemple A-279
4-[1-[2-(diethylamino)ethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine 01298 1 227
OH 2- [ (4-[3-(4-(fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]amino]éthanol
2-[[4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl)-2-10 pyridinyl]amino]éthanol 01298 1 228
3-114-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol
3 (or 5)-(4-fluorophenyl)-4-[2-[[(4-10 fluorophenyl) methyl] amino] -4-pyridinyl] -lH-pyrazole-1- ethanol 01298 1 229
Example A-2 84
N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-5 pyrazole-l-ethanamine
Example A-285
10 N-t(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-lH-pyrazol-4-yl] -2-pyridinamine
15 N-[5-(4-fluorophenyl)-4- (4-pyridinyl)-lH-pyrazol-3-yl]-4- morpholinepropanamine 01298 1 230
Ν' - [5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-N,N-dimethyl-l,3-propanediamine 5 Example A-2 88
5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazo1- 3 -amine
Example A-289
10 8ÜBSmUIE8HEET (RÜLE26Î 01298 1 231 3- (4-f luorophenyl) -4- [2 - [ [ (4-f luorophenyl) methyl] amino] - 4- pyridinyl]-ΙΗ-pyrazole-1-éthanol
Example A-290
5- (4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]- 4-pyridinyl]-ΙΗ-pyrazole-l-éthanol
4-[3-[(4-fluorophenyl)-lH-pyrazol-4-yl]quinoline 01298 1 232
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-5 yl]glycine methyl ester
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-10 yl]glycine
F
0 1298 T 233 4- [3-(4-fluorophenyl)-1-(2-propynyl)-lH-pyrazol-4-yl]pyridine
4-[5-(4-fluorophenyl)-1-(2-propynyl)-lH-pyrazol-4-ylj pyridine
4,4' -(lH-pyrazole-3,4-diyl)bis[pyridine]
15 0 1298 1 234 4-[3-(3,4-dichlorophenyl)-lH-pyrazol-4-yl]pyridine
Example Ά-298
N- [5-Ç4-chlorophenyI3-4-C4-pyrldinyl}-1H-pyrazol-3-yl3-4-pI per Idlnamine
The pyrimidine-substituted compounds of Examples A-299 through A-312 were synthesized in accordance with thechemistry described in Schemes I-XVIII by sélection ofthe corresponding starting reagents : 10 15
Step 1:
2-Chloro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine 01298 1 235
NMe2 A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g,0.031 mol), triethylamine (6.23 g, 0.062 mol) andcatalytic amount of 5% Pd/C in 100 mL of THF was 5 hydrogenated on a Parr apparatus under 40 psi at roomtempérature. After 0.5 hour, the catalyst was filteredand the filtrate was concentrated. The crude waspurified by chromatography on silica gel (ethylacetate/hexane, 3:7) to give 2.36 g of product as a pale 10 yellow crystal (50% yield) ,· mp: 47-49 °C.
2-(2-çMoro-4«pyr t dl ny uor opheny l)ethanone 15 To a solution of lithium diisopropylamide (generated from BuLi (0.045 mol) and diisopropylamine (0.048 mol) inTHF) at -78 ’C was added a solution of the compound prepared in step 1 (5.5 g, 0.037 mol) in THF slowly over 30 minutes. After 1 hour, a solution of ethyl 4- 20 fluorobenzoate (7.62 g, 0,045 mol) in THF'was added and 01298 1 236 the reaction mixture was stirred overnight and allowed towarm up to room température. Water was added and theaqueous phase was extracted with ethyl acetate. Organiclayer was washed with brine, dried over magnésium sulfate 5 and filtered. The filtrate was concentrated and thecrude product purified by chromatography on silica gel(ethyl acetate/hexane, 3:7) to give 4.78 g of a yellowsolid (51% yield), mp: 112-113 °C. 10 Step 3: Préparation of (E)-2-(2-chloro-4-pyrimidinyl)-3- (dimethvlamino)-1-(4-fluorophenvl)-2-propen-l-one
CE)-2-(2-chloro-1-pyr Imldl ny l)-3-(dlmethy lanil no) - 1-H-f luoroph»nyl)-2-pr«p«n-1-i>M A mixture of the compound prepared in step 2 (4.7 g,0.017 mol) in 100 mL of dimethylformamide dimethyl acetal 15 was stirred at room température overnight. Excessdimethylformamide dimethyl acetal was removed undervacuum to give 4.5 g of crude product as a thick brownoil, which was used without further purification. 20 Step 4: Préparation of 2-chloro-4-f3-(4-fluorophenvl)- lH-pyrazol-4-vl]pyrimidine A solution of the compound prepared in step 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirredat room température for 6 hours. The yellow precipitate 25 was collected by filtration and air-dried to give 1.85 gof 2-chloro-4-[3-(4-fluorophenyl)-lH-pyrazol-4- Ο 1298 1 237 yllpyrimidine as a yellow solid, mp: 204-205 °C; Anal.Calc'd for C13H8C1FN4: C, 56.84; H, 2.94; N, 20.40; Cl,12.91. Found: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97.
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2(1H)-pyrimidinonehydrazone 10 A solution of the compound prepared in step 3 ofExample A-299 (1.5 g) and hydrazine hydrate (5mL) inéthanol was heated at reflux overnight. After thereaction mixture was cooled, the solvent was removed. 15 The residue was partitioned between ethyl acetate andwater. The organic phase was washed with brine, driedover magnésium sulfate and filtered. The filtrate wasconcentrated and the crude product was purified byrecrystallization from ethyl acetate and hexane to give 20 0.5 g of product, 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]- 2(1H)-pyrimidinone hydrazone, as a pale yellow solid (38%yield) , mp: 149-150 °C; Anal. Calc'd for C13HnFNe: C,57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N,30.73. 01298 1 238
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N,N-dimethyl- 2-pyrimidinamine
Step 1: Préparation of
NMe2 A solution of the compound prepared in step 2 ofExample A-299 (3.0 g, 0.02 mol) and tert- io butylbis(dimethylamino)methane (10.45 g, 0.06 mol) in 40mL of DMF was stirred at 110 °C ovemight. After thesolvent was removed under vacuum, water was added andextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate and 15 filtered. The filtrate was concentrated and purified byrecrystallization from ethyl acetate and hexane to give1.23 g of a yellow solid product (32% yield), mp: 76-77°C; Anal. Calc'd for C10H16N4: C, 62.47; H, 8.39; N,29.14. Found: C, 62.19; H, 8.58; N, 29.02. 239
Step 2; Préparation of 4-[3-(4-fluorophenvl)-lH-pyrazol- 4-vll-N,N-dimethyl-2-pvrimidinamine
To a solution of the compound prepared in step 1 of the présent Example (1.2 g, 0.0064 mol) and triethylamine(0.65 g, 0.0064 mol) in 10 mL of toluene was added 4-fluorobenzoyl chloride dropwise. The mixture was heatedat reflux for 10 hours and the solvent was removed. Theresidue was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried overmagnésium sulfate and filtered. The filtrate wasconcentrated and the crude (1.6 g) was then dissolved in50 mL of éthanol. The solution was treated withhydrazine hydrate (0.36 g, 0.006 mol) and the mixture washeated at reflux for 2 hours. After éthanol was removed,the residue was partitioned between water and ethylacetate. The organic phase was washed with brine, driedover magnésium sulfate and filtered. The filtrate wasconcentrated and the crude was purified by chromâtographyon silica gel (ethyl acetate/hexane, 1:1) to give 0.6 gof product, 4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine, as a yellow solid (33% yield),mp : 155-156 °C; Anal. Calc'd for C15H14FN5 : C, 63.59; H,4.98; N, 24.72. Found: C, 63.32; H, 4.92; N, 24.31.
01298 1 240 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-methyl-2-pyrimidinamine A suspension of 2-chloro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine prepared in accordance withExample A-299 (0.3 g, 0.0011 mol) in 10 mL of methylamine(40% water solution) was heated in a sealed tube at 100°C overnight. The mixture was then cooled to rootntempérature and the precipitate was filtered, air-driedto give 0.2 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine, as a white solid (68% yield), mp: 217-218 °C; Anal Calc'd for C14H12FN5: C,62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N,25.90.
Exemple A-303
4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl) - 2-pyrimidinamine
This compound was synthesize by refluxing 2-chloro-4-(3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine preparedin accordance with Example A-299 in benzylamine overnight. The product, 4-(3-(4-fluorophenyl)-1H- pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217 °C; Ο 1298 1 241
Anal. Calc'd for C20H16FN5: C, 69.55; H, 4.67; N, 20.28.Found: C, 69.73; H, 4.69; N, 19.90.
N-cyclopropyl-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinamine
This compound was synthesized by stirring 2-chloro- 10 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 with excesscyclopropylamine in methanol at 50 °C for 12 hours. Theproduct, N-cyclopropyl-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinamine, was obtained as a white solid in 15 26% yield, mp: 203-204 °C; Anal. Calc'd for C16H14FNS : C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N,23.58. 01298 1 242
4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine 5
This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine preparedin accordance with Example A-2 99 in 4-methoxybenzylamineovernight. The product, 4-[3-(4-fluorophenyl)-1H- 10 pyrazol-4-yl]-N- [ (4-methoxyphenyl)methyl]-2- pyrimidinamine, was obtained as a off-white solid in 80%yield, mp: 183-185 °C; Anal. Calc'd for C2lHxeFN5O: C,67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N,18.93.
01298J 243 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinamine A solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -N- [ (4-methoxyphenyl)methyl) -2-pyrimidinamine preparedin accordance with Example A-305 (0.35 g, 0.00093 mol) in15 mL of trifluoroacetic acid was heated at reflux for 16hours. Solvent was removed and the residue was partitioned between ethyl acetate and 1 N ammoniahydroxide. Organic layer was washed with brine, driedover magnésium sulfate and filtered. The filtrate wasconcentrated and purified by chromatography on silica gel(ethyl acetate) to give 0.14 g of product,4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl)-2-pyrimidinamine, as apale yellow solid (59% yield), mp: 273-274 °C; Anal.Calc'd for C13H10FN5 0.25 H2O: C, 60.11; H, 4.07; N, 26.96.Found: C, 60.15; H, 3.82; N, 26.38.
N-(4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl)-2-pyrimidinyl]-N-(phenylmethyl)acetamide
To a mixture of 4-[3-(4-fluorophenyl)-lH-pyrazol-4- yl)-N-(phenylmethyl)-2-pyrimidinamine prepared in
accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP 01298 1 244 (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g,0.00066 mol) in 10 mL of THF was added triethylamine(0.053 g, 0.00052 mol). The solution was stirred at roomtempérature overnight. After the removal of solvent, the 5 residue was partitioned between ethyl acetate and water.The organic layer was washed with saturated NaHCO3, washedwith brine, dried over magnésium sulfate and filtered.
The filtrate was concentrated and the crude product wastriturated with ether to give 0.1 g of product, N-[4-[β- ίο (4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl]-N- (phenylmethyl)acetamide, as a white solid (60% yield),mp: 176-178 °C; Anal. Calc'd for C22H18FN5 : C, 68.21; H,4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Ethyl [4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl]carbamate 20 To a suspension of 4-[3-(4-fluorophenyl)-lH-pyrazol- 4-yl]-2-pyrimidinamine prepared in accordance withExample A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine wasadded ethyl chloroformate dropwise. After the addition,the clear solution was stirred at room température for 6 01298 1 245 hours. Water was added and the aqueous phase wasextracted with ethyl acetate. The organic layer waswashed with brine, dried over magnésium sulfate andfiltered. The filtrate was concentrated and the crude 5 was trituated with ether to give 0.15 g of product, ethyl(4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] -2-pyrimidinyl]carbamate, as a white solid (46% yield), mp:163-165 °C; Anal. Calc'd for C16H14FN5O2 : C, 58.71; H, 4.31;N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
4-(3-(3-methylphenyl)-lH-pyrazol-4-yl]pyrimidine 15 This compound was prepared by the same procedure as described for Example A-208 except that l-methyl-3-(4'-pyrimidinylacetyl) benzene (prepared as set forth in Step1 of Example A-19 from 4-methyl-pyrimidine and methyl 3-methylbenzoate) was used in place of 4-fluorobenzoyl-4- 20 pyridinyl methane.
Anal. Calc'd for C14H12N4 (236.27): C, 71.17; H, 5.12; N,23.71. Found C, 70.67; H, 5.26; N, 23.53. m.p. (DSC):151.67 °C. Ο 1298 1 246
4-[3-(4-chlorophenyl)-ΙΗ-pyrazol-4-yl]pyrimidine 5 This compound was prepared according to the chemistry described in Schemes VI and IX by sélection ofthe corresponding pyrimidine starting material in placeof the pyridine starting material. 10 Anal. Calc'd for C13H9N4Cl«O.2 5MH2O: C, 59.78; H, 3.67; N,21.45. Found: C, 59.89; H, 3.32; N, 21.56. m.p. (DSC):218.17 ’C.
4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine
This compound was prepared according to the chemistry described in Schemes VI and IX by sélection of 01298 1 247 the corresponding pyrimidine starting material in placeof the pyridine starting material.
Anal. Calc'd for C13H9N4F (240.24): C, 64.99; H, 3.78; N,5 23.22. Found: C, 64.78; H, 3.75; N, 23.31. m.p. (DSC): 168.58 °C.
10 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine
This compound was prepared according to thechemistry described in Schemes VI and IX by sélection ofthe corresponding pyrimidine starting material in place 15 of the pyridine starting material.
Anal. Calc'd for C13HgN4F (240.24): C, 64.99; H, 3.78; N,23.32. Found: C, 64.94; H, 3.56; N, 23.44. m.p. (DSC):191.47 °C. 20
Additional compounds of the présent invention whichcould be prepared using one or more of the reactionschemes set forth in this application include, but arenot limited to, the following: ο 1298 Î 248
\ 4 -[3 - C 4-c hloropheny1)-5-C1-piperaz i nyI)-1H-pyrazo I-4-y I]pyr i m i dI ne
1-[5-C4-bromopheny I )-4- (4-pyr ldinyI)-1H-pyrazol-3-yl]plperaz i ne 0-1298 1 249
\ 1-[ 4-( 4-pyr i dInyI)-5-C 4 - ζ t r if luoromethy Qpheny I ] -1H-pyrazol-3-yl]piperazine
4-[5-C1-piperazinyl-4-C4-pyrld!nyl3-1H-pyrazol-3-yl]benzonltr i le 01298 1 250
1 - [ 5-C4-ethyny Ipheny l}-4-C4-pyr i d i ny I)-1H-pyrazoI -3-y l]piperazlne
5- ζ 4-f I uorophenyI)-4- (4-pyrldlnyl)-N-3-pyrrolidlnyI -1H-pyrazoI-3-ami ne
5-C4-chloropheny I} - 4- Ç4-pyridlnyl)-N-3-pyrrol idinyl-1H-pyrazol-3-amine 01298 1 251
N-[5-C 4 - fIuorophenyl)-4-C4-pyridinyl)-1H-pyrazol-3-yl]-4-piper idlnsmine
H 3-C 4-f I uorophenyl3-5-C1—piperazi nyl }-4-C4-pyridinyl3-1 H--py r azo I e-1-ethanoi 01298 1 252
3-C4-chlorophenyI } - 5-Ç 1 —plperazlnyO-4-C4-pyridinyl)-1H-pyrazoie- 1-et hanot
4-[2-amlnoethyl)-2-C4-fluoropheny I 5-4,5,6.,7-tetrahydro- 3-C4-pyri d i nyl)pyrazolo[1,5-a]pyrimldin-6-ol OJ 298 τ 253
4- [ 2 - am l noethy l3-2-C4-chlorophe-ny I ~) - 4 , 5, 6, 7-tetrahydro-3-C4-pyr idinyIJpyrazolo[ 1,5-a] py r l m i d i n-6-ο I
OH 3-C^-ch lorophenyl)-4-Ç4-pyr imldtnyl)-1H-pyrazole-1-ethanol 01298 1
5-C 4 -fIuorophenyI3-4-Ç4-pyrimidInyI3 -1H-pyrazole-3-ethanamlne
5 - C 4 - c h I oropheny I 3-4-C4-pyr imid ! ny I 3 -1H-pyrazole-3-ethanamI ne
4-C3~C4-fluorophenyl3-5-C4-piperldlnyl3-1H-pyrazol-4-yI ]pyrImldlne 01298 1
4-[3 - C 4-c hlorophenyI5-5-C^-plper i d i ny I ) -1H-pyrazol-4-yl]pyrImidine
N-[.4-[3-C4-f luorophenyl)-1H-pyrazol-4-yI]-2-pyrlmidlnyl]acetamide
N-[4-[3-Ç4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrlmidlnyI ]acetamlde 0 1 298 1 256
N-[4-[3-C4-f IuorophenyI)-1H-pyrazol-4-y I ) -2-pyr i midiny Ipropanamlde
NHCOEt N-[4 - [3-C 4-fIuoropheny l)-1H-pyrazol-4-yI]-2-pyrimidlnyl]propanamide
6 -[3-Ç 4 -f luoropheny l}-1H-pyrazol-4-y I]- 1 H-p uri ne - Ο 1298 3 257
6 - [3-Ç 4-c h lorophenyI3-1H-pyrazoI-4 - y I]-1 H-p ur i ne
N - [4-[3-C 4-c hlorophenyI) -1H-pyr azoI - 4 - y I ]-2-pyr imidinyI]-N-CphenyImethyl}acetamlde
N-[4-[3-C4-f luorophenyl}-1H-pyrazol-4-yI]-2-pyrlmIdlrtyI J-N-CphenyImethyI)propanamide Ο 1298 7 258
N-[4-[3 - C 4-c hlorophenyl3-1H-pyrazol-4-yI]-2-pyr i ml di ny I] - N-Cpheny Imethy I. )propanamide
BIOLOGICAL EVALUATION p38 Kinase Assay 5
Clonïng of human p38a:
The coding région of the human p38a cDNA wasobtained by PCR-amplification from RNA isolated from thehuman monocyte cell line THP.l. First strand cDNA was 10 synthesized from total RNA as follows: 2 gg of RNA wasannealed to 100 ng of random hexamer primers in a 10 μΐreaction by heating to 70 °C for 10 minutes followed by 2minutes on ice. cDNA was then synthesized by adding 1 μΐof RNAsin (Promega, Madison WI) , 2 μΐ of 50 mM dNTP's, 4 15 μΐ of 5X buffer, 2 μΐ of 100 mM DTT and 1 μΐ (200 U) ofSuperscript II ™ AMV reverse transcriptase. Randomprimer, dNTP's and Superscript ™ reagents were ailpurchased from Life-Technologies, Gaithersburg, MA. Thereaction was incubated at 42 °C for 1 hour. 20 Amplification of p38 cDNA was performed by aliquoting 5μΐ af the reverse transcriptase reaction into a 100 μΐPCR reaction containing the following: 80 μΐ dH20, 2 μΐ50 mM dNTP's, 1 μΐ each of forward and reverse primers 01298 1 259 (50 pmol/μΐ), 10 μΐ of 10Χ buffer and 1 μΐ Expand TMpolymerase (Boehringer Mannheim). The PCR primeraincorporated Bam HI sites onto the 5' and 3' end of theamplified fragment, and were purchased from Genosys. Thesequences of the forward and reverse primers were5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3' and5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3 · respectively. ThePCR amplification was carried out in a DNA Thermal Cycler(Perkin Elmer) by repeating 30 cycles of 94 °C for 1minute, 60 “C f°r 1 minute and 68 ’C for 2 minutes.
After amplification, excess primers and unincorporateddNTP's were removed from the amplified fragment with aWizard ™ PCR prep (Promega) and digested with Bam HI(New England Biolabs). The Bam HI digested fragment wasligated into BamHI digested pGEX 2T plasmid DNA (PharmaciaBiotech) using T-4 DNA ligase (New England
Biolabs) as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The ligationreaction was transformed into chemically competent E.coli DH10B cells purchased from Life-Technologiesfollowing the manufacturer' s instructions. Plasmid DNAwas isolated from the resulting bacterial colonies usinga Promega Wizard™ miniprep kit. Plasmids containing theappropriate Bam HI fragment were sequenced in a DNAThermal Cycler (Perkin Elmer) with Prism™ (AppliedBiosystems Inc.). cDNA clones were identified that coded for both human p38a isoforms (Lee et al. Nature 372, 739). One of the clones which contained the cDNA forp38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T,3' of the GST coding région was designated pMON 35802.
The sequence obtained for this clone is an exact match ofthe cDNA clone reported by Lee et al. This expressionplasmid allows for the production of a GST-p38a fusionprotein. -ί î 260
Expression of human p38a: GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E. coli, stain DH10B (Life
Technologies, Gibco-BRL). Overnight cultures were grownin Luria Broth (LB) containing 100 mg/ml ampicillin. Thenext day, 500 ml of fresh LB was inoculated with 10 ml ofovernight culture, and grown in a 2 liter flask at 37 °Cwith constant shaking until the culture reached anabsorbance of 0.8 at 600 nm. Expression of the fusionprotein was induced by addition of isopropyl b-D-thiogalactosidse (IPTG) to a final concentration of 0.05mM. The cultures were shaken for three hours at roomtempérature, and the cells were harvested by centrifugation. The cell pellets were stored frozenuntil protein purification.
Purification of p38 Kinase-a;
Ail Chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet collectedfrom five 1 L shake flask fermentations was resuspendedin a volume of PBS (140 mM NaCl, 2.7 mM KC1, 10 mMNa2HPO4, 1.8 mM KÜ2PO4/ pH 7.3) up to 200 ml. The cellsuspension was adjusted to 5 mM DTT with 2 M DTT and thensplit equally into five 50 ml Falcon conical tubes. Thecells were sonnicated (Ultrasonics model W375) with a 1cm probe for 3X1 minutes (pulsed) on ice. Lysed cellmaterial was removed by centrifugation (12,000 x g, 15minutes) and the clarified supernatant applied toglutathione-sepharose resin (Pharmacia).
Glutathione-Sepharose Affinitv Chromatographv:
Twelve ml of a 50% glutathione sepharose-PBSsuspension was added to 200 ml clarified supernatant andincubated batchwise for 30 minutes at room température.The resin was collected by centrifugation (600 x g, 5min) and washed with 2 x 150 ml PBS/1% Triton X-100, _ 01298 1 261 followed by 4 x 40 ml PBS. To cleave the p38 kinase fromthe GST-p38 fusion protein, the glutathione-sepharoseresin was resuspended in 6 ml PBS containing 250 unitsthrombin protease (Pharmacia, spécifie activity > 7500units/mg) and mixed gently for 4 hours at roomtempérature. The glutathione-sepharose resin was removedby centrifugation (600 x g, 5 min) and washed 2 x 6 mlwith PBS. The PBS wash fractions and digest supernatantcontaining p38 kinase protein were pooled and adjusted to0.3 mM PMSF.
Mono 0 Anion Exchanoe Chromatography:
The thrombin-cleaved p38 kinase was further purified
by FPLC-anion exchange chromatography. Thrombin-cleavedsample was diluted 2-fold with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycérophosphate, 2 mM DTT, 5% glycerol)and injected onto a Mono Q HR 10/10 (Pharmacia) anionexchange column equilibrated with Buffer A. The columnwas eluted with a 160 ml 0.1 M-0.6 M NaCl/Buffer Agradient (2 ml/minute flowrate). The p38 kinase peakeluting at 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).
Sephacryl S100 Gel Filtration Chromatography;
The concentrated Mono Q- p38 kinase purified sample was purified by gel filtration chromatography (PharmaciaHiPrep 26/60 Sephacryl S100 column equilibrated withBuffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5%glycerol)). Protein was eluted from the column withBuffer B at a 0.5 ml/minute flowrate and protein wasdetected by absorbance at 280 nm. Fractions containingp38 kinase (detected by SDS-polyacrylamide gelelectrophoresis) were pooled and frozen at -80 °C.Typical purified protein yields from 5 L E. coli shakeflasks fermentations were 35 mg p38 kinase. 01298 ΐ 262
In Vitro Assay
The ability of compounds to inhibit human p38 kinasealpha was evaluated using two in vitro assay methods. Inthe first method, activated human p38 kinase alphaphosphorylâtes a biotinylated substrate, PHAS-I (phosphorylated heat and acid stable protein-insulininducible) , in the presence of gamma 32P-ATP (32P-ATP) .PHAS-I was biotinylated prior to the assay and provides ameans of capturing the substrate which is phosphorylatedduring the assay, p38 Kinase was activated by MKK6.Compounds were tested in 10 fold serial dilutions overthe range of 100 μΜ to 0.001 μΜ using 1% DMSO. Eachconcentration of inhibitor was tested in triplicate.
Ail reactions were carried out in 96 wellpolypropylene plates. Each reaction well contained 25 mMHEPES pH 7.5, 10 mM magnésium acetate and 50 μΜ unlabeledATP. Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated PHAS-I wasused at 1-2 μg per 50 μΐ reaction volume, with a finalconcentration of 1.5 μΜ. Activated human p38 kinasealpha was used at 1 μg per 50 μΐ reaction volumerepresenting a final concentration of 0.3 μΜ. Gamma 32P-ATP was used to follow the phosphorylation of PHAS-I.32P-ATP has a spécifie activity of 3000 Ci/mmol and wasused at 1.2 μΩϊ per 50 μΐ reaction volume. The reactionproceeded either for one hour or overnight at 30 °C.
Following incubation, 20 μΐ of reaction mixture wastransferred to a high capacity streptavidin coated filterplate (SAM-streptavidin-matrix, Promega) prewetted withphosphate buffered saline. The transferred reaction mixwas allowed to contact the streptavidin membrane of thePromega plate for 1-2 minutes. Following capture ofbiotinylated PHAS-I with 32P incorporated, each well waswashed to remove unincorporated 32P-ATP three times with2M NaCl, three washes of 2M NaCl with 1% phosphoric,three washes of distilled water and finally a single wash 01298 1 263 of 95% éthanol. Filter plates were air dried and 20 μΐof scintillant was added. The plates were sealed andcounted. Results are shown in Table 4. A second assay format was also employed that isbased on p38 kinase alpha induced phosphorylation ofEGFRP (epidermal growth factor receptor peptide, a 21mer) in the presence of 33P-ATP. Compounds were tested in10 fold serial dilutions over the range of ΙΟΟμΜ toΟ.ΟΟΙμΜ in 1% DMSO. Each concentration of inhibitor wastested in triplicate. Compounds were evaluated in 50μ1reaction volumes in the presence of 25 mM Hepes pH 7.5, 10 mM magnésium acetate, 4% glycerol, 0.4% bovine sérumalbumin, 0.4mM DTT, 50μΜ unlabeled ATP, 25 μg EGFRP(200μΜ), and 0.05 uCi gamma 33P-ATP. Reactions wereinitiated by addition of 0.09 μg of activated, purifiedhuman GST-p38 kinase alpha. Activation was carried outusing GST-MKK6 (5:1,p38:MKK6) for one hour at 30 °C inthe presence of 50μΜ ATP. Following incubation for 60minutes at room température, the reaction was stopped byaddition of 150μ1 of AG 1X8 resin in 900 mM sodiumformate buffer, pH 3.0 (1 volume resin to 2 volumesbuffer). The mixture was mixed three times withpipetting and the resin was allowed to settle. A totalof 50μ1 of clarified solution head volume was transferred from the reaction wells to Microlite-2 plates. 150μ1 ofMicroscint 40 was then added to each well of theMicrolite plate, and the plate was sealed, mixed, andcounted. 01298 1 4.6 1.5 <0.1 3.8 1.5 2.60.70.32.58.012.10.81.11.30.3<0.1<0.1<0.1<0.1 3.21.8 2.3<0.10.10.90.7 6.4<0.1 264 TABLE 4
Example p38 kinase _IC50 (mM) 128 1623 25 2628 33 3436 38 39 40 42 43 44 45 46 47 48 50 51 52 53 54 55143 TNF Cell Assays
Method of Isolation of Human Peripheral Blood Mononuclear
Cells:
Human whole blood was collected in Vacutainer tubescontaining EDTA as an anticoagulant. A blood sample (7ml) was carefully layered over 5 ml PMN Cell IsolationMedium (Robbins Scientific) in a 15 ml round bottomcentrifuge tube. The sample was centrifuged at 450-500 xg for 30-35 minutes in a swing out rotor at roomtempérature. After centrifugation, the top band of cellswere removed and washed 3 times with PBS w/o calcium ormagnésium. The cells were centrifuged at 400 x g for 10minutes at room température. The cells were resuspended 01298 1 265 in Macrophage Sérum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml. LPS Stimulation of Human PBMs: PBM cells (0.1 ml, 2 million/ ml) were co-incubated with 0.1 ml compound (10-0.41 μΜ, final concentration)for 1 hour in fiat bottom 96 well microtiter plates.Compounds were dissolved in DMSO initially and diluted inTCM for a final concentration of 0.1% DMSO. LPS(Calbiochem, 20 ng/ml, final concentration) was thenadded at a volume of 0.010 ml. Cultures were incubatedovernight at 37 °C. Supernatants were then removed andtested by ELISA for TNF-a and ILl-b. Viability wasanalyzed using MTS. After 0.1 ml supernatant wascollected, 0.020 ml MTS was added to remaining 0.1 mlcells. The cells were incubated at 37 °C for 2-4 hours,then the O.D. was measured at 490-650 nM.
Maintenance and Différentiation of the U937 Human
Histiocvtic Lvmphoma Cell Line: U937 cells (ATCC) were propagated in RPMI 1640containing 10% fêtai bovine sérum, 100 IU/ml penicillin,100 μg/ml streptomycin, and 2 mM glutamine (Gibco).
Fifty million cells in 100 ml media were induced toterminal monocytic différentiation by 24 hour incubationwith 20 ng/ml phorbol 12-myristate 13-acetate (Sigma).
The cells were washed by centrifugation (200 x g for 5min) and resuspended in 100 ml fresh medium. After 24-48hours, the cells were harvested, centrifuged, andresuspended in culture medium at 2 million cells/ml. LPS Stimulation of TNF production bv U937 Cells: U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound (0.004-50 μΜ, final concentration) for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in 01298 1 266 culture medium to yield a final DMSO concentration of0.1% in the cell assay. LPS (E coli, 100 ng/ml finalconcentration) was then added at a volume of 0.02 ml.After 4 hour incubation at 37°C, the amount of TNF-a 5 released in the culture medium was quantitated by ELISA.Inhibitory potency is expressed as IC50 (μΜ). Résulte of these TNF Cell Assays are shown in Table 5. 01298 1 267 TABLE 5
Exemple. Human PBM AsaayIC50 (uM) U937 CellIC50 ((uM 1 0.5 2 1.6 0.578 4 0.1 0.222 5 0.274 7 0.2 0.201 8 <0.1 9 0.4 10 0.7 1.687 12 8.5 13 4.8 14 1.2 17 1.1 19 0.3 0.484 20 1.089 21 0.077 22 3.2 24 8.2 26 <0.1 0.029 27 2.7 28 0.1 29 2.2 30 2.6 31 0.8 1.053 32 2.696 33 0.4 34 0.5 35 0.7 36 1.4 37 1.5 0.099 38 0.2 0.208 39 0.7 0.244 40 0.4 41 1.0 42 0.7 43 <0.1 0.243 44 0.4 0.477 45 <0.1 0.04 46 0.329 47 2.359 48 2.2 0.522 49 6.8 50 0.9 51 0.074 54 0.2 0.13 55 <0.1 0.228 143 0.301 01298 î 268
Rat Assay
The efficacy of the novel compounds in blocking theproduction of TNF also was evaluated using a model basedon rats Challenged with LPS. Male Harlen Lewis rats[Sprague Dawley Co.] were used in this model. Each ratweighed approximately 300 g and was fasted overnightprior to testing. Compound administration was typicallyby oral gavage (although intraperitoneal, subcutaneousand intravenous administration were also used in a fewinstances) 1 to 24 hours prior to the LPS challenge.
Rats were administered 30 gg/kg LPS [salmonella typhosa,Sigma Co.] intravenously via the tail vein. Blood wascollected via heart puncture 1 hour after the LPSchallenge. Sérum samples were stored at -20 °C untilquantitative analysis of TNF-α by Enzyme Linked-Imtnuno-Sorbent Assay ("ELISA") [Biosource]. Additional detailsof the assay are set forth in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated by reference in this application.
Mouse Assay
Mouse Model Of LPS-Induced TNF Alpha Production: TNF alpha was induced in 10-12 week old BALB/cfemale mice by tail vein injection with 100 nglipopolysaccharide (from S. Typhosa) in 0.2 ml saline.
One hour later mice were bled from the retroorbital sinusand TNF concentrations in sérum from clotted blood werequantified by ELISA. Typically, peak levels of s’erum TNFranged from 2-6 ng/ml one hour after LPS injection.
The compounds tested were administered to fastedmice by oral gavage as a suspension in 0.2 ml of 0.5%methylcellulose and 0.025% Tween 20 in water at 1 hour or6 hours prior to LPS injection. The 1 hour protocolallowed évaluation of compound potency at Cmax plasmalevels whereas the 6 hour protocol allowed estimation of 01298 1 269 compound duration of action. Efficacy was determined ateach time point as percent inhibition of sérum TNF levelsrelative to LPS injected mice that received vehicle only. 5 Additional résulte obtained using the above- described assays are set forth in Table 6 below. p38assay and U937 cell assay résulta are expressed as IC50(μτη) . Mouse-LPS assay résulta are expressed as percentinhibition. 01298 1 270 TABLE 6
Example p38x p38s U937 xnLPS mLPS mLPS 8h 6h dose Lh, 30mpk A-212 0.49 0.74 C >.0967 20 10 93 A-208 3.104 >.049 ( ).1896 98 30 97 A-227 0.06 96 A-228 0.76 0.339 >.4173 32 30 92 A-229 1.4 >.4622 76 91 A-230 0.42 0.178 96 A-231 0.174 >.3225 86 30 94 A-232 0.048 96 A-233 0.044 53 A-234 0.103 A-235 0.104 56 A-236 0.237 94 A-237 0.093 0.087 60 A-238 0.177 0.4016 A-239 0.034 51 30 87 A-240 0.961 78 30 85 A-241 0.338 79 30 87 A-242 0.047 95 30 87 A-243 0.729 82 A-244 0.099 A-245 <.001 0.0337 65 A-246 0.403 0.592 0.4952 A-247 <0.01 0.166 A-249 0.432 73 30 86 A-250 2.873 A-251 0.637 32 87 A-252 0.774 1.197 48 30 75 A-253 <.001 0.0044 61 A-254 0.081 0.1411 A-215 2.34 0.2976 38 30 80 A-256 0.813 0.4562 A-257 1.081 <•01 0.516Ί A-213 0.22 57 A-258 0.48 1.208: 68 A-259 0.17 0.757z 62 A-210 0.16 0.1981 J 85 30 93 A-260 0.23 1.282: L 47 30 79 A-214 0.06 1.400( 5 70 A-261 0.00£ 0.254: 2 48 30 92 A-216 0.01Î î 1.828 7 27 30 91 A-262 <0.1 0.326 7 45 A-263 <0.0 1 <0.1 0.543 4 49 01298 1 271
Exemple p38* p382 U937 mLPS mLPS mLPS 8h 6h dose lh, 30mpk A-264 0.2594 61 A-265 <0.1 0.6016 32 A-266 0.5393 0 A-267 0.43 2.6681 80 A-268 <0.01 0.0074 11 A-217 0.697 0.3486 9 A-269 >10 UM 51 A-270 0.015 0.3466 53 A-271 0.216 4.2144 68 A-272 0.073 0.583 -8 A-273 6.98 >10 43 A-274 <0.1 0.92 21 30 A-275 10.14 2 >10 A-276 0.176 0.45 -24 30 A-277 0.026 33 30 A-278 0.285 2.3 62 30 A-279 0.005 0.7 64 30 A-280 0.134 15 30 A-281 0.053 22 30 A-218 0.044 18 30 A-282 0.045 0.0973 30 30 A-283 <0.1 0.7998 -20 30 A-284 0.98 0.5088 -1 A-285 <0.1 0.1795 11 30 A-286 0.057 0.09 29 30 A-287 0.041 0.27 -24 30 A-288 0.017 0.3 40 30 A-289 <0.1 0.14 44 30 A-290 6.0191 4 30 A-291 0.388 1.1309 36 30 A-292 1.15 >10 A-293 0.73 A-294 0.015 0.5 61 30 A-295 7.66 >10 94 30 A-296 26 A-297 0.52 0.17 89 30 1 ρ38α in vitro assay résulte based on PHAS-I assay procedure 2 p38a in vitro assay results based on EGFRP assay procedure 01298 ΐ 272
Induction And Assessment Of Collagen-Induced Arthritis In
Mice :
Arthritis w^s induced in mice according to theprocedure set forth in J.M. Stuart, Collagen AutoimmuneArthritis, Annual Rev. Immunol. 2:199 (1984), which isincorporated herein by reference. Specifically,arthritis was induced in 8-12 week old DBA/1 male mice byinjection of 50 μg of chick type II collagen (Cil)(provided by Dr. Marie Griffiths, Univ. of Utah, SaitLake City, UT) in complété Freund's adjuvant (Sigma) onday 0 at the base of the tail. Injection volume was 100μΐ. Animais were boosted on day 21 with 50 μg of Cil inincomplète Freund's adjuvant (100 μΐ volume). Animaiswere evaluated several times each week for signs ofarthritis. Any animal with paw redness or swelling wascounted as arthritic. Scoring of arthritic paws wasconducted in accordance with the procedure set forth inWooley et al., Genetic Control of Type II Collagen
Induced Arthritis in Mice: Factors Influencing DiseaseSuspectibility and Evidence for Multiple MHC AssociatedGene Control., Trans. Proc., 15:180 (1983). Scoring ofseverity was carried out using a score of 1-3 for eachpaw (maximal score of 12/mouse). Animais displaying anyredness or swelling of digits or the paw were scored as 1. Gross swelling of the whole paw or deformity wasscored as 2. Ankylosis of joints was scored as 3.
Animais were evaluated for 8 weeks. 8-10 animais per group were used.
Préparation And Administration Of Compounds:
The compounds tested on mice having collagen-induced arthritis were prepared as a suspension in 0.5%methylcelluose (Sigma, St. Louis, MO), 0.025% Tween 20(Sigma). The compound suspensions were administered byoral gavage in a volume of 0.1 ml b.i.d. Administrationbegan on day 20 post collagen injection and continued 01298 1 273 daily until final évaluation on day 56. Scoring ofarthritic paws was conducted as set forth above. Assayrésulte are set forth in Table 7. TABLE 7
Compound % Inhibition of Arthritis A-210 58.5 @ 15 mpk A-172 49.3 @ 100 mpk A-189 51.6 @ 30 mpk A-208 97.5 @ 60 mpk A-208 75.0 @ 60 mpk
Also embraced within this invention is a class ofpharmaceutical compositions comprising the activecompounds of this invention in association with one ormore non-toxic, pharmaceutically-acceptable carriersand/or diluents and/or adjuvants (collectively referredto herein as "carrier" materials) and, if desired, otheractive ingrédients. The active compounds of the présentinvention may be administered by any suitable route,preferably in the form of a. pharmaceutical compositionadapted to such a route, and in a dose effective for thetreatment intended. The active compounds and compositionmay, for example, be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly(IM) or topically. For oral administration, thepharmaceutical composition may be in the form of, forexample, a tablet, hard or soft capsule, lozenges,dispensable powders, suspension or liquid. Thepharmaceutical composition is preferably made in the formof a dosage unit containing a particular amount of theactive ingrédient. Examples of such dosage units aretablets or capsules. The active ingrédient may also beadministered by injection (IV, IM, subcutaneous or jet)as a composition wherein, for example, saline, dextrose,or water may be used as a suitable carrier. The pH of 01 298 1 274 the composition may be adjusted, if necessary, withsuitable acid, base, or buffer. Suitable bulking,dispersing, wetting or suspending agents, includingmannitol and PEG 400, may also be included in thecomposition. A suitable parentéral composition can alsoinclude a compound formulated as a stérile solidsubstance, including lyophilized powder, in injectionvials. Aqueous solution can be added to dissolve thecompound prior to injection. The amount oftherapeutically active compounds that are administeredand the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this inventiondépends on a variety of factors, including the âge,weight, sex and medical condition of the subject, theseverity of the inflammation or inflammation relateddisorder, the route and frequency of administration, andthe particular compound employed, and thus may varywidely. The pharmaceutical compositions may containactive ingrédients in the range of about 0.1 to 1000 mg,preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferablybetween about 0.1 and about 50 mg/kg body weight and mostpreferably between about 0.5 to 30 mg/kg body weight, maybe appropriate. The daily dose can be administered inone to four doses per day. In the case of skin conditions, it may be préférable to apply a topicalpréparation of compounds of this invention to theaffected area two to four times a day. For disorders ofthe eye or other external tissues, e.g., mouth and skin,the formulations are preferably applied as a topical gel,spray, ointment or cream, or as a suppository, containingthe active ingrédients in a total amount of, for example,0.075 to 30% w/w, preferably 0.2 to 20% w/w and mostpreferably 0.4 to 15% w/w. When formulated in anointment, the active ingrédients may be employed witheither paraffinie or a water-miscible ointment base.
275
Alternatively, the active ingrédients may be formulatedin a cream with an ôil-in-water cream base. If desired,the aqueous phase of the cream base may include, forexample at least 3 0% w/w of a polyhydric alcohol such aspropylene glycol, butane-1,3-diol, mannitol, sorbitol,glycerol, polyethylene glycol and mixtures thereof. Thetopical formulation may desirably include a compoundwhich enhances absorption or pénétration of the activeingrédient through the skin or other affected areas.Examples of such dermal pénétration enhancers includedimethylsuifoxide and related analogs. The compounds ofthis invention can also be administered by a transdermaldevice. Preferably topical administration will beaccomplished using a patch either of the réservoir andporous membrane type or of a solid matrix variety. Ineither case, the active agent is delivered continuouslyfrom the réservoir or microcapsules through a membraneinto the active agent permeable adhesive, which is incontact with the skin or mucosa of the récipient. If the active agent is absorbed through the skin, a controlledand predetermined flow of the active agent isadministered to the récipient. In the case ofmicrocapsules, the encapsulating agent may also functionas the membrane. The transdermal patch may include thecompound in a suitable solvent System with an adhesiveSystem, such as an acrylic émulsion, and a polyesterpatch. The oily phase of the émulsions of this inventionmay be constituted from known ingrédients in a knownmanner. While the phase may comprise merely anemulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and anoil. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilie emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and 01298 1 276 the wax together with the oil and fat make up the so-called emulsifying ointment base which forma the oilydispersed phase of the cream formulations. Emulsifiersand émulsion stabilizers suitable for use in theformulation of the présent invention include Tween 60,
Span 80, cetostearyl alcohol, myristyl alcohol, glycerylmonostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulationis based on achieving the desired cosmetic properties,since the solubility of the active compound in most oilslikely to be used in pharmaceutical émulsion formulationsis very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or othercontainers. Straight or branched chain, mono- or dibasicalkyl esters such as di-isoadipate, isocetyl stéarate,propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate,butyl stéarate, 2-ethylhexyl palmitate or a blend ofbranched chain esters may be used. These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids suchas white soft paraffin and/or liquid paraffin or otherminerai oils can be used. Formulations suitable fortopical administration to the eye also include eye dropswherein the active ingrédients are dissolved or suspendedin suitable carrier, especially an aqueous solvent forthe active ingrédients. The anti-inflammatory activeingrédients are preferably présent in such formulationsin a concentration of 0.5 to 20%, advantageously 0.5 to10% and particularly about 1.5% w/w. For therapeuticpurposes, the active compounds of this combinationinvention are ordinarily combined with one or moreadjuvants appropriate to the indicated route ofadministration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder,
277 cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnésium stéarate, magnésiumoxide, sodium and calcium saits of phosphoric andsulfurie acids, gelâtin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and thentableted or encapsulated for convenient administration.Such capsules or tablets may contain a controlled-releaseformulation as may be provided in a dispersion of activecompound in hydroxypropylmethyl cellulose. Formulationsfor parentéral administration may be in the form ofaqueous or non-aqueous isotonie stérile injectionsolutions or suspensions. These solutions and suspensions may be prepared from stérile powders orgranules having one or more of the carriers or diluentsmentioned for use in the formulations for oral administration. The compounds may be dissolved in water,polyethylene glycol, propylene glycol, éthanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol,sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known inthe pharmaceutical art.
Ail patent documents listed herein are incorporatedby reference.
Although this invention has been described withrespect to spécifie embodiments, the details of theseembodiments are not to be construed as limitations. 01298 1 _ 278
Description of parallel array synthesis methodologyutilized to préparé compounàs of Exemples B-i, B-ii, andB-iii.
Scheme B-l describes the parallel array reaction blocksthat were utilized to préparé compounds of Exemples B-0001 through B-1574, and by analogy could also be used topréparé compounds of Exaniples B-1575 through B-2269.Parallel reactions were performed in multi-chamberreaction blocks. A typical reaction block is capable ofperforming 48 parallel reactions, wherein a uniquecompound is optionally prepared in each reaction vesselBl. Each reaction vessel B1 is made of either polypropylene or pyrex glass and contains a frit B2toward the base of the vessel. Each reaction vessel isconnected to the reaction block valve assembly plate B3via leur-lock attachaient or through a threadedconnection. Each vessel valve B4 is either opened orclosed by controlling the leur-lock position or by theopening or closing of levers B5 within a valve assemblyplate row. Optionally, solutions can be either drained or maintained above the vessel frits by leaving thevalves in the opened position and controlling the backpressure beneath the valve assembly plate by control ofinert gas f low through the inert gas inlet valve B6. Theparallel reactions that are performed in these reactionblocks are allowed to progress by incubation in ajacketed, température confcrolled shaking station.Température control of the reaction chambers is effectedby passing a heat-transfer liquid through jacketedaluminum plates that make contact with the reaction block 01298 1 279 mantle B7. Mixing is effected at the shaking station byeither vertical orbital shaking of the up-right reactionblock or by latéral shaking of the reaction block tiltedon its side.
Functionalized resins are optionally added to eachreaction vessel B1 during the course of reaction or atthe conclusion of the reaction. These functionalizedresins enable the rapid purification of each reactionvessel product. Vacuum filtration of the reaction blockapparatus by opening of the vacuum valve B8 allowspurified products to be separated from resin-sequesterednon-product species. Valve B8 is located on the bottomreaction block chamber B10 which houses the quadrantcollection vial racks Bll. The desired products areobtained as filtrâtes in unique collection vials B9.Removal of solvent from these collection vials affordsdesired products. 01298 1 280
SchemeB-I
Scheme B-2 illustrâtes the various utilizations offunctionalized resins to purify reaction vessel products 5 B22 prior to filtration from the fritted vessels Bl into collection vials B9. Said functionalized resins performas 1) resin-bound reagents B12, which give rise to resin- bound reagent byproducts B13; 2) séquestrants B14 or B15of excess solution-phase reactants B16 or B17, 10 respectively. Solution-phase reactants B16 and B17contain inhérent reactive functionality -rfx and -rf2 01298 1 281 which enable their chemoselective séquestration by thecomplementary reactive functionality -Crfx and -Crf2attached to resins B14 and B15; 3) séquestrants B18 of solution-phase byproducts B19. Byproduct B19 containsmolecular récognition functionality -mr2 which enables itschemoselective séquestration by the complementaryfunctionality -Cmr2 attached to resin B18; 4) reaction- quenching resins B20 which give rise to quenched resinsB21. Resin B20 contains functionality -Q which médiatesreaction quenching (for instance, proton transfer) ofproduct B22 to form a desired isolable form of productB22. Upon performing reaction quench, the resin B20 isconverted to resin B21 wherein -q représente the spentfunctionality on resin B21 ; 5) séquestrants B23 of chemically-tagged reagents B24 and their correspondingreagent byproducts B25. The soluble reagent B24 containsa bifunctional Chemical group, -tag, which is inert tothe reaction conditions but is used to enable the post-reaction séquestration of B24 by the complementary functionality -Ctag attached to resin B23. Additionally,the soluble reagent byproduct B25, formed during thecourse of reaction, contains the same Chemical function -tag that also enables its séquestration by resin B23.Additionally, some reactants B16, particularlysterically-hindered reactants and/or électron déficientnucleophiles, contain poorly séquestrable functionality(rfl in this case is a poorly sequestable functionality).These poorly sequestable reactants B16 can be transformedin situ to more robustly sequestrable species B27 throughtheir reaction with sequestration-enabling-reagents B26.B26 contain highly reactive, complementary functionalityCrfi which reacts with B16 to form B27 in situ. The 01298 1 282 bifunctional molecular récognition functionality, mr,contained within B26 is also présent on the in situderivatized B27. Both B26 and B27 are sequestered by the complementary molecularattached to resin B28: récognition functionalityBy analogy, sortie reactionscontain poorly sequestable byproducts B19, wherein themolecular récognition functionality mr2 in this case isnot able to médiate the direct séquestration of B19 bythe complementary functionality attached to resin B18.Similar use of the bifunctional sequestration-enabling-reagent B29 transforms B19 into the more readilysequestrable species B30. The imparted molecularrécognition functionality, mr, présent in B30 is readilysequestered by the complementary functionality, Cmr,attached to resin B31. In some reactions, multipleséquestration resins are utilized simultaneously toperform reaction purifications. Even resins containingincompatible (mutually reactive) functional groups can beused simultaneously because these resins scavengecomplementary functionalized solution phase reactants,reagents, or byproducts from solution phase faster thanresin cross-neutralization. Similarly, resins containingmutually reactive or neutralizing reaction-quenchingfunctionality are able to quench solution phasereactants, products, or byproducts faster than resincross-neutralization.
ü I 283
Scheme B3 describes the modular robotics laboratory 5 environment that was utilized to préparé compounds ofExamples B0001 through Bxxxx. Chemicals that are utilized in the robotics laboratory are weighed and thendissolved or suspended into solvents at Station #1(Automated Chemistry Prep Station). Thus, solutions or 10 suspensions of known molarity are prepared for use at theother robotics workstations. Station #1 also optionallybar-code labels each Chemical solution so that itsidentity can be read by bar-code scanning at this andother robotics workstations. 15 Reactions are initiated at the modular Stations #2 and #2DUP. Station #2DUP is defined as a duplicate of Station#2 and is used to increase capacity within the roboticslaboratory. A reaction block is mounted at Station #2 or#2 DUP. Also, racks containing reactants, reagents, 20 solvents, and resin slurries are also mounted at Station#2 or #2 DUP. Under the control of a Chemical 01 298 1 284 informâtics mapping file, reactions are initiated by thetransfer of reactant solutions, reagent solutions,solvents, and/or resin slurries into each mountedreaction block vessel. The transfer of known volumes of 5 solutions^ suspensions, or solvents is mediated bysyringes which control a one-up septum piercing/argonpurging cannula, a wide-bore resin slurry-despensingcannula, or by a six-up cannula which can simultaneouslydeliver volumes to a row of six reaction vessels. The 10 reaction block and/or Chemical solution racks may beoptionally cooled below room température during theChemical solution transfer operations. After the transfer of Chemical solutions and solvents has beenperformed by Station#2 or #2DUP, incubation of the 15 reaction block may occur while the reaction block ismounted at the robot station. Preferably, however, thereaction block is removed after ail volume transfers arecomplété and the reaction block is brought to ambienttempérature. The reaction block is transferred off-line 20 to either a ' vertical- or latéral shaking IncubatorStation #5.
The Automated weighing/archivai Station #3 performs thefunctions of weighing empty collection vials (to obtaintare weights of collection vials) and also performs the 25 functions of weighing collection vials containingfiltered, purified products (to obtain gross weights ofcollection vials). After product-containing collectionvials hâve been weighed (gross weight déterminations) atworkstation #3, the collection vial products are 30 optionally redissolved into an organic solvent . atworkstation #3. Transfer of solvents is accomplishedwith syringes which control a mounted one-up septum-piercing/argon purging cannula. Each product-containing 01298 1 285 collection vial is prepared as a solution of knownmolarity as directed and recorded by the Chemicalinformatics System. These product solutions may besubsequently mounted at Station #2 or #2DUP forsubséquent reaction steps or taken to Station #7 or #7DUPfor analytical processing.
Rapid solvent évaporation of product-containingcollection vials is accomplished by mounting thecollection racks at Savant Automated Solvent EvaporationStations #4, #4 DUP, or #4 TRIP, wherein #4DUP and #4TRIPare defined as a duplicate and a triplicate of Station #4to increase the capacity for solvent removal within therobotics laboratory. Commercially available solventremoval stations were purchased from the Savant Company(model # SC210A speedvac unit equipped with model #RVT4104 vapor trap and model # VN100 vapornet cryopump).
Station #7laboratory.mounted at
Stations #7 and #7DUP perform analytical Processing functions. Station #7DUP is defined as a duplicate of to increase capacity within the robotics
Product-containing collection racks are either of these stations. Each product- containing collection vial is then prepared as a solution of known molarity as directed and recorded by the
Chemical informatics mapping file. Optionally, this dissolution function is performed by prior processing of the collection vial rack at Station #3 as described above. Station#7 or #7DUP, under the control of the«
Chemical informatics mapping file, transfers aliquots ofeach product vial into unique and identifable microtiterplate wells that are utilized to perform analyticaldéterminations.
01298 J 286
One such microtiter plate is prepared at . Station #7 or#7DUP for subséquent utilization at the AutomatedHPLC/Mass Spectrometer Station #8 or #8DUP. Station #8DUPis a duplicate of Station #8 to increase the analyticalcapacity of the robotics laboratory. Stations #8 and#8DUP are commercially available benchtop LC/Mass specunits purchased from Hewlett Packard (model HP1100 HPLCconnected to HP1100 MSD (G1946A) mass spectrometer; thisunit is also equipped with a model# G1322A solventdegasser, model # G1312A binary pump, a model # G131SAcolumn heater, and a modçl # G1315A diode array detector.The HP unit has been interfaced with a commerciallyavailable autosampler rack (Gilson Company # 215autosampler). Station #8 or #8DUP is utilized for thedétermination of product purity and identity byperforming high performance liquid chromatography (HPLC)and companion atmospheric pressure chemi-ionization (APCI) or electrospray mass spectrometry for molecularweight détermination.
Another microtiter plate is prepared at Station #7 or#7DUP for subséquent utilization at a commerciallyavailable flow-probe Varian NMR spectrometer Station #10(Varian Instruments flow probe NMR, 300 MHz, interfacedwith a commercially available Gilson 215 autosampler).Proton, 13-Carbon, and/çr 19-Fluorine NMR spectra aredetermined at this Station #10.
Other microtiter plates are optionally mounted at Station#7 or #7DUP for the purpose of preparing product-containing plates for biological assays. Aliquots ofproduct-containing collection vials are transferred tothese biological assay microtiter plates under thecontrol of the Chemical informatics mapping file.Identity and amount of each transferred product is 01298 ί 287 rècorded by the Chemical informatics System for retrievalby biologists who perform the biological assaying ofProducts. 5 The Fourier Transfrom InfraRed (FT-IR) SpectrometerStation #11 is utilized tô analyze resins for theidentity of organic functional groups chemically attachedto these resins. The resins, as mentioned above, containChemical functionality utilized as reagents, 10 chemosélective séquestrants, or reaction quenching mediafor the workup and purification of the crude productmixtures contained within reaction block vessels. Therobotics laboratory utilizes a commercially available FT-IR spectrometer purchased from Nicolet Instruments (model 15 # MagnaIR 560 interfaced with an InspectIR microscope for resin mounting and positioning).
Scheme B-3
The Unes interconnecting the modular Stations dénoté the 20 transfer of Chemical racks, reaction blocks, and/orcollection vial racks from one modular Station toanother. 01298 1 288
AutomatedChemistry Prep
Station #1
Automated weighing/archival
Station #3
AutomatedReaction BuildingStation #2
AutomatedReaction buildingStation #2 DUP
Offline ReactionIncubatorStation #5
Automated Solvent Evap. Station #4 AutomatedSolvent Evap.Station #4 DUP AutomatedSolvent Evap.Station #4 TRIP AutomatedAnalytical Prep.Station #7 AutomatedAnalytical Prep.Station #7 DUP Automated HPLC/Mass Spec Station #8 _1_\____________ FT-IR Station #11 Flow Probe NMR Station #10 Automated HPLC/Mass Spec Station #8 DUP
The ChemLib IT System is a composite of software runningon the client's desktop and software running on a remote 5 server.
The ChemLib IT System is a client/server softwareapplication developed to support and document the datahandling flow in the robotics laboratory described above. 10 This IT System intégrâtes the chemist with the roboticssynthesis laboratory and manages the data generated bythis processes.
The software running on the server warehouses ail the 15 electronic data for the robotics chemistry unit. This 01298 1 289 server, a Silicon Graphics IRIX station v6.2, runs thedatabase software, Oracle 7 V7.3.3.5.0, that warehousesthe data. Connection from the client's desktop to theserver is provided by Oracle's TCP/IP Adapter v2.2.2.1.0 5 and SQL*Net v2.2.2.1.OA. SQL*Net is Oracle's networkinterface that allows applications running on theclient's desktop to access data in Oracles' database.
The client's desktop is Microsoft Windows 95. TheChemLib IT System client software is composed of Omnis7 10 v3.5 and Microsoft Visual C++ v5.0. This composition onthe client side is what is herein referred to as ChemLib.ChemLib communicates with the server for its data viaOracle's PL/SQL V2.3.3.4.0. These PL/SQL calls withihChemLib créâtes a network socket connection to Oracle's 15 SQL*Net driver and the TCP/IP Adapter thereby allowingaccess to the data on the server. A "library" is defined as a composite number of wells,where each well defines a single compound. ChemLib 20 defines a library in a module called the ElectronicSpreadsheet. The Electronic Spreadsheet is then acomposite of n-number of wells containing the componentsthat are required to synthesize the compound that existin each these well(s). 25 .
The chemist begins by populating the ElectronicSpreadsheet with those components required for thecompound synthesis. The identity and the availability ofthese components are defined in the Building Block 30 Catalog module of ChemLib. The Building Block Catalog isa catalog of a listing of ail reagents, solvents,peripherals available in the robotics laboratory. Uponselecting the components for each compound we also 290 déclaré the quantity of each component to be utilized.The quantity of each component can be identified by itsmolarity and volumétrie amounts (ul) or by it's solidState form (mg) . Therefore a well in the ElectronicSpreadsheet defines a compound that is identified by itscomponents and the quantity of each of these components.
The assembly or the synthesis of these components foreach compound in the Electronic Spreadsheet is defined inthe WS Sequence module of ChemLib. The De fine WSSequence module identifies the synthesis steps to beperformed at the robotics workstations and any activitiesto be performed manually or off-line from the roboticsworkstation. With this module we identify whichcomponents from the Electronic Spreadsheet and theactivity that should, be performed with this component inthe robotics laboratory. In the Define WS Sequencemodule the chemist chooses from a list of activities tobe performed in the robotics laboratory and assemblesthem in the order in which they are to occur. TheChemLib system takes these set of activities identified,and with the component data in the Electronic Spreadsheetassembles and reformats these instructions into terminology for the robotics workstation use. Thisrobotics terminology is stored in a 'sequence' file on acommon server that is accessible by the roboticsworkstation.
The robotics workstation performs. the synthesis in areaction block apparatus as described. Each well in theElectronic Spreadsheet is tracked and mapped to a uniquelocation in the reaction block apparatus on the roboticsworkstation. The compound or product synthesized at the 01298 1 291 robotics workstation in the reaction block is thencaptured into collection vials.
The collection vials are first tarred then grossed onthe robotics workstation after colLecting their productsfrom the reaction block. These weights (tare and gross)are recorded into the ChemLib system with the Tare/GrossSession module. The Tare/Gross Session module thencalculâtes the product or compound yields and its finalmass.
Préparation of the compound for analytical analysis andscreening is defined by the Analytical WS Setup module inChemLib. The Analytical WS Setup module identifies thedilution factor for each well in the ElectronicSpreadsheet, based on the compound's product yield andthe desired molar concentration. This identifies thequantity, in uL, to be transferred at the roboticsworkstation, to a spécifie location on the MTP(microtiter plate) to be sent for analysis and/orbiological assaying. The mass spectrométrie and HPLCresults for each well are recorded and scored into theChemLib system.
The Di lu te/Archive WS module further identifies eachcompound by mapping the compound's well from theElectronic Spreadsheet to a spécifie MX block locationfor long term storage and archivai as part of theregistration process.
Ail communications between ChemLib and the robotics workstations are by ASCII files. These files are placed on a server by the ChemLib system that is accessible by 0 0 s u the 292 the robotics workstations. Reports generated byrobotics workstations are also placed on the server wherethe ChemLib system can read these files to record thedata generated. Each robotics workstation consists ofrobotics hardware by Bohdan Automation, Inc. Mundelein,Illinois, and a PC currently running Microsoft Windowsfor Workgroup v3.11 and Ethernet software. The roboticsworkstation PC is logged into the network for one-waycommunication that allows the workstation to access theserver for file access only.
General Scheme B4
Scaffold C-i with a primary amine functionalitycontained within the R4 substituent is reacted inspatially addressed, parallel array reaction blockvessels with excess of electrophiles RJ-Q wherein Q ischloro, bromo, or an acid activating group including butnot limited to N-hydroxysuccinimide. RJ-Q includes acidchlorides, alkyl chloroformâtes, sulfonyl chlorides,activated esters of carboxylic acids, activatedcarbamates, and isocyanates. Reaction of scaffold C-iwith Ra-Q’is effected in the presence of a tertiary aminebase at room température in a mixture of a polar aproticsolvent and/or a halogenated solvent. As illustrated inScheme B-4 the products of the general formulae B-i are isolated in purified form by addition of a carbonyl-functionalized resin B32 which covalently seguesters anyunreacted primary amine scaffold C-i as resin-boundadduct B35, and also by the addition of a primary amine-functionalized resin B33 which covalently sequesters anyremaining electrophile RJ-Q from each reaction mixture as 01298 1 293
resin-bound adduct 834. Resin B33 also sequesters the HQ byproduct from the reaction mixture' by proton transfer from solution-phase Baee-HQ. Incubation at room température, filtration, rinsing of the resin cake, and 5 concentration of the filtrâtes affords purified productsB-i filtered away from resin-bound adducts B32, B33, B34, B35, and B36 .
Scheme B-5 specifically illustrâtes thedérivâtization of the primary amine-containing scaffoldCl to afford the desired products B-i in a parallelarray synthesis format. In a parallel array synthesisreaction block, individual reaction products are preparedin each of multiple reaction block vessels in a spatially 15 01298 1 294 addressed format. A solution of the desired primaryamine-containing scaffold Cl (limiting amount,) indimethylformamide (DMF) is added to the reaction vesselsfollowed by a 4.0 fold stoichiometric excess solution ofN-methylmorpholine in DMF. To each reaction vessel isthen added the electrophiles : either a 2.0 foldstoichiometric excess when RJ-Q is an acid chloride oralkyl chloroformate, or a 1.5 fold stoichiometric excesswhen RJ-Q is a sulfonyl chloride, or a 1.25 foldstoichiometric excess when RJ-Q is an isocyanate. Excesselectrophiles and N-methylmorpholine were used to effectmore rapid and/or more complété conversion of scaffold Clto products B-0001-B-0048 compared to reactions that donot utilize stoichiometric excesses of electrophiles andN-methylmorpholine. The reaction mixtures are incubatedat ambient température for 2-3 h. Each reaction vesselis then charged with a large excess (15-20 foldstoichiometric excess) of the amine-functionalized resinB33 and the aldehyde-functionalized resin B32. Theresin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient température toallow optimum agitation of the resin-containing vesselmixtures. The excess electrophiles RJ-Q and any unreacted scaffold amine Cl are removed from the reactionmedium as insoluble adducts B34 and B37 respectively. Inaddition the N-methylmorpholine hydrochloride sait formedduring the course of the reaction is also neutralized toits free base form by proton transfer reaction to theamine-functionalized resin B33. Simple filtration of theinsoluble resin- adducts B32, B33, B34, B36, and B37,rinsing of the resin cake with dichloroethane, andévaporation of the filtrâtes affords the desired productsB-x in purified form. 01298 1 295
containing a secondary amine functionality within thedéfinition of the R4 substituent. Each reaction vessel ischarged with the secondary amine-containing scaffold Ο-χι, followed by the introduction of a stoichiometric 10 excess of an optionally unique electrophile RL-Q into eachvessel, wherein Q is chloro, bromo, or an acid activàtinggroup including but not limited to N-hydroxysuccinimide.Rl-Q includes acid chlorides, alkyl chloroformâtes, 01298 1 296 sulfonyl chlorides, activated esters of carboxylic acids,activated carbamates, and isocyanates. Reaction ofscaffold C-ii with RL-Q is effected in the presence oftertiary amine base at room température or elevatedtempérature in a mixture of a polar aprotics solventand/or a halogenated solvent. After solution-phasereactions hâve progressed to afford crude productmixtures in each vessel, the products B-ii are isolated in purified form by the addition of theisocyanate-functionalized resin B38 which covalentlysequesters remaining secondary amine scaffold C-ii asresin-bound adduct B39, and also by the addition of theprimary amine-functionalized resin B33 which çovalentlysequesters remaining electrophile RL-Q from each reactionvessel as resin-bound adducts B40. Resin B33 alsosequesters the HQ byproduct in each vessel as B36, formedby proton transfer from solution-phase Base-HQ.Incubation with these resins, either simultaneously orsequentially, followed by filtration, rinsing, andconcentration of the filtrâtes affords purified productsB-ii filtered away from resin-adducts B33, B36, B38, B39,and B40. 01298 1 297
Scheme B-7 illustrâtes the conversion of the secondary- 5 amine containing scaffold C-2 to the desired products B-ii. In a parallel array synthesis reaction block,individual reaction products are prepared in each of 48multiple reaction block vessels. A solution of thescaffold C-2 (limiting amount) in dimethylformamide 10 (DMF) is added to the reaction vessels followed by a 4.0-fold stoichiometric excess solution of N-methylmorpholinein DMF. To each reaction vessel is then added an
electrophile RL-Q as a dichloroethane (DCE) solution:either a 2.0 fold stoichiometric excess is used when RL-Q 15 is an acid chloride or alkyl chloroformate, or a 1.5 foldstoichiometric excess when RL-Q is a sulfonyl chloride, ora 1.25 fold stoichiometric excess when RL-Q is anisocyanate. The reaction mixtures are incubated at 01298 1 298 ambient température for 2-6 h. Each reaction vessel isthen charged with a large excess (15-20 foldstoichiometric excess) of the amine-funetionalized resinB33 and the isocyanate-functionalized resin B32. The 5 resin-charged reaction block is shaken vertically for14-20 h on an orbital shaker at ambient température toallow optimum agitation of the resin-containing vesselmixtures. The excess electrophiles RL-Q and unreactedscaffold amine C-2 are removed from the reaction medium 10 as insoluble adducts B40 and B39, respectively. ResinB33 also sequesters the HQ byproduct in each vessel asB36, formed by proton transfer from solution-phase Base-HQ. Incubation with these resins, followed by filtrationand rinsing with solvent mixtures of DMF and/or DCE, 15 affords purified product solutions in collection vialsfiltered away from resin-adducts B33, B36, B38, B39, andB40. Concentration of filtrâtes affords purified
Products B-ii. 20 01298 1 299
5 Scheme B-8 illustrâtes another general synthetic methodinvolving the parallel array reaction of a scaffold C-iicontaining a secondary amine functionality within thedéfinition of the R4 substituent. Each reaction vessel ischarged with the secondary amine-containing scaffold C- 10 ii, followed by the introduction of a stoichiometricexcess of an optionally unique electrophile RL-Q into eachvessel. Reaction of scaffold C-ii with RL-Q is effected inthe presence of tertiary amine base at room températureor elevated température in a mixture of a polar aprotic 15 solvent and/or a halogenated solvent. 01 298 1 300
Excess electrophiles and N-methylmorpholine are used toeffect more rapid and/or more complété conversion ofscaffold C-ii to products B-ii compared to reactions thatdo not utilize stoichiometric excesses of electrophilesand N-methylmorpholine. The reaction mixtures areincubât ed at ambient température for 2-8 h. Eachreaction vessel is then charged with the sequestration-enabling reagent phenylsulfonylisocyanate B41. Thisreagent B41 reacts with remaining secondary aminescaffold C-ii, converting C-ii to the in situ-derivatizedcompound B42. Subséquent incubation of these vesselmixtures with a large excess (15-20 fold stoichiometricexcess) of the amine-functionalized resin B33 sequestersthe solution-phase species RL-Q, HQ, B41, and B42 as theresin-bound adducts B40, B36, B44, and B43, respectively.The resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient température toallow optimum agitation of the resin-containing vesselmixtures. Filtration of the insoluble resin- adductsB33, B36, B40, B43 and B44 and subséquent rinsing of thevessel resin-bed with DMF and/or DCE affords filtrâtescontaining the purified products B-ii. Concentration ofthe filtrâtes affords the purified products B-ii. 01298 1 301
Scheme B-9 illustrâtes the method of Scheme B-8 usingscaffold C-2. A solution of the scaffold C-2 (limiting 5 0 12.98 1 302 amount) in dimethylformamide (DMF) is added to thereaction vessels followed by a 4.0-fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added an electrophile Rl-Q as a dichloroethane (DCE) solution: either a 2.0 fold stoichiometric excess is used when RL-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when RL-Q is a sulfonyl chloride, ora 1.25 fold stoichiometric excess when RL-Q is anisocyanate. The reaction mixtures are incubated at ambient température for 2-6 h. After solution-phasereactions hâve progressed to afford crude productmixtures, each reaction vessel is then charged with adichloroethane solution of the sequestration-enablingreagent phenylsulfonylisocyanate B41. This reagent B41reacts with remaining secondary amine scaffold C-2,converting C-2 to the in situ-derivatized compound B45.Subséquent incubation of these vessel mixtures with alarge excess (15-20 fold stoichiometric excess) of theamine-functionalized resin B33 sequesters the solution-phase species RL-Q, HQ, B41, and B45 as the resin-boundadducts B40, B36, B44, and B46, respectively. The resin-charged reaction block is shaken vertically for 20 h onan orbital shaker at ambient température to allow optimum agitation of the resin-containing vessel mixtures.Filtration of the insoluble resin- adducts B33, B36, B40,B44, and B46 and subséquent rinsing of the vessel resin-bed with DCE affords filtrâtes containing the purifiedProducts B-ii. Concentration of the filtrâtes affordsthe purified products B-ii. 01298 1 303
Another general method for the parallel array reactionblock synthesis is illustrated in Scheme B-10 for thederivatization of the carboxylic acid-containing scaffold
01298J 304 C-iii. Scaffold C-iii with a free carboxylic acid functionality is reacted in spatially addressed, parallelarray reaction block vessels with excesses of optionallydifferent primary or secondary amines B47 in the presenceof the polymer-bound carbodiimide reagent B48 and atertiary amine base in a mixture of a polar aproticsolvent and/or a halogenated solvent. After filtrationof each crude vessel product misture away from resins B48and B49, each reaction mixture is purified by treatmentwith the sequestration-enabling-reagent B50 (tetra- fluor ophthalic anhydride). The reagent B50 reacts withremaining excess amine B47 to afford the in situ-derivatized intermediates B51 which contain carboxylicacid molecular récognition functionality. Subséquentincubation of each reaction mixture with a 15-20-foldstoichiometric excess of the primay amine-functonalizedresin B33 sequesters B51, B50, and any remaining acid scaffold C-iii as resin-bound adducts B52, B53, and B54,respectively. Filtration of soluton-phase products B-iiiaway from these resin-bound adducts and rinsing of theresin beds with a polar aprotic solvent and/orhalogenated solvent affords filtrâtes containing purifiedproducts B-iii. Concentration of the filtrâtes affordspurified B-iii. 01298 1 305
01258 1 306
Scheme B-ll illustrâtes the conversion of the acidcontaining scaffold C-49 to the desired amide products B-iii in a parallel synthesis format. A limiting amount of « the scaffold C-49 is added as a solution in5 dimethylformamide to each reaction vessel containing thepolymer bound carbodiimide reagent B48 (5 fold stoichiometric excess). A solution of pyridine (4 foldstoichiometric excess) in dichloromethane is added tothis slurry, followed by addition of an excess amount of 10 a dimethylf ormamide solution of a unique amine B47 (1.5 fold stoichiometric excess) to each vessel. The parallelreaction block is then agitated vertically on an orbitalshaker for 16-18 h at ambient température and filtered toseparate the solution phase product mixture away from 15 resin-bound reagent B48 and resin-bound reagent byproductB49. The resulting solutions (filtrâtes) containing amixture of the desired amide products B-iii, excessamines B47 and any unreacted acid containing scaffold C-49, are treated with tetrafluorophthalic anhydride B50. 20 B50 converts the excess amines B47 in each filtrate vessel to its respective sequestrable half acid form B51.After two h incubation time, an excess of the amine-functionalized resin B33 and dichloromethane solvent areadded to each reaction vessel. The amine-containing 25 resin B33 converts B51, any remaining B50, and anyremaining C-49 to their resin-bound adducts B52, B53, andB55, respectively. The resin-charged reaction block isshaken vertically for 16 h on an orbital shaker atambient température to allow optimum agitation of the 30 resin-containing vessel mixtures. Filtration of theinsoluble resin- adducts B33, B52, B53, and B55 and subséquent rinsing of the vessel resin-bed with Ο 1298 Î 307 dimethylf ormamide affords filtrâtespurified Products B-iii. Concentrationaffords the purified products B-iii. containing theof the filtrâtes 5 308
Scheme B-ll
\ / 309
Although Schemes B-l through B-ll describe the use ofparallel array Chemical library technology to préparé 5 compounds of general formulae B-i, B-ii, and B-iii, it isnoted that one with ordinary skill in the art ofclassical synthetic organic chemistry would be able topréparé B-i, B-ii, and B-iii by conventional means (onecompound prepared at a time in conventional glassware and 10 purified by conventional means such as chromatographyand/or crystallization). A general synthesis of pyridylpyrazole scaffolds C-i, C- 15 ii, and C-iii is depicted in Scheme C-l.
Step A: Picoline is treated with a base chosen from butnot limited to n-butyllithium (n-BuLi), lithium di-iso-propylamide (LDA), lithium hexamethyldisilazide (LiHMDS),potassium t-butoxide (tBuOK), or sodium hydride (NaH) in 20 an organic solvent such as tetrahydrofuran (THF), diethylether, t-butyl methyl ether, t-BuOH or dioxane from -78 °Cto 50 °C for a period of time from 10 minutes to 3 hours.The metallated picoline solution is then added to asolution of ester B56. The reaction is allowed to stir 25 from 30 minutes to 48 hours during which time thetempérature may range from -20 °C to 120 °C. The mixtureis then poured into water and extracted with an organicsolvent. After drying and removal of solvent the pyridylmonoketone B57 is isolated as a crude solid which can be 30 purified by crystallization and/or chromatography. 01298 1 310
Step B: A solution of the pyridyl monoketone B57 inether, THF, tBuOH, or dioxane is added to a base chosenfrom but not limited to n-BuLi, LDA, LiHMDS, tBuOK, orNaH contained in hexane, THF, diethyl ether, t-butyl 5 methyl ether, or t-BuOH from -78 °C to 50 °C for a periodof time from ranging from 10 minutes to 3 hours. Anappropriately substituted activated ester or acid halidederived from R4-CC>2H is then added as a solution in THF,ether, or dioxane to the monoketone anion of B57 while 10 the température is maintained between -50 °C and 50 °C.The resulting mixture is allowed to stir at the specifiedtempérature for a period of time from 5 minutes to threehours. The resulting pyridyl diketone intermediate B58is utilized without purification in Step C. 15
Step C: The solution containing the pyridyl diketone B58is quenched with water and the pH is adjusted to between4 and 8 utilizing an inorganic or organic acid chosenfrom HOAc, H2SO4, HCl, or HNO3. The température during 20 this step is maintained between -20 °C and roomtempérature. Hydrazine or hydrazine hydrate was thenadded to the mixture while maintaining the températurebetween -20 °C and 40 °C for a period of 30 minutes tothree hours. The mixture is then poured into water and 25 extracted with an organic solvent. The pyridyl pyrazoleC-i or C-ii is obtained as a crude solid which ispurified by chromatography or crystallization.
Step: D In some cases the pyridyl pyrazole C-i or C-ii is 30 alkylated with Q-C (RA) - (CH2) nCC>2alkyl wherein Q ishalogen. C-i or C-ii is treated with a base chosen fromNaH, NaOEt, KOtBu, or NEt3 in an organic solvent such asTHF, methylene chloride, dioxane, or DMF at températures g 1298 1 311 between -20 °C and 150 °C and reaction times between 3 0minutes and 12 hours. The resulting alkylated pyridylpyrazole ester is then hydrolyzed to the acid by treamentwith NaOH or LiOH in aqueous/alcohol solvent mixtures or 5 in THF/water solvent mixtures. Alternatively, the esterfunction is removed by treatment with an organic orinorganic acid if the alkyl residue is t-butyl.Acidification, followed by extraction with an organicsolvent affords C-iii which may be purified by 10 chromâtography or crystallography. In some cases,regioisomeric alkylated products C-iv are also formed.The desired C-iii can be separated away from C-iv bychromatographie purification or by fractionalcrystallization. 15 01298 1 312
5 A synthesis of pyridylpyrazole scaffold C-l is depictedin Scheme C-2.
Step A: 01298 1 313
Picoline îs added to a solution of LiHMDS in THF at room température over a time period ranging from 30 minutes to 1 hour. The resuitingadditional 30 minutes toThis solution is thenfluorobenzoate B60 at roommixture is then allowed to16-24 h. Equal portions o solution is stirred for an1 hour at room température,added to neat ethyl p-temperature over 1-2 h. Thestir at room température forf water and ethyl acetate are then added to the reaction and the mixture is partitionedin an extraction funnel. The organic layer is dried,filtered, and evaporated to give an oily solid. Hexanesare then added and the solid is filtered and washed withcold hexanes leaving the pyridyl monoketone B61 for usein Step B.
Step B:
The pyridyl monoketone B61 is added as a solution in THFto a flask maintained at room température which containst-BuOK in a THF/ t-BuOH cosolvent. A yellow precipitateforms and stirring at room température is continued for1-3 h. After this time, N-Cbz-protected glycine N-hydroxysuccinimide B62 is added dropwise at roomtempérature as a solution in THF over 1-3 h. Thissolution, containing crude diketone B63, is used directlyin Step C.
Step C:. The solution from step C is treated with waterand the pH is adjusted to between 6 and 7 with aceticacid. Hydrazine hydrate is then added dropwise to themixture as a solution in water over 3 0 minutes to lh atroom température. Water and ethyl acetate are then addedto the flask and the mixture is then partitioned in aseparatory funnel. The organic layer is dried, filtered,and evaported to give a crude oil which is purified by 314 silica gel chromatography, giving rise to purified C- lCbz.
Step: D 5 The Cbz protecting group contained in compound C-lCbzis cleaved using hydrogen gas under pressure and Pd-C inmethanol solvent. The resulting amine C-l is obtainedby filtration and concentration. 01298 1 315
5 01298 1 316 A number of pyridyl pyrazole scaffolds of type C-v are prepared as shown in Scheme C-3.
Step A: Picoline is treated with a base chosen from butnot limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in anorganic solvent such as THF, ether, t-BuOH or dioxanefrom -78 °C to 50 °C for a period of time from 10 minutesto 3 hours. The metallated picoline solution is thenadded to a solution of an appropriately activated esteranalog of a carboxylic acid CbzNRH-(CH2) nCRF(RG) -CO2H orBocNRh-(CH2) nCRF (Rg)-CO2H, preferably but not limited tothe N-hydroxysuccinimide B64. The reaction is allowed tos tir from 3 0 minutes to 48 hours during which time thetempérature may range from -20 °C to 120 °C. The mixtureis then poured into water and extracted with an organicsolvent. After drying and removal of solvent the pyridylmonoketone B65 is isolated as a crude solid which can bepurified by crystallization and/or chromatography.
Step B: A solution of the pyridyl monoketone B65 inether, THF, tBuOH, or dioxane is added to a base chosenfrom but not limited to π-BuLi, LDA, LiHMDS, tBuOK, orNaH contained in hexane, THF, ether, dioxane, or tBuOHfrom -78 °C to 50 °C for a period of time from 10 minutesto 3 hours. The anion sometimes précipitâtes as a yellowsolid. An appropriately substituted activated ester suchas the N-hydroxysuccinimide B66 is then added as asolution in THF, ether, or dioxane to the monoketoneanion while the température is maintained between -50 °Cand 50 °C. The resulting mixture is allowed to stir atthe specified température for a period of time fromranging from 5 minutes to 3 hours. The resulting pyridyldiketone intermediate B67 is utilized without further purification in Step C. 01298 1 317
Step C: The solution containing the pyridyl diketone B67is quenched with water and the pH is adjusted to between4 and 8 utilizing an inorganic or organic acid chosenfrom HOAc, H2SO4, HCl, or HNO3. The température duringthis step is maintained between -20 °C and roomtempérature. Hydrazine or hydrazine hydrate is thenadded to the mixture while maintaining the températurebetween -20 °C and 40 °C for a period of 30 minutes tothree hours. The mixture is then poured into water andextracted with an organic solvent. The pyridyl pyrazoleC-vBoc or C-vCbz is obtained as a crude solid which ispurified by chromatography or crystallization.
Step: D
The carbamate protecting groups from C-vBoc or C-vCbz areremoved to afford the scaffolds C-v containing either afree primary amine (RH is hydrogen) or a free secondaryamine (RH not equal to hydrogen) . The Boc protectingcarbamate groups are cleaved utilizing 1:1trifluoroacetic acid (TFA)/methylene chloride at roomtempérature for several hours. The CBZ carbamateprotecting groups are cleaved using hydrogen gas underpressure and Pd-C in an alcoholic solvent. The resultingamines C-v are then optionally crystallized or purifiedby chromatography. Ο 1298 ? 318
5 01298 Ί 319
The synthesis of scaffolds C-vi is accomplished as shownin Scheme C-4.
Step A: A Boc protected pyridylpyrazole B68 is treated withbenzaldehyde in methylene chloride at room température inthe presence of a drying agent for a period of timeranging from 1-24 h. Solvent is then evaporated and theresulting imine B69 is used in step B without furtherpurification.
Step B:
The pyridylpyrazole imine B69 is dissolved in THF andstirred under nitrogen at températures ranging from -78to -20 °C. A base such as LDA, n-BuLi, or LiHMDS is addeddropwise to the mixture which is then stirred for anadditional 10 minutes to 3 h. Two-five équivalents of analklyating agent RF-Q are then added to the mixture andstirring is continued for several hours. The mixture isthen quenched with acid and allowed to warm to roomtempérature and stirred several hours until cleavage ofthe Boc and the imine functions is complété. The pH isadjusted to 12 and then the mixture is extracted with anorganic solvent, which is dried and evaporated. The crude pyridylpyrazole is then crystallized and/orchromatographed to give C-vi. 01298 1 320
5
The synthesis of maleimide-containing scaffolds C-vii isaccomplished as shown in Scheme C-5.
The maleimide pyrazole scaffolds C-vii are10 synthesized as depicted in scheme C-5. Condensationreaction of a primary amine H2N-R with a maleic anhydrideB7 0 that is substituted at position 3 with either abromo, chloro, or triflate group generates compound B71.The formed maleimide dérivative B71 then reacts with an 15 acetophenone dérivative B72 in the presence of a Pd(0) 321 01298 1 catalyst and base to afford compound B73. The methylene position of B73 is then acylated with an acid anhydride B74 or an activated acid ester B75, forming the di-ketone dérivative B76 . The di-ketone B76 condenses with 5 hydrazine to afford the desired maleimide pyrazolescaffold C-vii.
Scheme C-6 illustrâtes the synthesis of themaleimide pyrazole scaffold C-63 wherein R4 is hydrogen.The synthesis starts with the condensation reaction of 15 bromomaleic anhydride B77 with 2, 4-dimethoxybenzylamine in acetic acid and acetic anhydride, giving rise tointermediate B78. The maleimide B78 is then treated with4'-fluoroacetophenone in the presence of catalytic amount Ο 129.8 1 322
Pd2(dba)3 and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. The B79 is treated with tert-butoxybis(dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is 5 condensed with hydrazine to form the maleimide pyrazoleskeleton B81. The 2, 4-dimethoxybenzyl group protectinggroup is optionally removed with ceric ammonium nitrate(CAN) to give compound C-63.
Scheme C-6
Scheme C-7 illustrâtes the synthesis of maleimide-15 containing scaffolds C-64 and C-65, These scaffolds C-49and C-50 are synthesized according to the general methods Ο 1298 ί 323 illustrated in Scheme C-5 and exemplified with theutilization of N-hydroxysuccinimides B82 and B83 toafford the maleimide-containing pyrazoles B86 and B87,respectively. Optional removal of the 2,4-dimethoxylbenzyl groups with CAN and subséquent removalof the Boc-protecting groups with trifluoroacetic acid(TFA) affords the scaffolds C-64 and C-65.
Scheme C-7
MeO 10 0Ί298 1 324
The various functionalized resins and sequestration-enabling-reagents utilized to préparé and purify parallel 5 reaction mixtures are more fully described below,including their commercial source or literature referenceto their préparation. B32 //
CHO 4-benzyloxybenzaldehyde functionalized polystyrène.Novabiochem cat. #01-64-0182 B33
Rrepared as reported in D. L. Flynn ef a/, J. American Chemical Society (1997) 119. 4874-4881. B38
N=C=O
Methylisocyanate functionalized polystyrène.Novabiochem cat. # 01-64-0169 B48
Polymerbound EDC, prepared as reportedby M. C. Desai ef al, Tetrahedron Letters(1993) 34, 7685. B41
Benzenesulfonylisocyanate, purchased fromAldrich Chemical Company. Cat# 23,229-7 B50
Tetra-fluorophthalic anhydride, purchasedfrom Aldrich Chemical Company. Cat # 33,901-6
10 325
Experimental procedure for the parailel synthesis of asériés of amides, carbamates, ureas and sulfonamides B-0001 through B-0048 from scaffold C-l.
Examples 6-0001 through B-0048
To each reaction vessel (polypropylene syringe tubesfitted with a porous frit, closed at the bottom) of aparallel reaction apparatus was added 200 uL ofdimethylformamide. A stock solution of the scaffoldamine C-l in dimethylformamide (0.1 M, 500 uL) was addedto each reaction vessel followed by the addition of astock solution of N-methylmorpholine in dimethylformamide(1.0 M., 200 uL) . A stock solution of each of theelectrophiles was then added to the appropriate reactionvessels: a) 500 uL of a 0.2 M solution of the acidchlorides in dichloroethane or b) 500 uL of a 0.2 Msolution of the chloroformâtes in dichloroethane or c)313 uL of a 0.2 M solution of the isocyanates indichloroethane or d) 375 uL of a 0.2 M solution of the sulfonyl chlorides in dichloroethane. The parallel reaction apparatus was then orbitally shaken (Labline
Benchtop orbital shaker) at 200 RPM at ambient 0·1 298 1 326 température (23-30 °C) for a period of 2-3 h, under agentle flow of nitrogen. At this time each reactionvessel was treated with approximately 250 mg of polyamineresin B33 (4.0 meq N/g resin) and approximately 100 mg ofpolyaldehyde resin B32 (2.9 mmol/g resin). Each reactionvessel was diluted with 1 mL dimethylformamide and 1 mLdichloroethane and the orbital shaking was continued at200 RPM for a period of 14-20 h at ambient température.Each reaction vessel was then opened and the desiredsolution phase products separated from the insolublefiltration and collected inEach vessel was rinsed twice with dichloroethane (1 mL) and the rinsings were alsocollected. The solutions obtained were then evaporatedto dryness in a Savant apparatus (an ultracentrifugeequipped with high vacuum, scalable température settingsand a solvent trap to condense the volatile solventvapors). The resulting amide, carbamate, urea andsulfonamide products were then weighed and characterized.The yields and analytical data for the products obtainedusing this method are shown below. quenched byproducts byindividual conical vials. 01298 1 327
Observed
Example# Ra RJ %Yleld .. a ® ' Mass Spec u»>Spec
01298 1 328
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 329
Calcd Observed
Example# R2 RJ %Yield ,, _ ’ Mass Spec
MassSpec (M+H)
330
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 331
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
ΟΊ 298 1
Example# R8 332
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
333 10
By analogy to the procedure identified above for thepréparation of Examples B0001-B0048, the followingexamples B-0049 through B-1573 were prepared. 15 20 30 01298 ί 334
Example#
R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
335
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0056 B-0057 B-0058 B-0059 B-0060 B-0061 B-0062 B-0063 B-0064 B-0065
Ο 1298 1
Example# R2 336
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 337
Exemple#
Observed %Yleld ,, 8 c ' Mass SpecMass Spec
01298 1
Example#
Rs B-0086
B-0087 F-
B-0088 F-
B-0089 F^
r\ B-0090 F-
B-0091
B-0092 ΛΛ
B-0093 B-0094 B-0095 338
O— %Yield
Calcd,Mass Spec
ObservedMass Spec(M+H) /·
O
jT\
Γ-/Λ
F-O
hp / 88 95
Ο 1298 1
Example# R* 339
RJ %Yie»d
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 340
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0097 II Xy o “paa H 14 486 487 B-0098 Lrv» i â 8 465 - B-0099 (3 75 464 465 B-0100 0 72 388 389 B-0101 fW 23 408 409 B-0102 f~Oh ktz-A 0 ‘‘SSa/'"0 37 487 488 B-0103 fOh Cl H-Q HO \ 11 492 493 01298 1 341
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 342
Example# _ Observed %Yield a ® ' Mass SpecMassSpec B-0114 |XQ N0a 14 453 454 B-0115 f-O-^ vyCr 33 453 • B-0116 f-CM 11 459 487 B-0117 -Oi rü~° 77 438 439 B-0118 O 52 422 423 B-0119 i îl 7 I h V—« ? 82 434 435 B-0120 49 422 423 B-0121 4Ό O 64 414 415 B-0122 § LQ O-< 87 501 502 B-0123 -04 0 100 450 451 343
Example# Ο 1298 1 R4
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
344
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1
Example# R2 345
RJ %Yield
Caicd.Mass Spec
ObservedMass Spec(M+H)
01298 1 346
RJ
Example# R2 %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0145 s--· /"O 0 48 433 434 B-0146 Ô i 32 415 416 B-0147 'f^CM i-Ç/· c 67 471 472 B-0148 79 465 - B-0149 HH î 1-^· i 65 353 354 B-0150 i 53 465 466 B-0151 r-Oi Λ 68 401 402 01298 1 347
Example# R* . Observed %Yie,d Mass Soec MaSS Spe°
Mass spec (M+H) B-0152
O .^g.o bc 39 383 B-0153
,,51 96 427 428 B-0154
44 459 460 B-0155
A.XX I 74 479 480 B-0156 F-<^ B-0157 B-0158 B-0159 B-0160 B-0161
.xr 44 459 460 --0-¾
~CH F-/
□5 72 415 416
96 445 446
LS
rn r
97 411 49 417 93 459 412 418 460 01 298 1 348
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 349
Example# B-0172
B-0173
B-0174
/ fc
B-0175 F—<
B-0176 Γ-Π hr"
25 415 B-0177 B-0178
ί> B-0179
B-0180 :Oh B-0181 r\
À
Observed %Yield ζ Mass sPec
Mas'Spec * 62 471 472 40 455 92 405 96 387 100 397 34 429 72 429 91 463 100 463 456 406 388 416 398 430 430 464 464
01298 J 350
Exemple# R2 R·* %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
Exemple# R2 351
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 352
Calcd Observed%Yield ' Mass Spec
MassSSpec (M+H^
Example#
01298 1 353
Observed %Yleld ® ' Mass Spec
Ma^Spee
Example# 8-0200
J 1
Wl 78 373 374 B-0201
> \nrv 95 352 353 B-0202
100 416 417 B-0203
69 354 355 B-0204
/N 93 340 341 B-0205 Λ-Ι 94 354 355 B-0206
79 424 425 B-0207 -O: 327 B-0208
s II 88 I 378 379 B-0209
~QH
83 362 363 01298 1 354
01298 1 355
Exemple#
RJ _ Observed %Yleld „ ί Mass SpecMa.sSpec
356
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0222 -‘rW- Ο ï 96 486 487 B-0223 100 465 466 4-----1 B-0224 vOd j 75 486 509a B-0225 \Xr" v% 100 442 443 B-0226 VK. ° \ K Ï-IT\ 88 482 483 B-0227 -OH 0 0 X 73 482 483 B-0228 i’-^ï 37 | 452 01298 1 357
Exemple# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
f 01298 1 358
Exemple# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 359
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 360
Calcd Observed
Example# R2 RJ %Yield ‘ Mass Spec
Mass spec (M+H)
Θ1298 1 361
Observed
Example# R2 RJ %Yield 8 ® ' Mass Spec
Utanspec (tM1’
01298 1 362
Observed
Example# R2 RJ %Yleld .. 8 ® ' Mass Spec
Mass spec (M+H)
363
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
364
Exemple# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298Ί 365
01298 1 366 _ . . Observed
Exemple# R® rj %Yleld 8 ® ' Mass Spec
Mass spec (M+H)
01298 1 367
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 368
Observed %Yleld Ca Mass Spec «»« S».c
Example# R2
01298 1 369
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 370
Example# R®
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 371
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0352 σ r hr^ 0 51 397 398 Ο 1 298 1 372
01298 1 373 c i Observed
Example# R2 RJ %Yield 8 ' Mass Spec
MassSpec (M+H)
01298 1 374
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 375
Calcd Observed
Example# R2 RJ %Yleld * Mass Spec
Mass spec (M+H)
Ο 1298 1 376
Example#
Observed %Yield .. 8 ® ' Mass SpecMassSp« B-0385 rO4
r\ 83 440 441 B-0386
99 422 423 B-0387 B-0388 B-0389 B-0390 B-0391
ίρΎΛ
l w \
Γ \
o
II
O 47 100 71 100 45 388 389 448 436 458 414 449 437 459 415 Ο 1298 1 377 %Yleld
Example# RJ
RJ
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 378
Calcd Observed
Example# R2 rj %Yield .. ' Mass Speç
Mass spec (M+H)
379
Example#
Observed %Yield .. p ' Mass SpecMass Spec B-0412
91 365 366 B-0413
79 367 368 B-0414
85 429 430 B-0415
-CH
82 401 402 B-0416
93 429 430 B-0417 ΛΛ
Y
97 429 430 B-0418
100 419 420 B-0419
100 431 432 B-0420 /Λ
ΎΊ B-0421
I SYT‘ 36 381 96 353 382 354 380
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 381
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 382 %Yield
Example# R2
RJ
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 383 . Observed
Example# R2 RJ %Yield * *' Mass Spec
Mass Spec (|/|+H)
01298 1 384
Exemple# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) / B-0457 H" 93 482 483 B-0458 fi 0 CF 3 -b 100 490 491 B-0459 -V O -θ'· 100 490 491 01298 1 385
Example# cairri Observed %Yleld „ ® Mass Spec
Massue B-0460
83 450 451 B-0461 <H! iq 84 452 453 B-0462
96 456 457 CI! B-0463
66 456 457 B-0464
-GH |4<5 ο Λ 69 490 491 B-0465 ΖΛ
490 491 B-0466
78 474 475 01298 î 386 . Observed
Exemple# R2 RJ %Yleld * ' Mass Spec
Mass spec (M+H)
01298 1 387
Calcd Observed
Example# R® RJ %Yield " Mass Spec
MassSpec (M+H)
01298 1 388
Example# R®
RJ %Vield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0487 ’O-i > Il /fl \ 32 389 390 B-0488 V +crb 100 568 569 B-0489 /^° 91 500 501 B-0490 y 40 473 474 B-0491 H-Ô" 73 514 515 389
Exemple#
Observed %Yield 8 * ' Mass SpecM8SsSpeC (M+H). B-0492 B-0493 B-0494 B-0496 B-0497 B-0498 }F-
89 400 401
IF-
B-0495
ÎF-
Y3"” O_ 100 420 421
!O 100 400 401
100 454 455
Cl 100 442 443 50 100 512 513 454 455 01298 1 390
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 391
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 392
Example# R: %Yield
RJ
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 393
01298 t 394
Example# R8 RJ %Yield „ Ca,cd. Mass gpgC
MassSpec
01298 1 395
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1
Example# R2 396
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 397
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 398
Exemple# _ . Observed %Yield .. ca Mass Spec
Massepec B-0562
88 440 441 B-0563 F-^
68 422 423 B-0564
O
II -s-
II
O 47 388 389 B-0565
jo 100 448 449 B-0566 ÎF-/v
76 436 437 B-0567 ΖΛ
99 458 459 B-0568
|F
o
II
-S-CF 45 414 415 01298 1 399
01298 1 400
Example# R2 %Yleld
RJ
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 401
Example# R2 %Yield
RJ
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 402
Example# R8
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 403
Observed
Example# R2 RJ %Yield .. a ® ' Mass Spec
M...5WC B-0607 +V 34 500 501 B-0608 >1 100 479 480 B-0609 ver* 82 500 501 B-0610 HLO~c 0 100 456 457 B-0611 fOh, o o \ K Hn 76 496 497 B-0612 !FOd 0 1 69 496 497 B-0613 κ>-ί lAS. : o c 61 » 506 01298 1 404
Observed
Mass Spec (M+H)
Example# R2
RJ %Yield
Calcd.Mass Spec
01298 1 405
Observed
Mass Spec (M+H) %Yield
Example# Rz
RJ
Calcd.Mass Spec
Ο 1 298 1 406
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-O634 63 482 483 B-O635 -OH CF, H-b 95 490 491 B-0636 »P"" O 100 490 491 01298 1 407
Example#
Calcd Observed%Yletd .. „ ' Mass Spec M8SSSpeC (M+H) B-0637
•-CH
.LTV 91 450 451 B-0638 IF-
96 436 437 B-0639 iF-O-r 100 456 457 B-0640
100 456 457 B-0641
88 490 491 B-0642
IF
99 490 491 B-0643 IF- r\
92 474 475 Ο 1298 1 408
Ο 1298 1 409
Observed
Exemple# R2 RJ %Yleld .. a 8 ' Mass Spec
MassSpec
Ο 1298 1 410
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0664 Z 1 1 30 389 390 B-0665 v° 100 568 569 B-0666 KH Ky /^° 93 500 501 B-0667 îf-O^ H'—xZ/ ____fi_zz___ 54 473 474 B-0668 KH H-0 66 514 515 01298 1 411
Ο 1298 1 412
Observed
Exemple# r2 RJ %Yield M a ® ’ Mass Spec
Mass spec (M+H)
01298 1 413
Observed
Mass Spec (M+H) %Yield
Example# R2
RJ
Calcd.Mass Spec
01298 1 414
Calcd Observed
Example# R2 RJ %Yield ' Mass Spec
MassSpec (||+H)
01298 1
Example# R2 415
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 416
01298 1 417
Observed
Example# R2 RJ %Yleld ® Mass Spee
Mass spec (M+H)
Ο 1298 1 418
Observed
Mass Spec (M+H) %Yleld
Example# R2
Calcd.Mass Spec
01298 1 419
Exempte# Rs
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 420
Caled Observed
Example# R2 RJ %Yield .. _ ' Mass Spec
MassSpec (M+H)
01298 1 421
422
Example# R2 R·1 %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 423
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 424
Observed
Mass Spec (M+H)
Example# R2
RJ %Yleld
Calcd.Mass Spec
01298 1 425
01298 1 426
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0797 ί 0 ' 90 458 459 B-0798 fX2h fi; 90 588 589 B-0799 ’O-i 82 428 429 B-0800 if O~^ 92 480 481 B-0801 82 442 443 B-0802 95 486 487 B-0803 !f~OH 89 400 401 ο 1298 1 ΙΛΊ
Exemple# R2
RJ ’AYIeld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 428
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 429
Cflied Observed
Example# R2 RJ %Yield ' Mass Spec M,KSp« (MtH'
01298 1 430
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-0829 Oi 0 J 0 63 458 459 B-830 F-θ— 70 588 589 B-0831 100 428 429 B-0832 81 480 481 B-0833 f-OH H ! 73 442 443 B-0834 !f^CH Hi/i 79 486 487 B-0835 f~CH J 5 400 401 01298 1 431
Example# R2
RJ %Yleld
Caicd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 432 c Observed
Example# R2 RJ %Yleld a ® * Mass Spec
Mass Spec (M+H)
û1298 1 433
Ο 1298 1
NHCH3|
Example#
Calcd Observed %Yield „ ï Mass Spec
MassSpec (M+H) B-0861
/
84 583 584 B-0862
96 475 476
B-0863 ic_/ \
69 423 424 B-0864 r\
86 437 438 B-0865
F-< !
62 395 B-0866
:X2M
81 421 422 B-0867
100 535 536 01298 ί 435
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1298 1 436
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
0 1298 1 437
NHCH3i
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 î 438
Observed
Mass Spec (M+H)
Example# R2
RJ %Yield
Calcd.Mass Spec
Ο 1298 1 439
Observed
Mass Spec (M+H)
Example# R2
RJ %Yield
Calcd,Mass Spec
440
Calcd Observed
Example# R2 RJ %Yield ' Mass Spec
MosSpec (MtH"
01298 1 441
Observed
Mass Spec (M+H)
Example# R2
RJ %Yleld Çalcd.Mass Spec
01298 1 442 _ . . Observed
Example# R* rj %Yield ® ’ Mass Spec
Mass spec (||+H)
01298 1
ο 1298 1 444
Observed
Mass Spec (M+H)
Example# R2 %Yleld
RJ
Calcd. MassSpéc
01298 î 445
Example# R2 %Yield
RJ
Calcd. MassSpec
ObservedMass Spec(M+H)
Ο 1298 1 446
Example# R® RJ %Yield Ca,®d·Mass Mass Spec
Spec (M+H)
01298 J 447 _ . . Observed %YhHd MaseSpec
Spec (M+H)
Example#
Ο 1298 1
Example# R2 448
RJ %Yield
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 449
01298 1 450
01298 î 451
452
01298 1 453
01298 1 454 _ , . ., _ Observed
Example# R2 rj %Yield 8 8 ' 88 Wlaas Spec
Spec (M+H)
01298 1 455
Observed
Mass Spec (M+H)
Example# R2 %Yleld
Calcd. MassSpec
01298 1 456
Observed
Mass Spec (M+H) %Yleld
Example# R2
RJ
Calcd. MassSpec
- 01298 1 457
01298 1 458
Example# R! RJ %Yield Cal Mass Mass Spec B-1058 4V 0 «. 35 500 501 B-1059 'Ό4 Ho/J 77 479 480 B-1060 if^Oh 37 500 501 B-1061 if^CM %χτα 86 456 457 B-1062 f-Oh Vk 0 \H r\ 58 496 497 B-1063 H°rH^ 59 496 497 B-1064 HO 58 506 - 01298 1 459 _ , . .. Observed %Yleld Ca ®d*Ma8S Mass Spec
Spec (M+H)
Example#
01298 1 460
Observed
Mass Spec (M+H) %Yleld
Example# R2
RJ
Calcd. MassSpec
01298 1 461
Example# R2
RJ %Yield
Calcd. MassSpec
ObservedMass Spec(M+H) B-1085 fhCH — 93 482 483 B-1086 F"O“i CF, H-b 92 490 491 B-1087 f<M Q i Jaj 100 490 491 01298 1 462
Example# R*
RJ %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H) B-1088 O ._t i/p hrvr\ 0 97 450 451 B-1089 -CM iJr<5 100 436 437 B-1090 JrÔ 100 456 457 B-1091 ri-p 100 456 457 B-1092 Mp .....ç» 96 490 491 B-1093 -CM ° «a^aZ^c* Cl 100 490 491 B-1094 F O~i ψΡ 100 474 475 01298 1 463 %Yield
Example# R2
RJ
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 464
Observed
Mass Spec (M+H) %Yleld
Example# R2
RJ
Calcd. MassSpec
Ο 1 298 1 465
Example# R2
RJ %Yield
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 466
Example# _ , . Observed %Yield MassSpec
Spec (M+H)
Ο 1298 1 467
Observed
Mass Spec (M+H)
Example# R2 %Yield
RJ
Calcd. MassSpec
Ο 1 298 1 468
Observed
Mass Spec (M+H)
Example# R2 %Yield
RJ
Calcd. MassSpec
01298 1 469
Observed
Mass Spec (M+H)
Example# R2 %Yield
RJ
Calcd. MassSpec
01298 1
Example# R2 470
RJ %Yield
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 471
Calcd Observed
Example# R2 RJ %Yleld .. 1 MassSpec
««“SP.C (M4(P
01298 1 472
Example# rz
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 473
Calcd.
Mass Spec
Example# R2
RJ %Yleld
ObservedMass Spec(M+H)
01298 1 474
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-1185 '-Oi Q O / 90 430 431 B-1186 --W O O Z H O 86 444 445 B-1187 σ V 74 396 397 B-1188 rO-Î 76 597 598 B-1189 1 rf? 60 452 453 01298 1 6ZV 92V 23 o r ' E dO-S-% I Il *1 O ! 96U-a EZV ZZV 1-9 A^J-1 O~di 361. L-a LSV OSV 6V .OÙ-, i II * O HX mi-a E9V 29 V 29 (Xj I Il «0 v~O-"* C6U-S EOV 20V OS l\ y >: X'î 1 MX* 2611.-3 ζεν 9EV ZV C+i O n> L6U-8 SSV VSV W ——w------- ό0=0=0 ! MX oeu-a (H+W) aads ssewaadsssew ’ " PI3!A%
paAjasqo . J
rU #a|duiexa szv
(H+W)39ds SSBIflpaAJssqo
oads ssbiaiPO|BO PI®IÀ% #a|duiex3 92?7 ο 1298 1
LLÏÏ 01298 1
#3|dlU8X3 8Z?7 01298 1
(H+W)oads ssBi/ypaAjasqo
aads ssbw•P3|BQ P|8!À% #a|duiexa
6£V 01298 1 OZS εζ K |Z OH bO~di L«ZL-S LLS OLS zz o«zl*s 0 HZY us OLS LZ '"'"Λ ! ' O i 6£ZL-a LZ« 0Z« 00 L 8£ZL-S HO-1" S LS «LS 16 zczL-a □a k-O-' «6« £6« 00 L sezL-a ^O+ï 0 0 ' HZ S LS «LS OS ! ό k ΛIl ;Y^J » i 0 N-V 0 HO-' sezL-a (H+W)oads ssewpaAJasqo
oads ssewPO|BO PI8!A%
rH jH #a|duiBX3 08^7 01298 1
#a|duuex3 18^ 01298 1
(η+ιλι)aads ssb|npaAjasqo
oads sseiAiPO|BO ΡΙ3'λ% #a|duiexa £8*7 01298 1 483
Example# R2
RJ %Yield
Calcd,Mass Spec
ObservedMass Spec(M+H)
01298 1 484
Calcd Observed
Exemple# Rs RJ %Yleld g ’ Mass Spec nnass spec (M+H)
01298 1 485
Calcd.
Mass Spec
Exemple# R2
RJ %Yield
ObservedMass Spec(M+H)
01298 1 486
Calcd.
Mass Spec
Example# R2
RJ %Yleld
ObservedMass Spec(M+H)
01298 1 487
Example# R2
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) 35 403 404 B-1292 4 h / * fl \ B-1293 HoP / 0 73 582 583 B-1294 «OH S+O 49 514 515 B-1295 fhCH ---77?— u° o \ <ry) 48 487 - B-1296 l+^t 76 528 529 01298 1 488
Example# R:
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H) B-1297 /S : 0 Γ Lil? i 62 447 448 B-1298 66 452 453 B-1299 ../Aj 0 J^\J —a—r \ H 65 479 431 B-1300 f Ch J i ,fvol 71 444 445 B-1301 ? H 100 472 473 B-1302 JL \ 1/ ! 75 410 411 B-1303 74 424 425 01298 î 489
Calcd.
Mass Spec
Example# R2
RJ %Yleld
ObservedMass Spec(M+H) B-1304 B-1305 B-1306 B-1307 B-1308 B-1309 B-1310 B-1311 B-1312 B-1313
01298 1 490
Example# R2
RJ %Yleld
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 491
Example# _ . Observed %Yield 8 c ’ Mass SpecMassSpec B-1321
63 414 415 B-1322 B-1323 B-1324 B-1325 B-1326 B-1327 ZΛ
!f OH
K
I
CI !
Cl
45 53 32 45 50 55 434 414 468 456 526 468 435 415 469 457 527 469
492
Calcd.
Mass Spec
Example# R2
RJ %Yleld
ObservedMass Spec(M+H)
01298 1 493
Calcd.
Mass Spec
Exemple# R2
RJ %Yleld
ObservedMass Spec(M+H)
01298 1 494
Example#
Observed %Y,e,d Mass Spec B-1349 B-1350 B-1351 B-1355 B-1356 B-1348 ZΛ
39 468 469 o-;
O F 68 436 437
73 454 455 B-1357 F—<
O 54 418 419 B-1352 F- i
77 436 437 B-1353 |F-
Λ %
i O 66 436 437 B-1354 I |f-
ci 58 434 435
Br
77 478 479
F“< $
CFj 50 468 469 ρΎΛ
36 406 407 01298 1
Example# R2 495
RJ %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
Ο 1 298 1 496
Example# R2
Rl %Yield
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 497
Calcd. Mass
Spec
Example# %Yleld
ObservedMass Spec(M+H) B-1366 4
l !\·
100 552 553 B-1367 ,-T',
100 417 418 B-1368 --04¾¼ 86 394 395 B-1369 r\
100 456 457 B-1370
100 470 471 B-1371 B-1372 B-1373 B-1374 B-1375 r\
77 440 441
F—< !
Λ
O 100 444 42 427 60 476 445 428 477 94 414 415 01298 1 498
Calcd. Mass
Spec
Example# R2
Rl %Yield
ObservedMass Spec(M+H)
01298 1 495
Example# r®
Rl %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H) B-1383 -OH 0 46 416 417 B-1384 0 : 56 432 433 B-1385 ’-üi S-oi i. O ! 59 426 427 B-1386 -CH HrO'i ο I 50 427 428 B-1387 12 427 428 ΉΌ! ! 0 ......J B-1388 66 504 505 O B-1389 iHCi S-O' 0 48 460 461 01298 1 500
Example# R2 %Yield
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 501
Example# R2 %Yleld
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 502
Calcd Mass Observed %Yleld Calcd, ™ Mass Spec
Spec (M+H)
Example# B-1410
o cf3 B-1411 f-ΛΛ
B-1412 f-ΓΛ
B-1413
Cl,
Cl B-1414
B-1415
B-1416
Cl
B-1417 // \
xi B-1418
Cl
Cl B-1419
//
Cl
Cl 42 512 19 462 74 462 75 494 68 462 48 462 48 494 57 494 49 494 39 494 513 463 463 495 463 463 495 495 495 495 01298 1 503
Example# R2 %Yield
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 504
Example# R2
Rl %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 505
Example# R2 %Yield
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 506
Example# R2 %Yield
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 507 Λ , . Observed
calai. Mass MmsS ερ" (M.H)
Example#
01298 1 508
01298 1 509
01298 1 510
Example# R2
Rl %Yield
Calcd.Mass Spec
ObservedMass Spec(M+H)
01298 1 511
Observed
Mass Spec (M+H) %Yleld
Example# R2
Rl
Calcd.Mass Spec
01298 1 512
Observed %Yleld iui»« ÏL. Mass Spec
MassSpec (M+H)
Example*
01298 1 513
Observed
Mass Spec (M+H) %Yleld
Exemple# r2
Rl
Calcd.Mass Spec
01298 1 514 _ Observed
Example# Ra RL %Yield 1Mass Spec
Mass spec (M+H)
01298 1 515
01298 1
Exemple# R2 516
Rl %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H) B-1526 jl i çr- Cl I "T I o^! 0 73 410 411 B-1527 [ ςχ- ci i rr Ο i 66 520 521 B-1528 J μ .Cn . 91 467 468 B-1529 I g- ci j 73 432 433 B-1530 ςή ci J |XO 91 443 444 B-1531 çd Cl 74 422 423 B-1532 çr«, . Cl . I 66 436 439 01298 1 517 %Yield
Example# R2
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 518
Example# %Yield
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 519
Exemple# %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 520 %Yield
Example# R2
Rl
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1
Example# R2 521
Rl %Yleld
Calcd. MassSpec
ObservedMass Spec(M+H)
01298 1 522
Proton NMR data for selected members from Examples B-0001through B-1573 are shown in the following table. 15 20 25 30 01298 1 523
Plate ID H NMR(solvent), d ppm B-0120 2 DMF-d7) d 8.53(bd, J = 4.99Hz, 2H), 7.44-7.24(m, 11 H), 4.41 (s, 2H), 4.31 (br, H) B-0224 < DMF-d7) d 8.56(bd, J = 4.98Hz, 2H), 7.78-7.69(m, 4H), 7.39-7.19(m, 6H), L23(br, 2K) B-0235 DMF-d7) d 8.47(br, 2H), 7.91-7.75(m, 3H), 7.57-7.53(m, 1K), 7.38-7.34(m. >H), 7.21-7.13(m, 4H), 4.20(br, 2H) B-0244 t CDCI3/CD3OD) d 8.38(d, J = 5.38 Hz, 1 H), 7.62-7.32(m, 9H), 7.04-6.95(m,tH), 6.86-6.80(m, 2H), 4.52(q, J = 6.96 Hz, 1H), 1.4O(d, J = 6.88 Hz, 3H) B-0256 DMF-d7) d 8.45(bd, J = 2.85, 2H), 7.87(br s, 4H), 7.76-7.75(m, 2H), 7.53-r.33(m, 5H), 7.18-7.13(br, 4H) B-0426 DMF-d7), 1.32(br, 3H), 1.67(br, 3H), 4.17(br, 2H), 5.12(br, 1 H), 7.50(m, 6H),3.77(m, 2H), 13.54(br, 1H). B-0438 DMSO), 1.14(t, J = 6.9 Hz, 3H), 4.54(m, 1H), 6.99(br, 2H), 7.21 (br, 4H), .45(s, 1H), 7.61 (q, J = 8.7 Hz, 2H), 8.52(d, J - 5.2 Hz, 2H). B-0466 DMF-d7), 1.61 (brd, J = 30.6 Hz, 3H), 4.61 (br, 1H), 7.25{m, 6H), 7.65(m, 3H),B.59(br, 2H), 13.34(brd, J « 34.8 Hz, 1 H). B-0473 (CD3OD), 1,53(d, J = 7.2 Hz, 3H), 4.59(q, J » 7.2 Hz, 1 H), 6.88(d, J = 4 Hz, 1H). 7.09(m, 3H), 7.15(dd, J = 4.4,1.6 Hz, 2H), 7.26(m, 2H), 8.46(d, J = 6.0 Hz, 2H). B-0477 (DMF), 1.80(br, 3H), 2.35(s, 1H), 4.98(br, 1H), 7.38(m, 6H), 7.85(m, 2H), 8.45(br, 1H), 8.75(d, J = 6.0 Hz, 2H). B-0479 (Methanol-d4), 1.57(d, J = 5.6 Hz, 3H), 4.74(br, 1H), 7.23(m, 4H), 7.60(m, 2H),7.81 (m, 4H), 8.67(br, 2H). B-0487 (DMF), 1.78(s, 3H), 2.76(br, 6H), 4.85(br, 1H), 7.42(br, 2H), 7.54(br, 2H), 7.66(br, 3H), 8.82(s, 2H). B-0566 (CD3OD), 1,38(d, J = 7.2 Hz, 3H), 4.15(br, 2H), 4.50(br, 1 H), 7.04(br, 2H),7.18(br, 2H), 7.30(m, 7H), 8.45(m, 2H). B-0569 (CD3OD), 1.56(br, 3H), 4.66(q, J = 6.7 Hz, 1H), 7.17(m, 8H), 7.56(m, 2H), 8.47(s, 2H). B-0574 (Methanol-d4), 1.49(br, 3H), 3.86(br, 3H), 4.60(br, 1H), 6.92(br, 2H), 7.19(br, 2H), 7.31 (br, 2H), 7.76(m, 4H), 8.60(br, 2H). B-0639 (DMF-d7), 1.58(brd, J = 30.0 Hz, 3H), 4.62(br, 1 H), 7.25(m, 6H), 7.60(m, 4H),8.59(br, 2H), 13.30(brd, J = 12.3 Hz). B-0643 7.18(m, 2H), 7.32(dd, J =6.0, 4.4 Hz, 1H), 7.70(dd, J = 9.0, 5.8Hz, 1H), 8.43(dd, J = 4.8,3.2 Hz, 2H). B-0650 (CD3OD), 1.58(br, 3H), 4.62(q, J = 6.6 Hz, 1H), 6.93(br, 1H), 7.17(m, 5H), 7.31 (br, 2H), 8.51 (br, 2H). B-0656 (CDCI3/CD3OD) d 8.48 (d, J = 5.30 Hz, 2H), 7.72-7.59(m, 4H), 7.14-7.10(m, 2H), 7.03-6.97(m, 4H), 4.60(q, J = 7.57Hz, 1H), 1.43(d, J = 7.26Hz, 3H) B-0663 (CD3OD), 1.52(d, J = 6.8 Hz, 3H), 3.75(s, 3H),7.21(m, 2H), 7.42(m, 2H), 7.57(8, 1 H), 7.76(s, 1 H), 7.98(br, 2H), 8.76(br, 2H). B-1165 Hz, 2H), 3.06(m, 1H), 3.43(q, J = 6.1 Hz, 2H), 7.02(m, 2H), 7.14(m, 2H), 7.41 (m, 2H), 8.59(d, J = 5.6 Hz, 2H). B-1169 = 1.6 Hz, 1H), 7.04(t, J = 8.6 Hz, 2H), 7.14(m, 2H), 7.36(m, 2H), 8.39(d, J = 1.8Hz, 1H), 8.60(m, 2H). B-1171 6.83(br, 1H), 7.02(t, J = 8.7 Hz, 2H), 7.15(d, J = 5.6 Hz, 2H), 7.40(m, 2H), 8.59(d, J = 5.0 Hz, 2H). 01298 1 524
Plate ID H NMR(solvent), d ppm B-1179 (CDCI3), 1.94(br, 2H), 2.53(s, 3K), 2.85(t, J = 6.2 Hz, 2H), 3.65(br, 2H), 6.15(br, 1 H), 7.04(m, 3H), 7.22(m, 3H), 7.41(br, 4H), 8.60(br, 2H). B-1183 (CDCI3), 2.00{br, 2H), 2.85(br, 2H), 3.64(br, 2H), 7.03(br, 3H), 7.17(br, 2H),7.36(br, 2H), 7.66(br, 2H), 8.60(br, 2H), 8.77(br, 2H). B-1194 (DMSO), 1.76(br, 2H), 2.66(br, 2H), 2.91 (br, 2H), 4.30(s, 2H), 7.18(br, 5H),7.35(m, 6H), 8.54(d, J = 5.8 Hz, 2H). B-1200 (DMSO), 1,17(br, 3H), 1.76(br, 2H), 2.71(br, 2H), 2.97(br, 4H), 7.18(br, 4H),7.36(br, 2H), 8.54(br, 2H). B-1206 (DMSO), 1.03(s, 6H), 1.68(br, 2H), 2.63(br, 2H), 3.00(br, 2H), 3.65(br, 1H),5.69(m, 2H), 7.16(br, 4H), 7.35(br, 2H), 8.54(br, 2H). B-1216 (DMSO), 1.75(m, 2H), 2.14(s, 6H), 2.66(br, 2H), 3.10(br, 2H), 7.04(br, 3H),7.18(br, 4H), 7.35(m, 2H), 7.47(br, 1H), 8.54(d, J = 4.8 Hz, 2H). B-1226 (DMF), 1.25(br, 3H), 2.01 (br, 2H), 3.35(br, 4H), 6.20(s, 1H), 6.30(s, 1H), 7.42(br, 4H), 7.65(br, 2H), 8.77(s, 2H). B-1360 (DMSO-d6), 1.8O(br, 4H), 2.82(br, 1H), 2.94(br, 1H), 3.10(br, 1H), 3.60(br, 1H),4.54(br, 1H), 7.18(m, 4H), 7.30(m, 4H), 7.46(m, 2H), 8.54(br, 2H). B-1361 (DMSO-d6), 0.99(br, 6H), 1.73(br, 4H), 2.89(br, 2H), 3.03(m, 1H), 4.04(br, 2H),4.44(m, 1H), 7.18(m, 4H), 7.30(m, 2H), 8.57(d, J = 4.64 Hz, 2H). B-1363 (DMSO-d6), 1.78(br, 4H), 2.01 (s, 3H), 2.89(br, 1H), 3.05(br, 1H), 3.34(br, 1H),3.85(br, 1H), 4.48(br, 1H), 7.12(br, 2H), 7.21(br, 2H), 7.30(br, 2H), 8.69(br, 2H). B-1364 (CDCI3), 0.78(dd, J = 3.0, 2.9 Hz, 2H), 1.00(s, 2H), 1.78(m, 1H), 1.86(b, 4H),2.64(m, 1H), 2.99(m, 1H), 3.16(m, 1H), 4.33(br, 1H), 4.70(br, 1H), 6.99(m, 2H),7.14(s, 2H), 7.29(m, 2H), 8.64(s, 2H). B-1368 (CDCI3), 1.89(s, 4H), 2.65(m, 1H), 2.96(m, 1H), 3.06(m, 1H), 3.43(s, 3H),3.93(d, J = 13.2 Hz, 1H), 4.09(d, J = 13.5 Hz, 1H), 4.18(d, J = 13.5 Hz, 1H),4.68(d, J = 12.4 Hz, 1H), 7.60(m, 2H), 7.12(s, 2H), 7.26(m, 2H), 8.63(s, 2H). 01298 1 525
By analogy to the procedure identified above for thepréparation of Examples B0001-B0048, the followingexamples B-1574 through B-2269 are prepared. 01298 1
Examples B-1574 through B-1597 are prepared from Scaffold C-27
Example# R2 rl
01298 1 527
01298 1 528
Ο 1298 7
Examples Β-1598 through Β-1621 are prepared from Scaffold C-28
Example# R2 rl
B-1598 H3C t H B-1599 H3C OH < H, B-1600 H3C B-1601 H3C wH 1 O v -_1 B-1602 h3c Ch 8-1603 h3c Oh H B-1604 h3c Oh H BR 01298 1 530
Exemple# R2 RL
01298 î » 531
Example# r! rl
01298 1
Examples B-1622 through B-1645 are prepared from Scaffold C-38
01298 1 533
. 01298 l 534
Example# R2 Ri B-1639 F— SssO /'o B-1640 fOh B-1641 fhCH NH B-1642 - — r H / Vïj B-1643 x{z> B-1644 f-Ch R Λ i HNÂ B-1645 f-<M ' ΗΝΛ 01298 1 535
N-NH
Examples B-1646 through B-1669 are prepared from Scaffold C-39
01298 1 536
01298 r 537
Example# R2 RL
01298 1
Examples B-1670 through B-1693 are prepared from Scaffold C-65
01298 T
01298 1 540
ο 1298 1 541
Examples Β-1694 through Β-1717 are prepared from Scaffold C-66
Ο 1298 1
01298 1 543
Exemple# R2 R1
B-1711 ^5 gstfU /*0 B-1712 -<O gsstO B-1713 ^.NH B-1714 -^5 P B-1715 f-"CM B-1716 H Λ : ""A I o B-1717 O 01298 1
Examples B-1718 through B-1741 are prepared from Scaffold C-69
01298 1 545
Π
V
546
Example# R! RL B-1735 o s L J----i B-1736 f-CH o S V° B-1737 /NH B-1738 Oi t B-1739 0 H I ρΛθ B-1740 •^-5 I i- i i i A A ΗΝ-ς O B-1741 ' ΗΝΛ 01298 1
Examples B-1742 through B-1765 are prepared from Scaffold C-70
•ί i 548
01298 ί
Example# R2 RL
55σ
Examples Β-1766 through Β-1789 are prepared from Scaffold C-71
Ο 1298 1 551
01298 î 552
Example# R2 RL
01298 1
Examples B-1790 through B-1813 are prepared from Scaffold C-72
Example# R2 RL B-1790 fHOH B-1791 Ό B-1792 r-CH B-1793 If-Q— B-1794 Oi B-1795 0 B-1796 01 298.1 554
01298 1 555
Example# R2 rl B-1807 04 -rî^o /*0 B-1808 rs^s° b'’ B-1809 -04 NH B-1810 fOH vô B-1811 '04 3ψ B-1812 -04 K Λ i HNÀ B-1813 -^5 ' HN<o 01298 1
Examples B-1814 through B-1837 are prepared from Scaffold C-73
01298 1 557
01298 1 558
Example# R* pL B-1831 /V! Z 0 B-1832 i ! i i i a y S O B-1833 i I i ^.NH B-1834 Oh J Y"0 B-1835 •O-§ B-1836 •Oh H Λ ί ΗΝΛ i B-1837 I i i i< J. 01298 1
Examples B-1838 through B-1861 are préparée! from Scaffold C-33
Example# R2 RL
B-1838 i B-1839 XJ?a, B-1840 f~CH B-1841 O B-1842 ~Ch B-1843 -Ch 0 B-1844 BR 01298 1 560
01298 1 561
Example# R2 rl B-1855 /¼ B-1856 ο S B-1857 f-0H NH B-1858 _r H / YYj B-1859 0 H I_____. □ΙΛ/Ά ' Y? B-1860 f~OH K 24, ΗΝ-ς I ο B-1861 -Oh ' HN-\ 01298 1
Examples B-1862 through B-1885 are prepared from Scafiold C-45
η 1 563
564
Example# R2 RL
565
Examples B-1886 through B-1909 prepared from Scaffold C-42
Ο 1 298 J 566
01298 1 567
01298 1
Examples B-1910 through B-1933 are prepared from Scaffold C-44
01298 1 569
01298 1 — ί 570
01298 1
Examples B-1934 through B-1957 are prepared from Scaffold C-41
01298 1
01298 1 573
01298 1 574
Examples B-1958through B-1981 are prepared from Scaffold C-43
U i ζ,^ϋ 575
Γ\ ο '> 576
Example# R2 RL
01298 J
Examples B-1982 through B-2005 are prepared from Scaffold C-30
Example# R2 RL
B-1982 •Oi B-1983 C/Η B-1984 sC/H O B-1985 Oh O I B-1986 sQh < 0 kk B-1987 sQh k> B-1988 G^· BR 01298 1 578
Example# R2 RL
B-1989 O-i hx B-1990 sQh H B-1991 sCh Ïa B-1992 CH I I l 'V B-1993 B-1994 CH fiAV5'· B-1995 Ch licH*0 B-1996 sO“i I B-1997 O-‘ i h al 0 B-1998 CH -<o Ss!îU 01298 1 579
Example# R2 rl B-1999 sCM XÎO /V ' O B-2000 sQh gssiO B-2001 sQh NH B-2002 sCm F _r h / jX .,N\ ÏU B-2003 sOh ο H I___ B-2004 C^< SA i HN\ B-2005 sQh ' HN<o 01298 1
01298 1
01298 1 582
01298 1
Examples B-2030 through B-2053 are prepared from Scaffold C-36
Example# R2 rj
Ο 1298 1 584
Example# R2 RJ B-2037 j B-2038 fXZM B-2039 B-2040 B-2041 B-2042 B-2043 FO-) B-2044 B-2045 Odç 3 B-2046 -^o --/'ο 01298 1
01298 1
Examples B-2054 through B-2077 are préparée! from Scaffold C-34
Example# R2 rJ
01298 1 587
- 01 298 1 _
Example# R2 RJ
! B-2071 f“CH |-<o i ! ' 0 B-2072 ; xSo rd" B-2073 f-€H ' /NH B-2074 F B-2075 FOd B-2076 fhCH "îï.Z 0 B-2077 If X=M 01298 1 589
Examples B-2078 through B-2101 are prepared from Scaffold C-57
Example# R2 RJ
ο 1298 1 590
Example# R2 RJ
01298 1 591
Example# R2 RJ
01298 1 592
Examples B-2102 through B-2125 are prepared from Scaffold C-52
Example# R2 RJ
01298 1
Example# R2 RJ
01298 1 594
Example# R2 RJ
595
Examples B-2126 through B-2149 are prepared from Scaffold C-56
Example# r2 rj
01298 1
Exampie# R* RJ
Ο 1298 1 597
Exemple# R8 RJ
01298 1
01298 J
01298 7 600
01298 1
0 1 298 1
603
01298 1
Ο 1298 1
606
01298 1
Examples B-2222 through B-2245 are prepared from Scaffold C-29
Example# R2 rj
Ο 1 298 1
01298 1 609
01298 1
01298 1
01298 J 612
01298 1 613
Examples B-2270 through B-2317
In a parallel array reaction block containing 48fritted vessels, each reaction vessel was charged with250 mg of polymer bound carbodiimide B48 (1.0 mmol/gresin) and a solution of the acid-containing scaffold C-49 in dimethylformamide (0.1 M, 500 uL) . To each slurrywas added a solution of pyridine in dichloromethane (0.2M, 1000 uL) followed by a solution of a unique amine B47(0.2 M, 375 uL) in dimethylf ormamide. The reaction mixtures were agitated on a Labline benchtop orbitalshaker at 250 RPM for 16-20 h at ambient température.The reaction mixtures were filtered into conical vialsand the polymer was washed with 1.5 mL ofdimethylf ormamide and 2.0 mL of dichloromethane. Thefiltrâtes were evaporated to dryness in a Savantapparatus and dimethylf ormamide (350 uL) was added to each conical vial to dissolve the residue. A solution oftetraf luorophthalic anhydride (1.0 M, 150 uL) in 01298 1 614 dimethylformamide was added to the reconstituted conicalvials and the mixture incubated for 2 hours at ambienttempérature. Polyamine polymer B33 (4.0 meq N/g resin, 250 mg) and 1.0 mL dichloromethane was then added to thereaction mixture in each conical vial. After agitatingthe reaction mixtures for 16 h at 250 RPM on an orbitalshaker at ambient température, the mixtures were filteredthrough a polypropylene syringe tube fitted with a porousfrit. The polymers were washed twice with dimethylformamide (1.0 mL each) and the filtrâtes andwashings collected in conical vials. The filtrâtes wereevaporated to dryness and weighed to afford the desiredamide products B-2270 through B-2317 as oils or solids.The analytical data and yields for the products preparedin this manner are listed below. Ο 1298 1 615
616
0 1 298 1 617
01298 618
01298 1 619
620
Rb
Yield
Calcd. MassSpec.
ObservedMass SpecM+H B-2317 36 42S - 01298 1 621 ΙΟ
By analogy to the procedure identified above for thepréparation of Examples B-2270 through B-2317, thefollowing examples B-2318 through B-2461 were prepared. 15 20 30 01298 1 622 N —R '
Ο 1 298 1 623
01298 1 624
01298 1 625
ο 1298 î 626
01298 1 627
Ο 1298 1
01298 1 629
01298 1 630
Yleld
Calcd. MassSpec.
ObservedMass SpecM+H
01298 1 631
01298 1 632 _ . , Observed
Yield 3 q 88 Mass Spec
Spe°· M+H B-2400 B-2401 B-2402 B-2403 B-2404 B-2405 B-2406 B-2407 R2 rb N—Rc
ÎF-fA iF-
B-2408 N4
34 32 381 378 382 379
~JO 71 519 520
ÎF—* IF- /Λ
y >
£1 68 62 71 527 447 536 528 448 537
47 65 34 394 508 495 395 509 496 01298 1 633
01298 1 635
04298 1 636
01298 1 637
Ο I29 b 1 638
01298 1 639 R2 RB ! i N—Rcl ΐ ? 0 1 Yield Calcd. MassSpec. ObservedMass SpecM+H B-2457 ! ° i !ήΛνη iàXLj 55 540 - B-2458 0 Άη 0 22 488 489 B-2459 f~OH ! ° iV^NH ! CL, ! CF 3 8 486 487 B-2460 13 534 535 B-2461 r />· LjcH l<A, 13 542 - 01298 1 640 10
Exemple C-l 15
5-AMXNOMETHYL-4-(4-PYRIDYL) -3- (4-FLUOROPHENYL) FYRAZOLE
20 1-(4-fluorophenyl)-2-(4-pyridyl)-1-ethanone. 4- picoline (40 g, 0.43 mol) was added to a LiHMDS solution(0.45 mol, 450 mL of a 1.0 M solution in THF) over 30minutes at room température (a slight exotherm wasobserved) The resuiting solution was stirred for 1 h. 25 This solution was added to ethyl 4-fluorobenzoate (75.8g, 0.45 mol, neat) over 1 h. The mixture was stirredovernight (16 h) . Water (200 mL) was added and the mixture was extracted with EtOAc (2x200 mL). The organiclayer was washed with brine (1x200 mL) and dried over 01298 î 641
Na2SO4. The organic layer was filtered and the solventwas removed to leave oily solid. Hexane was added to theoil and the resulting solid was filtered and washed withhexane (cold) . A yellow solid was isolated (50 g, 54%) : 5 XH NMR (CDC13) δ 8.58 (d, J = 5.7 Hz, 2H) , 8.02 (dd, J = 5.5, 8.0, 2H) , 7.12-7.21 (m, 4H) , 4.23 (s, 2H) ; 19F NMR(CDCI3) δ -104.38 (m) ; LC/MS, tr = 2.14 minutes (5 to 95%acetonitrile/water over 15 minutes at 1 mL/min, at 254 nmat 50°C), M+H = 216; High Resolution MS Calcd for 10 C23H20N4O2F (M+H): 216.0825. Found: 216.0830 (Δ mmu = 0.5) . N-benzyloxycarbonyl-5-aminomethyl-4- (4-pyriclyl) -3-(4-fluorophenyl) pyrazole. A 3L round bottom flask 15 fitted with a mechanical stirrer, N2 inlet and an additionfunnel was was charged wtih 557 mL (0.56 mol) of 1 M t-BuOK in THF and 53 mL (0.56 mol) of t-BuOH. The ketone, 1(60 g, 0.28 mol) was dissolved in 600 mL of THF and addedto the stirred mixture at room température. A yellow 20 precipitate formed and the mixture was stirred for 1 h.N-benzyloxycarbonyl-glycinyl N-hydroxysuccinimide (128.6g, 0.42 mol) was dissolved in 600 mL of THF and addeddropwise at r.t. over lh. The mixture was stirred for
another 5 minutes and 150 mL of water was added. the pH 25 was adjusted to 6.7 with 70 mL of AcOH. Hydrazinemonohydrate (41 mL inlOO mL of water) was added via anaddition funnel. The mixture was stirred for 1 h and wasdiluted with 500 mL of water and 500 mL of ethyl acetate.The biphasic mixture was transferred to a sep funnel and 30 the layer s were separated. The aqueous layer wasextracted with EtOAc (3x300 mL) . The organic layer was 01298 1 642 dried (Na2SO4) , filtered and evaporated to leave 157 g ofa crude reddish oil.
The oil was suspended in CH2CI2 and filtered torénové any insoluble material (DCU, hydrazone of themonoketone). The solution was split into two portionsand each portion was chromatographed (Biotage 75L, 3%
EtOH/CH2Cl2 then 6% EtOH/CH2Cl2) . The appropriate fractions were concentrated (some contamination from themonoketone and the hydrazone) from each portion to leavea yellow solid. The solid was suspended in ethyl acetateand heated to boiling for 10 minutes. The solution wasallowed to cool to R.T. overnight. The precipitate wasfiltered to give 30 g of a white solid (27% yield of 2) :hï NMR (DMF-d7) δ 13.36 (s, lH) , 8.57 (d, J = 5.8 Hz, 2H) ,7.16-7.52 (m, 11H) , 5.11 (s, 2H) , 4.48 (d, J = 5.4 Hz,2H) ; 19F NMR (DMF-d7) δ -114.9 (m) , -116.8 (m) (split fluorine signal is due to the pyrazole tautomers); LC/MS,tr = 3.52 minutes (5 to 95% acetonitrile/water over 15minutes at 1 mL/min, at 254 nm at 50°C) , M+H = 403; HighResolution MS Calcd for C23H20N4O2F (M+H): 403.1570.
Found: 403.1581 (Δ mmu = 1.1). 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole. To a IL Parr bottle was added 7 g (17.4 mmol)of 2 and 180 mL of MeOH and 90 mL of THF to give a clearsolution. The bottle was purged with nitrogen and 1.5 gof 10% Pd/C (wet Degussa type E101) was added. The Parrbottle was pressured to 40 psi (H2) and was agitated.Hydrogen uptake was 5 psi after 5 h. The bottle wasrepressured to 42 psi and was agitated overnight. Thebottle was purged with N2 and was filtered through
Celite. The Celite was washed with MeOH (3x50 mL) and 01298 1 643 the filtrate was concentrated to give 4.5 g of an off-white solid (94%). XH NMR (DMSO-d6) δ 8.52 (d, J = 4.63
Hz, 2H), 7.36 (dd, J = 5.64, 8.1 Hz, 2H), 7.16-7.30 (m, 4H) , 3.79 (s, 2H) ; 19F NMR (DMSO-d6) δ -114.56 (m) ; LC/MS, 5 tr = 1.21 minutes (5 to 95% acetonitrile/water over 15minutes at 1 mL/min, at 254 nm at 50°C), M+H = 269 m/z;High Resolution MS Calcd for Ci5Hi4N4F (M+H): 269.1202.
Found: 269.1229 (Δ mmu = 2.7). 10
The following pyridylpyrazoles (C-2 through C-21, TableC-l) were prepared according to the experimentalprocedure described above for example C-l. 15
Table C-l.
Examp1 e No. Structure MW, M + H Calculât ed Found ÀH NMR (solvent) , ppm C-2 N-NH /ΓνΑΛγ" 323.1672 (DMF-d7) : 8.77 (t, J = F-'\_=s/ Γ 1 Ô N ZNH 323.1670 4.4 Hz, 2H), 7.60 (m, 2H), 7.44 (t, J = 4.4 Hz, 2H), 7.35 (m, 2H), 3.22 (bd, 2H), 3.01 (septet, J = 5.3 Hz, 1H), 2.74 (m, 2H), 1.95 (m, 4H) 01298 1 644 C-3
N-NH
282.127 (M) 282.1245(M, El) (DMF-d7) : 8.77 (br s, 2H), 7.64-7.62 (m, 2H),7.50 (br s, 2H), 7.38-7.34 (m, 2H) , 4.40-4.37 (m, 1H) , 1.56 (br s, 3H) C-4 C-5 C-6 C-7 C-8
N-NH
N-NH
323.1672 323.1687
N-NH
N-NH
N-NH
282.127 (M) 282.1147(M, El) 359 359 359 359 313.1465 313.1492 (DMF-d7) : 8.77 (br s, 2H), 7.64-7.62 (m, 2H) ,7.50 (br s, 2H), 7.38-7.35 (m, 2H) , 4.40-4.37 (m,1H) , 1.57 (br s, 3H) (DMSO-dg) : 8.56 (br, 2H) , 7.32 (m, 2H), 7.18 (m,4H), 2.91 (m, 2H), 2.71 (m, 2H) 1.88 (m, 1H), 1.65(m, 2H), 1.40 (m, 2H) (DMSO-dg) : 8.46 (d, J = 4.6 Hz, 2H), 7.32-7.13 (m,7H), 6.98-6.96 (m, 4H),4.06 (t, J = 7.0 Hz, 1H),2.98-2.95 (m, 2H) (DMSO-dg) : 8.46 (d, J = 5.4 Hz, 2H), 7.32-7.28 (m,2H), 7.20-7.12 (m, 5H),6.98-6.96 (m, 4H), 4.06(t, J = 7.0 Hz, 1H), 2.98-2.94 (m, 2H) (DMSO-dg): 13.83 (bs, 1H), 8.61 (d, J = 5.7 Hz,2H), 8.33 (bs, 1H), 7.33 (m, 6H), 4.44 (m, 1H),3.63 (m, 2H), 3.27 (s, 3H) 01298 1 645 (DMSO-d6) : 8.55 (dd, J = 1.5, 4.4 Hz, 2H), 7.37-
7.32 (m, 2H), 7.26 (dd, J =1.6, 4.4 Hz, 2H) , 7.22- C-9
F
N-NH
NHz OCH3 313.1465 313.1457 7.16 (m, 2H) , 4.06 (t, J = 6.5 Hz, 1H) , 3.49 (d, J = 6.6 Hz, 2H) , 3.20 (s, 3H) C-10 C-ll
F
354 354 (DMSO-de) : 13.03 (bs, 1H), 8.50 (dd, J=1.6, 2.7
Hz, 2H), 7 .58 (bq, J=4.3 Hz, 1H), 7.3 (m, 2H) , 7.12-7.21 (m, 4H) , 3.77 (t, J= 6.3 Hz, 1H) ,. 2.45 (d, J=4.5 Hz, 3H) , 1.97 (t, J= 7.4 Hz, 2H) , 1.85
F
N-NH
NH
nh2 354 354 283.1359 283.1363 297.1515 297.1515 (dt, J=7.3, 7.1 Hz, 2H) (DMSO-de) : 13.03 (bs, 1H), 8.50 (dd, J=1.6, 2.7Hz, 2H), 7.58 (bq, J=4.3
Hz, 1H), 7.3 (m, 2H) , 7.12-7.21 (m, 4H) , 3.77 (t, J= 6.3 Hz, 1H) , 2.45 (d, J=4.5 Hz, 3H), 1.97 (t, J= 7.4 Hz, 2H) , 1.85 (dt, J=7.3, 7.1 Hz, 2H)(DMSO-de) : 8.53 (d, J = 5.0 Hz, 2H), 7.37-7.32 (m,2H), 7.21-7.17 (m, 4H), 2.83(d, J = 6.0 Hz, 2H),2.77 (d, J = 6.0 Hz, 2H)(DMSO-de) : 8.53 (d, J = 5.4 Hz, 2H) , 7.34 (dd, J 5.8, 8.2 Hz, 2H), 7.18 01298 1 646 (dd, J = 5.8, 9.8 Hz, 4H), 2.68 (t, J = 7.3 Hz, 2H), 2.52 (m, 2H), 1.64 (m, 2H) C-14 Cl. N-NH yyçMH, 284.0829 284.0806 ( CD3OD): 8.74 (br, 2H), 7.77 (br, 2H), 7.45-7.58 (m, 3H), 7.30-7.40 (m, 1H), 4.43 (s, 2H) C-15 N-NH nh2 285 285 (DMSO-de) : 8.53 (br, 2H) , 7.56 (br, 2H), 7.26 (m, 4H), 3.75 (br, 2H) C-16 N-NH ΊΓ 329, 331 329, 331 (DMSO-dç) : 8.53 (d, J = 4.4 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 4.6 Hz, 2H), 3.76 (bs, 2H) C-17 Cl_ N-NH C==tJ^^X^nh 339 339 (DMSO-dg) : 8.53 (t, J = 4.3 Hz, 2H), 7.33 (m, 3H), 7.19 (t, J = 4.6 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 3.23 (m, 2H), 2.88, (m, 3H), 1.92, (m, 3H), 1.70 (m, 1H) C-18 ' N-NH cl''^«==^J^''k^NH ΊΨ 339 339 (DMSO-d6) : 8.57 (d, J = 4.6 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 4.8 Hz, 2H), 3.18 (bd, 2H), 2.88 (m, 1H), 2.76 (m, 2H), 1.82 (br, 4H) C-19 N-NH Br'^«=^J^^CxNI- ΪΓ 383, 385 383, 385 (DMSO-d6) : 8.56 (br, 2H), 7.52 (br, 2H), 7.14-7.29 (m, 4H) , 2.99 (br, 2H), 01298 1 647 2.71 (br, 1H) , 2.51 (b'r, 2H) , 1.68 (br, 4H) ΙΟ
The following pyridylpyrazoles (C-22 through C-40, TableC-2) are prepared utilizing the general schemes C-l andC-2 and the experimental procedure described for example 15 C-l above.
Table C-2
Cmpd. No. Structure C-22 N-NH .nh2 O N 1? C-23 F-'VaJ N-NH .NH;, O NH N=/ C-24 N-NH ^.nh2 ή S^NH N=/ 01298 1 648
C-25 Br\ Λ N-NH J I XNH2 Γιΐ k JJ N C-26 H3C ÏÏ N-NH vu- XNHZ cs=· rîi k J) N C-27 B\ Γ N-NH rîl ^,ΝΗ k JJ N C-28 HgC ï N-NH Lit NH N C-29 S- Jl N-NH Λ ,nh2 k jj N C-30 s- J/ N-NH /il·/ 11 ^NH JJ N C-31 F3C-" i N-NH ï γΊι k^-NH k JJ N C-32 P"* f N-NH xnh2 r^N k J1 N C-33 F·' O N-NH J' ï. t^N x^NH k J1 XN ο 1298 1 649
01298 1 650 C-45 F' N-NH U FT H '-NH C-46 F'' N-NH ô X ch3 C-47 J f-A N-NH ô N /CH, N H C-48 Γ FPnh û N H CH,
Exemple C-49 10
15
Step A
The pyrazole (2.60 g, 10.3 mmol) from example 4 wassuspended in 52 mL of dichloroethane and 52 mL of 2.5 M 01298 1 651 ΙΟ
NaOH. Tetrabutylammonium hydroxide (0.5 mL of a 1 Maqueous solution) was added to the stirred mixture. Tothis mixture was added t-butyl bromoacetate (2.10 g, 10.8mmol). The reaction mixture was stirred at roomtempérature for 4 h. The mixture was poured onto 200 mLof CH2C12 and 200 mL of H2O. The phases were separatedand the organic phase was washed with water (1x10 0 mL)and brine (1x100 mL) . The organic layer was dried overThe solvent was removed to leaveThis solid was triturated with hexane and the resùlting solid isolated by filtration.The solid was washed with hexane to leave 3.4 g of awhite solid (90%).
Na2SC>4 and was filtered.an off-white solid. 15
Step B 20 The alkylated pyrazole (3.7 g, 10.1 mmol) from Step A was treated with 57 mL of 4 N HCL in dioxane. The solution was stirred at room température for 4 h. The solvent was removed under reduced pressure and theresidue was dissolved in THF. The solution was treated 25 with propylene oxide (10.3 mmol) and was stirred for lhat room température. The solvent was removed to leave anoil. The residual solvent was chased with severalportions of EtOH. The resùlting solid was trituratedwith Et2O and the title compound Example C-49 was 30 isolated by filtration to afford 3.0 g of an off-whitesolid (95%). Mass spec: M+H cald: 312; found 312. XHNMR (DMSO-d6): 8.81 (d, J = 6.4 Hz, 2H) , 7.73 (d, J = 01298 1 652 5.8 Hz, 2H), 7.40 (m, 2H), 7.23 (t, J = 8.5 Hz, 1H), 5.16(s, 2H), 2.40 (s, 3H). 5 Example C-50
According to the procedure described above in Example C-10 49, Example C-50 was also prepared starting from 4-[3-(4-
fluorophenyl)-lH-pyrazole-4-yl]pyridine. Mass spec: M+H cald: 298; found 298. *H NMR (DMSO-d6): 8.75 (d, J = 6.4 Hz, 2H), 8.68 (s, 1H), 7.78 (d, J = 6.6 Hz, 2H), 7.52(dd, J = 5.4, 8.5 Hz, 2H) , 7.31 (t, J = 8.9 Hz, 2H) , 15 5.16 (s, 2H) .
Example C-51 20
Starting with the N-Boc-piperidinyl analog of Example C- 2, Example C-51 is also prepared according to the methods described in Scheme C-l. 01298 1 653
Example C-52
N-NH
li X
N
Step A: Picoline is treated with a base chosen from butnot limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in anorganic solvent such as THF, ether, t-BuOH or dioxane 10 from -78 °C to 50 °C for a period of time from 10 minutesto 3 hours. The picoline solution is then added to asolution of N-Cbz-(L)-phenylalaninyl N- hydroxysuccinimide. The reaction is allowed to stir from30 minutes to 48 hours during which time the température 15 may range from -20 °C to 120 °C. The mixture is then poured into water and extracted with an organic solvent.Af ter drying and removal of solvent the pyridyl monoketone is isolated as a crude solid which could be purified by crystallization and/or chromatography. 20
O
Cbz 25 Step B: A solution of the pyridyl monoketone in ether,THF, tBuOH, or dioxane is added to a base chosen from but 0 1 298 1 654 not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaHcontained in hexane, THF, ether, dioxane, or tBuOH from -78 °C to 50 °C for a period of time from 10 minutes to 3hours. Formyl acetic anhydride is then added as a 5 solution in THF, ether, or dioxane to the monoketoneanion while the température is maintained between -50 °Cand 50 °C. The resulting mixture is allowed to stir atthe specified température for a period of time from 5minutes to several hours. The resulting pyridyl diketone 10 intermediate is utilized without purification in Step C.
Step C: The solution containing the pyridyl diketone is 15 quenched with water and the pH is adjusted to between 4and 8 utilizing an inorganic or organic acid chosen fromHOAc, H2SO4, HCl, or HNO3. The température during thisstep is maintained between -20 °C and room température.Hydrazine or hydrazine hydrate is then added to the 20 mixture while maintaining the température between -20 °Cand 40 °C for a period of 3 0 minutes to several hours.The mixture is then poured into water and extracted withan organic solvent. The N-Cbz-protected pyridyl pyrazoleis obtained as a crude solid which is purified by 25 chromatography or crystallization. 01298 1 655
5 Step: D
The CBZ protecting group is cleaved using hydrogen gasunder pressure and Pd-C in an alcohol solvent, affordingscaffold C-52 after filtration and concentration.
15 The following compounds C-53 through C-59 in Table C-3 are prepared according to the general procedure describedabove for the préparation of C-52.
Table C-3
Example No. Structure C-53 N-NH H2hk 1 1 N ο 1298 1 656
C-54 h2n^ a' N-NH Jt Y ô N Ns Boc C-55 h2n. (j N-NH J Y ό N Boc C-56 h2n z= H c } ô N C-57 h2n n-nh Ή Y Λ ιΨ C-58 h2n N-NH jf (^NH-Boc w rii ίγ C-59 h2n N-NH ΛΛλ NH-Boc O γΊι ks JJ N
Example C-60 5 Step A: A Boc protected pyridylpyrazole is treated withbenzaldehyde in methylene chloride at room température in 01298 1 657 the présence of a drying agent for a period of time ranging from 1-24 h. Solvent is then evaporated and the resulting imine is used in step B without further purification.
Step B:
The pyridylpyrazole imine is dissolved in THF and stirred 10 under nitrogen at températures ranging from -78 to -20 °C.A base such as LDA, n-BuLi, or LiHMDS is added dropwiseto the mixture which is then stirred for an additional 10minutes to 3 h. Two équivalents of a methyl iodide arethen added to the mixture and stirring is continued for 15 several hours. The mixture is then quenched with acidand allowed to warm to room température and stirredseveral hours until cleavage of the Boc and the iminefunctions is complété. The pH is adjusted to 12 and thenthe mixture is extracted with an organic solvent, which 20 is dried and evaporated. The crude pyridylpyrazole isthen crystallized and/or chromâtographed to give purifiedC-60. Ο I298 1 658
Step B
1 ) Base 2) Mel
3) Acid, H2O
5
Exemple C-61
10 Exemple C-61 is prepared according to the methoddescribed in example C-60, substituting 1,4-dibromobutanefor methyl iodide. 15 20
Exemple C-62 01298 1 659
Example C-62 is prepared according to the methoddescribed in example C-60, substituting 1,3-dibromoethanefor methyl iodide. 5
Exemple C-63
The synthesis of compound C-63 starts with the 10 condensation reaction of bromomaleic anhydride B77 with2, 4-dimethoxybenzylamine in acetic acid and acetic anhydride. The maleimide B78 is then treated with 4'-fluoroacetophenone in the presence of catalytic amountPd2(dba)3 and sodium t-butoxide to form the 15 fluoroacetophenone substituted maleimide B79. B79 is then treated with tert-butoxybis(dimethylamino)methane toyield the a-ketoenamine B80. The a-ketoenamine B80 iscondensed with hydrazine to form the N-protectedmaleimide pyrazole B81. The 2,4-dimethoxybenzyl group is 20 cleaved with ceric ammonium nitrate (CAN) to give thetitle compound C-63. 01298 1 660
Example C-64
Using the method described in Schemes C-6 and C-7,10 Example 64 is prepared. 01298 1 661
Exemple C-65
Using the method described in Schemes C-6 and C-7,Exemple 65 is prepared.
Example C-66
Using the method described in Schemes C-6 and C-7,Example C-66 is synthesized, substituting N-2,4- 20 dimethoxybenzyl-4-bromopyridone for B78. 25 01298 ί 662
Example C-67
Using the method described in Schemes C-6 and C-7,Example C-67 is synthesized, substituting N-2,4- 10 dimethoxybenzyl-4-bromopyridone for B78, and substitutingN-Boc-glycyl N-hydroxysuccinimide for B82.
Exemple C-68
Using the method described in Schemes C-6 and C-7,20 Example C-68 is synthesized, substituting N-2,4- dimethoxybenzyl-4-bromopyridone for B78. 25 ο I298 1 663
Exemple C-69
Using the method described in Schemes C-6 and C-7,Example 69 is prepared, substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.
Exemple C-70
15 Using the method described in Schemes C-6 and C-7,Example 70 is prepared, substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.
Example C-71
01298 î 664
Using the method described in Schemes C-6 and C-7,Exemple 71 is prepared, substituting N-methyl-3-bromomaleimide for B78. 5 Example C-72
10 Using the method described in Schemes C-6 and C-7,Example 72 is prepared, substituting N-methyl-3-bromomaleimide for B78, and substituting N-Boc-nipecotylN-hydroxysuccinimide for B83. 15 Exemple C-73
Using the method described in Schemes C-6 and C-7,20 Example 73 is prepared, substituting N-methyl-3-bromomaleimide for B78 and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83. 25 01298 1 665
Biological data from compounds of Examples B-0001 through B-1573 and of Examples B-2270 through B-2462 are shown in the following tables.
In vitro P38-alpha kinase inhibitory data are shown inthe column identified as: "P38 alpha kinase IC50, uM or % inhib @ conc. (uM)"
In vitro whole cell assay for measuring the ability ofthe compounds to inhibit TNF production in human U937 cells stimulated with LPS are shown in the column identified as: "U937 Cell ICsOr uM or % inhib @ conc., (uM)" In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the mouse is shownin the column identified as: "Mouse LPS Model, % TNF inhib @ dose @ predose time"wherein in the dose is milligram per kilogram (mpk)administered by oral gavage and the predose timeindicates the number of hours before LPS challenge whenthe compound is administered.
In vivo assessment of the ability of the compounds toinhibit LPS-stimulated TNF release in the rat is shown inthe column identified as: "Rat LPS Model, % TNF inhib @ dose @ predose time" wherein in the dose is milligram per kilogram (mpk)administered by oral gavage and the predose time 01298 1 666 indicates the number of hours before LPS challenge whenthe compound is administered. 0.1298 Î 667
Example# P38 alpha kinaseIC5O.UM or %lnhlb@conc. (uM) U937 Cell IC50,uMor % inhlb@conc. (uM) Mo use LPS Model 7erNF Inhib © dose@predose time Rat LPS Model % Inhib ©dose©predose time B-OOO1 53.0%® 1.0uM 40.07« ®1.0uM B-0002 71.0%@1.0uM 28.0%® 10. OU M B-OOO3 70.0%@1.0uM 76.0% 10.0UM B-0004 80.0%@1.0uM 4.61 uM B-0005 95.0%@1.0uM 2.97uM B-0006 82.0%@1.0uM 80%@10.0uM B-0007 74.0%@1.0uM 85.0%@ 10.Ou M B-0008 42.07o@1.0uM 65.0%@10.0uM B-0009 0.04 uM 0.72uM B-OO1O 0.52 uM 0.65uM B-OO11 0.03 uM 4.47UM B-0012 30.0%@1.0uM 44.07o @1.0uM B-0013 70.07o@1.0uM 84.0%@10.0uM B-OO14 79.07o@1.0uM 80.0%®10.0uM B-0015 82.0%@1.0uM 80.0% @10.0 uM B-0016 94.07o@1.0uM 3.98UM B-OO17 56.07o@1.0uM 79.0%@10.0uM B-OO18 60.0%@1.0uM 59.0%@10.0uM B-0019 84.0%@1.0uM 100.0%@10.0uM B-0020 73.0%@1.0uM 81.0%®10.0uM B-0021 68.0%@ 1.0uM 76.07o@10.0uM B-0022 69.0%@1.0uM 44.0®1.0uM B-0023 90.0%@1.0uM 77.0%@10.0uM B-0024 94.0%@1.0uM 52.0%@1.0uM B-0025 89.0%@1.0uM 79.0%@10.0uM B-0026 96.0%@1.0uM 3.27uM B-0027 94.0%@1.0uM 11.0uM B-OO28 69.0%@1.0uM 45.0%@10.0uM B-OO29 91.0%@1.0uM 58.0%@10.0uM B-0030 92.0%@1.0uM 75.0%@10.0uM B-OO31 94.0%@1.0uM 100.0%® 10.0uM B-0032 94.0%@1.0uM 78.0%@10.0uM B-0033 97.0%@1.0uM 10.0uM B-0034 95.0%@1.0uM 10.0uM B-0035 94.0%@1.0uM 10.0UM B-0036 92.07e @1.0uM 8.24uM B-OO37 91.0%@1.0uM 86.0%@10.0uM B-OO38 71.0%@1.0uM 84.0%®10.0uM B-OO39 89.0%@1.0uM 72.0%@10.0uM B-0040 93.07e @1.Ou M 2.3uM B-0041 65.0%@1.0uM 66.0%@10.0uM B-0042 94.0%@1.0uM 2.76uM 01298 1 668
Example# Ρ38 alpha kinaseIC50,uM or %inhlb ©conc. (uM) U937. Cetl IC5O,uMor % 1 inhib@conc. (uM) Mouse LPS Model %INF Inhlb @ dose©predose time Rat LPS Model % Inhlb ©dose©predose time Β-0043 0.22 UM 0.54UM Β-0044 0.14 UM 0.19UM Β-0045 94.0%@1.0uM 1.01 uM Β-0046 96.0%@1.0uM 54.0%@1.0uM Β-0047 94.0%@1,0uM 74.0%@10.0uM Β-0048 94.0%@1.0uM 76.0%®10.0uM Β-0049 88%@1.0uM 33.0%@1.0uM Β-0050 73%@1.0uM 34.0%@1.0uM Β-0051 3.3uM 2.15uM 47%@100mpk@-6h 79%@3mpk@-4h Β-0052 92%@1.0uM 15.0%@1.0uM Β-0053 95%@1.0uM 34.0%@1.0uM Β-0054 90%@1.0uM 30.0%@1.0llM Β-0055 93%@1.0uM >1.0uM Β-0056 96%@1.0uM 21.0%@1.0uM Β-0057 96%®1.0uM 29.0%@1.0uM Β-0058 79%®1.0uM 18.0%@1.0uM Β-0059 83%@1.0uM 35.0%@1.0uM Β-0060 73%@1.0uM 22.0% @1.Ou M Β-ΟΟ61 62%®1.0uM 27.0%@1.0uM Β-0062 94%@1.0uM 36.0%@1.0uM Β-ΟΟ63 96%®1.0uM 40.0%@1.0uM Β-0064 90%@1.0uM 4.0%@1.0uM Β-0065 83%®1.0uM 21.0%@1.0uM Β-0066 94%®1.0uM 28.0%®1.0uM Β-0067 91%®1.0uM 1.0%@1.0uM Β-0068 72%@1.0uM 22.0%@1.0uM Β-0069 96%@1.0uM 37.0%@1.0uM Β-0070 92%®1.0uM 30.0%©1.0uM Β-0071 86%@1.0uM 31.0%® 1.0 U M Β-0072 77%@1.0uM 32.0%®1.0uM Β-0073 91%@1.0uM 24.0%@1.0uM Β-0074 92%®1.0uM 42.0%@1.0uM Β-0075 91%@1.0uM 35.0%@1.0uM Β-0076 58%®1.0uM 21.0%@1.0uM Β-0077 0.8uM 10.0UM Β-0078 80%@1.0uM 20.0%®1.0uM Β-0079 93%®1.0uM 13.0%@1.0uM Β-0080 73%®1.0uM 73.0%®1.0uM Β-0081 92%®1.0llM 13.0%@1.0uM Β-ΟΟ82 47%@1.0uM 27.0%@1.0uM Β-0083 0.22UM 8.51 uM Β-ΟΟ84 56%@1.0uM 30.0%@1.0uM 01298 1 669
Example# Ρ38 alpha kinaseIC50,uMor%inhib@conc. (uM) U937 Cell IC50,uMor % inhib@conc. (uM) Mouse LPS Model %rNF Inhlb 9 dose@predose time Rat LPS Model % Inhlb 9dose©predose tlme Β-0085 83%@1.OuM 21.0%91.0uM Β-0086 91%@1.0uM 37.0%@ 1.Ou M Β-0087 0.55UM 2.26uM 38%@30mpk@-6h Β-0088 96%®1.0uM 9.0%@1.0uM Β-0089 0.04uM 3.33uM Β-0090 9 8% 91.Ou M 52.0%@ 1.Ou M Β-0091 96%@1.0uM 40.0%91.0uM Β-0092 97%@1.0uM 34.0%@1.0uM Β-ΟΟ93 3.18 uM 1.25UM 30%930mpk@-6h Β-0094 96%@1.0uM 52.0%@1.0uM Β-0095 98%@1.0uM 38.0%91.0uM Β-0096 91%@1.0uM 22.0%91.0uM Β-0097 72.0%®10.0uM 38.0%91.0uM Β-0098 66.0%@10.0uM 12.O%91.0uM Β-0099 43.0% 91.0uM >1.0uM Β-Ο1ΟΟ 75.0% 91.0UM 5.0uM Β-Ο1Ο1 71.0% 91.0uM 2.11uM Β-0102 81.0%91.0uM 15.0%91.0uM Β-0103 71.0%91.0uM 6.0%91.0uM Β-Ο1Ο4 56.0% 91.0uM 2.78UM Β-Ο1Ο5 78.0%91.0uM 5.0uM Β-Ο1Ο6 62.0%@1.0uM 5.0uM Β-0107 0.27uM 5.0UM Β-Ο1Ο8 61.0%91.0uM 4.85UM Β-Ο1Ο9 45.0%91.0uM 19.0%91.0uM Β-Ο11Ο 66.0%@1.0uM 13.0%91.0uM Β-0111 57.0%@1.0uM >1.0uM Β-0112 97.0%@1.0uM 1.12uM Β-0113 75.0%@1.0uM 43.0%91.0uM Β-0114 45.0%91.0uM 3.92UM Β-0115 47.0%91.0uM 2.0%91.0uM Β-Ο116 73.0%91.0uM 35.0%91.0uM Β-Ο117 0.46 uM 1.78 uM 30%@30mpk@-6h Β-0118 1.18 uM 1.29 UM Β-Ο119 89.0%910.0uM 2.78UM Β-0120 0.008 uM 0.21 uM 77%@100mpk@-6l· 70%@3mpk@-4h Β-Ο121 79.0%@1.0uM 1.22uM Β-0122 79.0%910.0uM 2.0%@ 1.0 uM Β-0123 59.0%® 1.Ou M >1.0uM Β-Ο124 73.0%91.0uM 15.0%91.0uM Β-Ο125 70.0%910.0uM 17.O%91.0uM Β-0126 66.0%91.0uM 1.57UM 01298 1 670
Exemple# P38 alpha kinase IIC50,uM or % I inhib@conc. (uM) U937 Cell IC50,uMor. % 1 inhib@conc. (uM) Mouse LPS Model %rNF Inhib ® dose©predose time Rat LPS Model %inhib @dose@predose time B-0127 82.0%@1.0uM 0.96uM B-0128 78.0%@1.0uM 1.81uM B-0129 51.0%@1.0uM 31.0%@1.0uM B-0130 69.0°/o@1.0uM 58.0%®1.0uM B-0131 43.0%@1.0uM 46.0%®1.0uM B-0132 76.0%@1.0uM 8.0%®1.0uM B-0133 51.0%@1.0uM 42.0%@1.0uM B-0134 60.0%@1.0uM 2.17uM B-0135 78.0%@1.0uM 58.0%@1.0uM B-0136 77.0%@1.0uM 44.0%@1.0uM B-0137 41.0%@1.0uM 37.0%@1.0uM B-0138 50.0%@1.0uM 32.0%@1.0uM B-0139 54.0%@10.0uM 17.0%@1.0uM B-0140 67%@10.0uM 9.0%@1.0uM B-0141 78.0%@1.0uM 10.0%®1.0uM B-0142 86.0%@1.0uM 12.0%®1.0uM B-0143 42.0% ® 1.0uM 3.63uM B-0144 86.0% @1.Ou M 43.0%®1.0uM B-0145 54.0% ®10.0uM 12.0% @1.0uM B-0146 77.0% ®10.0uM 28.0%@1.0uM B-0147 44.0% ®1.0uM 22.0% ®1.0uM B-0148 51.0% ©1.0uM >1.0uM B-0149 1.15 uM 10.0 uM B-0150 27.0% @10.0uM 35.0% @1.0uM B-0151 43.0% ©1.0uM 30.0% @1.0uM B-0152 51.0% ®1.0uM 24.0% @1.0uM B-0153 57.0% ®1.0uM 21.0% @1.0uM B-0154 65.0% ®10.0uM 14.0% ®1.0uM B-0155 40.0% ®10.0uM 26.0% @1.0uM B-0156 42.0% @10.0uM 13,0% @1. Ou M B-0157 48.0% @10.0uM 9.0% ®1.0uM B-0158 58.0% @10.0uM 39.0% ®1.0uM B-0159 54.0% @10.0uM 5.0% ®1.0uM B-0160 59.0% ®10.0uM 26.0% @1.0uM B-0161 72.0% ®10.0uM 13.0% ®1.0uM B-0162 23%@1.0uM 2.05 UM B-0163 20.0% ®10.0uM 10.0% @1.0uM B-0164 37.0% ®10.0uM 20.0%@1.0uM B-0165 70.0% @10.0uM 19.0% @1.0uM B-0166 45.0% ®10.0uM 37.0%@1.0uM B-0167 40.0% @1.0uM 37.0% @1.0uM B-0168 44%@1.0uM I 2.36 uM 01298 1 671
Example# P38 alpha kinaseIC50,uM or %inhib @conc. (uM) U937 Cell IC50,uMor. % inhib @conc. (uM) Mouse LPS Model %rNF inhib @ dose@predosetime Rat LPS Model %inhib @dose@predose time B-0169 43.0% @1.0uNI 21.0% @1.0uNI B-O17O 43.0% @1.0uM 30.0% @1 .OuM B-0171 61.0% @10.0uNI 21.0% @1.0uM B-0172 16.0% @10.0uNI 11.0% @1.0uNI B-0173 33.0% @10.0uM 48.0% @1.0uNI B-0174 54.0% @10.0uM 43.0% @1.0uNI B-0175 41.0% @10.0uNI 31.0% @1.0uM B-0176 50.0% @1.0uM 30.0% @1.0uM B-0177 70.0% @10.0uNI 27.0% @1.0uNI B-0178 12.0% @10.0uNI 35.0% @1.0uM B-0179 27.0% @10.0uM 37.0% @1.0uM B-0180 34.0% @10.0uM 23.0% @1.0uNI B-0181 5.0%@1.0uM 2.0% @1.0uM B-0182 39.0% @10.0uNI 40.0% @1.0uNI B-0183 12.0% @10.0uNI 34.0% @1.0uNI B-0184 66.0% @10.0uM 17.0% @1.0uNI B-0185 65.0% @10.0uM 25.0% @1.0uNI B-0186 40.0% @1.0uM 25.0% @1.0uNI B-0187 4.0% @10.0uM 14.0% @1.0uNI B-0188 70.0% @10.0uM 35.0% @1.0uWl B-0189 42.0% @10.0uNI 9.0%@1.0uNI B-0190 59.0% @10.Ou NI 31.0% @1.0uNI B-0191 40.0% @1.0uM 29.0% @1.Ou M B-0192 12.0% @10.0uM 47.0% @1.0uNI B-0193 0.54 UM 6%@1.0uM B 0194 1.31 uM 22%@1.0uM B-0195 1.03 uM 55%@1.0uM B-0196 2.24 UM >1.0uNI B-0197 2.0 uM 14%@1.0uNI B-0198 1.2 uNI 2%@1.0uNI B-0199 1.34 uM 3%@1.0uM B-0200 1.31 UNI 16%@1.0uNI B-0201 0.29 uM 59% @1. Ou NI B-O2O2 0.55 UNI 2.26 UNI B-0203 0.16 uM 65%@1.0uNI B-0204 0.21 uNI 48%@1.0uNI B-0205 0.096 uM 54%@1.0uNI B-0206 5.76 UNI 14%@1.0uNI B-0207 0.12 UNI 52% @1.0 U M B-0208 0.067 UNI >1.0uNI B-0209 0.29 UNI 8%@1.0uNI B-0210 0.057 UNI 67%@1.0uNI 01298 1 672
Exemple# P38 alpha kinaselC50,uMor%inhib@conc. (uM) U937 Cell IC50,uMor % 1 inhib@conc. (uM) Mouse LPS Model %rNF inhib 9 dose9predose time Rat LPS Model %inhlb ©dose©predose time B-0211 0.2S uM 30%91.0uM B-0212 0.12 uM 28%91.0uM B-0213 0.31 UM 39%@1.0uM B-0214 0.16 UM 50%@1.0uM B-0215 0.11 uM 51%91.0uM B-0216 0.56 uM >1.0uM B-0217 0.55 UM >1.0uM B-0218 0.53 uM 18%@1.0uM B-0219 0.01 uM 18%@1.0uM B-0220 0.13 uM 40%91.0uM B-0221 2.4 uM I >1.0uM B-0222 0.4uM 29.0%@1.0uM B-0223 0.2uM 1.0%@1.0uM B-0224 <0.1 uM 93.0%©1.0uM B-0225 0.047UM 37.0%91.0uM B-0226 0.074UM 20.0%©1.0uM B-0227 0.045UM 1.0%91.0uM B-0228 0.15UM 44.0%91.0uM B-0229 <0.1 uM 61.0%91.0uM B-0230 0.041UM 30.0%91.0uM B-0231 0.055UM 40.0%1.0uM B-0232 0.048UM 24.0%91.0uM B-0233 0.095uM 43.0%91.0uM B-0234 0.1 luM 68.0%91.0uM B-0235 1.31UM 90.0%91.0uM B-0236 0.077UM 46.0%91.0uM B-0237 0.13uM 60.0%91.0uM B-0238 0.47 U M 82.0%91.0uM B-0239 5.73UM 84.0%91.0uM B-0240 0.2uM 70.0%91.0uM B-0241 0.1 UM 45.0%91.0uM B-0242 <0.1 uM 78.0%91.0uM B-0243 0.039uM 53.0%91.0uM B-0244 0.02uM 57.0%91.0uM B-0245 0.13uM 24.0%91.0uM B-0246 <0.1 UM >1.0uM B-0247 0.082UM 75.0%91.0uM B-024B <0.1 uM 11.0%91.0uM B-0249 <0.1 uM 75.0%91.0uM B-0250 0.28uM 36.0%91.0uM B-0251 0.31 uM 1.0%91.0uM B-0252 0.041 uM 1 54.0%91.0uM 01298 1 673
Example# P38 alpha kinaseIC50,uMor%inhib@conc. (uM) U937 Cell IC5O.UMor % Ί InhlbQconc. (uM) Mouse LPS Model %IMF Inhlb @ dose@predose time Rat LPS Model % Inhlb @dose@ p redose tlme B-0253 0.061 UM 74.0%@1.0uM B-02S4 0.12UM 59.0%@1.0uM B-0255 0.32uM 68.0%@1.0uM B-0256 <0.1 uM 88.0%@1.0uM B-0257 1.71uM 11.0%@1.0uM B-02S8 0.37UM 63.0%@1.0uM B-02S9 0.35uM 5 8.0% @1. Ou M B-0260 0.56uM 23.0%@1.0uM B-0261 0.49uM 23.0%@1.0uM B-0262 0.41 uM 89.0%@1.0uM B-0263 0.62uM 64.0%@1.0uM B-0264 0.14uM 18.0%@1.0uM B-0265 O.S2uM 24.0%@1.0uM B-0266 0.25uM 24.0%@1.0uM B-0267 0.48UM 11.0%@1.0uM B-0268 3.39uM 19.0%@1.0uM B-0269 9.81 uM 19.0%@1.0uM B-0270 5.79UM 13.0%@1.0uM B-0271 7.S5UM 12.0%@1.0uM B-0272 1.81 uM 48.0%@1.0uM B-0273 5.03UM 13.0%@1.0uM B-0274 2.68uM 2S.0%@1.0uM B-0275 2.67UM 33.0%@1.0uM B-0276 1.25UM 26.0%@1.0uM B-0277 0.68uM 34.0%@1.0uM B-0278 1.26UM 36.0%@1.0uM B-0279 1.39UM 33.0%@1.0uM B-0280 Q.86UM 18.0%@1.0uM B-0281 7.37UM 24.0%@1.0uM B-0282 0.75UM 38.0%@1.0uM B-0283 6.66UM 29.0%@1.0uM B-0284 0.083UM 65.0%@1.0uM B-0285 4.57UM 29.0%@1.0uM B-0286 0.33UM 50.0%@1.0uM B-0287 4.0uM 22.0%@1.0uM B-0288 4.46uM 26.0%@1.0uM B-0289 0.15UM 55.0%@1.0uM B-0290 0.66UM 44.0%@1.0uM B-0291 1.33UM 20.0%@1.0uM B-0292 0.22uM 28.0%@1.0uM B-0293 0.66uM 53.0%@1.0uM B-0294 0.68UM 45.0%@1.0uM 01298 1 674
Exemple# P38 alpha kinaseIC50,uM or %inhib ©conc. (uM) U937 Celi IC50.UMor % 1 inhib@conc. (uM) Mouse LPS Model %rNF inhib © dose©predose time Rat LPS Model %inhib ©dose I©predose time I B-0295 0.82uM 45.0%@1.0uM B-0296 8.03uM 36.0% @1. OU M B-0297 0.78uM 30.0%@1.0uM B-0298 0.58UM 48.0% @1.Ou M B-0299 0.87UM 54.0%@1.0uM B-0300 0.78UM 32.0%@1.0uM B-0301 0.19uM 50.0%@1.0uM B-O3O2 4.02UM 24.0%@1.0uM B-0303 0.22uM 10.0%@1.0uM B-0304 0.56uM 28.0%@1.0uM B-0305 B-O3O6 B-0307 B-0308 B-0309 B-0310 B-0311 B-0312 1 B-0313 1 B-0314 B-0315 B-0316 B-0317 B-0318 B-0319 B-0320 B-0321 B-0322 B-0323 B-0324 B-0325 B-0326 B-0327 B-0328 1 B-0329 B-0330 B-0331 1 B-0332 B-0333 B-0334 B-0335 B-0336 1 01298 1 675 I Example# B-0337 I B-0338 lB-0339 B -0340 IB-0341 IB-0342 IB-0343 I B-0344 B-0345 I B-0346 B-0347 B-0348 I B-0349 B-0350 B-0351 I B-0352 I B-0353 B-0354 B-0355 lB-0356 B-0357 B-0358 B-0359 IB-0360 lB-0361 B-0362 B-0363 B-0364 B-0365 B-0366 B-0367 B-0368 B-0369 B-0370 IB-0371 lB-0372 B-0373 B-0374 B-0375 B-0376 B-0377 B-0378 P38 alpha kinaseIC50,uMor%inhib@conc. (uM)
1.37uM
1.0UM
0.75uM
0.66uM
1.46UM
0.37uM
0.45UM
1.6uM
0.33uM
0.52UM
4.67uM
1.44uM
0.96uM
0.7uM
1.0uM
1.0uM
0.16uM
0.65UM
0.49uM
0.35uM
0.45uM
1.38UM
1.0uM
2.99uM
1.29uM
1.1 uM U937 Cell IC5O,uM I Mouse LPS Model %or % TNF Inhlb © dose lnhib@conc. (uM) ©predose time
55%@1.0uM
0.66UM
40.0% @ 1.0 uM
24.0%@1.0uM
0.66uM
17.0%@1.0uM
47.0%@1.0uNI
19.0%@1.0uM
46.0%@1.0uM
27.0%@1.0uM
25.0%@1.0uM
27.0%®1.0uM
27.0%@1.0uM
46.0%@1.0uM
23.0%@1.0uM
0.64uM
57.0%@1.0uM
28.0%®1.0uM
28.0%® 1.Ou M
29.0%@1.0uM
18.0%@1.0uM
12.0%@1.0uM
19.0%@1.0uM
12.0%@1.0uM
36.0%®1.0uM
36.0%@1.0uM 51%®30mpk®-6h 37%@30mpk®-6h
Rat LPS Model %inhib ©dose©predose time 54%® 3mpk® -4h 01298 1 676
Example# P38 alpha kinaseIC5O,uM or%lnhib@conc. (uM) U937 Cell IC5O,UMor % 1 inhib@conc. (uM) Mouse LPS Model %rNF inhlb @ dose©predose time Rat LPS Model % Inhlb ©dose©predose time B-0379 0.53uM 24.0%@1.0uM B-0380 1.41uM 32.0%@1.0uM B-0381 0.22uM 47.0%@1.0uM B-0382 0.41 uM 32.0% @1. Ou M B-0383 1.43UM 10.0%@1.0uM B-0384 4.02uM 16.0%@1.0uM B-0385 0.057UM 0.9uM 30%@30mpk@-6h 0%@3mpk@-4h B-0386 0.13uM 54.0%@1.0uM B-0387 0.41 uM 52.0%@1.0uM B-0388 <0.1 uM 36.0%@1.0uM B-0389 0.01 uM 0.05UM 62%@3mpk@-4h B-0390 0.089UM 55.0%@1.0uM B-0391 O.86uM 18.0%@1.0uM B-0392 0.13uM 57.0%@1.0uM B-0393 0.043UM 66.0%@1.0uM B-0394 0.13uM 45.0%@1.0uM B-0395 0.087UM 48.0%@1.0uM B-0396 0.097UM 0.44UM B-0397 0.17 uM 41.0%@1.0uM B-0398 0.054UM 66.0%@1.0uM B-0399 0.14UM 39.0%@1.0uM B-0400 0.16uM 25.0%@1.0uM B-0401 0.46UM 52.0%@1.0uM B-0402 0.14UM 1.51UM B-0403 1.77uM 2.42uM B-0404 0.31 UM 48.0%@1.0uM B-0405 0.79uM 30.0%@1.0uM B-0406 0.54UM 35.0%@1.0uM B-0407 0.76uM 27.0%@1.0uM B-0408 0.5uM 50.0%@1.0uM B-0409 0.53uM 30.0%@1.0uM B-0410 0.38UM 44.0%@1.0uM B-0411 0.62UM 50.0%@1.0uM B-0412 0.24uM 48.0%@1.0uM B-0413 0.18UM 55.0%@1.0uM B-0414 2.54uM 25.0%@1.0uM B-0415 0.42UM 43.0%@1.0uM B-0416 0.32UM 34.0%@1.0uM B-0417 0.91 UM 28.0%®1.0uM B-0418 0.22UM 27.0%@1.0uM B-0419 0.85uM 41.0%21.0uM B-0420 0.83UM 49.0%@1.0uM 01298 1 677
Example# P38 alpha kinaseIC50,uM or %inhib@conc. (uM) U937 Cell IC50,uMor % inhib@conc. (uM) Mouse LPS Model %rNF inhib © dose©predose time Rat LPS Model %inhib ©dose©predose time B-0421 0.46UM 57.0%@1.0uM B-0422 <0.1 UM 40.0%@1.0uM B-0423 0.18UM 33.0%@1.0uM B-0424 0.083UM 32.0%@1.0uM B-0425 0.26UM 54.0%@1.0uM B-0426 0.055UM 0.74uM 41%@3mpk@-4h B-0427 0.63uM 39.0%@1.0uM B-0428 0.99uM 27.0%@1.0uM B-0429 0.27uM 45.0%@1.0uM B-0430 0.29uM 75.0%@1.0uM B-0431 0.21 U M 64.0%@1.0uM B-0432 <0.1 UM 89.0%@1.0uM B-0433 <0.1uM 92.0%@1.0uM B-0434 0.12uM 65.0%@1.0uM B-0435 0.3UM 61.0%@1.0uM B-0436 1.11uM 71.0%@1.0uM B-0437 0.58UM 59.0%@1.0uM B-0438 <0.1 uM 91.0%@1.0uM B-0439 2.12uM 65.0%@1.0uM B-0440 0.66uM 63.0%@1.0uM B-0441 0.8uM 58.0%@1.0uM B-0442 <0.1 uM 91.0%@1.0uM B-0443 2.01uM 71.0%@1.0uM B-0444 1.01UM 51.0%@1.0uM B-0445 <0.1 uM 83.0%@1.0uM B-0446 0.78UM 80.0%@1.0uM B-0447 0.19uM 71.0%@1.0uM B-0448 0.4uM 79.0%@1.0uM B-0449 0.83UM 81.0%@1.0uM B-0450 0.26UM 81.0%@1.0uM B-0451 0.071 uM 83.0%@1.0uM 42%@30mpk@-6h B-0452 0.7UM 75.0%@1.0uM B-0453 0.47UM 75.0%@1.0uM B-0454 0.11UM 80.0%@1.0uM B-0455 <0.1 UM 95.0%@1.0uM 36%@3mpk%-4h B-0456 1.B1UM 67.0%@1.0uM B-0457 O.OSSuM 81.0%@1.0uM B-0458 0.033uM 70.0%@1.0uM B-0459 0.099UM 76.0%@1.0uM B-0460 0.061 U M 92.0%@1.0uM B-0461 0.025uM 96.0%@1.0uM B-0462 <0.1 uM 97.0%@1.0uM 01298 1 678
Example# P38 alpha kinase I U937 Cell IC50,uMIC50,uMor% or % inhib@conc. (uM) I inhib@conc. (uM) Mouse LPS Model %IMF inhib @ dose©predose time Rat LPS Model % Inhib ©dose©predose time B-0463 0.052UM 95.0%®1.0uM B-0464 <0.1 uM 91.0%@1.0ukl B-0465 0.084uM 98.0%@1.0uM B-0466 <0.1 uM 98.0%@1.0uM 0%®3mpk@-4h B-0467 <0.1 uM 77.0%@1.0uM B-0468 0.031 UM 93.0%@1.0uM B-0469 0.056UM 92.0%® 1. Ou M B-0470 0.063UM 92.0%@1.0uM B-0471 0.027UM 97.0%@1.0uM B-0472 0.19UM 54.0%@1.0uM B-0473 0.004UM 95.0%®1.0uM B-0474 0.024uM 86.0%@1.0uM B-0475 0.21 u M 74.0%®1.0uM B-0476 O.S6uM 69.0%@ 1.Ou M B-0477 1.48uM 96.0%@1.0uM B-0478 0.034uM 87.0%@1.0uM B-0479 0.031UM 90.0%@1.0uM 15%@3mpk@-4h B-0480 0.12uM 88.0%®1.0uM B-0481 0.014uM 95.0%@1.0uM 56%@3mpk@-4h B-0482 0.97uM 68.0%@1.0uM B-0483 0.57uM 68.0%@1.0uM B-0484 0.28uM 62.0% @1.Ou M B-0485 0.04uM 95.0%@1.0uM B-0486 0.24uM 80.0%@1.0uM B-0487 0.1 luM 89.0%@1.0uM 54%@3mpk@-4h B-0488 0.62uM 88.0%@ 1.Ou M B-0489 0.3uM 80.0%®1.0uM B-0490 0.91 uM 74.0%@1.0uM B-0491 0.43UM 66.0%@1.0uM B-0492 0.069UM 42.0%® 1.Ou M B-0493 0.3uM 36.0%@1.0uM B-0494 0.13UM 30.0%@1.0uM B-0495 0.12uM 25.0%®1.0uM B-0496 0.83UM 16.0%®1.0uM B-0497 0.44uM 31.0%@1.0uM B-0498 0.33uM 11.0%@1.0uM B-0499 0.39uM ] 37.0%@1.0uM B-0500 0.26uM 41.0%®1.0uM B-O5O1 0.049UM 52.0%@1.0uM B-0502 0.065UM 48.0%@1.0uM B-0503 0.16UM 73.0%@1.0uM B-0504 0.4uM 43.0%@1.0uM 679
Example# P38 alpha kinaseICSO,uM or%inhib@conc. (uM) U937 Cell IC50,uMor % nhib@conc. (uM) Mouse LPS Model %rNF inhib @ dose©predose time Rat LPS Model % Inhib ©dose©predose time B-0505 0.28uM 44.0%@1.0uM B-0506 0.94UM 43,0%@1.0uM B-0507 0.18uM 75.0%@1.0uM B-0506 2.0uM 48.0%@1.0uM B-0509 0.1 uM 86.0%@1.0uM B-0510 0.69uM 61.0%@1.0uM B-0511 0.007UM 90.0%@1.0uM B-0512 1.0UM 53.0%@1.0uM B-0513 0.72UM 52.0%@ 1 .OuM B-0514 0.14uM 87.0%@1.0uM B-0515 0.42UM 61.0%@1.0uM B-0518 0.37UM 84.0%@1.0uM B-0517 0.094UM 52.0%@1.0uM B-0518 0.11uM 64.0%@1.0uM B-0519 0.043UM 87.0%@ 1.OuM B-0520 0.4UM 67.0%@1.0uM B-0521 1.37UM 52.0% @1.OuM B-0522 0.15uM 75.0%@1.0uM B-0523 0.19uM 83.0%@1.0uM B-0524 0.4uM 77.0%@1.0uM B-0525 0.16UM 76.0%@1.0uM B-0526 0.031 UM 87.0%@1.0uM B-0527 1.09uM 63.0%@1.0uM B-0528 0.14UM 70.0%@1.0uM B-0529 0.11uM 73.0%@1.0uM B-0530 5.53UM 45.0%@1.0uM B-0531 0.5uM 48.0%®1.0uM B-0532 0.45uM 1.01 UM 41%@30mpk@-6h B-0533 1.23UM 47.0%@1.0uM B-0534 0.41 UM 54.0%@1.0uM B-0535 0.44UM 0.87UM B-0536 0.46UM 0.15uM B-0537 3.44uM 51.0%®1.0uM B-0538 1.13uM 45.0%@1.0uM B-0539 2.84UM 21.0%@1.0uM B-0540 3.62uM 54,0%@1.0uM B-0541 3.24uM 28.0%@1.0uM B-0542 1.55UM 50.0%@1.0uM B-0543 1.56uM 43.0%@1.0uM B-0544 1.12UM 27.0%@1.0uM B-0545 1.06UM 41.0%@1.0uM B-0546 1.04UM 18.0%@1.0uM B-0547 1.24UM 21.0%®1.0uM B-0548 1.77UM 28.0%@ 1.OuM B-0549 2.22uM 22.0%® 1.OuM 680
Mouse LPS Model % Rat LPS Model % TNP inhib® dose I inhib ©dose @predosetlme ©predosetime
U937 Cell IC50.UM or % lnhib@conc. (uM)
Example# B-0550 B-0551 B-0552 B-0553 B-0554 B-0555 B-0556 B-0557 B-0558 B-0559 B-0560 B-0561 B-0562 B-0563 B-0564 B-05S5 B-0566 B-0567 B-0568 B-0569
B-O57O B-0571 B-0572 B-0573 B-0574 B-0575 B-0576 B-0577 B-0578 B-0579 B-0580 B-0581 B-0582 B-0583 B-0584 B-0585 B-0586 B-0587 B-0588 B-0589 B-0590 B-0591 B-0592 B-0593 B-0594 B-0595 B-0596 B-0587 B-0598 P38 alpha kinaseIC50,uM or %Inhib @conc. (uM)
2.41 uM
1.08uM
0.13uM
1.44uM
2.68uM
1.87uM
0.49uM
1.37UM
0.85UM
0.53UM
2.S7UM
2.07UM
0.22uM
0.18uM
0.82uM
0.23UM
<0.1 uM
0.14UM
1.22UM
0.15UM
0.27UM
0.38UM
0.27UM
0.36UM
0.13uM
0.032uM
0.068uM
0.091 uM
1.88uM
0.11uM
2.23UM
0.26UM
1.03UM
3.93UM
0.66UM
0.83uM0.81 uM
6.84uM
12.8UM
1.71 uM
1.57UM
3.59UM
1.62UM
1.22UM
2.42UM
20.0uM
1.68UM
2.12UM
14.0%®1.0uM
56.0%®1.0uM
46.0%®1.0uM
47.0%®1.0uM
20.0%«1.0uM
34.0%®1.0uM
39.0%®1.0uM
32.0%®1.0uM
33.0%®1.0uM
49.0%© 1 .OuM
31.0%®1.0uM
40.0%® 1 .OuM
0.3UM
_0.13uM
58%®1.0uM
0.S9uM
0.17UM
0.28uM
46.0%® 1.0UM
0.26UM
46.0%®1.0uM
44.0%® 1.OuM
41.0%®1.0uM
1.7UM
0.66uM
0.17UM
0.38uM
66.0%® 1.OuM
47.0%®1.0uM
79.0%® 1 .OuM
0.84UM
2.17UM
37.0%®1.0uM
26.0%®1.0uM
54.0%® 1.OuM
79.0%® 1.OuM
51.0%®1.0uM
[ 38%®1.0uM I 42%®1.0uM~ 42%®1.0uM~
38,0uM 29.o%® 1 .oiïiSr 45.0%®1.0uM~ I 36.0%® 1.OuM-
I 41.0%®1.0ÜM
I 22.0%® 1 .OuM
I 41.0%®1.ÔÛM
I 63.0%®1.ÔÜM
50.0%@1.0uM 5%®3mpk@-4h 0%®3mpk®-4h 37%®3mpk@-4h 65%@3mpk@-4h 50%@30mpk@-6h
01298 J 681
Example* P38 alpha kinasetC50,uMor%inhibOconc. (uM) U937 Cell IC50,uMor % inhib®conc. (uM) Mouse LPS Model %rNF inhib © dose©predosetime Rat LPS Model %inhib © dose©predose time B-0599 4.16UM 21.0%@1.0uM B-0600 0.002UM 28.0%@1.0uM B-0601 0.089uM 1.31UM 43%93mpk%-4h B-0602 0.97 U M 61.0%®1.0uM B-0603 0.09uM 51.0%91.0uM B-0604 0.3uM 20.0%@1.0uM B-0605 0.18uM 47.0%®1.0uM B-0606 0.17uM 53.0%®1.0uM B-0607 2.79uM 70.0%@1.0uM B-0608 0.059uM 73.0%91.0uM B-0609 <0.1 uM 87.0%91.0uM B-0610 <0.1 uM 88.0% @1.OU M B-0611 0.65uM 60.0%@1.0uM B-0612 0.16UM 60.0%@1.0uM B-0613 0.17uM 76.0%@1.0uM B-0614 0.76UM 70.0%91.0uM 0%93mpk9-4h B-0615 0.08uM 83.0%®1.0uM B-0616 0.38uM 87.0%91.0uM B-0617 0.045UM 92.0%91.0uM B-0618 0.37UM 80.0%®1.0uM B-0619 <0.1 UM 88.0%91.0uM B-0620 1.59uM 58.0%91.0uM B-0621 0.36uM 68.0%91.0uM B-0622 0.076UM 78.0%®1.0uM B-0623 0.12uM 76.0%91.0uM B-0624 0.085UM 54.0%®1.0uM B-0625 0.023UM 88.0%91.0uM B-0626 <0.1 uM 85.0%91.0uM B-0627 0.25uM 69.0%®1.0uM B-0628 0.023UM 72.0%®1.0uM B-O629 0.2uM 79.0%®1.0uM B-O63O O.OGuM 77.0%®1.0uM B-0631 0.065UM 81.0%91.0uM B-0632 <0.1 UM 79.0%91.0uM B-0633 0.6uM 80.0%91.0uM B-0634 0.6uM 40.0%®1.0uM B-0635 0.15uM 55.0%91.0uM B-0636 <0.1 uM 86.0%91.0uM B-0637 0.11UM 92.0%91.0uM B-0638 0.25uM 89.0%91.0uM B-O639 0.051 uM 93.0%91.0uM 50%@3mpk9-4h B-0640 0.36uM 94.0%91.0uM B-0641 0.58uM 65.0%91.0uM B-0642 0.49uM 90.0%91.0uM B-0643 0.069UM 85.0%91.0uM 0%93mpk9-4h B-O644 0.058UM 89.0%91.0uM B-O645 0.58uM 80.0%91.0uM B-0646 0.26uM 94.0%91.0uM B-0647 1.61uM 76.0%91.0uM 01298 1 682
Exemple# P38 alpha kinaseIC5O,uM or %inhib@conc. (uM) U937 Cell ICSO.uMor % inhib® conc. (uM) Mouse LPS Model %rNF inhib @ dose©predose time Rat LPS Model %inhib @dose©predose time B-0648 <0.1uM 83.0%@1.0uM B-0649 0.83uM 39.0%@1.0uM B-0650 O.OOSuM 95.0%@1.0uM 8%e3mpke-4h B-0651 1.78UM 81.0%@1.0uM B-0652 0.19uM 83.O%@1.OUM B-0653 2.01 U M 74.0%@1.0uM B-0654 5.97uM 78.0%©1.0uM B-0655 1.25uM 76.0%©1.0uM B-0656 0.007UM 95.0%©1.0uM 28%@3mpk@-4h B-0657 0.17uM 83.0% @1.Ou M B-0658 1.14uM 91.0%©1.0uM B-0659 2.64uM 87.0%©1.0uM B-0660 0.088UM 92.0%©1.0uM B-0661 <0.1 uM 90.0%©1.0uM B-0662 <0.1 uM 95.0%©1.0uM B-0663 0.88uM 74.0%@1.0uM B-0664 0.39uM 80.0%©1.0uM B-0665 0.47uM 72.0%@1.0uM B-0666 0.17uM 73.0%©1.0uM B-0667 0.83uM 75.0%@1.0uM B-0668 0.27UM 78.0%©1.0uM B-0669 0.89uM 34.0%ei.0uM B-0670 3.15uM 32.0%e1.0uM B-0671 6.38uM 36.0%©1.0uM B-0672 6.59uM 32.0%©1.0uM B-0673 8.54UM 48.0%©1.0uM B-0674 2.81 UM 42.0%e1.0uM B-0675 5.42uM 3.0%ei.0uM B-0676 2.09UM 22.o%e1.OUM B-0677 1.63uM 25.0%ei.0uM B-0678 0.38uM 52.0%ei.0uM B-0679 0.062UM 45.o%e1.OUM B-0680 0.42UM €7.0%ei.0uM B-0681 1.96uM 17.0%ei.0uM B-0682 0.76UM 39.o%e1.OUM B-0683 13.0uM 32.0%ei.0uM B-0684 0.54UM 68.o%e1.OUM B-0685 15.4uM 33.o%e1.OUM B-0686 0.42uM 59.o%e1.OUM B-0687 10.1 uM 15.0%ei.0uM B-0688 0.66UM 58.0%ei.0uM B-0689 14.6uM 27.0%ei.0uM B-0690 27.1 uM 36.0%ei.0uM B-0691 0.16uM 48.0%ei.0uM B-0692 0.38UM 29.0%ei.0uM B-0693 0.39uM 28.0%@1.0uM B-0694 0.62UM 21.0%ei.0uM B-0695 0.23uM 32.0%ei.0uM B-0696 0.085UM 35.o%e1.OUM 01298 1 683
Example# P38 alpha kinaseIC50,uM or %inhlb@conc. (uM) U937 Cell IC50,uMor % 1 lnhlb@conc. (uM) Mouse LPS Model %ÎNF Inhib @ dose©predose tlme Rat LPS Model % Inhib ©dose©predose tlme B-0697 0.45UM 44.0%@1.0uM B-0698 2.33UM 43.0%@1.0uM B-0699 0.34UM 31.0%@1.0uM B-0700 0.24uM 56.0%@1.0uM B-0701 0.39uM 45.0%@1.0uM B-0702 0.036uM 39.0%@1.0uM B-0703 0.12uM 39.0%@1.0uM B-0704 2.19uM 29.0%@1.0uM B-0705 0.44uM 21.0%@1.0uM B-0706 0.44uM 32.0%@1.0uM B-0707 1.7uM B-0708 2.1 U M B-0709 0.84uM B-0710 1.99uM B-0711 1.99uM B-0712 2.9uM B-0713 4.3UM B-0714 3.7uM B-0715 3.2UM B-0716 4.6uM B-0717 4.3UM B-0718 1.4uM B-0719 3.4uM B-0720 1.3uM B-0721 3.8uM B-0722 0.07uM >1.0uM B-0723 0.47uM B-0724 0.06UM 17.0%@1.0uM B-0725 9.7uM B-0726 1.4UM B-0727 0.51 UM B-0728 20.0uM B-0729 0.87UM B-0730 0.25uM 11.0%@1.0uM B-0731 0.87UM >1.0uM B-0732 14.0uM B-0733 32.0uM B-0734 0.92uM B-0735 1.0uM B-0736 26.0uM B-0737 2.6uM B-0736 2.7uM B-0739 4.1 uM B-0740 4.4uM B-0741 26.0UM B-0742 2.2uM B-0743 1.2UM B-0744 23.0uM B-0745 6.0uM 01298 1 684
Exemple# P38 alpha kinaseIC50,uM or%inhib@conc. (uM) U937 Cell IC50,uMor % lnhib@conc. (uM) Mouse LPS Model %rNF inhlb @ dose©predose time Rat LPS Model % Inhlb ©dose©predose tlme B-0746 0.01 U M 22.0%@1.0uM B-0747 1.1 uM B-0748 1.2uM B-0749 4.4uM B-0750 0.92uM B-0751 1.6uM B-0752 0.33UM B-0753 0.37UM B-0754 0.55UM B-0755 2.3llM B-0756 0.94UM B-0757 0.54uM 16.0%@1.0uM B-0758 1.5uM B-0759 0.3uM B-0760 0.01 uM 13.0%@1.0uM B-0761 <0.1uM B-0762 0.13UM 5.0%@1.0uM B-0763 0.015uM 17.0%@1.0uM B-0764 0.67uM 26.0%@1.0uM B-0765 0.3UM 29.0%@1.0uM B-0766 0.95UM B-0767 O.OBuM B-0768 1.4uM B-0769 12.7UM B-0770 2.3uM B-0771 0.5uM B-0772 0.8uM B-0773 14.0UM B-0774 1.5uM B-0775 O.OuM >1.0uM B-0776 0.9uM >1.0uM B-0777 21.0uM B-0778 51.0uM B-0779 0.5uM B-0780 1.1 uM B-0781 48.0UM B-0782 22.0uM B-0783 8.0uM B-0784 7.0uM B-0785 23.0UM B-0786 24.0UM B-0787 1.SUM B-0788 1.2uM B-0789 33.0UM B-0790 1.0UM 4.0%@1.0uM B-0791 0.3UM >1.0uM B-0792 1.1 UM B-0793 0.3UM B-0794 2.9uM 2.0%@1.0uM 685
Example* P38 alpha kinaseIC50,uM or %lnhlb@conc. (uM) U937 Cell IC50,uMor % 1 lnhib@conc. (uM) Mouse LPS Model %FNF inhib © dose©predose tlme Rat LPS Model % Inhib ©dose©predose tlme B-079S 1.9uM 11.0%@1.0uM B-0796 1.4uM B-0797 1.04uM - B-0798 1.73uM - B-0799 - >1.0uM B-0800 1.01uM >1.0uM B-0801 0.67uM >1.0uM B-0802 - >1.0uM B-0803 0.057UM 53.0%@ 1.OuM B-0804 0.3uM 32.0%@ 1. OuM B-0805 0.71 uM >1.0uM B-0806 3.28uM >1.0uM B-0807 10.8uM - B-0808 3.09UM >1.0uM B-0809 1.22uM 7.0%@ 1.OuM B-0810 1.11uM >1.0uM B-0811 2.79uM 2.0%® 1.OuM B-0812 2.12uM >1.0uM B-0813 3.02uM >1.0uM B-0814 - >1.0uM B-0815 2.11uM >1.0uM B-0816 3.46uM >1.0uM B-0817 3.07uM 33.0%@1.0uM B-0818 4.97uM >1 .OuM B-0819 1.08uM >1.0uM B-0820 1.64uM 3.0%@ 1.OuM B-0821 1.44uM - B-0822 1.33uM - B-0823 2.39uM >1.0uM B-0824 3.41 uM - B-0825 - - B-0826 1.74uM - B-0827 15.6UM - B-0828 7.9uM - B-0829 0.61 UM 65.0%® 1.OuM B-0830 0.54uM 34.0%@ 1.OuM B-0831 0.9uM >1.0uM B-0832 1.49uM - B-0833 0.95uM 23.0%@ 1.OuM B-0834 1.25uM - B-0835 - - B-0836 1.24UM - B-0837 1.96UM >1 .OuM B-0838 3.1 uM - B-0839 4.3uM B-0840 0.63UM 47.0%@ 1.OuM B-0841 0.32uM 36.0%@ 1.OuM B-0842 0.74UM 63.0%@ 1.OuM B-0843 0.61 u M >1.0uM
686
Example# P38 alpha kinaseIC50,uM or%inhib@conc. (uM) U937 Cell IC50,uMor % inhib@conc. (uM) Mouse LPS Model %FNF Inhlb @ doseOpredose time Rat LPS Model %inhlb ©dose@predose time B-0844 0.4UM 25.0%@1.0uM B-0845 1.78uM - B-0846 1.8uM - B-0847 0.73UM 21.0%@1.0uM B-0848 1.56UM - B-0849 1.25llM - B-0850 1.81UM - 6*0851 0.91 llM 39.0%@1.0uM B-0852 1.02uM - B-0853 - 38.0%@1.0uM B-0854 - 25.0%@1.0uM B-0855 - 8.0%@1.0uM B-0856 - 38.0%@1.0uM B-0857 6.25uM - B-0858 2.1 uM 48.0%@1.0uM B-0859 39.5UM - B-0860 38.1 UM - B-0861 1.32UM 12.0%@1.0uM B-0862 2.1SUM 4.0%@1.0uM B-0863 0.81 uM 25.0%@1.0uM B-0864 0.39UM 40.%@1.0uM B-0865 O.6611M 46.0%@1.0uM B-0866 1.38UM 28.0%@1.0uM B-0867 0.62uM >1.0uM B-0868 3.28UM 8.0%@1.0uM B-0869 4.19uM >1.0uM B-0870 3.13uM >1.0uM B-0871 1.9UM >1.0uM B-0872 3.13uM 3,0%@1.0uM B-0873 6.92UM >1.0uM B-0874 1.92UM >1.0uM B-0875 2.13uM 8%@1.0uM B-0876 0.89UM >1.0uM B-0877 1.17UM 13.0%@1.0uM B-0878 0.6SUM 19.0%@1.0uM B-0879 0.87uM 1.0%@1.0uM B-0880 0.15uM 40.0%@1.0uM B-0881 1.36UM >1.0uM B-0882 1.48UM 9%@1.0uM B-0883 1.06IIM >1.0uM B-0884 1.89UM - B-0885 B-0886 B-0887 B-0888 B-0889 B-0890 B-0891 B-0892 01298 1 687
Example# P38 alpha kinaseIC50,uMor%inhibdconc. (uM) U937 Cell IC5O.UMor % inhlb@conc. (uM) Mouse LPS Model %ITIF Inhlb ® dose@predose time Rat LPS Model % Inhlb ddosedpredose time B-0893 B-0894 B-0895 B-0896 B-0897 B-0898 B-0899 B-0900 B-0901 B-0902 B-0903 B-0904 B-0905 B-0906 B-O9O7 B-O9O8 B-0909 B-0910 B-0911 B-0912 B-0913 B-0914 B-0915 B-0916 B-0917 B-0918 B-0919 B-0920 B-0921 B-0922 B-0923 B-0924 B-0925 B-0926 B-0927 B-0928 B-0929 B-0930 B-0931 B-0932 B-0933 47.0%@1.0uM 37.0%@1.0uM B-0934 67.0%d1.0uM 36.0%@1.0uM B-0935 69.0%@1.0uM 54.0%@1.0uM B-0936 69.0%@1.0uM >1.0uM B-0937 64.0%d1.0uM 1.74UM B-0938 51.0%@1.0uM 29.0%d1.0uM B-0939 78.0%@1.0uM 14.0%d1.0uM B-0940 56.0%@1.0uM 22.0%d1.0uM B-0941 81.0%@1.0uM 25.0%d1.0uM 01298 1 688
Example# P38 alpha kinaseIC50,uM or%inhlb@conc. (uM) U937 Cell IC50,uMor % ' lnhib@conc. (uM) Mouse LPS Model %rNF inhib ® dose@predose time Rat LPS Model % Inhib 9dose©predose time B-0942 82.0%@1.0uM 2.0%91.0uM B-0943 63.0% @1O.OuM 24.0%91.0uM B-0944 45.0%@1.0uM 27.0%91.0uM B-0945 96.0%@1.0uM 0.93UM B-0946 76.0%@1.0uM 31.0%91.0uM B-0947 69.0%@1.0uM 34.0%91.0uM B-0948 68.0%@1.0uM 1.81UM B-0949 90.0%@1.0uM 17.0%91.0uM B-0950 81.0%@1.0uM 0.58uM B-0951 82.0%®1.0uM 20.0%91.0uM B-0952 44.0%@1.0uM 21.0%91.0uM B-0953 63.0%@1.0uM 25.0%91.0uM B-0954 62.0%@1.0uM 0.52UM B-0955 49.0%@1.0uM 0.54uM B-0956 56.0%@1.0uM 1.33UM B-0957 79.0%@1.0uM 22.0%91.0uM B-0958 74.0%@1.0uM 0.38uM B-0959 83.0%@1.0uM 39.0%91.0uM B-0960 48.0%@1.0uM 4.0%91.0uM B-0961 79.0%@1.0uM 23.0%91.0uM B-0962 85.0%®1.0uM 2.71UM B-0963 76.0%®1.0uM 39.0%91.0uM B-0964 94.0%@1.0uM 5.0UM B-0965 74.0%@1.0uM 1.1 uM B-0966 50.0%®1.0uM 5.0%91.0uM B-0967 80.0%@1.0uM 29.0%91.0uM B-0968 35.0%@1.0ulUI 26.O%91.OUM B-0969 63.0%@1.0uM 35.0%91.0uM B-0970 76.0%@10.0uM 0.88UM B-0971 61.0%@1.0uM 39.0%91.0uM B-0972 85.0%@1.0uM 2.0%91.0uM B-0973 66.0%®10.0uM 48.0%91.0uM B-0974 57.0%@1.0uM 47.0%91.0uM B-0975 82.0%91.0uM 32.0%91.0uM B-0976 78.0%91.0uM 36.0%91.0uM B-0977 60.0%91.0uM 26.0%91.0uM B-0978 59.0%91.0uM 36.0%91.0uM B-0979 56.0%910.0uM 23.0%91.0uM B-0980 68.0%91.0uM 31.0%91.0uM B-0981 62.0%91.0uM 57.0%91.0uM B-0982 65.0%91.0uM 23.0%91.0uM B-0983 75.0%91.0uM 0.8UM B-0984 60.0%91.0uM 51.0%91.0uM B-0985 86.0%91.0uM 0.75UM B-0986 70.0%91.0uM 71.0%91.0uM B-0987 78.0%91.0uM 79.0%91.0uM B-0988 72.0%91.0uM 65.0%91.0uM B-0989 85.0%91.0uM 0.85UM B-0990 - 26.0%91.0uM 01298 1 689
Example# P38 alpha kinaseIC50,uM or%inhib@conc. (uM) U937 Cell IC50,uMor % lnhlb@conc. (uM) Mouse LPS Mode! %l"NF Inhlb @ dose@predose time Rat LPS Model %inhlb @dose©predose time B-0991 58.0%91.0uM 33.0%91.0uM B-0992 77.0%@1.0uM 45.0%91.0uM B-0993 57.0%91.0uM 73.0%91.0uM B-0994 55.0%91.0uM 43.0%91.0uM B-0995 53.0%91.0uM 14.0%91.0uM B-0996 54.0%91.0uM 27.0%91.0uM B-0997 69.0%91.0uM 22.0% @1. Ou M B-0998 67.0%91.0uM 25.0%91.0uM B-0999 61.0%91.0uM 24.0%91.0uM B-1OOO 55.0%91.0uM 42.0%91.0uM B-1OO1 63.0%91.0uM 31.0%91.0uM B-1002 70.0%91.0uM 41.0%91.0uM B-1003 74.0%91.0uM 29.0%91.0uM B-1004 79.0%91.0uM 45.0%91.0uM B-1005 58.0%91.0uM 23.0%91.0uM B-1006 69.0%91.0uM 38.0%91.0uM B-1007 52.0%91.0uM 34.0%91.0uM - B-1008 54.0%91.0uM 23.0%91.0uM B-1009 80.0%91.0uM 55.0%91.0uM B-1010 75.0%91.0uM I.OuM B-1011 72.0%21.0uM 17.0%91.0uM B-1012 - 20.0%91.0uM B-1013 85.0%91.0uM 7.0%91.0uM B-1014 88.0% @1.Ou M 20.0%91.0uM B-1015 77.0%91.0uM 34.0%91.0uM B-1016 58.0%91.0uM 10.0%91.0uM B-1017 96.0%91.0uM 58.0%91.0uM B-1018 88.0%91.0uM 34.0%91.0uM B-1019 82.0%91.0uM 66.0%91.0uM B-1020 87.0%91.0uM 36.0%91.0uM B-1021 82.0%91.0uM 35.0%91.0uM B-1022 84.0%91.0uM 53.0%91.0uM B-1023 93.0%91.0uM 70.0%91.0uM B-1024 89.0%91.0uM 57.0%91.0uM B-1025 61.0%91.0uM 23.0%91.0uM B-1026 87.0%91.0uM 53.0%91.0uM B-1027 58.0%91.0uM 18.0%91.0uM B-1028 70.0%91.0uM 17.0%91.0uM B-1029 69.0%91.0uM 54.0%91.0uM B-1030 76.0%91.0uM 60.0%91.0uM B-1031 69.0%91.0uM 42.0%91.0uM B-1032 76.0%91.0uM 37.0%91.0uM B-1033 86.0%91.0uM 34.0%91.0uM B-1034 66.0%91.0uM 39.0%91.0uM B-1035 75.0%91.0uM 52.0%91.0uM B-1036 68.0%91.0uM 68.0%91.0uM B-1037 - 41.0%91.0uM B-1038 57.0%91.0uM 0.57UM B-1039 - 1.33UM 01298 1 690
Example* P38 alpha kinaseIC50,uM or% Inhib @conc. (uM) U937 Ce» IC50,uMor % inhibdconc. (uM) Mouse LPS Model %rNF inhib ® dosedpredose tlme Rat LPS Model %inhib ©dose©predose time B-1040 72.0%@1.0uM 0.38UM B-1041 70.0%@1.0uM 73.0%d1.0uM B-1042 79.0%@1.0uM 12.0%@1.0uM B-1043 64.0%@1.0uM 53.0%d1.0uM B-1044 94.0%d1.0uM 0.93UM B-1045 78.0%@1.0uM 25.0%d1.0uM B-1046 72.0%@1.0uM 66.0%d1.0uM B-1047 72.0%d1.0uM 58.0%d1.0uM B-1048 67.0%@1.0uM 19.0%d1.0uM B-1049 67.0%d1.0uM 65.0%d1.0uM B-1050 - 0.54uM B-1051 68.0%d1.0uM 41%d1.0uM B-1052 69.0%d1.0uM 66%@1.0uM B-1053 78.0%d1.0uM 0.4uM B-1054 79.0%d1.0uM 55.0%d1.0uM B-1055 89.0%d1.0uM 63.0%d1.0uM B-1056 89.0%d1.0uM 0.76uM B-1057 85.0%d1.0uM 0.72uM B-1056 0.66uM 43.0%d1.0uM B-1059 0.18uM 24.0%d1.0uM B-1060 0.11uM 32.0%d1.0uM B-1061 0.03uM 19.0%d1.0uM B-1062 <0.1 UM 26.0%d1.0uM B-1063 0.16uM 44.0%d1.0uM B-1064 0.39uM 50.0%d1.0uM B-1065 0.56uM 40.0%d1.0uM B-1066 <0.1 uM 39.0%d1.0uM B-1067 1.6uM 32.0%d1.0uM B-1068 0.48uM 24.0%d1.0uM B-1069 0.22uM 27.0%d1.0uM B-1070 <0.1 UM 44.0%d1.0uM B-1071 <0.1 uM 48.0%d1.0uM B-1072 0.38UM 28.0%d1.0uM B-1073 <0.1 uM 2T.0%d1.0uM B-1074 0.23uM 33.0%d1.0uM B-1075 0.03uM 29.0%d1.0uM B-1076 0.08uM 31.0%d1.0uM B-1077 <0.1 uM 38.0%d1.0uM B-1078 0.26uM 48.0%d1.0uM B-1070 <0.1 uM 40.0%d1.0uM B-1080 0.19uM 28.0%d1.0uM B-1081 <0.1 uM 37.0%d1.0uM B-1082 <0.1uM 54.0%d1.0uM B-1083 <0.1 uM 23.0%d1.0uM B-1084 0.43uM 29.0%d1.0uM B-1085 <0.1 uM 29.0%d1.0uM B-1086 <0.1 UM 42.0%d1.0uM B-1087 0.05uM 32.0%d1.0uM | B-1088 0,73uM 49.0%d1.0uM 01298 1 691
Example# P38 alpha kinaseIC50,uMor%Inhib© conc. (uM) U937 Cell IC50.UMor % lnhib@conc. (uM) Mouse LPS Model %rNF inhib © dose©predose tlme Rat LPS Model % Inhib ©dose©predose time B-1089 <0.1 UM 39.0%@1.puM B-1090 <0.1 uM 90.0%@1.0uM B-1091 <0.1 UM 73.0%91.0uM B-1092 0.27uM 85.0%91.0uM B-1093 0.33uM 36.0%91.0uM B-1094 0.013uM 69.0%@1.0uM B-1095 <0.1 uM 70.0%91.0uM B-1096 <0.1uM 32.0%@1.0uM B-1097 <0.1 uM 44.0%91.07uM B-1098 <0.1 uM 82.0%91.0uM B-1099 0.26uM 74.0%91.0uM B-1100 0.22UM S6.0%91.0uM B-1101 0.026uM 82.0%91.0uM B-1102 0.035UM 83.0%91.0uM B-1103 0.094UM 90.0%91.0uM B-1104 0.12uM 69.O%91.OUM B-1105 <0.1 uM 84.0%91.0uM B-1106 <0.1 uM 86.0%91.0uM B-1107 0.0S7UM 84.0%91.0uM B-1108 0.22UM 81.0%91.0uM B-1109 0.054uM 80.0%91.0uM B-1110 0.47uM 64.0%91.0uM B-1111 0.19uM 64.0%91.0uM B-1112 0.58uM 43.0%91.0uM B-1113 <0.1uM 72.O%91.0uM B-1114 0.069uM 51.0%91.0uM B-1115 0.024UM 89.0%91.0uM B-1116 0.41UM 81.0%91.0uM B-1117 0.13uM 73.0%91.0uM B-111B 0.33UM 91.0%91.0uM B-1119 0.35uM 8O.O%91.OUM B-1120 0.47UM 9.0% 91. Ou M B-1121 3.58UM 29.0%91.0uM B-1122 1.84uM 32.0%©1.0uM B-1123 2.93UM 27.0%91.0uM B-1124 1.49UM 52.0% 91.Ou M B-1125 0.56uM 41.0%91.0uM B-1126 1.5uM >1.0uM B-1127 0.71 UM 7.0%91.0uM B-1128 2.55UM 26.0%91.0uM B-1129 1.07UM 46.0%91.0uM B-1130 0.5uM 29.0%91.0uM B-1131 0.076UM 34.0%91.0uM B-1132 0.72UM 11.0%91.0uM B-1133 0.38UM 33.0%91.0uM B-1134 1.71UM 33.0%91.0uM B-1135 0.23UM 38.0%91.0uM B-1136 1.17uM 40.0%91.0uM B-1137 0.038UM 35.0%91.0uM 01298 1 692
Example# P38 alpha kinaseIC50,uM or %inhib@conc. (uM) U937 Cell IC50,uMor % lnhlb@conc. (uM) Mouse LPS Model %rNF inhlb @ dose©predose time Rat LPS Model %inhlb ©dose©predose time B-1138 1.82uM >1.0uM B-1139 0.041 uM 29.0%@1.0uM B-1140 1.68uM 39.0%@1.0uM B-1141 2.47uM 32.0%@1.0uM B-1142 0.11uM 37.0%@1.0uM B-1143 0.17UM 40.0%@1.0uM B-1144 0.44uM 72.0%@1.0uM B-1145 1.07UM 71.0%®1.0uM B-1146 0.47uM 61.0%®1.0uM B-1147 0.085UM 53.0%@1.0uM B-1146 0.43uM 61.0%@1.0uM B-1149 1.55UM 48.0%@1.0uM B-1150 0.47UM 75.0%@1.0uM B-1151 0.32UM 72.0%@1.0uM B-1152 0.73UM 53.0%@1.0uM B-1153 2.22UM 52.0%@1.0uM B-1154 O.OSSuM 46.0%@1.0uM B-1155 3.22UM 30.0%@1.0uM B-1156 0.27uM 78.0%@1.0uM B-1157 0.26uM 66.0%®1.0uM B-1158 74%@1.0uM 0.68UM 53%@30mpk@-6h B-1159 66.0%@1.0uM 1.03UM 60%@30mpk®-6ti B-1160 79.0%@1.0uM 0.38UM B-1161 64.0%21.0uM 0.93UM 40%@30mpk@-6h 45%®3mpk@-4h B-1162 79.0%@1.0uM 0.59UM 40%@30mpk®-6h B-1163 74.0%@1.0uM 0.37UM B-1164 - 0.35UM B-1165 66.0%@1.0uM 0.99 U M B-1166 77.0%@1.0uM 0.39 U M 50%@30mpk@-6h 50%@3mpk@-4h B-1167 70.0%@1.0uM 1.06UM B-1168 66.0%@1.0uM 0.63UM B-1169 80.0%@1.0uM 0.11uM B-1170 82.0%@1.0uM 0.57UM B-1171 78.0%®1.0uM 0.23uM . B-1172 68.0%@1.0uM 1.95UM B-1173 65.0%®1.0uM 62%@1.0uM B-1174 80.0%®1.0uM 0.86UM B-1175 72.0%®1.0uM 1.83UM B-1176 67.0%@1.0uM 67.0%®1.0uM B-1177 70.0%@1.0uM 1.16UM B-1178 92.0%@1.0uM 1.61 uM B-1179 86.0%@1.0uM 0.41 uM B-1180 78.0%@1.0uM 0.S3UM B-1181 79.0%@1.0uM 66%@1.0uM B-1182 72.0%@1.0uM 0.65uM B-1183 77.0%@1.0uM 0.2uM B-1184 69.0%@1.0uM 0.63uM B-1185 71.0%@1.0uM 0.79uM B-1186 83.0%@1.0uM 60%@1.0uM 01298 1 693
Example# P38 alpha kinaseIC50,uM or %inhibdconc. (uM) U937 Cell ICSO.uMor % 1 Inhibdconc. (uM) Mouse LPS Model %rNF inhib @ dose©predose lime Rat LPS Model %inhib ddosedpredose time B-1187 76.0%@1.0uM 1.89UM B-1188 - 36.0%d1.0uM B-1189 68.0%@1.0uM 0.83uM B-1190 78.0%@1.0uM 62.0%d1.0uM B-1191 74.0%@1.0uM 57.0%d1.0uM B-1192 84.0%d1.0uM 0.47UM B-1193 69.0%@ I.OuM 65.0%d1.0uM B-1194 87.0%@1.0uM 0.58UM B-1195 52.0%@1.0uM 60.0%d1.0uM B-1196 74.0%@1.0uM 68.0%d1.0uM B-1197 77.0%®1.0uM 45.0%d1.0uM B-1198 92.0%d1.0uM 0.46uM B-1199 87.0%d1.0uM 49.0%d1.0uM B-1200 95.0%@1.0uM 0.64UM B-1201 84.0%@ I.OuM 0.51 uM B-1202 71.0%@1.0uM 58.0%d1.0uM B-1203 84.0%®1.0uM 58.0%d1.0uM B-1204 68.0%d1.0uM 59.0%d1.0uM B-1205 74.0%d1.0uM 46.0%d1.0uM B-1206 81.0%d1.0uM 0.34UM B-1207 90.0%d1.0uM 58.0%d1.0uM B-1208 82.0%d1.0uM 5l.0%d1.0uM B-1209 86.0%d1.0uM 55.0%d1.0uM B-1210 82.0%d1.0uM 57.0%d1.0uM B-1211 88.0%d1.0uM 59.0%d1.0uM B-1212 90.0%d I.OuM 57.0%d1.0uM B-1213 84.0%d1.0uM 0.62UM B-1214 76.0%d1.0uM 58.0%d1.0uM B-1215 86.0%d1.0uM 0.23UM B-1216 88.0%d1.0uM 0.18UM B-1217 87.0%d1.0uM 0.46UM B-1218 88.0%d1.0uM 76.0%d1.0uM B-1219 85.0%d1.0uM 37.0%d1.0uM B-1220 81.0%®1.0uM 53.0%d1.0uM B-1221 82.0%d1.0uM 44.0%d1.0uM B-1222 65.0%d1.0uM 9.0%d1.0uM B-1223 80.0%d1.0uM 61.0%d1.0uM B-1224 82.0%d1.0uM 74.0%d1.0uM B-1225 89.0%d1.0uM 73.0%d1.0uM B-1226 89.0%d1.0uM 0.18UM B-1227 83.0%d1.0uM 0.22UM B-1228 90.0%d1.0uM 0.72UM B-1229 87.0%d1.0uM 0.65UM B-1230 90.0%d1.0uM 0.25UM B-1231 94.0%d1.0uM 0.56uM B-1232 81.0%d1.0uM 54.0%d1.0uM B-1233 85.0%@1.0uM 0.36uM B-1234 89.0%d1.0uM 0.49UM B-1235 0.04UM 76.0%@1.0uM 01298 1 694
Example# P38 alpha kinaseIC50,uMor%Inhib9conc. (uM) U937 Cell IC50,uMor. % 1 inhlb@conc. (uM) Mouse LPS Model %rNF Inhlb « dose9predosetime Rat LPS Model % Inhlb @dose©predosetime B-1236 0.1 UM 53.0%@1.0uM B-1237 0.22uM 39.0% @1.Ou M B-1238 0.14UM 16.0%@1.0uM B-1239 <0.1 uM 38.0%@1.0uM B-1240 <0.1 uM 59.0%®1,0uM B-1241 0.04uM 81.0%91.0uM B-1242 O.OBuM 83.0%®1.0uM B-1243 0.04uM 47.0%®1.0uM B-1244 0.26uM 44.0%91.0uM B-1245 0.49uM 42.0%®1.0uM B-1246 0.27UM 40.0%®1.0uM B-1247 <0.1 uM 58.0%®1.0uM B-1248 <0.1 uM 68.0%®1.0uM B-1249 0.24uM 60.0%91.0uM B-1250 0.14uM 18.0%®1.0uM B-1251 0.41 uM 38.0%®1.0uM B-1252 0.17UM 46.0%®1.0uM B-1253 0.15UM 57.0%®1.0uM B-1254 0.16uM 68.0%®1.0uM B-1255 12.9UM 75.0%®1.0uM B-1256 0.12uM 41.0%®1.0uM B-1257 1.48UM 40.0%®1.0uM B-1258 0.07UM 56.0%®1.0uM B-1259 <0.1 UM 0.48UM B-1260 0.11uM 48.0%®1.0uM B-1261 0.74UM 44.0%®1.0uM B-1262 <0.1 UM 63.0%®1.0uM B-1263 1.05UM 57.0%®1.0uM B-1264 0.32uM 47.0%®1.0uM B-1265 0.43UM 51.0%®1.0uM B-1266 <0.1 uM 58.0%®1.0uM B-1267 <0.1uM 73.0%®1.0uM B-1268 <0.1 uM 79.0%®1.0uM B-1269 0.46UM 84.0%®1.0uM B-1270 0.47UM 83.0%®1.0uM B-1271 0.13uM 74.0%®1.0uM B-1272 0.014UM 38.0%®1.0uM B-1273 <0.1 UM 36.0%®1.0uM B-1274 <0.1 uM 41.0%®1.0uM B-1275 <0.1 uM 50.0%®1.0uM B-1276 0.062uM 11.0%®1.0uM B-1277 <0.1 uM 47.0%®1.0uM B-1278 0.12UM 85.0%®1.0uM B-1279 <0.1 U M 79.0%®1.0uM B-1280 0.039UM 83.0%®1.0uM B-1281 <0.1 uM 85.0%®1.0uM B-1282 <0.1uM 75.0%®1.0uM B-1283 <0.1 uM 64.0%91.0uM B-1284 <0.1 UM 75.0%®1.0uM 01298 1 695
Example# P38 alpha kinaseIC50,uM or%inhib® conc. (uM) 11937 Cell IC50,uMor % inhib@conc. (uM) Mouse LPS Nlodel %’NF inhib @ dose@predose time Rat LPS Model % Inhib ©dose©predose time B-1285 0.057UM 80.0%@1.0uM B-1286 0.1 5uM 78.0%21.0uM B-1287 0.25UM 55.0%@1.0uM B-1288 0.15uM 74.0%@1.0uM B-1289 0.73UM 35.0%@1.0uM B-1290 0.26uM 75.0%@1.0uM B-1291 0.097UM 55.0%@1.0uM B-1292 0.01 uM 74.0%@1.0uM B-1293 0.31 uM 48.0%@1.0uM B-1294 0.013uM 54.0%@1.0uM B-1295 0.079UM 74.0%@1.0uM B-1296 0.038U M 48.0%@1.0uM B-1297 0.02UM >1.0uM B-1298 0.055UM 20.0%@1.0uM B-1299 0.091 uM >1.0uM B-1300 0.071 UM 18.0%@1.0uM B-1301 0.12UM 15.0%@1.0uM B-1302 0.023uM 11.0%@1.0uM B-1303 O.O&amp;uM >1.0uM B-1304 0.11uM 10.0%@1.0uM B-1305 0.64uM 9.0%@1.0uM B-1306 0.11uM >1.0uM B-1307 0.009UM 16.0%@1.0uM B-1308 <0.1 uM >1.0uM B-1309 0.045UM >1.0uM B-1310 0.12UM 11.0%@1.0uM B-1311 0.05UM 57.0%@1.0uM B-1312 0.35uM >1.0uM B-1313 0.035UM 37.0%@1.0uM B-1314 0.045uM 24.0%@1.0uM B-1315 0.055UM 12.0%@1.0uM B-1316 0.026uM 36.0%@1.0uM B-1317 0.019uM 9.0%®1.0uM B-1318 <0.1 uM 1.0%@1.0uM B-1319 0.24UM >1.0uM B-1320 0,047uM 43.0%@1.0uM B-1321 0.47uM 66.0%@1.0uM B-1322 0.12uM 87.0%®1.0uM B-1323 0.013uM 85.0%®1.0uM B-1324 0.16uM 83.0%@1.0uM B-1325 0.27uM 95.0%@1.0uM B-1326 0.092uM 84.0%®1.0uM B-1327 0.13uM 65.0%@1.0uM B-1328 0.032uM 86.0%®1.0uM B-1329 0.66uM 54.0%@1.0uM B-1330 0.053UM 85.0%@1.0uM B-1331 0.004UM 85.0%@1.0uM B-1332 0.007uM 81.0%@1.0uM B-1333 0.45uM 76.0%@1.0uM 01298 1 696
Example# P38 alpha kinaseIC50,uM or %inhib@conc. (uM) U937 Cell IC50,uMor % inhib@conc. (uM) Mouse LPS Model %rNF inhib 9 dose@predose time Rat LPS Model %inhib 9 dose@predose time B-1334 0.13uM 73.0%@1.0uM B-1335 0.097UM 63.0%91.0uM B-1336 0.072UM 83.0%@1.0uM B-1337 0.4uM 90.0%@1.0uM B-1338 0.18uM 73.0%@1.0uM B-1339 0.12uM 67.0%@1.0uM B-1340 0.043uM 63.0%91.0uM B-1341 0.42uM 52.0%91.0uM B-1342 0.25UM 59.0%91.0uM B-1343 0.065UM 83.0%91.0uM B-1344 0.014uM 86.0%91.0uM B-1345 0.27uM 73.0%91.0uM B-1346 0.043UM 86.0%91.0uM B-1347 0.021 UM 84.0%91.0uM B-1348 0.009UM 69.0%91.0uM B-1349 0.037UM 86.0%91.0uM B-1350 0.019uM 78.0%91.0uM B-1351 0.068UM 78.0%91.0uM B-1352 0.013uM 76.0%91.0uM B-1353 0.062uM 80.0%91.0uM B-1354 0.013uM 83.0%91.0uM B-1355 0.07uM 76.0%91.0uM B-1356 0.059uM 91.0%91.0uM B-1357 0.18uM 84.0%91.0uM B-1358 0.16UM 76.0%91.0uM B-1359 0.005 84.0%91.0uM B-1360 0.11 0.15uM ‘ 54%93mpk9-4h B-1361 0.03 0.29uM B-1362 0.003 0.29uM B-1363 0.009 0.28UM 51.0%@30pmk 9-6H 53%93mpk9-4h B-1364 0.009 0.27uM 53.0%@30mpk@- 6.0H 17%93mpk9-4h B-1365 0.17 88.0%91.0uM B-1366 0.04 0.27UM B-1367 <0.1 0.22uM B-1368 0.031 0.33UM 44.0%930mpk 9- B-1369 <0.1 0.29UM B-1370 <0.1 0.77UM B-1371 0.06 83.0%91.0uM B-1372 <0.1 0.41 UM 48.0%930mpk 9* B-1373 0.016 0.17uM B-1374 <0.1 0.28uM B-1375 0.01 0.25uM B-1376 0.009 0.26uM 3.0%930mpk 9-61- B-1377 0.12 5.0uM B-1378 0.02 1.04uM B-1379 <0.1 0.092UM B-1380 <0.1 0.26uM 01298 1 697
Example# P38 alpha kinaseIC50,uM or%inhib@conc. (uM) U937 Cell IC50,uMor % 1 inhib@conc. (uM) Meuse LPS Model %ΓΝΡ inhib @ dose@predose time Rat LPS Model %inhib @dose@p redose time B-1381 0.055 0.73uM B-1382 <0.1 0.44uM B-1383 0.0012 0.15uM B-1384 0.57 0.37UM B-1385 <0.1 0.11uM B-1386 <0.1 0.25uM B-1387 <0.1 0.1 uM B-1388 0.57 1.38uM B-1389 0.06 0.57uM B-1390 <0.1 71.0%@1.0uM B-1391 0.016uM 82.0%@1.0uM B-1392 0.059uM 82.0%@1.0uM B-1393 3.17uM 80.0% @1. Ou M B-1394 0.32UM 78.0%@1.0uM B-1395 1.48 61.0%@1.0uM B-1396 1.55 73.0%@1.0uM B-1397 0.92 85.0%@1.0uM B-1398 0.67 83.0%@1.0uM B-1399 0.14 74.0%@1.0uM B-1400 0.024 83.0% @1.Ou M B-1401 0.033 75.0%@1.0uM B-1402 0.12 76.0%@1.0uM B-1403 4.54 71%@1.0uM B-1404 0.6 70%@1.0uM B-1405 0.28 70%@1.0uM B-1406 1.39 56.0%@1.0uM B-1407 0.4 71.0%@1.0uM B-1408 0.27 69.0%@1.0uM B-1409 <0.1 72.0%@1.0uM B-1410 <0.1 69%@1.0uM B-1411 <0.1 81.0%@1.0uM B-1412 0.097 80.0%@1.0uM B-1413 0.016 78.0%@1.0uM B-1414 0.025 83.0%@1.0uM B-1415 1.41 79.0%@1.0uM B-1416 0.14 81.0%@1.0uM B-1417 0.069 69.0%@1.0uM B-1418 1.01 82.0%@1.0uM B-1419 0.3 84.0%@1.0uM B-1420 <0.1 82.0%@1.0uM B-1421 0.014 75.0%@1.0uM B-1422 0.58 68.0%®1.0uM B-1423 1.58 84.0%@1.0uM B-1424 0.86 76.0%®1.0uM B-1425 0.09 83.0%@1.0uM B-1426 0.19 80.0%@1.0uM B-1427 <0.1 84.0%®1.0uM B-1428 <0.1 86.0%@1.0uM B-1429 <0.1 87.0% @1. Ou M 01298 1 698
Example# P38 alpha kinaseIC50,uMor%inhibOconc. (uM) U937 Cell IC50,uMor % lnhib@conc. (uM) Mouse LPS Model %rNF inhib @ dose@predose time Rat LPS Model %inhib @doseOpredose time B-1430 0.75uM 35.0% 91.0uM B-1431 0.36uM 58.0% @1.0uM B-1432 0.11uM 51.0%91.0uM B-1433 026uM 21.0% 91.0uM B-1434 0.19uM | KWtlKtlTMl B-1435 1.8uM l 45.0%91.0uM B-1436 1.0uM I 20.0% 91.0uM B-1437 0.3uM 23.0%91.0uM B-1438 2.01 uM 27.0% 91.0uM B-1439 1.7uM 17.0%91.0uM B-1440 0.87uM 3.0% 91.0uM B-1441 1.95uM 66.0%91.0uM B-1442 1.54uM 18.0% 91.0UM B-1443 0.014uM 83.0%91.0uM B-1444 0.3uM 24.O%91.OUM B-1445 0.43uM 27.0% 91.0UM B-1446 0.77uM 36.0%91.0uM B-1447 0.5uM 34.0%91.0uM B-1448 1.43uM 22.0% 91.0UM B-1449 1.61uM 50.0%91.0uM B-1450 2.1 uM 49.0%91.0uM B-1451 2.88uM 50% 91.0UM B-1452 2.41 uM 47.0%91.0uM B-1453 2.53uM 49.0%91.0uM B-1454 1.6uM 12.0%91.0uM B-1455 1.21 u M 8.0%91.0uM B-1456 1.29UM >1.0uM B-1457 0.43uM 43.0% 91.0UM B-1458 0.95uM 65.0% 91.0uM B-1459 0.67uM 46.0%91.0uM B-1460 0.96uM 29.0% 91.0uM B-1461 0.4uM 39.0% 91.0uM B-1462 0.22UM 50.0% 91.0uM B-1463 2.34uM 26.0% 91.0UM B-1464 1.18uM 27.0% 91.0UM B-1465 3.23UM 31.0% 91.0UM B-1466 1.69uM >1.0uM B-1467 1.22uM 1.0% 91.0UM B-1468 ... 1.61uM 10.0%91.0uM B-1469 0.37 uM 14.0%91.0uM B-1470 0.6uM 28.0% 91.0UM B-1471 0.85uM 25.0%91.0uM B-1472 0.93uM 12.0%91.0uM B-1473 1.24uM 14.0% 91.0uM B-1474 1.23uM 31.0%91.0uM B-1475 2.1 UM 24.0% 91.0uM B-1476 0.047UM 42.0% 91.0uM B-1477 2.5uM 34.0% 91.0uM B-1478 01298 1 699
Example# P38 alpha kinaseIC50,uM or %inhib@conc. (uM) U937 Cell IC50,uMor % inhlb @conc. (uM) Mouse LPS Model %TNF inhlb @ dose©predose time Rat LPS Model %inhlb ©dose©predose time B-1479 01298 1 700
Example# I P38 alpha kinase lIC5O,uM or % nhlb@conc. (uM) I 1937 Cell IC50.UM «or % nhib@conc. (uM) c flouse LPS Model 7OTNF inhib @ (ose @p redose time Rat LPS Model %inhib @dose©predose time IB-2270 0.72uM 31%@10.0uM lB-2271 0.93uM 387e@10.0uM IB-2272 0.26UM 53.07e@10.0uM Ib-2273 1.92uM 39.07e@10.0uM IB-2274 0.26uM 59.07e@10.0uM IB-2275 2.16uM 53.0%@10.0uM IB-2276 11.5uM 37.07o@10.0uM IB-2277 14.9uM 44.0%@10.0uM B -2278 0.8uM 51.07o@10.0uM B-2279 0.32uM 36.07o@10.0uM B-2280 0.4uM 57.07o@10.0uM lB-2281 0.81 uM 60.07o@10.0uM B-2282 0.91 uM 41.0%@10.0uM B-2283 0.04uM 53.07o@10.0uM B-2284 4.61 uM 62.0%@10.0uM B-2285 2.29uM 49.07o@10.0uM I B-2286 0.017uM 0.78UM 25%@30mpk@-1h IB-2287 2.56uM 61.07o@10.0uM B-2288 6.51 uM 46.07o@10.0uM B-2289 3.0uM 30.07o@10.0uM B -2290 2.37UM 59.07o@10.0uM lB-2291 0.019UM 41%@10.0uM I B-2292 8.82uM 57.07o@10.0uM B-2293 2.11uM 56.0%@10.0uM lB-2294 1.68uM 50.0%@10.0uM B-2295 1.79uM 56.07o@10.0uM B-2296 17.3uM 63.0%@10.0uM IB-2297 3.59uM 57.07o@10.0uM B-2298 0.29uM 4.22UM B-2299 1.97UM 62.07o@10.0uM IB-2300 0.07UM 43.07o@10.0uM B-2301 0.18uM 44.07o@10.0uM IB-2302 1.0uM 58.0%@1.0uM B-2303 0.011uM 54.07o@10.0uM B-2304 1.41UM 50.07o@10.0u IB-2305 0.54UM 60.07o@10.0u lB-2306 S.88UM 39,0% @10.0 U B-2307 2.29UM 69.07o@10.0u jB-2308 0.66uM 56.07o@10.0uW IB-2309 0.29UM 47.07o@10.0uW 01298 1 701
Example# 1 P38 alpha kinase lIC50.UM or% nhib@conc. (uM) I 1937 Cell IC50,uM «or 7o nhlb@conc. (uM) c Aouse LPS Model 7oTNF inhib @lose ©predose tlme Rat LPS Model 7oinhib @dose©predose tlme B-2310 0.12UM 1.2uM 50%@30mpk@-6h B-2311 7.18uM 607o@10.0uM B-2312 2.93uM 43.0%@10.0uM B-2313 42.3uM 58.07o@10.0uM B-2314 11.0uM 66.0%@10.0uM B-2315 0.49uM 36.07o@10.0uM B-2316 0.46uM 58.07o@10.0uM B-2317 1.0uM 60.07o@10.0uM B-2318 73.07o@10.0uM 25.07o@10.0uM B-2319 75.07o@10.0uM 40.0%@10.0uM B-2320 44.07o@10.0uM 35.07o@10.0uM B-2321 69.07o@10.0uM 27.07o@10.0uM B-2322 76.07o@10.0uM 38.07o@10.0uM B-2323 69.07o@10.0uM 46.0%@10.0uM B-2324 58.07o@10.0uM 36.07o@10.0uM B-2325 60.0%@10.0uM 51.07o@10.0uM B-2326 76.0%@10.0uM 33.07o@10.0uM B-2327 76.07o@10.0uM 23.0%@10.0uM B-2328 65.07o@10.0uM 28.07o@10.0uM B-2329 72.07o@10.0uM 53.07o@10.0uM B-2330 81.0%@10.0uM 37.0%@10.0uM B-2331 74.07o@10.0uM 44.07o@10.0uM B-2332 70.0%@10.0uM 47.07o@10.0uM B-2333 58.0%@10.0uM 36.0%@10.0uM B-2334 81.0%@10.0uM 45.0%@10.0uM B-2335 82.07o@10.0uM 50.07o@10.0uM B-2336 48.07o@10.0uM 35.07o@10.0uM B-2337 46.0% @10.Ou M 59.0%@10.0uM B-2338 73.0%@10.0uM 50.07o@10.0uM B-2339 84.0%@10.0uM >10.0uM B-2340 35.0%@10.0uM 12.0%Q10.0uM B-2341 75.07o@10.0uM 50.0%@10.0uM B-2342 83.0%@10.0uM 46.07o@10.0uM B-2343 43.0%@10.0uM 27.0%@10.0uM B-2344 71.0%@10.0u 50.07o@10.0uM B-2345 64.07o@10.0u 38.07o@10.0u B-2346 45.07o@10.0uM 48.07o@10.0u . B-2347 49.07o@10.0u 50.0%@10.0u B-2348 76.07o@10.0uM 48.07o@10.0u B-2349 75.07o@10.0uW 27.07o@10.0u 01298 1 702
Example# 1 F»38 alpha kinase Iu937 Cell IC50,uM PIC50,uMor% I or % nhib@conc. (uM)|inhib@conc. (uM) c Aouse LPS Model %TNF inhib @iose ©predose time Rat LPS Model %inhib @dose©predose time B-2350 38.0% @10. Ou M 56.0%@10.0uM B-2351 77.0% @10. Ou Μ I 1.0%@10.0uM B-2352 37.0%@10.0uM 19.0%@10.0uM B-2353 38.0%@10.0uM 33.0%@10.0uM B-2354 65.0%@10.0uM 25.0%@10.0uM B-2355 84.0%@10.0uM 50.0%@10.0uM B-2356 77.0%@10.0uM I 45.0%@10.0uM B-2357 47.0% @ 10.OuM | 41.0% @10.0uM B-2358 17.0%910.0uM 52.0%@10.0uM B-2359 76.0%@10.0uM 35.0%@10.0uM B-2360 45.0%@10.0uM >10.0uM B-2361 19.0%@10.0uM 46.0%@10.0uM B-2362 60%@100.0uM 39.0%@10.0uM B-2363 44.0%@10.0uM 1.0%910.0uM B-2364 47.0%@10.0uM 4.0%@10.0uM B-2365 82.0%@10.0uM 43.0%@10.0uM B-2366 70.0%@10.0uM 59.0%910.0uM B-2367 46.0%®10.0uM 40.0%91.0uM B-2368 65.0%910.0uM 55.0%910.0uM B-2369 32.0%910.0uM >10.0uM B-2370 73%9100.0uM 20.0%910.0uM B-2371 54.0%910.0uM 36.0%910.0uM B-2372 55.0%9100.0uM >10.0uM B-2373 50.0%9100.0uM 6%910.0uM B-2374 35.0%910.0uM 20.0%910.0uM B-2375 62.0%9100.0uM >10.0uM B-2376 32.0%910.0uM 17.0%910.0uM B-2377 34.0%910.0uM 17.0%910.0uM B-2378 48.0%910.0uM 61.0%910.0uM B-2379 73.0%9100.0uM 45.0%91.0uM B-2380 81%9100.0uM 53.0%910.0uM B-2381 68%9100.0uM 2.0%910.0uM B-2382 51.0%910.0uM 24.0%910.0uM B-2383 63.0%910.0uM 35.0%910.0uM • B-2384 49%9100.0uM 10.0%910.0uM B-238S 79.0%910.0uM 19.0%910.0uM B-2386 38.0%910.0uM 19.0%910.0uM B-2387 50.0%9100.0uM >10.0uM B-2388 42.0%910.0uM 24.0%910.0uN B-2389 39.0%910.0uM | 29.0%910.0uN » 01298 1 703
Example# i P38 alpha kinase lICSO,uM or % nhib@conc. (uM) i J937 Cell IC50.UM Bor % nhib@conc. (uM) c /louse LPS Mode! %TNF inhib @lose ©predose «me Rat LPS Model %inhib @dose©predose time B-2390 34.07o@10.0uM 27.0%@1.0uM B-2391 40.0% @ 10.0 U M 59.07o@10.0uM B-2392 63.0%@10.0uM 46.0%@10.0uM B-2393 43.0%@10.0uM >10.0uM B-2394 37.0%@10.0uM 22.07o@10.0uM B-2395 32.07o@10.0uM 28.0%@10.0uM B-2396 75.0%@10.0uM >10.0uM B-2397 83.0% @ 10.Ou M 22.0%@10.0uM B-2398 55%@100.0uM 10.0%@10.0uM B-2399 69.07o@10.0uM 18.0%@10.0uM B-2400 60.0%@10.0uM 40.0%@10.0uM B-2401 78.0%@10.0uM 44.0%@10.0uM B-2402 43.07o@10.0uM 52.07o@10.0uM B-2403 727o@1Q0.0uM 52.0%@10.0uM B-2404 587o@100.0uM 52.07o@10.0uM B-2405 477o@100.0uM >10.0uM B-2406 45.0%@10.0uM 24.0%@10.0uM B-2407 47%@100.0uM 27.0%@10.0uM B-2408 39.07o@10.0uM 10.07o@10.0uM B-2409 78.07o@10.0uM 26.07o@10.0uM B-2410 33.0%@10.0uM 32.0%@10.0uM B-2411 26%@100.0uM 13.0%@10.0uM B-2412 40.07o@10.0uM 31.07o@10.0uM B-2413 75.07o@10.0uM 37.0%@10.0uM B-2414 86.0%@10.0uM 38.0%@10.0uM B-2415 94.0%@10.0uM 50.0%@10.0uM B-2416 85.07o@10.0uM 43.07o@1.0uM B-2417 83.0%@10.0uM 18.0%@10.0uM B-2418 88.0%@10.0uM 34.07o@10.0uM B-2419 86.07o@10.0uM 66.07o@10.0uM B-2420 70.0%@10.0uM 34.0%@10.0uM B-2421 89.0%210.0uM 38.0%@10.0uM B-2422 90.0%@10.0uM 17.0%@10.0uM B-2423 85.0%@10.0uM >10.0uM B-2424 86.07o@10.0uM 43.0%@10.0uM B-2425 79.0%@10.0uM 42.0%@10.0uM B-2426 88.07o@10.0uM 53.07o@10.0uM B-2427 87.0%@10.0uN ί 59.07o@10.0u B-2428 82.0%@10.0uW ï 50.0%@10.0uM B-2429 92.07o@10.0uW 32.0%@10.0u 01298 1 704
Example# P38 alpha kinaseIC50,uM or%nhib@conc. (uM) J937 Cell IC50,uMor % nhib@conc. (uM) toouse LPS Model %TNF inhib ®dose ©predose time Rat LPS Model %inhib ®dose©predose time B-2430 90.0%@10.0uM 61.0%@10.0uM B-2431 85.0%210.0uM 68.0%@10.0uM B-2432 86.0%210.0uM 40.0%@10.0uM B-2433 94.0%®10.0uM 84.0%@10.0uM B-2434 92.0% @ 10.Ou M 63.0%@10.0uM B-2435 84.0% @ 10.Ou M 4.0%@10.0uM B-2436 80.0%@10.0uM 54.0%@10.0uM B-2437 82.0%® 10.Ou M 41.0%@10.0uM B-2438 75.0%@10.0uM 40.0%®10.0uM B-2439 81.0%®10.0uM 44.0%@10.0uM B-2440 77.0%@10.0uM 78.0%® 10.Ou M B-2441 86.0%@10.0uM 46.0%@10.0uM B-2442 86.0%®10.0uM >10.0uM B-2443 84.0%@10.0uM 44.0%® 10.Ou M B-2444 89.0% @10. Ou M 7.0%@10.0uM B-2445 94.0%®10.0uM 15.0%@10.0uM B-2446 90.0%@10.0uM 28.0%@10.0uM B-2447 94.0%@10.0uM >10.0uM B-2448 75.0%® 10.0uWI 30.0%@1Q.0uM B-2449 86.0%@10.0uM 42.0%@10.0uM B-2450 87.0%@10.0uM 46.0%@1.0uM B-2451 87.0%@10.0uM 45.0%@10.0uM B-2452 89.0% @10. Ou M 33.0%@10.0uM B-2453 91.0%@10.0uM >10.0uM B-2454 88.0%@10.0uM 40.0%@10.0uM B-2455 87.0%@10.0uM 54.0%@10.0uM B-2456 86.0%@10.0uM 53.0%@10.0uM B-2457 90.0%@10.0uM 18.0%@10.0uM B-2458 83.0% @10.Ou M 36.0%@10.0uM B-2459 82.0%@10.0uM 81.0%@10.0uM B-2460 80.0%@10.0uM 79.0%@10.0uM B-2461 67.0%@10.0uM 59.0%@10.0uM

Claims (3)

  1. 01298 1 705 WHAT WE CLAIM IS: l. A compound of. Formula I R\ R2
    wherein R1 is selected from hydrido, alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl,cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl,alkenoxyalkyl, alkynoxyâlkyl, aryloxyalkyl,heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl,alkylthioalkylene, alkenylthioalkylene,alkylthioalkenylene, amino, aminoalkyl, alkylamino,alkenylamino, alkynylamino, arylamino, heterocyclylami.no,alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl,arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl,heterocyclylsulfonyl, alkylatninoalkylene,alkylsulfonylalkylene, acyl, acyloxycarbonyl,alkoxycarbonylalkylene, aryloxycarbonylalkylene,heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene,alkylcarbonylalkylene, arylcarbonylalkylene,heterocyclylcarbonylalkylene, alkylcarbonylarylene,arylcarbonylarylene, heterocyclylcarbonylarylene,alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene,heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, - 01298 1 706 arylcarbonyloxyarylene, andheterocyclylcarbonÿloxyarylene; or R1 has the formula f ' H zr26—ç-cch23(- d_N wherein: i is an integer from 0 to 9; R25 is selected from hydrogen, alkyl, aralkyl,heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylaminoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkylalkylene, aralkyl,alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl,aryl, heterocyclyl, aralkyl, cycloalkylalkylene,cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene,alkylaralkyl, aralkylarylene, alkylheterocyclyl,alkylheterocyclylalkylene, alkylheterocyclylarylene,aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene,alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene,aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene,alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl,alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl,alkylaminoalkylene, arylaminocarbonylalkylene,alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene,arylaminocarbonylalkylene, alkylaminocarbonylalkylene,arylcarbonylalkylene, alkoxycarbonylarylene,aryloxycarbonylarylene,·alkylaryloxycarbonylarylene,arylcarbonylarylene, alkylarylcarbonylarylene, 01298.1 707- alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene,cycloalkylthloalkylene, alkylthioarylene,aralkylthioarylene, heterocyclylthioarylene,arylthioalklylarylene, arylsulfonylaminoalkylene,alkylsulfonylarylene, alkylaminosulfonylarylene; whereinsaid alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl,heterocyclylalkylene, alkylheterocyclylarylene,alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene,aryloxycarbonylarylene, arylcarbonylarylene,alkylthioarylene, heterocyclylthioarylene,arylthioalklylarylene, and alkylsulfonylarylene groupeare optionally substituted with one or more radicaleindependently selected from alkyl, halo, haloalkyl,alkoxy, keto, amino, nitro, and cyano; or R21 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29is selected from aralkyl, aralkoxyalkylene,heterocyclylalkylene, alkylheterocyclylalkylene,alkoxycarbonylalkylene, alkylthioalkylene, andaralkylthioalkylene; wherein said aralkyl andheterocylcyl groups are optionally substituted with oneor more radicale independently selected from alkyl andnitro; or R26 and R27 together with the nitrogen atom to whichthey are attached form a heterocycle, wherein saidheterocycle is optionally substituted with one or moreradicale independently selected from alkyl, aryl,heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene,alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl,alkoxycarbonyl, aralkoxycarbonyl, alkylamino andalkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; 01298 1 708 and R2 is selected from hydrido, halogen, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl,aralkyl, alkylheterocyclyl, heterocyclylalkyl,alkylamino, alkenylamino, alkynylamino, arylamino,heterocyclylamino, heterocyclylalkylamino, aralkylamino,aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene,alkylaminoarylene, alkylaminoalkylamino, cycloalkyl,cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio,arylthio, heterocyclylthio, carboxy, carboxyalkyl,carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl,alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl,alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino,alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;wherein the aryl, heterocyclyl, heterocyclylalkyl,cycloalkyl and cycloalkenyl groupe are optionallysubstituted with one or more radicale independentlyselected from halo, keto, amino, alkyl, alkenyl, alkynyl,aryl, heterocyclyl, aralkyl, heterocyclylalkyl,epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy,aralkoxy, haloalkyl, alkylamino, alkynylamino,alkylaminoalkylamino, heterocyclylalkylamino,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl,arylsulfonyl, and aralkylsulfonyl; or R2 has the formula: RJU I R31 H I c •34L R3J -N ,32 ,33 wherein: j ie an integer from 0 to 8 ; andm is 0 or 1; and R30 and R31 are independently selected from hydrogen, (III) 0129 θ 1 709 alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,aminoalkyl, alkylamïnoalkyl, aminocarbonylalkyl,alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl,heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene,aminoalkyl, alkylamïnoalkyl, arylaminoalkyl,alkylcarbonylalkylene, arylcarbonylalkylene, andheterocyclylcarbonylaminoalkylene; R33 is selected from hydrogen, alkyl, -C(O)R35,-C(0)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35,R36, R37, R38, R39 and R40 are independently selected fromhydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl,alkylaminocarbonyl, and arylaminocarbonyl; orR2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl,quinolinyl, purinyl,
    (IV) (V) wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl·, alkenoxyalkyl, and aryloxyalkyl;and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl andpurinyl groupe are optionally substituted with one ormore radicale independently selected from halo, alkyl,aralkyl, aralkenyl, arylheterocyclyl, carboxy,carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl,aralkoxÿ, heterocyclylalkoxy, amino, alkylamino, 01298 1 710 alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylami.no, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl,alkoxycarbonylami.no, alkoxyaralkylami.no, aminosulfinyl,aminosulfonyl, alkylaminoalkylami.no, hydroxyalkylamino,aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl,alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl,alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl oramino, and R4S is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, whereinR4 is optionally substituted with one or more radicalsindependently selected from halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, alkylthio, arylthio,alkylthioalkylene, arylthioalkylene, alkylsulfinyl,alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene,arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy,aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano,nitro, alkylamino, arylamino, alkylaminoalkylene,arylaminoalkylene, aminoalkylamino, and hydroxy;provided R3 is not 2-pyridinyl when R4 is a phenyl ringcontaining a 2-hydroxy substituent and when R1 is hydrido;further provided R2 is selected from aryl, heterocyclyl,unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is notmethylsulfonylphenyl; or a pharmaceutically-acceptable sait or tautomerthereof. 01298 1 711
  2. 2. A compound bf Claim 1 wherein R1 is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lowerheterocyclyl, lower cycloalkylalkylene, lower haloalkyl, 5 lower hydroxyalky1, lower aralkyl, lower alkoxyalkyl,lower mercaptoalkyl, lower alkylthioalkylene, amino,lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene,· orR1 hae the formula Γ H /6 — ç-cch2)(-C_nI \_?7 10 H R (II) wherein: i is 0, 1 or 2; and R2B is selected from hydrogen, lower alkyl, lowerphenylalkyl, lower heterocyclylalkyl, lower 15 alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl,lower alkylaminoalkyl, lower phenoxyaminoalkyl, loweralkylcarbonylalkylene, lower phenoxycarbonylalkylene, andlower heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, lower alkyl, lower 20 alkenyl, lower alkynyl, lower cycloalkylalkylene, lowerphenylalkyl, lower alkoxycarbonylalkylene, and loweralkylaminoalkyl; and R27 is selected from lower alkyl, lower cycloalkyl,lower alkynyl, aryl selected from phenyl, biphenyl and 25 naphthyl, lower heterocyclyl, lower phenylalkyl, lowercycloalkylalkylene, lower cycloalkenylalkylene, lowercycloalkylarylene, lower cycloalkylcycloalkyl, lowerheterocyclylalkylene, lower alkylphenylene, loweralkylphenylalkyl, lower phenylalkylphenylene, lower 30 alkylheterocyclyl, lower alkylheterocyclylalkylene, loweralkylheterocyclylphenylene, lower 01298 1 712 phenylalkylheterocycly1, lower alkoxyalkylene, loweralkoxyphenylene, lower alkoxyphenylalkyl, loweralkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lowerphenoxyphenylene, lower phenylalkoxyphenylene, loweralkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene,lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, loweraminoalkyl, lower alkylaminoalkylene, lowerphenylaminocarbonylalkylene, loweralkoxyphenylaminocarbonylalkylene, loweraminocarbonylalkylene, arylaminocarbonylalkylene, loweralkylaminocarbonylalkylene, lower phenylcarbonylalkylene,lower alkoxycarbonylphenylene, lowerphenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lowerphenylcarbonylphenylene, loweralkylphenylcarbonylphenylene, loweralkoxycarbonylheterocyclylphenylene, loweralkoxycarbonylalkoxylphenylene, lowerheterocyclylcarbonylalkylphenylene, loweralkylthioalkylene, cycloalkylthioalkylene, loweralkylthiophenylene, lower phenylalkylthiophenylene, lowerheterocyclylthiophenylene, lowerphenylthioalklylphenylene, lowerphenylsulfonylaminoalkylene, loweralkylsulfonylphenylene,-lower alkylaminosulfonylphenylene; wherein said lower alkyl,lower cycloalkyl, aryl selected from phenyl, biphenyl andnaphthyl, lower heterocyclyl, lower phenylalkyl, lowerheterocyclylalkylene, lower alkylheterocyclylphenylene,lower alkoxyphenylene, lower phenoxyphenylene, lowerphenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene,lower alkylthiophenylene, lowerheterocyclylthiophenylene, lower 01298 1 713 phenylthioalklylphenylene, and lower alkylsulfonylphenylene groupa are optionally substitutedwith one or more radicale independently selected fromlower alkyl, halo, lower haloalkyl, lower alkoxy, keto,amino, nitro, and cyano; or R21 is -CHR46R47 wherein R46 is lower alkoxycarbonyl,and R47 is selected from lower phenylalkyl, lowerphenylalkoxyalkylene, lower heterocyclylalkylene, loweralkylheterocyclylalkylene, lower alkoxycarbonylalkylene,lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl andheterocylcyl groupe are optionally substituted with oneor more radicale independently selected from lower alkyland nitro; or R26 and R27 together with the nitrogen atom to whichthey are attached form a 4-8 membered ring heterocycle,wherein said heterocycle is optionally substituted withone or more radicale independently selected from loweralkyl, aryl selected from phenyl, biphenyl and naphthyl,heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, loweralkoxyphenylene, lower alkylphenoxyalkylene, loweralkylcarbonyl, lower alkoxycarbonyl, lowerphenylalkoxycarbonyl, lower alkylamino and loweralkoxycarbonylamino; wherein said aryl selected fromphenyl, biphenyl and naphthyl, lower heterocyclylalkyleneand lower phenoxyalkylene radicale are optionallysubstituted with one or more radicale independentlyselected from halogen, lower alkyl and lower alkoxy; and R2 is selected from hydrido, halogen, lower alkyl,aryl selected from phenyl, biphenyl, and naphthyl, lowerhaloalkyl, lower hydroxyalkyl, 5- or 6-membered heterocyclyl, lower alkylheterocyclyl, lowerheterocyclylalkyl, lower alkylamino, lower alkynylamino,phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower 01298 1 714 aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl,lower alkoxycarbonylalkyl, lower cycloalkenyl, lowercarboxyalkylamino, lower alkoxycarbonyl, lowerheterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl,lower alkoxycarbonylheterocyclylcarbony1, alkoxycarbonylalkyl, lower alkoxyalkylamino, loweralkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lowerheterocyclylthio; wherein the aryl, heterocylyl,heterocyclylalkyl, cycloalkyl, and cycloalkenyl groupaare optionally substituted with one or more radicalsindependently selected from halo, keto, lower alkyl,lower alkynyl, phenyl, 5- or 6-membered heterocyclyl,lower phenylalkyl, lower heterocyclylalkyl, lowerepoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lowerphenylalkoxy, lower haloalkyl, lower alkylamino, loweralkylaminoalkylamino, lower alkynylamino, loweramino(hydroxyalkyl) , lower heterocyclylalkylamino, loweralkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl,lower phenylalkylsulfonyl R2 has the formula: R30 Γ I — C-CCHPj-R31 wherein: j ie 0, 1 or 2; andm is 0 ; R30 and R31 are independently selected from hydrogen,alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, , and phenylsulfonyl; or h Ί è n3j (III) 01298 1 715 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylehe, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R33 is selected from hydrogen, alkyl, -C{O)R3S, -C(O)OR35, -SOjR36, -C(O)NR37R38, and -SO2NR39R40; wherein R35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl,arylarylene, arylheterocyclyl, alkoxy, alkenoxy,alkoxyalkylene, alkoxyaralkyl, alkoxyarylene,aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene,alkoxycarbony1, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene,alkoxycarbonylalkylene, alkoxycarbonylarylene,aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl,arylcarbonyloxyalkylarylene, and alkylthioalkylene;wherein said aryl, heterocyclyl, aralkyl, alkylarylene,arylheterocyclyl, alkoxyarylene, aryloxyalkylene,cycloalkoxyalkylene, alkoxycarbonylalkylene, andalkylcarbonylheterocyclyl groupe are optionallysubstituted with one or more radicale independentlyselected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy,keto, amino, nitro, and cyano; or R35 is CHR4eR49 wherein R4e ie arylsulfonylamino oralkylarylsulfonylamino, and R49 is selected from aralkyl,amino, alkylamino, and aralkylamino; or R35 is -NR50R51 wherein R50 is alkyl, and R51 is aryl; and wherein R3S is selected from alkyl, haloalkyl, aryl,heterocyclyl, cycloalkylalkylene, alkylarylene,alkenylarylene, arylarylene, aralkyl, aralkenyl,heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene,alkoxycarbonylarylene, alkylcarbonylaminoarylene,alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, 01298 1 716 alkylamino, alkylaminoarylene, alkylsulfonylarylene,alkylsulfonylaralkyl, and arylsulfonylheterocyclyl;wherein said aryl, heterocyclyl, cycloalkylalkylene,aralkyl, alkylcarbonylaminoheterocyclyl, andalkylsulfonylarylene groupe are optionally substitutedwith one or more radicals independently selected fromalkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy,keto, amino, nitro, and cyano; and wherein R37 is selected from hydrogen and alkyl ; andwherein R39 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene,arylcycloalkyl, arylarylene, cycloalkylalkylene,heterocyclylalkylene, alkylheterocyclylalkylene,aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene,aryloxyarylene, arylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkylene, alkoxycarbonylarylene,alkylcarbonylcarbonylalkylene, alkylaminoalkylene,alkylaminoaralkyl, alkylcarbonylaminoalkylene,alkylthioarylene, alkylsulfonylaralkyl, andaminosulfonylaralkyl; wherein said aryl, heterocyclyl,aralkyl, and heterocyclylalkylene groups are optionallysubstituted with one or more radicals independentlyselected from alkyl, halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, keto, amino, nitro, and cyano; or R3® is -CR52R53 wherein R52 is alkoxycarbonyl, and R53is alkylthioalkylene; or R37 and R38 together with the nitrogen atom to whichthey are attached form a heterocycle; and R39 and R40 hâve the same définition as R26 and R27 inclaim l; or R2 is -CR54RS5 wherein R54 is phenyl and R55 is hydroxy; or R2 is selected from the group consisting of 01298 1 717
    ,58 205 ,58
    N I CCH25k : a nd
    0 CCH2)k_ (VI) (VII) (VIII) wherein k is an integer from 0 to 3; andR56 is hydrogen or lower alkyl; and 210 R57 is hydrogen or lower alkyl? or Rsi and R57 form a lower alkylene bridge; and R58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl,alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(O)R59,
  3. 215 -SO2R60, and -C(O)NHRS1; wherein R59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl,alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy,alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein 220 said aryl, heterocyclyl, and aralkyl groupe areoptionally subs.tituted with one or more radicalsindependently selected from alkyl, halo, hydroxy,haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, andcyano ? and 225 wherein R60 is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl,heterocyclylheterocyclyl, alkoxyarylene, alkylamino,alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl? wherein said aryl, 230 heterocyclyl, and aralkyl groupe are optionally substituted with one or more radicals independentlyselected from alkyl, halo, hydroxy, haloalkyl, alkoxy,haloalkoxy, keto, amino, nitro, and cyano; and 01298 1 718 wherein RS1 is selected from alkyl, aryl,alkylarylene, and alkoxyarylene; wherein said aryl groupis optionally substituted with one or more radicaleindependently selected from alkyl, halo, hydroxy,haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, andcyano; and R3 is selected from pyridinyl, pyrimidinyl,quinolinyl, purinyl, and o 0
    (IV) wherein R43 is selected from hydrogen, lower alkyl,lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyland lower aryloxyalkyl; and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl andpurinyl groups are optionally substituted with one ormore radicals independently selected from loweralkylthio, lower alkylsulfonyl, aminosulfonyl, halo,lower alkyl, lower aralkyl, lower phenylalkenyl, lowerphenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano,lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, loweralkoxy, amino, lower cycloalkylamino, lower alkylamino,lower àlkenylamino, lower alkynylamino, lower aminoalkyl,arylamino, lower aralkylamino, nitro, halosulfonyl, loweralkylcarbonyl, lower alkoxycarbonylamino, loweralkoxyphenylalkylamino, lower alkylaminoalkylamino, lowerhydroxyalkylamino, lower heterocyclylamino, lowerheterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or -NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower 01298 1 719 265 phenylalkyl; and R4 is selected from hydrido, lower cycloalkyl, lowercycloalkenyl, aryl selected from phenyl, biphenyl, andnaphthyl, and 5- or 6- membered heterocyclyl; wherein thelower cycloalkyl, lower cycloalkenyl, aryl and 5-10 270 membered heterocyclyl groupe of R4 are optionally substituted with one or.more radicals independentlyselected from lower alkylthio, lower alkylsulfonyl, loweralkylsulfinyl, halo, lower alkyl, lower alkynyl, loweralkoxy, lower aryloxy, lower aralkoxy, lower 275 heterocyclyl, lower haloalkyl, amino, cyano, nitro, loweralkylamino, and hydroxy; or a pharmaceutically-acceptable sait or tautomer thereof.
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