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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.
• Mitogen-activated protein kinases is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation.
• the kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines.
• the p38 MAP kinase group is a MAP family of various isoforms, including p38 ⁇ , p38(S and p38 ⁇ , and is responsible for phosphorylating 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 are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF- ⁇ ) and interleukin-1 (IL-1) .
• pro-inflammatory cytokines including tumor necrosis factor (TNF- ⁇ ) and interleukin-1 (IL-1) .
• IL-1 interleukin-1
• the products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
• TNF- ⁇ is a cytokine produced primarily by activated monocytes and macrophages . Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid
• 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 including herpes simplex virus type-1 (HSV-1) , herpes simplex virus type-2 (HSV-2) , cytomegalovirus (CMV) , varicella-zoster virus (VZV) , Epstein-Barr virus, human herpesvirus-6 (HHV- ⁇ ) , human herpesvirus-7 (HHV-7) , human herpesvirus-8 (HHV-8) , pseudorabies and rhinotracheitis, among others.
• IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
• IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
• TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions.
• the inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
• EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides.
• Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides.
• Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase .
• the invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.
• a class of substituted pyrazolyl compounds useful in treating p38 mediated disorders is defined by Formula I:
• R 1 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 , alky
• i is an integer from 0 to 9;
• R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl , arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
• R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl;
• R 27 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,
• R 27 is -CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene , alkylheterocyclylalkylene , alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
• R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more
• R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl , aryl , heterocyclyl , haloalkyl , hydroxyalkyl , aralkyl, alkylheterocyclyl , heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylammo, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylammoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalky
• j is an integer from 0 to 8 ; and m is 0 or 1;
• R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl , alkoxyalkyl, and alkylcarbonyloxyalkyl ; and
• R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
• R 33 is selected from hydrogen, alkyl, -C(0)R 35 , -C(0)OR 35 , -S0 2 R 36 , -C(0)NR 37 R 38 , and -S0 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl ; and
• R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl , and arylaminocarbonyl ; or
• R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy;
• R 3 is selected from pyridinyl, pyrimidinyl , quinolinyl , purinyl ,
• R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl , and aryloxyalkyl ; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more 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,
• R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently 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,
• R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl ; or a pharmaceutically-acceptable salt or tautomer thereof .
• Compounds of Formula I would be useful for, but not limited to, the treatment of any disorder or disease state in a human, or other mammal, which is excacerbated or caused by excessive or unregulated TNF or p38 kinase production by such mammal. Accordingly, the present invention provides a method of treating a cytokine- mediated disease which comprises administering an effective cytokine- interfering amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
• Compounds of Formula I would be useful for, but not limited 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 treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions.
• Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, and chronic pulmonary inflammatory disease.
• the compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS) , AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus .
• viral and bacterial infections including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS) , AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus .
• bone resorption diseases such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection.
• bone resorption diseases such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection.
• the compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE) , skin- related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders.
• Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn' s disease, gastritis, irritable bowel syndrome and ulcerative colitis.
• the compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue.
• Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis .
• the compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.
• SUBSfmUTESHEET(R ⁇ LE26) Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
• the present compounds may also be used in co- therapies, partially or completely, in place of other conventional anti-inflammatories , such as together with steroids, cyclooxygenase-2 inhibitors, DMARD's, immunosuppressive agents, NSAIDs, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors .
• TNF mediated disorder refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8.
• TNF a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
• p38 mediated disorder refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8.
• IL-1 IL-6
• IL-8 another factor to be released
• TNF-jS has close structural homology with TNF- ⁇ (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF- ⁇ and TNF-/3 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless
• a preferred class of compounds consists of those compounds of Formula I wherein
• R 1 is selected from hydrido, lower alkyl, lower 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 alkylammoalkylene, and lower heterocyclylalkylene; or
• R 1 has the formula a 2 5 0 C— C CH 3 ) C— N
• R 25 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl , lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and
• R 26 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and R 27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl , lower heterocyclyl , lower phenylalkyl , lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl , lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenyl lkyl , lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower
• heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano; or
• R 27 is -CHR 46 R 47 wherein R 46 is lower alkoxycarbonyl, and R 47 is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from lower alkyl and nitro; or
• R 26 and R 27 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl , lower alkylamino and lower alkoxycarbonylamino; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and R 2 is selected from hydrido
• R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl , alkoxyalkyl, and alkylcarbonyloxyalkyl ; and
• R 32 is selected from hydrogen, alkyl, aralkyl,
• heterocyclylalkyl alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R 33 is selected from hydrogen, alkyl, -C(0)R 35 , -C(0)OR 35 , -S0 2 R 36 , -C(0)NR 37 R 38 , and -S0 2 NR 39 R 40 ; wherein R 35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl , cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl , alkoxy, alkenoxy
• R 35 is CHR 48 R 49 wherein R 48 is arylsulfonylamino or alkylarylsulfonylammo, and R 49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or
• R 35 is -NR 50 R 51 wherein R 50 is alkyl, and R 51 is aryl; and wherein R 36 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl , carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl ,
• SUBSmWE8HEEr(RULE26) arylcarbonylaminoalkylheterocyclyl , alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl , and arylsulfonylheterocyclyl ; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl , and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and wherein R 37 is selected from hydrogen and alkyl; and wherein R 38 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, a
• R 38 is -CR 52 R 53 wherein R 52 is alkoxycarbonyl, and R 53 is alkylthioalkylene; or
• R 37 and R 38 together with the nitrogen atom to which they are attached form a heterocycle; and R 39 and R 40 have the same definition as R 2S and R 27 in claim 1; or
• R 2 is -CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
• R 2 is selected from the group consisting of
• R 56 is hydrogen or lower alkyl
• R 57 is hydrogen or lower alkyl
• R 5 ⁇ and R 57 form a lower alkylene bridge
• R 58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl , arylsulfonyl , -C(0)R 59 , -S0 2 R 60 , and -C(0)NHR 61 ; wherein R 59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, hal
• R 61 is selected from alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano ; and
• R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl , and
• R 43 is selected from hydrogen, lower alkyl, lower aminoalkyl , lower alkoxyalkyl , lower alkenoxyalkyl and lower aryloxyalkyl ; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl , halo, lower alkyl , lower aralkyl , lower phenylalkenyl , lower phenylheterocyclyl, carboxy, lower alkylsulfinyl , cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino,
• R 4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6- membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl , halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
• a class of compounds of particular interest consists of these compounds of Formula I wherein
• R 1 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
• R 2 is selected from hydrido, chloro, fluoro, bromo,
• R 3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or more 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 , fluorophenylpyrazo
• R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl , cyclohexadienyl , phenyl,
• Another class of compounds of particular interest consists of these compounds of Formula I wherein
• R 1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl , dimethylaminoethyl, diethylaminoethyl or morpholinylethyl ;
• R 2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N,N- dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl , and piperazinylamino; wherein the phenyl, piperidinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;
• R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl , hydroxyl, methoxy,
• R 4 is selected from phenyl, quinolyl , biphenyl, pyridinyl , thienyl , furyl , dihydropyranyl , benzofuryl , dihydrobenzofuryl , and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
• a class of compounds of specific interest consists of those compounds of Formula I wherein R 1 is hydrido or methyl;
• R 2 is selected from hydrido, methyl or ethyl
• R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl
• R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl , hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl ;
• R 4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
• Still another class of compounds of particular interest consists of those compounds of Formula I wherein R 1 is selected from hydrido, methyl, ethyl, propyl,
• StffiSmUTCSHEET(RULE26) 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 , pyrrolidiny
• R 2 has the formula:
• R 30 and R 31 are independently selected from hydrogen and lower alkyl ;
• R 32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene ;
• R 33 is selected from hydrogen, lower alkyl , -C (0) R 35 , -C (0) OR 35 , -S0 2 R 36 , -C (0) NR 37 R 38 , and -S0 2 NR 39 R 40 ;
• R 35 is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl , biphenyl and naphthyl , lower heterocyclyl , lower phenylalkyl, lower phenylcycloalkyl , lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl , lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl , lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl , lower alkylcarbon
• R 35 is CHR 48 R 49 wherein R 48 is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R 49 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or
• R 35 is -NR 50 R 51 wherein R 50 is lower alkyl, and R 51 is aryl selected from phenyl, biphenyl and naphthyl; and wherein R 36 is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and
• aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or
• R 38 is -CR 52 R 53 wherein R 52 is lower alkoxycarbonyl, and R 53 is lower alkylthioalkylene; or
• R 37 and R 38 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle
• R 39 and R 40 have the same definition as R 2S and R 27 in claim 2; or
• R 2 is selected from the group consisting of
• R 56 is hydrogen or lower alkyl
• R 57 is hydrogen or lower alkyl
• R 58 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl , -C(0)R 59 , -SO 2 R S0 , and -C(0)NHR 61 ; wherein R 59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl , lower heterocyclyl , lower
• R 3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl , methylsulfonyl , fluoro, chloro, bromo, aminosulfonyl , methyl, ethyl, isopropyl, tert-butyl,
• SUBSmUFESHEEr(RULE26) 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-
• R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl , cyclohexadienyl , phenyl, biphenyl, morpholinyl, pyrrolidinyl , piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl , isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl , isoquinolinyl , imidazolyl, benzimidazolyl , furyl, pyrazinyl, dihydropyranyl , dihydropyridinyl , dihydrofuryl , tetrahydropyranyl , tetrahydrof
• the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more 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, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
• Still another class of compounds of particular interest consists of those compounds of Formula I wherein
• R 1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl , dimethylaminoethyl, diethylaminoethyl or morpholinylethyl ;
• R 2 has the formula:
• R 30 is hydrogen
• R 31 is selected from hydrogen and lower alkyl
• R 32 is selected from hydrogen and lower alkyl; and R 33 is selected from lower alkyl, -C(0)R 35 , -C(0)OR 35 , -S0 2 R 36 , -C(0)NR 37 R 38 , and -SO 2 NR 39 R 40 ; wherein R 35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with
• R 36 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 37 is hydrogen; and wherein R 38 is selected from lower alkyl, phenyl, and lower alkylphenylene; wherein R 39 and R 40 have the same definition as R 26 and R 27 in claim 2
• R 2 is selected from the group consisting of
• R 56 is hydrogen
• R 57 is hydrogen
• R 58 is selected from -C(0)R 59 and -S0 2 R 60 ; wherein R 59 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently
• 3UeSTmreSHEET(RULE26) selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 60 is selected from lower alkyl; and R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or 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
• R 4 is selected from phenyl, quinolyl , biphenyl, pyridinyl, thienyl, furyl , dihydropyranyl , benzofuryl, dihydrobenzofuryl , and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
• Still another class of compounds of specific interest consists of those compounds of Formula I wherein
• R 1 is hydrido or methyl
• R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or 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
• R 4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl,
• the compounds of Formula I satisfy one or more of the following conditions:
• R 1 is hydrido or lower alkyl; more preferably, R 1 is hydrido or methyl; and still more preferably, R 1 is hydrido;
• R 2 is hydrido or lower alkyl; more preferably, R 2 is hydrido or methyl; and still more preferably, R 2 is hydrido ; R 3 is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl ; or
• R 4 is substituted or unsubstituted phenyl; and preferably, R 4 is phenyl substituted with halo.
• R 3 is substituted pyrimidinyl
• at least one R 3 substitutent is attached to the carbon atom positioned between two nitrogen atoms of the pyrimidinyl ring .
• a family of specific compounds of particular interest within Formula I consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:
• SUBSmUTESHEET(raJLE-a6) 4- [3 -methyl -5- (3-methylphenyl) -lH-pyrazol-4-yl] pyridine;
• 8U8STrrUTESHEET(RULE26) 4- (3-furyl) -3 -methyl -5-phenyl -lH-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;
• R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl
• R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6- membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl , lower hydroxyalkyl , lower alkoxycarbonyl , lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alky
• 8 ⁇ BS ⁇ TUTESHEET(R ⁇ L£2 ⁇ ) heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl ; or
• R 2 is -CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
• R 4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl , 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R 4 is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
• R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl , or -NR 62 R 63 wherein R 62 is lower alkylcarbony
• a preferred class of compounds consists of those compounds of Formula IX
• R 1 is selected from hydrido, methyl, ethyl,
• R 2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N- propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethyl minopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1- dimethyl) ethylcarbonyl, (1,1
• R 4 is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl , phenyl, quinolyl , biphenyl, pyridinyl, thienyl, furyl , dihydropyranyl , benzofuryl, dihydrobenzofuryl , and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
• R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl , fluorophenylethenyl , fluorophenylpyrazolyl , cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino,
• Z represents a carbon atom or a nitrogen atom
• R 1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl , lower aminoalkyl and lower alkylaminoalkyl;
• R 2 is selected from hydrido, lower alkyl, aryl
• 8UBSTTrtfTE8HEEr(RULE28) selected from phenyl, biphenyl, and naphthyl, 5- or 6- membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl , lower hydroxyalkyl , lower alkoxycarbonyl , lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl , lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonyla
• R 2 is -CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy;
• R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower
• a preferred class of compounds consists of those compounds of Formula X
• R 1 is selected from methyl, ethyl, hydroxyethyl and propargyl ; and R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N- ethylamino, N,N-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino , dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholin
• R 4 is selected from phenyl, quinolyl , biphenyl, pyridinyl, thienyl , furyl , dihydropyranyl , benzofuryl, dihydrobenzofuryl , and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
• R 5 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, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl , cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, meth
• Z represents a carbon atom or a nitrogen atom; and R 1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and
• R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6- membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl , lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonyla
• R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and
• R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62 R 63 wherein R 62 is lower alkylcarbonyl
• a preferred class of compounds consists of those compounds of Formula XI
• R 1 is selected from methyl, ethyl, hydroxyethyl and propargyl ;
• R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-
• R 4 is selected from phenyl, quinolyl , biphenyl, pyridinyl , thienyl , furyl , dihydropyranyl , benzofuryl , dihydrobenzofuryl , and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and
• R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl , fluorophenylethenyl , fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylammoethylamino, hydroxypropylamino, hydroxyethylamino , imidazolylamino, morpholinylethylamino, (1 -ethyl -2 -hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl,
• a preferred class of compounds consists of those compounds of Formula IX wherein
• Z represents a carbon atom or a nitrogen atom
• R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl;
• R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6- membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl , lower hydroxyalkyl , lower alkoxycarbonyl , lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl , lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxy
• R 2 is -CR 54 R 55 wherein R 54 is phenyl and R 55 is hydroxy; and R 4 is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino,
• a class of compounds of specific interest consists of those compounds of Formula IX wherein
• R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
• R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N- ethylamino, N,N-diethylamino, N- ropylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1, 1-dimethyl) ethylcarbonyl , (1,1-
• SUBSTTrUTCSHEEr(RULE26) a pharmaceutically-acceptable salt or tautomer thereof .
• Another class of compounds of specific interest consists of those compounds of Formula IX wherein
• Z represents a carbon atom or a nitrogen atom
• R 1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl ; and R 2 is selected from hydrido and lower alkyl;
• R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and
• R 5 is selected from hydrido, halo and alkylhydrazinyl ; or a pharmaceutically-acceptable salt or tautomer thereof .
• Still another class of compounds of specific interest consists of those compounds of Formula IX wherein
• Z represents a carbon atom; and R 1 is selected from hydrido, methyl, hydroxyethyl, propargyl ; and R 2 is hydrido; and
• R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo ; and R 5 is selected from hydrido, fluoro, and 1- methylhydrazinyl ; or a pharmaceutically-acceptable salt or tautomer thereof .
• a preferred class of compounds of specific interest consists of those compounds of Formula IX wherein
• ⁇ Ur ⁇ IU ⁇ ESHEET(RUlE26 ⁇ Z represents a carbon atom
• R 1 is selected from hydrido and methyl
• R 2 is hydrido
• R 4 is selected from phenyl that is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo;
• R 5 is selected from hydrido and fluoro; or a pharmaceutically-acceptable salt or tautomer thereof .
• hydro denotes a single hydrogen atom (H) .
• This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-) radical.
• haloalkyl alkylsulfonyl
• alkoxyalkyl alkoxyalkyl
• hydroxyalkyl hydroxyalkyl
• cyanoalkyl and "mercaptoalkyl”
• alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms.
• alkyl radicals are "lower alkyl” radicals having one to about ten carbon atoms . Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, iso-amyl, hexyl and the like.
• alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms.
• alkenyl radicals are "lower alkenyl” radicals having two to about six carbon atoms.
• alkenyl radicals include ethenyl, allyl, propenyl , butenyl and 4-methylbutenyl .
• alkenyl and lower alkenyl embrace radicals having "cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
• alkynyl embraces linear or
• cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms .
• cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms .
• More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• cycloalkylalkylene embraces alkyl radicals substituted with a cycloalkyl radical . More preferred cycloalkylalkylene radicals are "lower cycloalkylalkylene” which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl , cyclobutylmethyl , cyclopentylmethyl and cyclohexylmethyl .
• cycloalkenyl embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms.
• Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl” . More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl .
• halo means halogens such as fluorine, chlorine, bromine or iodine.
• haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl,
• a monohaloalkyl radical for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical .
• Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
• “Lower haloalkyl” embraces radicals having one to six carbon atoms.
• haloalkyl radicals include fluoromethyl , difluoromethyl , trifluoromethyl, chloromethyl , dichloromethyl , trichloromethyl , trichloromethyl, pentafluoroethyl, heptafluoropropyl , difluorochloromethyl , dichlorofluoromethyl , difluoroethyl , difluoropropyl , dichloroethyl and dichloropropyl.
• hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
• More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl , hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl .
• the terms "alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms . More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
• alkoxyalkyl embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
• the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals.
• aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
• aryl embraces
• aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
• Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl , alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl , alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl , alkoxycarbon
• heterocyclyl embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
• saturated heterocyclyl radicals include saturated 3 to 6 -membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl , imidazolidinyl , piperidino, piperazinyl, etc.); saturated 3 to 6 -membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g.
• heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals.
• heteroaryl embraces unsaturated heterocyclyl radicals.
• heteroaryl radicals examples include unsaturated 3 to
• 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms for example, pyrrolyl , pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2 , 4-triazolyl , 1H- 1, 2, 3 -triazolyl, 2H-1 , 2 , 3-triazolyl , etc.) tetrazolyl (e.g.
• unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms for example, indolyl , isoindolyl, indolizinyl, benzimidazolyl , quinolyl , isoquinolyl, indazolyl, benzotriazolyl , tetrazolopyridazinyl (e.g., tetrazolo [1, 5-b] pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl , furyl , etc.; unsaturated 3 to 6 -membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1
• benzoxazolyl benzoxadiazolyl , etc.
• unsaturated 3 to 6-membered heteromonocyclic 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.
• unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl , benzothiadiazolyl , etc.) and the like.
• heterocycle also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino.
• heterocyclylalkylene embraces
• heterocyclylalkylene radicals More preferred heterocyclylalkylene radicals are "lower heterocyclylalkylene” radicals having one to six carbon atoms and a heterocyclyl radicals.
• alkylthio embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms .
• alkylthioalkylene embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkylene radicals are "lower alkylthioalkylene” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl.
• alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl , ethylsulfonyl and propylsulfonyl .
• the "alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl
• halosulfonyl embraces halo radicals attached to a sulfonyl radical .
• halosulfonyl radicals include chlorosulfonyl , and bromosulfonyl .
• sulfamyl denotes NH2O2S- .
• acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and arpyl radicals.
• alkanoyl radicals examples include formyl , acetyl, propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl , and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, /3-hydroxybutyric, galactaric and galacturonic acids.
• carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO2H.
• carboxyalkyl embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl , carboxyethyl and carboxypropyl .
• alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
• lower alkoxycarbonyl radicals with alkyl portions having one to six carbons.
• lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl .
• alkoxycarbonylalkyl embraces alkyl radicals substituted with a alkoxycarbonyl radical as defined above. More preferred are "lower alkoxycarbonylalkyl” radicals with
• alkylcarbonyl includes radicals having alkyl, hydroxylalkyl , radicals, as defined herein, attached to a carbonyl radical.
• radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl , propylcarbonyl , butylcarbonyl , pentylcarbonyl , hydroxymethylcarbonyl , hydroxyethylcarbonyl .
• aralkyl embraces aryl- substituted alkyl radicals such as benzyl, diphenylmethyl , triphenylmethyl , phenylethyl, and diphenylethyl .
• the aryl in said aralkyl may be additionally substituted with one or more substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro.
• substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro.
• benzyl and phenylmethyl are interchangeable.
• heterocyclylalkylene embraces saturated and partially unsaturated heterocyclyl -substituted alkyl radicals (also can be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly) , such as pyrrolidmylmethyl, and heteroaryl -substituted alkyl radicals (also can be called heteroarylalkylene) , such as pyridylmethyl , quinolylmethyl , thienylmethyl , furylethyl, and quinolylethyl .
• heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
• aryloxy embraces aryl radicals attached through an oxygen atom to other radicals.
• aralkoxy embraces aralkyl radicals attached through an oxygen atom to other radicals.
• aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred are "lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like.
• alkylamino denotes amino groups which are substituted
• SUBSnTUTE8HEET(RULE26) with one or two alkyl radicals Preferred are "lower alkylamino" radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N- alkylamino, such as N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-diethylamino or the like.
• arylamino denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino.
• the "arylamino" radicals may be further substituted on the aryl ring portion of the radical.
• alkylaminocarbonyl denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom.
• N-alkylaminocarbonyl and “N,N- dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N- dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
• alkylcarbonylamino embraces amino groups which are substituted with one alkylcarbonyl radicals.
• alkylcarbonylamino radicals are "lower alkylcarbonylamino" having lower alkylcarbonyl radicals as defined above attached to amino radicals.
• alkylaminoalkylene embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical .
• hydrocarbon moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl . Preferably, these moieties comprise 1 to 20 carbon atoms.
• S ⁇ eS ⁇ TTUTESHEET(RULE26) herein are hydrocarbon moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, sulfur, or a halogen atom.
• substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.
• each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms; each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring
• the present invention comprises the tautomeric forms of compounds of Formulas I and IX.
• the pyrazoles of Formula I and I' are magnetically and structurally equivalent because of the prototropic
• the present invention also comprises compounds of Formula I, IX, X and XI having one or more asymmetric carbons. It is known to those skilled in the art that those pyrazoles of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof .
• the present invention comprises a pharmaceutical composition for the treatment of a TNF mediated disorder, a P38 kinase mediated disorder, inflammation, and/or arthritis, comprising a therapeutically-effective amount of a compound of Formula I, or a therapeutically- acceptable salt or tautomer thereof, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
• the present invention further encompasses substituted pyrazoles that specifically bind to the ATP binding site of p38 kinase. Without being held to a particular theory, applicants hypothesize that these substituted pyrazoles interact with p38 kinase as set forth below. As the substituent at the 3 -position of the pyrazole ring approaches the ATP binding site of p38
• a hydrophobic cavity in the p38 kinase forms around the 3 -position substitutent at the binding site.
• This hydrophobic cavity is believed to form as the 3- position substituent binds to a specific peptide sequence of the enzyme.
• it is believed to bind to the sidechains of Lys 52 , Glu 69 , Leu 73 , Ile 82 , Leu 84 , Leu 101 and the methyl group of the Thr 103 sidechain of p38 kinase at the ATP binding site (wherein the numbering scheme corresponds to the numbering scheme conventionally used for ERK-2) .
• the 3 -position substituent is aryl or heteroaryl
• such aryl or heteroaryl may be further substituted. It is hypothesized that such ring substituents may be beneficial in preventing hydroxylation or further metabolism of the ring.
• the substituent at the 4 -position of the pyrazole ring is one that is a partial mimic of the adenine ring of ATP, although it may be further elaborated.
• it is a planar substituent terminated by a suitable hydrogen bond acceptor functionality. It is hypothesized that this acceptor hydrogen bonds to the backbone N-H of the Met 106 residue while one edge of this substituent is in contact with bulk solvent.
• Substitution at the 5-position of the pyrazole ring is well tolerated and can provide increased potency and selectivity. It is hypothesized that such substituents extend out in the direction of the bulk solvent and that suitable polar functionality placed at its terminus can interact with the sidechain of Asp 109 , leading to increased potency and selectivity. Similarly, substitution on the nitrogen atom at the 1- or 2 -position of the pyrazole ring is well tolerated and can provide increased potency. It is hypothesized that a hydrogen substituent attached to one of the ring nitrogen atoms is hydrogen bonded to Asp 165 . Preferably, the nitrogen atom at the 2 -position is double bonded to the carbon atom at the 3 -position of the pyrazole while
• the 5-position substitutent and the 1- or 2-position substituent of the pyrazole can be selected so as to improve the physical characteristics, especially aqueous solubility and drug delivery performance, of the substituted pyrazole.
• these substituents each have a molecular weight less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight less than about less than about 250 atomic mass units. Still more preferably, these substituents have a combined molecular weight less than about 360 atomic mass units.
• a class of substituted pyrazoles of particular interest consists of those compounds having the formula:
• R 1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
• R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and
• R 4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; provided R 3 is not 2 -pyridinyl when R 4 is a phenyl ring containing a 2 -hydroxy substituent and when R 1 is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl ; or a pharmaceutically-acceptable salt or tautomer thereof .
• a class of substituted pyrazoles of particular interest consists of those compounds of Formula XI wherein R 1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and
• R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys 52 , Glu 69 , Leu 73 , Ile 82 , Leu 84 , Leu 101 , and Thr 103 sidechains at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site; and R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Met 106 of p38 kinase; and
• R 4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units.
• the present 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
• R 1 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
• R 1 has the formula r-, 2 5 n
• R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and
• R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 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, alkoxy
• aryloxycarbonylarylene alkylaryloxycarbonylarylene , arylcarbonylarylene , alkylarylcarbonylarylene , alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene , heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene , alkylthioarylene, aralkylthioarylene , heterocyclylthioarylene , arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene , alkylheterocyclylarylene , alkoxyarylene, aryloxyarylene, ary
• R 27 is -CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene , alkylheterocyclylalkylene , alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or
• R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals 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
• SUBSOTTU ⁇ ESHEET(RULE26) optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
• R 2 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, alkylammoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl , carboxy
• j is an integer from 0 to 8.
• n 0 or 1 ;
• R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl , alkoxyalkyl, and alkylcarbonyloxyalkyl ; and
• R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl , alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
• R 33 is selected from hydrogen, alkyl, -C(0)R 35 , -C(0)OR 35 , -S0 2 R 36 , -C(0)NR 37 R 38 , and -S0 2 NR 39 R 40 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and
• R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl ; or
• R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl , purinyl ,
• R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy,
• R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently 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
• pharmaceutically-acceptable salts are also included in the family of compounds of Formula I.
• pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
• Suitable pharmaceutically- acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
• organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes 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, ⁇ - hydroxybutyric, gal
• Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group la) salts, alkaline earth metal (group Ila) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-
• Scheme I shows the synthesis of pyrazole 5 by two
• ketone 3 is first converted to epoxide 4, such as by treatment with hydrogen peroxide solution at room temperature, in the presence of base such as sodium hydroxide. Treatment of epoxide 4 with hydrazine in ethanol or other suitable solvent at a temperature ranging up to reflux, yields pyrazole 5.
• ketone 3 is condensed directly with tosyl hydrazide in the presence of an acid such as acetic acid, at reflux, to provide pyrazole 5.
• an acid such as acetic acid
• the intermediate tosyl hydrazone 6 may be isolated, conversion of it to pyrazole 5 is effected by treatment with a base, such as potassium hydroxide, in a suitable solvent, such as ethylene glycol, at a temperature ranging from 25 °C up to 150 °C.
• Scheme II shows the synthesis of pyrazole 12 of the present invention.
• a base such as sodium bis (trimethylsilyl) amide
• a suitable solvent such as tetrahydrofuran
• ketone 9 Treatment of ketone 9 or a hydrohalide salt of ketone 9 with a halogenating agent, such as bromine, N-bromosuccinimide or N- chlorosuccinimide, in suitable solvents, such as acetic acid, methylene chloride, methanol, or combinations thereof, forms the ⁇ -halogenated ketone 10 (wherein X is halo) .
• a halogenating agent such as bromine, N-bromosuccinimide or N- chlorosuccinimide
• hydrohalide salts include the hydrochloride and hydrobromide salts.
• Reaction of haloketone 10 with thiosemicarbazide 11 (where R 6 and R 7 can be hyrido, lower alkyl, phenyl, heterocyclyl and the like or where R 6 and R 7 form a heterocyclyl ring optionally containing an additional heteroatom) provides pyrazole 12.
• reaction are ethanol and dimethylformamide .
• the reaction may be carried out in the presence or absence of base or acid at temperatures ranging from room temperature to 100 °C.
• Thiosemicarbazides which are not commercially available may be conveniently prepared by one skilled in the art by first reacting an appropriate amine with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide. Treatment of the resultant alkyl dithiocarbamate with hydrazine results in the desired thiosemicarbazide .
• This chemistry is further described in E. Lieber and R.C. Orlowski, J. Org . Chem. , Vol. 22, p. 88 (1957).
• Scheme III shows the synthesis of pyrazole 19 in more general form by three routes.
• ketone 13 is condensed with hydrazine 14 to give the substituted hydrazide 16, which is then reacted with acyl halide or anhydride 17 at low temperature to provide acyl hydrazone 18.
• acyl hydrazone 18 Upon heating at a temperature up to 200°C, acyl hydrazone 18 is converted to pyrazole 19.
• Route 2 acyl hydrazone 18 is formed directly by reaction of ketone 13 with acyl hydrazide 15, formed by reaction of hydrazine with a carboxylic acid ester, at room temperature.
• ketone 13 is treated with acyl hydrazide 15 at a suitable temperature, ranging from room temperature to about 200 °C, to give pyrazole 19 directly.
• this condensation may be carried out in an acidic solvent, such as acetic acid, or in a solvent containing acetic acid.
• Scheme V shows the two step synthesis of the 3- substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclization of hydrazone dianions with carboxylates .
• step 1 the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as later described in Scheme IX) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32.
• suitable hydrazines include, but are not limited to, phenylhydrazine and p-methoxyphenylhydrazine.
• step 2 the hydrazones 32 are treated with two equivalents of a base such as sodium bis (trimethylsilyl) amide in a suitable solvent such as tetrahydrofuran to generate dianions.
• a base such as sodium bis (trimethylsilyl) amide
• a suitable solvent such as tetrahydrofuran
• the dianions then are condensed with esters such as methyl isonicotinate, methyl cyclopropanecarboxylate, to give the desired pyrazoles 33. It may be necessary to treat the product from this step with a dehydrating agent, such as a mineral acid, to produce the target pyrazole in some instances.
• a dehydrating agent such as a mineral acid
• Scheme VI shows an alternative method for synthesizing pyrazoles which are unsubstituted at the 5 position of the ring.
• a heteroarylmethyl ketone 34 is synthesized by first treating a heteroarylmethane with a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide .
• suitable heteroarylmethanes are 4- methylpyridine, 4-methylpyrimidine, 2 , 4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine .
• the resulting heteroarylmethyl lithium species is then reacted with a substituted benzoate ester to produce ketone 34.
• Ketone 34 is converted to the aminomethylene derivative 35 by reaction with an aminomethylenating agent such as dimethylformamide dimethyl acetal or tert- butoxybis (dimethylamino) methane .
• Ketone 35 is converted to pyrazole 36 by treatment with hydrazine.
• Ketone 34 is first converted to hydrazone 37 by reaction with the appropriate substituted hydrazine.
• suitable hydrazines are N-methylhydrazine and N- (2- hydroxyethyl) hydrazine .
• Reaction of hydrazone 37 with an aminomethylenating agent produces pyrazole 38.
• suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tert- butoxybis (dimethylamino) methane .
• R 3 substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen
• subsequent treatment with an amine produces an amino- substituted heteroaromatic derivative.
• amines include benzylamine, cyclopropylamine and ammonia.
• the leaving group may also be replaced with other nucleophiles such as mercaptides and alkoxides.
• substitutable R 3 groups include, but are not limited to, 2-chloropyridinyl and 2 -bromopyridinyl groups.
• Oxidation of pyrazole 5 gives carboxylic acid 39, which is then reduced to hydroxymethyl compound 40, or coupled with amine NR 10 R 11 (wherein R 10 and R 11 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42.
• Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole 43.
• the alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished using conventional techniques.
• Treatment of pyrazole 43 with an appropriate base (for example, sodium hydride) followed by treatment with an alkyl halide (for example, CH 3 I) yields a mixture of isomers 44 and 45.
• an appropriate base for example, sodium hydride
• an alkyl halide for example, CH 3 I
• Scheme IX illustrates the synthesis of 3-aryl-4- pyridyl-pyrazoles of the present invention.
• Benzoate 46 is reacted with pyridine 47 in the presence of a strong base, such as an alkali metal hexamethyldisilazide (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give desoxybenzoin 48.
• Desoxybenzoin 48 is then converted to ketone 49 by treatment with an excess of dimethylformamide dimethyl acetal .
• R 12 represents one or more radicals independently selected from the optional substituents previously defined for R 4 .
• R 12 is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy .
• the 3 -aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized in the manner of Scheme IX by replacing pyridine 47 with the corresponding pyrimidine.
• Schemes X through XVII can be employed to synthesize 3 -aryl-4 -pyrimidinyl - pyrimidines corresponding to the 3 -aryl-4 -pyrimidinyl - pyrazoles shown in those schemes .
• Scheme X illustrates one variation of Scheme IX that can be used to synthesize 3 -aryl -4 -pyridyl -pyrazoles that are further substituted on the nitrogen atom at position 1 of the pyrazole ring. If desoxybenzoin 48 (prepared in accordance with Scheme IX) instead is first converted to hydrazone 51 by treatment with hydrazine and hydrazone 51 is then treated with dimethylformamide dimethyl acetal, then the resulting product is pyrazole 52.
• Schemes XI through XVIII illustrate further modifications that can be made to Scheme IX to synthesize other 3 -aryl -4 -pyridyl-pyrazoles having alternative substituents .
• X is chloro, fluoro or bromo
• R 13 is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino
• R 20 is, for example, hydrogen or alkyl.
• n is 1, 2 , 3 , 4 or 5 ; and R 14 and R 15 are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
• R 16 is selected, for example, from hydrogen, alkyl and phenyl.
• R 17 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.
• an oxidizing agent such as m-chloroperoxybenzoic acid.
• Treatment of the pyridine N-oxide with trimethylsilyl cyanide followed by dimethylcarbamoyl chloride produces the 2-cyano compound 68.
• Compound 68 is converted to its carboxamide 69 by reaction with hydrogen peroxide in the presence of a suitable base.
• suitable bases include potassium carbonate and potassium bicarbonate.
• Carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethyl acetal in methanol.
• the ester 70 is converted to its carboxylic acid 71 by saponification.
• Typical saponification conditions include reaction with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or ethanol and water or methanol and water or the like.
• Ester 70 is also convertible to substituted amide 72 by treatment with a desired amine, such as methylamine at a suitable temperature. Temperatures may range from room temperature to 180 °C.
• R 18 and R 19 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
• the following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I, XI, X and XI.
• Step 2 Preparation of 4- [5- (3-fluoro-4-methoxyphenyl) -3- methyl- IH-pyrazol -4 -yll pyridine
• 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 was heated to reflux for 6 hours.
• Acetic acid was removed by distillation from the reaction solution.
• the resulting residue was diluted with CH2CI2 (150 ml) , washed with H2O
• 4-Pyridylacetone was prepared according to the method of Ippolito et al , U.S. Patent 4,681,944.
• 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.
• Step 3 Preparation of 4-phenyl-3- (4-pyridyl) -3 , 4- epoxy-2-butanone
• step 2 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
• Step 4 Preparation of 4- (3 -methyl -5 -phenyl -IH-pyrazol - 4-yl) pyridine
• step 3 a solution of 4-phenyl-3- (4-pyridyl) -3 , 4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours.
• the crude product was purified by chromatography (silica gel, 1:1 acetone/hexane) .
• the product was recrystallized from ethyl acetate and hexane to give 4- (3 -methyl -5 -phenyl -IH-pyrazol -4-yl) pyridine (81 mg, 35%) as a crystalline solid: m. p.
• Step 1 Preparation of 4- (2-methylphenyl) -3- (4-pyridyl) - 3-butene-2-one
• Step 2 Preparation of 4- (2 -methylphenyl) -3- (4 -pyridyl ) - 3 , 4-epoxy-2-butanone
• step 1 To a solution of 4- (2 -methylphenyl) -3- (4 -pyridyl) -3- butene-2-one (step 1) (l.Og, 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 (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes.
• Step 3 Preparation of 4- [5-methyl-3- (2 -methylphenyl) IH- pyrazol -4 -yll yridine
• Step 2 the preparation of the intermediate epoxide was accomplished at 0-10 °C for 1 hour, and the reaction was quenched by being partitioned
• Example A-10 The same procedure as for the preparation of Example A-10 was used, substituting 4-formylbiphenyl in place of piperonal, to give 4- [5- [ (1, 1 ' -biphenyl) -4-yl] -3-methyl- lH-pyrazol-4-yl] pyridine as a white solid: MS (M+H): 312 (base peak) .
• Example A- 10 The same procedure for the preparation of Example A- 10 was used, substituting 3-phenoxybenzaldehyde in place of piperonal, to give 4- [3 -methyl -5- [3- (phenoxyphenyl) - lH-pyrazol-4-yl] pyridine as a white solid.
• Example A- 10 The same procedure for the preparation of Example A- 10 was used, substituting 3-benzyloxybenzaldehyde in place of piperonal, to give 4- [3 -methyl -5- [3 -
• Example A- 10 The same procedure for the preparation of Example A- 10 was used, substituting 2-benzyloxybenzaldehyde in place of piperonal, to give 4- [3 -methyl -5- [2-
• Example A- 10 The same procedure for the preparation of Example A- 10 was used, substituting 2-hydroxybenzaldehyde in place of piperonal, to give 2- [3-methyl-4- (4-pyridinyl) -IH- pyrazol -4-yl] phenol : MS (M + H): 252 (base peak).
• Example A- 10 The same procedure for the preparation of Example A- 10 was used, substituting 3-hydroxybenzaldehyde in place of piperonal, to give 3- [3 -methyl -4- (4 -pyridinyl) -1H- pyrazol-4-yl] phenol : MS (M+H): 252 (base peak).
• Step 2 Preparation of 1-fluoro-4- (4 ' - pyridylbromoacetyl ) benzene
• step 1 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 (8.2 g, 0.052 mol) in acetic acid (20 mL) dropwise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air-dried to give 1- fluoro-4- (4' -pyridylbromoacetyl) benzene (14.5 g) . The compound was used in next step without further purification.
• Step 3 Preparation of 5- (4 -fluorophenyl ) -N, N-dimethyl- 4- (4-pyridinyl) -lH-pyrazol-3-amine
• step 2 A mixture of 1-fluoro-4- (4 ' -pyridylbromoacetyl) - benzene (step 2) (3.8 g, 0.01 mol) and 4 , 4-dimethylamino- 3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark green solution was cooled and poured into water (100 mL) . The aqueous phase was extracted with methylene chloride (100 mL) . The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated.
• Step 1 Preparation of 1-fluoro-4- (40- pyridylacetyl) benzene N-benzoylhydrazone
• Step 2 Preparation of 4- F5- (4-fluorophenyl) -3 -phenyl- IH-pyrazol -4 -yll pyridine l-Fluoro-4- (4 ' -pyridylacetyl) benzene N- benzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180 °C under N 2 for 15 minutes, then cooled.
• Step 1 Preparation of 3- (4 ' -pyridylacetyl) toluene
• Step 3 Preparation of 4- 5- (3 -methylphenyl) -3 - (trifluoromethyl) -IH-pyrazol -4-yl] pyridine
• step 2 A mixture of 3- (4 ' -pyridylacetyl) toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 0.01 mol) was heated at 200 °C under N 2 for 15 minutes.
• Step 1 Preparation of 4-cyclohexyl-3 -pyridyl-3-butene- 2 -one 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 Preparation of 4- (5-cyclohexyl) -3-methyl-lH- pyrazol -4 -yl ) pyridine
• Example A-56 5- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol - 4-yl] pyrimidin-2 -amine ;
• Example A-66 4- [5- (4-chlorophenyl) -3 -methyl-IH-pyrazol - 4-yl] pyridin-2 -amine ;
• Example A-67 4- [5- (4-fluorophenyl) -3-methyl-lH-pyrazol-4- yl] pyridin-2 -amine;
• Example A-72 4- [5- (3 -chlorophenyl) -3 -methyl-IH-pyrazol- 4-yl] -2-methoxypyridine;
• Example A-79 4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol - 4-yl] pyridin-2-ol;
• Example A-80 4- [5- (3 -methylphenyl) -3 -methyl-IH-pyrazol-
• Example A-84 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol* 4-yl]pyridin-2-ol;
• Example A-86 4- [5- (3 -chlorophenyl) -3 -methyl -IH-pyrazol -
• Example A-101 4- [5- (4 -chloro-3 -methoxyphenyl) -3 -methyl-
• Example A-102 4- [5- (2 , 3-dihydrobenzofuran-6-yl) -3- methyl -IH-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 -
• Example A-106 4- [5- (1-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-109 4- (5-cyclohexyl -3 -methyl -IH-pyrazol -4- yl) pyridine;
• Example A-110 4- [5- (4 -methoxy-3 -methylphenyl) -3 -methyl - lH-pyrazol-4-yl] pyridine;
• Example A-112 4- [5- (3 -methoxy-5-methylphenyl) -3 -methyl -
• Example A-117 4- (3 -methyl -5-phenyl-IH-pyrazol-4- yl) yridine-2 -carboxamide ;
• Example A-118 1- [4- (3-methyl-5-phenyl-lH-pyrazol-4- yl) pyridin-2 -yl] ethanone;
• Example A-120 3-methyl-4- (3 -methyl-5-phenyl-IH-pyrazol - 4-yl) pyridine;
• Example A-122 methyl 4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridine-3 -carboxylate ;
• Example A-123 4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridine-3 -carboxamide ;
• Example A-124 1- [4- (3 -methyl-5-phenyl-IH-pyrazol-4- yl) pyridin-3 -yl] ethanone ;
• Example A-128 4- (3 -methyl -5-phenyl -IH-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- lH-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 -lH- pyrazole;
• Example A-138 4- (3-isoxazolyl) -3 -methyl-5-phenyl-1H- 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 -IH- pyrazole;
• Example A-143 2-methyl-4- [3- (3 -methylphenyl) -lH-pyrazol- 4-yl] pyridine;
• Example A- 144 4- (l-methyl-3-phenyl-lH-pyrazol-4-yl) pyridine;
• Example A-145 4- (3 -phenyl -IH-pyrazol -4-yl) pyridine;
• Example A-147 4- [3- (3 -chlorophenyl) -1-methyl -pyrazol -4- yl] pyridine;
• Example A-148 4- [3- (4-chlorophenyl) -1-methyl -pyrazol-4- yl] pyridine;
• Example A-149 4- [3- (3 -chlorophenyl) -lH-pyrazol-4- yl] pyridine;
• Example A-150 4- [3- (4 -chlorophenyl) -IH-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- IH-pyrazol - 4-yl] pyridine;
• Example A-153 4- [3- (3-fluorophenyl) -lH-pyrazol-4- yl] pyridine.
• Example A-154 4- [3- (3 -chlorophenyl) -1-methyl-pyrazol-4- yl] -2-methylpyridine.

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