JP2002514640A - 1,5-Diaryl-substituted pyrazoles as p38 kinase inhibitors - Google Patents

Abstract

(57) Abstract: The present invention provides a compound of the formula (I), which inhibits, among other things, the activity of p38 MAP kinase. Wherein A is = N- or = CH-, which corresponds to a 1,5-diaryl-substituted pyrazole compound or a pharmaceutically acceptable salt thereof. The present invention also relates to methods of making the compounds of the invention and methods of using the compounds of the invention in treating a mammalian host suffering from a p38 kinase- or TNF-mediated disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] Technical Field The present invention kinase inhibitors, particularly mitogen (mitogen: mitogen) - inhibits the activity of the activated protein kinase 1,5-diaryl-substituted pyrazole compounds, compositions of these inhibitors, these And a method of treating pathological mitogen-activated protein kinase activity. BACKGROUND OF THE INVENTION Mitogen-activated proteins (MAPs) are a family of proline-directed serine / threonine kinases that activate their substrates by dual phosphorylation. This kinase is
It is activated by various signals including nutrient and osmotic stress, UV light, growth factors, endotoxins and inflammatory cytokines.

[0002] The p38 MAP kinase family comprises various isoforms, including p38, p38 and p38.
It is a member of the MAP family and has the ability to phosphorylate and activate transcription factors (eg, ATF2, CHOP and MEF2C) and other kinases (eg, MAPKAP-2 and MAPKAP-3). The p38 isoform is used for bacterial lipopolysaccharide, physical and chemical stress and tumor necrosis factor alpha.
Activated by pro-inflammatory cytokines, including (TNF-) and interleukin-1 (IL-1). Products of p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.

[0003] TNF-a is a cytokine produced primarily by activated monocytes and macrophages. Many diseases have involved excessive or unregulated TNF production. Recent studies have shown that TNF acts as a etiology of rheumatoid arthritis. Further studies indicate that inhibition of TNF has wide application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

[0004] TNF includes, among others, HIV, influenza virus, and 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-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV- It was also associated with viral infections such as herpes virus, including 8), pseudorabies and rhinotracheitis.

[0005] IL-8 is another pro-inflammatory cytokine produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes (epidermal cells) and has been implicated in conditions such as inflammation.

[0006] IL-1 is produced by activated monocytes and macrophages and is also involved in the inflammatory response. IL-1 is involved in many pathomorphological responses, including rheumatoid arthritis, heat and reduced bone resorption.

[0007] TNF, IL-1 and IL-8 act on a wide variety of cells and tissues and are important inflammatory mediators of a wide range of disease states and conditions. Inhibiting these cytokines by inhibiting p38 kinase is effective in controlling, reducing and alleviating these conditions.

[0008] Various pyrazoles have already been described. For example, PCT Publication WO 95/33727, published December 14, 1995, discloses substituted pyrazoles as adrenocorticotropic hormone releasing factor (CFR) antagonists used in the treatment of diseases such as stress and anxiety related disorders. It has been described. PCT International Publication No.WO96 / 216 issued on July 18, 1996
No. 60 describes substituted pyrazoles and their use as ligands for dopamine receptors in the body. European Patent No. 0 699 43 issued March 6, 1996
No. 8A2 describes pyrazoles and their use as neurotensin antagonists. U.S. Pat. No. 2,833,779 to Fields et al. Describes the preparation of 1,3,5-trisubstituted pyrazoles. U.S. Pat.No. 4,957,971 to Picard et al. Discloses trans-6- [2- as a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase used to inhibit cholesterol biosynthesis. (N-
Heteroaryl-3,5-disubstituted) pyrazol-4-yl) ethyl- or ethenyl] tetrahydro-4-hydroxy-2H-pyran-2-ones are described. Lee et al. U.S. Patent No. 5,4
No. 41,975 describes pyrazoles useful for treating hypercholesterolemia or atherosclerosis in mammals. PCT issued March 4, 1993
WO 93/04052 describes pyrazoles having ACAT inhibitory activity. U.S. Pat.No. 5,102,893 to Picard et al. Discloses a potent inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a trans, useful as a hydrolipidemic and hypocholesterolemic agent. -6- [2- (N-heteroaryl-3,
5-disubstituted) pyrazol-4-yl) ethyl- or ethenyl] tetrahydro-4-hydroxy-2H-pyran-2-one. PCT publication WO 94/22838, published October 13, 1994, describes an angiotensin II antagonizing pyrazole useful for the prevention or treatment of hypertension, congestive heart failure, chronic renal failure, aldosteronism, and increased intracranial pressure. Compounds are described.

[0009] PCT International Publication No. WO 92/19615, published November 12, 1992, describes pyrazoles, pyrazolines and tetrahydropyridazines with fungicidal activity. Ha
U.S. Pat.No. 5,232,940 to tton et al. discloses that N-phenylpyrazole and
It describes their use against plant nematodes, roundworms and protozoan pests.
PCT International Publication No.WO95 / 01340, published on January 12, 1995, has a horticultural disinfecting effect (agrohorticu
A novel pyrazole compound having an ultural bactericidal effect is described. No. 5,201,938 to Costales et al. Discloses a novel substituted N-pyrazolyl-1,2,4-
Describes triazolo [1,5-c] -pyrimidine-2-sulfonamide compounds and their use as herbicides. PCT International Publication No. WO93 / 09100 issued May 13, 1993
No. 3 describes triazolocarboxamides with herbicidal action used to control blackgrass, wild oats, crabgrass, giant enokorogusa, and canine shrimp. PCT International Publication No. WO 94/29300, published December 22, 1994, describes pyrazoles 3-substituted by heterocycles and their use as agricultural fungicides. PCT International Publication No.WO9 issued on November 28, 1996
No. 6/37477 discloses substituted pyrazoles and insecticides against animal parasites and pests;
And use as a disinfectant.

[0010] Pyrazoles have also been described for use in treating inflammation. Wach
US Pat. No. 5,242,940 to ter and Murray describes 1,5-heterocyclic pyrazoles and their use in alleviating inflammatory and cardiovascular disease in mammals. U.S. Pat. No. 5,134,142 to Matsuo et al. Describes 1,5-diaryl and 1,3-diaryl substituted pyrazoles useful in treating inflammation, pain, thrombosis and rheumatism. U.S. Pat. No. 5,466,823 to Talley et al. Describes a class of pyrazolebenzenesulfonamide compounds and their use in treating inflammation and disorders associated with inflammation.

The pyrazolyl compounds of the present invention have been found to be particularly useful as p38 kinase inhibitors. SUMMARY OF THE INVENTION In accordance with the present invention, certain 1,5-diarylpyrazoles have been found to be useful for inhibiting mitogen-activated protein (MAP) kinase. Mitogen-activated protein kinases are thought to be involved in mediating many inflammatory diseases, among others. In particular, these particular 1,5-diarylpyrazoles have p38 M
It was found to be effective in inhibiting the AP kinase group and the MAP kinase subfamily. The compound of the present invention has the following formula:
I:

[0012]

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Or a pharmaceutically acceptable salt thereof. Methods for treating host mammals with conditions associated with pathological p38 MAP kinase activity are also discussed. The method comprises administering a p38 MAP kinase enzyme-inhibiting effective amount of a compound described herein to a mammalian host in such conditions. In particular, it also includes multiple administrations.

The p38 MAP kinase subfamily has various isoforms, including p38, p38 and p38, transcription factors (eg, ATF2, CHOP and MEF2C) and other kinases (eg, MAPKAP-2 and MAPKAP-3). It is responsible for phosphorylation and activation of. The p38 isoform is affected by bacterial lipopolysaccharide, physical and chemical stress, and by tumor necrosis factor (TNF-
) And interleukin-1 (IL-1). p38 phosphorylation products are inflammatory cytokines, including TNF- and IL-1,
And mediates the production of cyclooxygenase-2.

[0015] Excessive or unregulated TNF production has been implicated in the transmission of many diseases, including rheumatoid arthritis, inflammation, inflammatory bowel disease, multiple sclerosis, asthma, and viral infections. IL-8 is another pro-inflammatory cytokine and has been implicated in conditions involving inflammation. In addition, IL-1 has been implicated in the inflammatory response. IL-1 is associated with rheumatoid arthritis,
It is involved in many pathomorphological responses, including reduced heat and bone resorption. TNF-, IL-1 and IL-8 act on a wide variety of cells and tissues and are important inflammatory mediators of a wide range of conditions and conditions. Inhibiting the production of these cytokines by inhibiting p38 kinase helps control, alleviate and alleviate many of these conditions. As already mentioned detailed description of the preferred embodiment, the present invention is, among other activities, the compounds that inhibit the activity of p38 MAP kinase, as well as such compounds for treating conditions mediated by the enzyme or TNF How to use. One aspect of the invention pertains, inter alia, to 1,5-diarylpyrazoles that inhibit the activity of the p38 mitogen-activated protein kinase enzyme. Such compounds have the following formula I:

[0016]

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Wherein A is = N- or = CH-; Ar ¹ is halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano,
Aryl optionally substituted with one or more substituents selected from the group consisting of perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxide Group,
Here, the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,
Here, the substituent on the sulfonamide nitrogen atom is hydride or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclo Oxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroaryl-hydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbyl Amino, heterocycle, heteroaryl, hydroxycarbonyl-hydro Carbyloxy, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy,
Hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonyl Amino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino,
Heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino,
Arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino,
A cyclohydrocarbylsulfonylamino, a heterocyclohydrocarbylsulfonylamino, an N-monosubstituted or N, N-disubstituted aminohydrocarbyl group wherein the (single or plural) substituents on the aminohydrocarbyl nitrogen atom are hydrocarbyl, aryl , Arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and the two substituents attached thereto are 5- to 8- A heterocyclic or heteroaryl ring group), an amino, and an N-monosubstituted or N, N-disubstituted amino group wherein the substituent (s) on the amino nitrogen are Hydride, hydrocarbyl, aryl, aryl hydrocarb , Cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarbyl,
Selected from the group consisting of arylsulfonyl and hydrocarbylsulfonyl, or wherein the amino nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group]; Z is hydride, hydrocarbyl, halogen, carboxy, cyano, azide, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamide, and -XY [where -X is -O, -S or -NQ, and -Y is hydride Is independently selected from the group consisting of hydride, hydrocarbyl, hydroxyhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl; R ¹ is Azide, hydride, hydrocarbyl, amide, hydrocarbylamino, Rohydrocarbyl, perhalohydrocarbyl and halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryl Oxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyl Oxy, heteroaryl Hydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbiroyl, arylcarbonyl, arylhydrocarbylyl, hydrocarboyl Oxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy,
Hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, hetero Arylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfo Amino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and an N-monosubstituted or N, N-disubstituted aminohydrocarbyl group wherein the (single or plural) substituents on the aminohydrocarbyl nitrogen atom are The hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and the two substituents attached thereto are 5- to 8-membered. R ² is independently selected from the group consisting of aryl substituents optionally substituted by one or more substituents selected from the group consisting of: forming a heterocycle or heteroaryl ring; and R ² is azide, Hydride, hydrocarbyl, a Amide, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and an aryl group substituted by one or more substituents; Is a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, hetero Arylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbo Le-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbyl-amino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbyl Amino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarboyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, Hydrocarbyloxyhydrocarbi Ruthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino,
Cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, Selected from the group consisting of heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups, wherein the (one or more) Substituents are hydrocarbyl, aryl, aryl Wherein the aminohydrocarbyl nitrogen and the two substituents attached thereto are selected from the group consisting of drocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl; Or a heteroaryl ring group; and wherein A is = CH- and Z is hydride, hydrocarbyl, halogen or hydrocarbyl: 1) Ar ¹ is hydride, halogen, hydrocarbyl, perfluorohydrocarbyloxy , Nitro, perfluorohydrocarbyl, amino, aminosulfonyl,
Halohydrocarbyloxyhydrocarbyl, hydroxy, hydrocarbylsulfonylamino, hydrocarbylsulfonyl, acetylamino, carbonylhydrocarbylamino, perfluorohydrocarbylsulfonyl, hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, hydrocarbylthio, hydroxyhydrocarbyl, arylhydrocarbyl, hydrocarbyloxyhydrocarbyl,
2) R ¹ is other than an aryl group substituted with one or more substituents selected from the group consisting of hydrocarbyloxycarbonyl, hydrocarbyloxyarylhydrocarbyl, halohydrocarbyloxy, hydrocarbyloxyhydrocarbyl; or Hydride, hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, hydrocarbylaryl, cyano, perfluorohydrocarbyl, hydroxyhydrocarbyl, arylhydrocarbyl, carboxy, hydrocarbyloxycarbonyl, hydrocarbylhydrocarbyl, aminocarbonyl, arylhydrocarbyl-hydrocarboyl- Hydrocarbyl, monosubstituted aminocarbonyl, hydrocarbyl-hydrocarbyl-hydrocarbyl monosubstituted aminocap Boniru, hydrocarbyl - hydrocarbyl hydrocarbyloxy Boyle - hydrocarbyl-monosubstituted aminocarbonyl, hydrocarbyl - hydroxy - disubstituted aminocarbonyl hydrocarbyl or is other than a heteroaryl group 6 membered substituted by nitrogen atoms; or 3) R ² Is other than hydride, carboxy, hydrocarbyloxycarbonyl, halogen or aryl], or a pharmaceutically acceptable salt thereof.

In a particularly preferred implementation, A is = CH-, wherein the predicted substituent is a 4-pyridine group, as compared to a 4-pyrimidyl group. When considered predominantly on an activity basis, formula I comprises three particularly preferred subclasses of very important compounds. Particularly important one subclass, discussed in the following assays, is from about 1.5 shown in Table I (<) A preferred class of compounds which exhibit IC ₅₀ in vitro of less than 10 [mu] M. This embodiment is a compound of the formula I wherein Ar ¹ is an aryl group substituted by fluorine or a group selected from lower hydrocarbyl; R ¹ is hydride or lower hydrocarbyl; R ² is Z is hydride or -XY; -X is -O or -NQ; Q is aryl-lower hydrocarbyl; and -Y is selected from the group consisting of hydride, lower hydrocarbyl, and aminocarbonyl. Hydride or lower hydrocarbyl], or a pharmaceutically acceptable salt thereof.

A more preferred subclass of compounds is about 1.0 in the assays discussed below.
Shows an IC ₅₀ in vitro activity of less than (<) 1.5 μM. This more preferred aspect is
Formula I wherein Ar ¹ is a lower hydrocarbyl or an aryl group substituted by one or more substituents that are halogen (eg, fluorine); R ¹ is hydride or a lower hydrocarbyl; R ² is hydride or lower hydrocarbyl; Z is hydride or -XY; -X is -NQ; Q is lower hydrocarbyl or hydroxyl lower hydrocarbyl; and
-Y is hydride or lower hydrocarbyl], or a pharmaceutically acceptable salt thereof.

Most preferred compounds of the subclass of Formula I exhibit an IC ₅₀ in vitro activity of (<) less than 1.0 μM in the assays discussed below and shown in Table I. Compounds of this subclass are those of the formula I wherein Ar ¹ is a lower hydrocarbyl or an aryl group substituted by one or more substituents which are halo such as fluorine or chlorine; R ¹ is hydride, or a lower hydrocarbyl; R ² is hydrido; Z is located at the selected cyano or -XY; here, -X is an -O or -NQ; Q is hydrido, lower hydrocarbyl, Selected from the group consisting of aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 3-pyridyl lower hydrocarbyl; and -Y is hydride, lower hydrocarbyl, or aryl lower hydrocarbyl] or a pharmaceutically acceptable salt thereof. Including.

Certain 1,5-diarylpyrazoles are mitogen-activated proteins (MAP)
It was found to be effective in inhibiting kinases. Mitogen-activated protein kinases are thought to be involved in mediating many inflammatory diseases, among others.
In particular, these specific 1,5-diarylpyrazoles were found to be effective in inhibiting the p38 MAP kinase family of enzymes, a subfamily of MAPs.

Due to the interaction between p38 kinase and TNF, compounds of formula I produce or exacerbate excessive or unregulated TNF or p38 kinase production; ie, pathological p38 MAP kinase activity by mammals. , But is not limited to, treating diseases or conditions in humans or other mammals. Thus, the present invention is directed not only to compounds, but also to compounds of formula I, or a pharmaceutically acceptable salt or tautomer thereof.
It also relates to a method of treating a TNF-mediated disease, comprising administering an NF-inhibiting effective amount.

The compounds of formula I are also useful for, but not limited to, the use of antipyretics for the treatment of inflammation in patients and the treatment of fever. The compounds of the present invention are useful for treating arthritis, including rheumatoid arthritis, myeloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Useful, but not limited to. In addition, such compounds are useful for treating pulmonary diseases or inflammation of the lungs, including adult respiratory distress syndrome, pulmonary sarcoma, asthma, silicosis, and chronic pulmonary inflammatory diseases. The compounds of the invention are useful in treating sepsis, septic shock, gram-negative sepsis, malaria, meningitis, cachexia following infection or malignancy, cachexia after acquired immunodeficiency syndrome (AIDS), AIDS, It is also useful for treating viral and bacterial infections, including ARC (AIDS-related complex), pneumonia, and herpes virus.

The compounds disclosed herein may be used to treat bone resorption disorders, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disorders including graft-versus-host reactions and allograft reactions, atherosclerotic arteries It is also useful for treating cardiovascular diseases, including sclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease, and nephritis, and myalgia due to infection. The compounds of the present invention are useful for treating influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, and scar formation. Is also useful. The compounds of the present invention are also useful for treating gastrointestinal conditions such as, for example, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds of the present invention may also be useful in the treatment of ophthalmic diseases such as conjunctivitis, retinopathy, uveitis, glare, and acute damage to eye tissues. The compounds of the present invention are also useful for preventing cyclooxygenase-2 production.

In addition to being useful for treating humans, these compounds are also useful for veterinary treatment of companion animals, exotic animals, and livestock (eg, mammals, rodents, etc.). More preferred animals include horses, dogs and cats.

The compounds of the present invention may be partially or completely replaced with other conventional anti-inflammatory agents, for example, steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDs, immunosuppressants, 5-lipoxygenase inhibitors , together with LTB ₄ antagonists and LTA ₄ hydrolase inhibitors may also be used jointly therapy.

[0027] As used herein, "TNF-mediated disorder" refers to TNF-mediated disorder.
Under its own control or when TNF is released from another monokine (e.g., IL-1, IL-6 or L-8
(But not limited to), any and all diseases and conditions affected by TNF. Thus, for example, a condition in which IL-1 is the major component and whose production or effect is exacerbated or secreted in response to TNF is considered a TNF-mediated disease.

As used herein, “p38-mediated disease” refers to the control of p38 itself or to p38
38 is another factor (e.g., but not limited to, IL-1, IL-6I or L-8)
Refers to any and all diseases and conditions affected by p38. Thus, a condition in which, for example, IL-1 is the major component and whose production or action is exacerbated or secreted in response to p38, is considered a p38-mediated disease.

[0029] Because TNF- is structurally homologous to TNF (also known as cachectin),
Also, since each induces a similar biological response and binds to receptors on the same cell, both TNF- and TNF- are inhibited by the compounds of the present invention. TNF ".

Examination of the structure and then the reactivity of the functional groups among the 5- (4-pyridyl) pyrazole substituents reveals a particularly preferred subclass of compounds of formula I.
One subclass of particularly preferred compounds is the following Formula II:

[0031]

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Wherein R ³ is hydride or C ₁ -C ₆ (lower) hydrocarbyl; R ⁴ is hydride, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2-pyridyl lower hydrocarbyl, Selected from the group consisting of 3-pyridyl lower hydrocarbyl or 4-pyridyl lower hydrocarbyl;
Ar ¹ is an aryl group substituted by a halogen or halo group (e.g., chlorine, fluorine and bromine), lower hydrocarbyl, or hydrocarbyloxy group; R ¹ is hydride or C ₁ -C ₆ hydrocarbyl And R ² is hydride or lower hydrocarbyl], or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of formula II shown in Table I exhibit an IC ₅₀ in vitro activity of less than (<) and greater than 1.5 μM (>) in the assays discussed below. Compounds of this group include compounds of formula II wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl; R ¹ is lower hydrocarbyl; R ² is hydride; R ³ is hydride or be a C ₁ -C ₆ hydrocarbyl; and R ⁴ includes a C ₁ -C ₆ hydrocarbyl, or these compounds or a pharmaceutically acceptable salt of aryl are lower hydrocarbyl.

A more preferred group of compounds of Formula II shown in Table I exhibit an IC ₅₀ in virto activity in the assays discussed hereinafter of less than about 1.0-1.5 (<) μM. Compounds of this group include compounds of formula II wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl; R ¹ is a lower hydrocarbyl; R ² is a hydride; R ³ is a hydride or lower hydrocarbyl. And R ⁴ is lower hydrocarbyl, or hydroxyl lower hydrocarbyl], or a pharmaceutically acceptable salt thereof.

The most preferred group of compounds of formula II shown in Table I show an IC ₅₀ in vitro activity of less than (<) 1.0 μM in the assays discussed hereinafter. This group of compounds
Formula II wherein Ar ¹ is a lower hydrocarbyl or an aryl group substituted by a halogen (eg, fluorine or chlorine) group; R ¹ is a hydride or a lower hydrocarbyl; R ² is a hydride R ³ is hydride or lower hydrocarbyl; and R ⁴ is aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, or
3-pyridyl lower hydrocarbyl], or a pharmaceutically acceptable salt thereof.

A second subclass of preferred compounds within Formula I is Formula III:

[0037]

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Where R ⁵ is a hydride, C ₁ -C ₆ hydrocarbyl, or aryl lower hydrocarbyl; Ar ¹ is a halogen (eg, chlorine, fluorine or bromine), lower hydrocarbyl, or hydrocarbyloxy group R ¹ is C ₁ -C ₆ hydrocarbyl; and R ² is hydride] or a pharmaceutically acceptable salt thereof.

[0039] Preferred compounds of formula III are discussed below and in the assays shown in Table I less than 10 (
<) Indicates an IC ₅₀ in vitro activity exceeding (>) 1.0 μM. This group of compounds has the formula I
II wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl group; R ¹ is lower hydrocarbyl; R ² is hydride; and R ⁵ is lower hydrocarbyl or aryl lower hydrocarbyl. Or a pharmaceutically acceptable salt thereof.

A third subclass of preferred compounds in Formula I is Formula IV:

[0041]

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Wherein Ar ¹ is a halogen (eg, chlorine, fluorine or bromine), an aryl group substituted by a lower hydrocarbyl or a hydrocarbyloxy group; R ¹ is a lower hydrocarbyl; and R ² is , Hydride or lower hydrocarbyl] or a pharmaceutically acceptable salt thereof.

Preferred compounds of the formula IV are discussed below, and in the assays shown in Table I less than 10 (
<) Indicates an IC ₅₀ in vitro activity exceeding (>) 1.0 μM. This group of compounds has the formula I
V wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl group; R ¹ is lower hydrocarbyl; and R ² is hydride or a pharmaceutically acceptable compound thereof. It is composed of various salts.

The term “hydride” represents one hydrogen atom (H). This hydrido group may, for example, attached to an oxygen atom can form a hydroxyl group, and the two hydride groups a methylene bonded to the carbon atoms - can form a group (-CH _2).

The term “hydrocarbyl” is used herein as an abbreviation for straight and branched chain aliphatic and cycloaliphatic groups or groups containing only carbon and hydrogen. Thus,
Aromatic hydrocarbons, including alkyl, alkenyl and alkynyl groups, but also strictly hydrocarbyl groups (e.g., phenyl and naphthyl groups) are referred to herein as aryl groups or radicals as described below. I do. When referring to a particular aliphatic hydrocarbyl substituent, the group is listed, ie, alkyl, methyl or dodecenyl. A typical hydrocarbyl group contains a chain of 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms. The most preferred are
Lower hydrocarbyl groups containing 1 to about 6 carbon atoms.

Except for not always following the practice of removing the terminal “yl” and adding a suitable suffix, as the name given may resemble one or more substituents, When the term "hydrocarbyl" is used, it follows normal chemical suffix term nomenclature. Thus, although it may be more appropriate to follow the usual rules of chemical nomenclature, hydrocarbyl ethers are referred to as “hydrocarbyloxy” groups rather than “hydrocarboxy” groups. On the other hand, hydrocarbyl groups containing a -C (O) O-functional group are referred to as hydrocarbyl groups because their suffixes do not obscure. As will be appreciated by those skilled in the art, non-existent substituents, such as C ₁ alkenyl groups, shall not be included in the term “hydrocarbyl”.

[0047] Alone or other terms such as "haloalkyl", "alkylsulfonyl",
As used in "alkoxyalkyl" and "hydroxyalkyl", "thioalkyl", the term "alkyl" refers to from 1 to about 20 carbon atoms, preferably from 1 to about 20 carbon atoms.
Includes linear or branched saturated groups having about 12 carbon atoms. More preferred alkyl groups are groups having 1 to about 12 carbon atoms. Most preferred are lower alkyl groups having 1 to about 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te
rt-butyl, pentyl, iso-amyl, hexyl and the like.

The term “alkenyl” includes linear or branched groups having at least one carbon-carbon double bond of 2 to about 20 carbon atoms, preferably 2 to about 12 carbon atoms. More preferred alkenyl groups are "lower alkenyl" groups having from 2 to about 6 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl” refer to “cis” and “trans” orientations, or “
Include groups with "E" and "Z" orientations.

The term “alkynyl” includes linear or branched groups having at least one carbon-carbon triple bond of 2 to about 20 carbon atoms, preferably 2 to about 12 carbon atoms. More preferred alkynyl groups are "lower alkynyl" groups having from 2 to about 6 carbon atoms. Examples of alkynyl groups include ethenyl (acetylenyl), propynyl, butynyl and 4-methylbutynyl.

[0050] Alkyl groups are particularly preferred hydrocarbyl groups. To make it easier to understand,
In describing the nomenclature used herein for the various substituents, alkyl groups are used below. However, the term "alkyl" is used in place of the lesser known "hydrocarbyl" and it should be understood that such terms include not only alkyl groups but also alkenyl and alkynyl groups.

The term “cycloalkyl” includes saturated carbocyclic groups having 3 to about 12 carbon atoms. More preferred cycloalkyl groups are "lower cycloalkyl" groups having from 3 to about 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkylalkylene” includes an alkyl group substituted with a cycloalkyl group. A more preferred cycloalkylalkylene group is "lower cycloalkylalkylene," which includes a lower alkyl group substituted with a cycloalkyl group as defined above. Examples of such groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term “cycloalkenyl” is a partially unsaturated carbocyclic group having from 3 to 12 carbon atoms and not necessarily conjugated one or two double bonds (cycloalkyldienyl). )including. More preferred cycloalkenyl groups are "lower cycloalkenyl" groups having from 4 to about 8 carbon atoms. Examples of such groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “cycloalkenylalkylene” includes an alkyl group substituted with a cycloalkenyl group. A more preferred cycloalkenylalkylene group is "lower cycloalkenylalkylene", which includes a lower alkyl group substituted with a lower cycloalkenyl group, as defined above. Examples of such groups include cyclobutenylmethyl, cyclopentenylmethyl and cyclohexenylmethyl.

The term “halo” or “halogen” refers to halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" includes groups wherein any one or more alkyl carbon atoms is replaced by halo as defined above. Specifically, monohaloalkyl, dihaloalkyl and polyhaloalkyl groups are included. As an example, a monohaloalkyl group can include any of the iodo, bromo, chloro, or fluoro atoms in the group. Dihalo and polyhaloalkyl groups are
The same halo atom can have more than one or a combination of different halo groups. "
"Lower haloalkyl" includes groups having one to six carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl And dichloropropyl.

The term “hydroxyalkyl” includes linear or branched alkyl groups having from 1 to about 12 carbon atoms, any one of which may be replaced by one or more hydroxyl groups. More preferred hydroxyalkyl groups are "lower hydroxyalkyl" groups having one to six carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The terms “alkoxy” and “alkyloxy” include linear or branched oxy-containing groups having an alkyl portion of 1 to about 12 carbon atoms. More preferred alkoxy groups are "lower alkoxy" groups having one to six carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

The term “alkoxyalkyl” includes alkyl groups having one or more alkoxy groups attached to the alkyl group to form, for example, monoalkoxyalkyl and dialkoxyalkyl groups. An “alkoxy” group further comprises one or more halo atoms,
For example, it can be substituted with fluoro, chloro or bromo to give a "haloalkoxy" group.

The term “aryl”, alone or in combination, refers to a carbocyclic aromatic system containing one, two or three rings, wherein such rings are pendantly linked or fused. can do. More preferred aryl is a 6-12 membered aryl group. Examples of such groups include phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. A phenyl group is a preferred aryl group.

The aryl moiety is, at a substitutable position, alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, araalkoxy, hydroxyl, amino,
It can also be substituted with one or more substituents independently selected from halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and araalkoxycarbonyl.

The term “heterocyclyl” includes groups in the form of rings containing saturated, partially unsaturated, and aromatically unsaturated heteroatoms, each of which is
Also referred to as "heterocyclyl", "heterocycloalkenyl" and "heteroaryl", wherein the heteroatoms are nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl groups are saturated 3-6 containing 1 to 4 nitrogen atoms.
Membered heteromonocyclic groups (e.g., pyrrolidinyl, imidazolidinyl, piperidino,
A saturated 3- to 6-membered heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (e.g., morpholinyl etc.); 1-2 sulfur atoms and 1-2 A saturated 3- to 6-membered heteromonocyclic group containing three nitrogen atoms (for example, thiazolidinyl and the like) can be mentioned. Examples of partially unsaturated heterocyclyl groups include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. As the heterocyclyl group, for example, tetrazolium and pyridinium groups can include tetravalent nitrogen.

The term “heteroaryl” includes aromatically unsaturated heterocyclyl groups. Examples of heteroaryl groups include unsaturated 5- to 4-nitrogen containing atoms.
10-membered heteromonocyclic groups, 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)
, Tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.);
Unsaturated nitrogen-containing heterocyclyl groups containing, for example, indolyl,
Isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (eg, tetrazolo [1,5-b] pyridazinyl) and the like; unsaturated 5- or 6-membered containing oxygen atom Heteromonocyclic groups of, for example, pyranyl or furyl; unsaturated sulfur-containing
5- or 6-membered heteromonocyclic group, for example, thienyl; 1-2 oxygen atoms and 1-
Unsaturated 5- to 6-membered heteromonocyclic groups containing 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl) and the like; unsaturated condensed heterocyclyl group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (eg, benzoxazolyl, benzooxadiazolyl, etc.) Unsaturated, 5- to 6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl) , 1,3,4-thiadiazolyl, and 1,2,5-thiadiazolyl) and the like; unsaturated condensed heterocyclyl groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl Or benzothiadiazolyl) That.

The term “heteroaryl” also includes groups wherein a heterocyclyl group is fused to an aryl group. Examples of such fused bicyclic groups include benzofuran, benzothiophene, and the like.

A heterocyclyl group can contain 1 to 3 substituents, for example, alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
The term "heterocyclylalkylene" includes heterocyclyl-substituted alkyl groups. More preferred heterocyclylalkylene groups are "lower heterocyclylalkylene" groups having 1 to 6 carbon atoms and a heterocyclyl group.

The term “alkylthio” includes groups containing a linear or branched alkyl of 1 to about 12 carbon atoms attached to a divalent sulfur atom. More preferred alkylthio groups are "lower alkylthio" groups having an alkyl group of one to six carbon atoms.
Examples of such lower alkylthio groups include methylthio, ethylthio, propylthio, butylthio and hexylthio.

The term “alkylthioalkylene” includes groups containing an alkylthio group attached through a divalent sulfur atom to an alkyl group of 1 to about 12 carbon atoms. More preferred alkylthioalkylene groups are "lower alkylthioalkylene" groups having an alkyl group of one to six carbon atoms. Examples of such lower alkylthioalkylene groups include methylthiomethyl.

The term “alkylsulfinyl” refers to a group of 1 to about 12 attached to a divalent —S (= O) — group.
Includes groups containing linear or branched alkyl groups of carbon atoms. More preferred alkylsulfinyl groups are "lower alkylsulfinyl" groups having an alkyl group of 1 to 6 carbon atoms. Examples of such lower alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

The term “sulfonyl” used alone or in combination with other terms, for example, “alkylsulfonyl” or “halosulfonyl”, refers to a divalent group, —SO ₂ —. “Alkylsulfonyl” includes an alkyl group linked to a sulfonyl group, where alkyl is as defined above. More preferred alkylsulfonyl groups are 1
"Lower alkylsulfonyl" groups having up to 6 carbon atoms. Examples of such lower alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and propylsulfonyl.

An “alkylsulfonyl” group further comprises one or more halo groups (eg, fluoro,
Chloro or bromo) to give a haloalkylsulfonyl group. The term "halosulfonyl" includes a halo group attached to a sulfonyl group.
Examples of such halosulfonyl groups include chlorosulfonyl and bromosulfonyl.

The terms “sulfamyl,” “aminosulfonyl,” and “sulfonylamidyl” refer to NH ₂ O ₂ S—. Alone or other terms (e.g., "alkoxycarbonyl"
The term "carbonyl" used with) represents-(C = O)-. The term “carboxyl” used alone or in combination with other terms (eg, “carboxyalkyl”) refers to —CO ₂ —. The term "carboxyalkyl" includes an alkyl group substituted with a carboxy group. More preferred are "lower carboxyalkyl" groups, including carboxy-substituted lower alkyl groups as defined above. Examples of such lower carboxyalkyl groups include carboxymethyl, carboxyethyl and carboxypropyl.

The term “alkoxycarbonyl” refers to a group containing an alkoxy group as defined above attached to the carbonyl group via an oxygen atom. More preferred are:
"Lower alkoxycarbonyl" groups having an alkyl moiety having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

The term “alkoxycarbonylalkylene” includes an alkyl group substituted with an alkoxycarbonyl group as defined above. More preferred are "lower alkoxycarbonylalkylene" groups having an alkyl moiety having 1 to 6 carbons. Examples of such lower alkoxycarbonylalkylene groups include methoxycarbonylmethylene, ethoxycarbonylmethylene, methoxycarbonylethylene and ethoxycarbonylethylene.

The term “alkylcarbonyl” includes groups having an alkyl group attached to a carbonyl group. Examples of such groups include methylcarbonyl, ethylcarbonyl,
Propylcarbonyl, butylcarbonyl, and pentylcarbonyl.

The term “aralkyl” includes aryl-substituted alkyl groups. Preferred aralkyl groups are "lower aralkyl" having a lower alkyl group substituted with one or more aryl groups. Examples of such groups include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in such aralkyl groups can be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy moieties. The terms benzyl and phenylmethyl can be used interchangeably.

The term “heterocyclylalkylene” refers to saturated, partially unsaturated, and unsaturated heterocyclyl-substituted alkyl groups such as pyrrolidinylmethyl, pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl , And quinolylethyl. Heteroaryl in heteroaralkyl (unsaturated heterocyclyl-substituted alkyl groups) can be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy groups.

The term “aryloxy” includes aryl groups linked to another group through an oxygen atom. The term "aralkoxy" includes aralkyl groups attached to another group via an oxygen atom.

The term “aminoalkyl” includes an alkyl group substituted with an amino group. More preferred are "lower aminoalkyl" groups. Examples of such groups include aminomethyl, aminoethyl, and the like. The term "alkylamino"
Represents an amino group substituted with one or two alkyl groups. The preferred ones are
"Lower alkylamino" groups having an alkyl moiety having 1 to 6 carbon atoms. Suitable lower alkylamino groups are monosubstituted N-alkylamino or disubstituted N, N-
Alkylamino, for example, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.

The term “arylamino” refers to an amino group substituted by one or two aryl groups, for example, N-phenylamino. An “arylamino” group can be further substituted on the aryl ring portion of the group as described for other aryl-containing groups.

The term “aminocarbonyl” refers to an amide group of the formula: —C (= O) NH ₂ . The term "alkylaminocarbonyl" refers to an aminocarbonyl group substituted on the amino nitrogen atom with one or two alkyl groups. Preferred are the "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" groups. More preferred are "lower N-alkylaminocarbonyl" and "lower N, N-dialkylaminocarbonyl" groups having a lower alkyl moiety as defined above.

The term “alkylcarbonylamino” includes an amino group substituted with one or more alkylcarbonyl groups. More preferred alkylcarbonylamino group is
"Lower alkylcarbonylamino" having a lower alkylcarbonyl group as defined above bonded to an amino group. The term "alkylaminoalkylene" includes groups having one or more alkyl groups attached to an aminoalkyl group.

Tables 1 to 14 below show the substituent Ar¹, R¹, R^Two, R^Three, R^FourAnd R^FiveHydris on one of the
2 shows compounds of formulas II, III and IV showing preferred substituents other than amide. In the compound table
The remaining groups Ar described for each of the structures shown¹, R¹, R^Two, R^Three, R^FourAnd R ^Five Is described elsewhere herein.

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Methods of Treatment The present invention also includes methods of treating TNF-mediated diseases or p38 kinase-mediated diseases such as arthritis. The method comprises administering to a mammalian host with such a condition a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof (a p38 MAP kinase enzyme-effective amount). Mixtures of such compounds can also be used. In particular, it includes repeated multiple administration.

Included in the family of compounds of formula I (and formulas II, III and IV) are the pharmaceutically acceptable salts of these compounds already described. The term "pharmaceutically acceptable salts" includes those salts commonly used to form alkali metal salts or addition salts of free acids or free bases. If the salt is pharmaceutically acceptable, the nature of the salt is not important. Suitable pharmaceutically acceptable acid addition salts of Formula I are
It can be prepared from inorganic or organic acids.

Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid,
There are sulfuric acid and phosphoric acid. Suitable organic acids can be selected from the aliphatic, cycloaliphatic, aromatic, aliphatic aromatic, heterocyclic, carbonic and sulfonic acid types of organic acids. Specific pharmaceutically acceptable salts include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, Aspartic acid, glutamic acid, benzoic acid,
Anthranilic acid, methanesulfonic acid (mesylic), stearic acid, salicylic acid, p-
Hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (embonic) (pamoic), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
It may be selected from pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, algenic acid, hydroxybutyric acid, galactanoic acid and galacturonic acid.

Suitable pharmaceutically acceptable base addition salts of compounds of formula I include metal ionic salts and organic ionic salts. More preferred metal ion salts include, but are not limited to, suitable alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiologically acceptable metal ions. Such salts can be prepared from ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts are, for example, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (meglumine
: N-methylglucamine) and procaine can be prepared from tertiary amines and quaternary ammonium salts. All of the above salts can be prepared in a conventional manner from the corresponding compounds of the formula I, for example by reacting a compound of the formula I with a suitable acid or base.

Preferably, the compounds of the formula I are administered in a pharmaceutical composition. Such compositions will contain a therapeutically effective amount of a compound of Formula I together with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

Thus, one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as “carriers”);
Also included in the invention are types of pharmaceutical compositions that include a compound of Formula I as an active ingredient (drug or compound), optionally with other active ingredients.

The active compounds of the present invention can be administered in any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the desired treatment.
The active compounds and compositions can be administered, for example, orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (I
M) or topical application.

[0103] For oral administration, the pharmaceutical composition can be in the form of, for example, a tablet, hard or soft capsule, lozenge, dispensable powder, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.

The active ingredient can also be administered by injection (IV, IM, subcutaneous or jet) as a composition in which saline, dextrose or water can be used as a suitable carrier. The pH of the composition can be adjusted, if necessary, with a suitable acid, base or buffer. Suitable fillers, dispersants, wetting agents or suspending agents, such as mannitol and PSG400, can also be incorporated into the compositions. Suitable parenteral compositions can also include the compound formulated as a sterile solid material containing the lyophilized powder in an injection vial. Aqueous solutions can be added prior to injection to dissolve the compound.

The amount and dosage regimen of therapeutically active compound administered to treat a condition with the compounds and / or compositions of the present invention will depend on the age, weight, sex and condition of the patient, infection or infection-related disease. It may vary over a wide range depending on various factors, including the severity of the compound, the route and frequency of administration, and the particular compound used.

The pharmaceutical compositions may contain about 0.1-1000 mg, preferably about 7.0-350 mg, of the active compound. About 0.01 to 100 mg / kg of body weight, preferably about 0.1 to about 50 mg / kg of body weight,
Most preferably, a daily dose of about 0.5-30 mg / kg of body weight is suitable. The daily dose can be administered one to four times per day.

In the case of skin conditions, it is preferable to apply a topical formulation of a compound of the present invention to the affected area 2 to 4 times daily. In the case of diseases of the eye or other external tissues, for example mouth and skin, the formulation may be, for example, 0.075-30% w / w, preferably 0.2-20% w / w, most preferably 0.4
It is preferably applied as a topical gel, spray, ointment or cream, or suppository, containing the active ingredient in a total amount of 1515% w / w.

When formulated in an ointment, the active ingredient of the present invention may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. Optionally, the cream-based aqueous phase comprises, for example, at least 30% w / w of polyhydric alcohols (
For example, propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof).

Topical formulations may preferably include a compound that facilitates absorption or penetration of the active ingredient into the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and the like.

The compounds of the present invention can also be administered by transdermal means. It is preferred to administer topically using reservoirs and patches of either porous membrane type or solid matrix type. In each case, the active agent is continuously delivered through a membrane from a reservoir or microcapsule to an active ingredient permeable adhesive that contacts the skin or mucous membranes of the recipient. As the active agent is absorbed into the skin, a controlled, predetermined flow rate of the active ingredient is administered to the recipient. In the case of microcapsules, the encapsulated drug can also function as a membrane. Transdermal patches can include the compound in a suitable solvent system, along with an adhesive system, for example, an acrylic emulsion and a polyester patch.

[0111] The oil phase of the emulsions of the present invention can be constructed from known components by known methods. The phase merely contains an emulsifier, but at least one emulsifier,
(fat) or oil, or a mixture of both fats and oils.
The hydrophilic emulsifier is preferably formulated together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to include both oils and fats. The emulsifier (s) optionally comprising a stabilizer (s) creates a so-called emulsified wax, the wax together with the oils and fats, the oily dispersed phase of the cream formulation. A so-called emulsified ointment base is formed. Suitable emulsifiers and stabilizers for use in the formulations of the present invention include, among others, Tween® 60, Span® 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and lauryl sulfate. Sodium.

Since the solubility of the active compound in most oils to be used in pharmaceutical emulsion formulations is very low, the choice of suitable oils or fats for the formulation is based on obtaining the desired aesthetics. And Thus, the cream should preferably be non-greasy, non-staining and washable product with suitable consistency to prevent leakage from tubes or other containers. Straight or branched chain, monobasic or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate Rate, 2-ethylhexyl palmitate or a blend of branched esters can be used. These can be used alone or in combination depending on the properties desired. Alternatively, high melting lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical application to the eye may also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The anti-inflammatory active ingredient is preferably present in such a formulation in an amount of 0.5-20% w / w, advantageously 0.5-10% w / w.
/ w, especially at a concentration of about 1.5% w / w.

For therapeutic use, the active compounds of the invention in this combination are usually mixed with one or more adjuvants suitable for the indicated route of administration. When administered orally, the compound:
Lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia gum, sodium alginate , Polyvinylpyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be made into a dispersion of the active compound in hydroxypropylmethyl cellulose.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or particles of one or more of the carriers or diluents described for use in formulations for oral administration. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. Other adjuvants and dosage forms are known in the pharmaceutical art. Preparation of Useful Compounds The following Schemes I-IX are compounds useful in the present invention; that is, compounds of Formula I wherein R ¹ and R ² , substituents and Ar ¹ are as defined in Formula I unless otherwise stated. Chemical processes and transformations useful in the preparation of the compounds are described.

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Scheme I describes a 1,5-diarylpyrazole (5) wherein the pyridine ring is attached to the 5-position of the pyrazole ring, R ¹ is lower alkyl, and R ² is hydride or lower alkyl. Shows the synthesis of The synthesis is carried out by condensing a suitable ketone (2) with methyl isonicotinate (1) in the presence of a suitable base to give diketone 3. Examples of suitable ketones include acetone, methyl ethyl ketone, diethyl ketone, and the like. Examples of suitable bases include sodium methoxide, sodium ethoxide, and the like. Suitable solvents for this reaction include tetrahydrofuran (THF) or methanol (MeOH) at a temperature from room temperature to reflux.
Treatment of the diketone 3 with the arylhydrazine derivative 4 in a suitable solvent at a temperature ranging up to reflux gives the 1,5-diarylpyrazole, compound 5. Examples of suitable solvents for this reaction include ethanol, acetic acid, ethanol-acetic acid mixtures and the like. Substitution at the 5-position of Ar ₁ is controlled by appropriate choice of the starting hydrazine 4. When R ^{2 of} ketone 2 is hydride, R ² of pyrazole 5 is hydride.

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Scheme II illustrates the synthesis of a pyrazole, compound 8, where R ² is a lower alkyl group and R ¹ is hydride or lower alkyl. The compound [wherein R ¹ is a hydride and R ² is a lower alkyl group] can be synthesized by treating pyridyl ketone 6 with dimethylformamide dimethyl acetal (DMF acetal). Examples of suitable pyridyl ketones 6 include propionyl pyridine and butanoyl pyridine. This reaction can be carried out in DMF acetal itself or in a suitable solvent (eg, dimethylformamide). This gives enamine 7 which is converted to pyridylpyrazole 8 by reaction with a suitably substituted phenylhydrazine. This step is performed as described in Scheme I, and the substitution of pyrazole 8 on Ar ₁ is controlled by selecting a suitably substituted hydrazine. Scheme II also describes the synthesis of pyrazoles, where R ¹ and R ² are both lower alkyl groups. This involves reacting ketone 6 with a carboxylic acid ester (such as methyl acetate or methyl propionate) in a suitable solvent (such as methanol or tetrahydrofuran) in the presence of a base (such as sodium methoxide). Obtained by The resulting diketone 7a is converted to pyrazole 8 (R ¹ and R ² are lower alkyl groups) using the above method.

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Scheme III describes a pyrazole in which the pyridine ring carries a chlorine atom in the 2-position, compound 1
3, shows the synthesis of analogs of compound 5. 2-chloropyridine-4-carboxylic acid, compound 9
Is treated with thionyl chloride in a solvent (e.g., toluene) and heated to reflux to give 2-chloropyridine-4-carboxylic acid chloride, compound 10, which is then treated with methyl 2
-Convert to chloroisonicotinate, compound 11. Compound 11 in a solvent (e.g., tetrahydrofuran) in the presence of a base (e.g., sodium methoxide) at 25C
Treatment with ketone 2 at a temperature below reflux gives diketone, compound 12. Treatment of the diketone, compound 12, with the aryl hydrazine derivative 4, in ethanol or other suitable solvent at a temperature below reflux, gives the pyrazole compound 13. When R ^{2 of} ketone 2 is a hydride, R ² of 13 is a hydride.

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Scheme IV illustrates the synthesis of various pyrazole derivatives from compound 13 by operating on the 2-chloropyridine ring. The chlorine atom is a labile group and is substituted with various nucleophiles to provide a 2-substituted pyridine derivative. Compound 13 is usually used in an amount of about 100 to about 200.
Treatment with amine 14 at a temperature of 0 ° C. and a pressure of about 70 to about 200 (or more) psi in xylene,
Pyrazole 15 forms. Examples of substituents for R ³ of amine 14 include hydrogen, lower alkyl, hydroxyalkyl, or aralkyl.

When R ³ is benzyl, the benzyl group is removed by hydrogenation of the compound to form amino compound 16. When the benzyl group carries a paramethoxy substituent, another method of removing the benzyl group is treatment with refluxing trifluoroacetic acid.

Treatment of compound 13 with alcohol 17 in a suitable solvent in the presence of a base gives pyrazole compound 18. Examples of suitable alcohols include benzyl alcohol and methanol. Suitable bases include triethylamine and pyridine.

Compound 13 can also be treated with a sodium sulfite derivative, compound 19, at an elevated temperature in a suitable solvent (eg, dimethylformamide: DMF) to give pyrazole compound 20. An example of a sodium sulfite is sodium methane sulfite, which is converted to methyl sulfone.

Ultimately, treatment of compound 13 with sodium azide in a suitable solvent (eg, DMF) gives azidopyridine 21.

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Scheme V illustrates the preparation of pyrazole compounds 31 and 32 bearing hydroxy and methoxy substituents at the 2-position of the pyridine ring. Methyl 2-chloroisonicotinate, ketone with methyl 2-methoxyisonicotinate compound 29 derived from compound 28,
Treatment with compound 2 gives compound 30, diketone. Treatment of compound 30 with an arylhydrazine derivative under standard conditions described in the previous synthetic scheme gives pyrazole 31. When compound 31 is treated with an acid (eg, hydrochloric acid), the pyridine ring 2
Pyrazole 32 carrying a hydroxyl at the position is obtained. When R ^{2 of} ketone 2 is hydrogen (hydride), R ² of pyrazoles 31 and 32 is hydrogen (hydride).

[0130]

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Scheme VI illustrates the synthesis of pyrazole compounds 37 and 38 bearing cyano and carboxamide substituents at position 2 of the pyridine ring, respectively. Methyl 2-cyanoisonicotinate 35 is synthesized from methylisonicotinate 33 in two steps by oxidation with hydrogen peroxide in an acid solvent (eg, acetic acid). Treatment of the resulting pyridine N-oxide 34 with dimethylcarbamoyl chloride in the presence of trimethylsilyl cyanide gives the ester 35. Treatment of ester 35 with ketone 2 according to the general conditions described for similar reactions in the previous scheme gives diketone 36. Treatment of 36 with a substituted aryl hydrazine produces pyrazole 37. The desired substitution on Ar ₁ is performed by selecting an appropriately substituted aryl hydrazine.

The cyanopyrazole 37 is converted to the carboxamide compound 38 by oxidation with hydrogen peroxide in the presence of a base. Suitable bases include sodium carbonate, potassium carbonate and sodium hydroxide. By selecting the appropriate ketone 2, to operate the substituent R ^2. When R ² of compound 2 is hydrogen, R ² pyrazole 37 and 38 are hydrogen (hydrido).

[0133]

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Scheme VII illustrates a two-step synthesis of 3-amino-1,5-diarylpyrazoles 40. In the first stage, treatment of 4-acetylpyridine (A, R ² = H) with a suitable base produces the enolate anion. Examples of suitable bases include lithium hexamethyldisilazide, sodium hexamethyldisilazide and lithium diisopropylamide. Suitable solvents for this reaction include tetrahydrofuran and diethyl ether. Treatment of the resulting intermediate enolate anion with a suitable isothiocyanate gives beta-ketothioamide 39.
Examples of suitable isothiocyanates include ethyl isothiocyanate and trimethylsilyl isothiocyanate. The reaction of thioamide 39 with arylhydrazine 4 forms pyrazole 40. This reaction is performed using the conditions described in the previous example. Substituents on Ar ₁ are controlled by appropriate choice of substituted phenylhydrazine.

When an alkyl isothiocyanate is used in this sequence, R in compound 40 is an alkyl group. When using trimethylsilyl isothiocyanate,
R in 40 is a trimethylsilyl group, which can be easily removed to produce a primary amino compound in which R in compound 40 is hydrogen. Examples of reaction conditions used to remove silyl groups are acetic acid or aqueous sodium bisulfate in water and tetrahydrofuran. If R ² of the starting ketone is a substituent other than H, the substituent will be a substituent R ² at the 4-position of pyrazole 40.

[0136]

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Scheme VIII illustrates the synthesis of 1,5-diarylpyrazoles, where R ² is a derivatized carboxyl or amino group. Treatment of the ester of isonicotinic acid with a carboxylic ester in the presence of a base gives the beta ketoester 41. Suitable esters of isonicotinic acid include methyl and ethyl esters and the like. Suitable esters of carboxylic acids also include methyl and ethyl esters. Bases such as sodium methoxide and sodium ethoxide are suitable for this reaction. The reaction can be performed in an alcoholic solvent (eg, methanol or ethanol). The ketoester 41 is used neat or in a solvent (
For example, conversion to enamine intermediate 42 by reaction with dimethylformamide dimethyl acetal in dimethylformamide). Reaction with an appropriately substituted aryl hydrazine 4 gives the carboxylic acid ester 43. Reaction of this ester with various amines (eg, piperazine) gives amide 44 (R = substituted amine).

Similarly, saponification of 43 produces acid B. Saponification can be performed using a base (eg, sodium hydroxide) in an aqueous solvent (eg, aqueous methanol or ethanol, etc.). Acid B is converted to amine C by reaction with diphenylphosphoryl azide (DPPA) in a solvent (eg, tetrahydrofuran or dioxane) in the presence of a base (eg, triethylamine).

[0139]

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Scheme IX illustrates the synthesis of 4-amino-1,5-diarylpyrazole, compound 48. In step 1, bromination of 4-acetylpyridine with bromine in the presence of a solvent (eg, 48 percent hydrobromic acid) provides the bromoketone, compound 45. In Step 2, the reaction of compound 45 with an amine (eg, N-tert-butoxycarbonylpiperazine) in the presence of a solvent (eg, DMF) and a base (eg, triethylamine) gives intermediate compound 46. It is. Other suitable amines include piperidine and dimethylamine. In step 3, the reaction of intermediate compound 46 with dimethylformamide dimethyl acetal (DMF-DMA) in a solvent (eg, tetrahydrofuran or dimethylformamide) gives intermediate enamine 47. In step 4, the desired pyrazole, compound 48, is obtained by condensation of intermediate compound 47 with a substituted aryl hydrazine (eg, 4-fluorophenylhydrazine) in a solvent (eg, ethanol).

In the above scheme, when using a suitably substituted pyrimidine starting material,
It will be appreciated that the pyridine ring can be replaced by a pyrimidine ring. Suitable starting materials are recognizable to those skilled in the art, and their synthesis is readily available in the scientific literature. For example, the ethyl ester of pyrimidine-4-carboxylic acid can be synthesized according to the method described in Wong et al., J. Org. Chem., Vol. 30, page 2398 (1965). The methyl ester of 2-methoxypyrimidine-4-carboxylic acid is described by Warczzykowski and Wojciechowski, Pol. J. Chem., 54, 335-340 (1980). 2-Diethylaminopyrimidine from 2-chloropyrimidine-4-carbonitrile
The synthesis of 4-carboxylic acids is also described in such articles. 2-chloropyrimidine-4
Synthesis of 2-aminopyrimidine-4-carboxylic acid from -carbonitrile is described by Daves et al., J.
Het. Chem., Vol. 1, p. 130 (1964). The synthesis of 2-chloropyrimidine-4-carbonitrile is described in DJ Brown et al., Aust. J. Chem., 37, 155-163 (1984).
And AEFriesen et al., Tetrahedron, 45, 5151-5162 (1989). Conversion of 2-methylpyrimidine-4-carboxylic acid methyl ester to 1,3-diketone by enolate anion of acetophenone is described by T. Sakamoto, Chem. Pharm. Bull.
30, pp. 1033-1035 (1982). Without best mode for carrying out the invention More specifically, to those skilled in the art using the above description, it may be possible to fully utilize the present invention. Accordingly, the following preferred specific embodiments are merely exemplary and should not be construed as limiting the remainder of the disclosure.

[0142]

【Example】

 Example 1

[0143]

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Step 1: Preparation of 1- (4-pyridinyl) -2-methyl-1,3-propanedione 4-Propionylpyridine (5 g, 36.99 mmol) and dimethylformamide dimethyl acetal (10 mL, 75.28 mmol) Heated to reflux overnight. After cooling to room temperature,
Removal of the in-situ generated methanol under reduced pressure gave a brown solid. The crude product was purified by column chromatography (silica gel, 3: 7 EtOAc / hexane) to give the title compound (5.73 g, 81%) as a brown oil. Step 2: 1- (4-pyridinyl) -2-methyl-1,3-propanedione (0.5 g, 2.63 mmol), 4-fluorophenylhydrazine.HCl (0.514 g, 3.16 mmol), and 15 M ammonium hydroxide
A mixture of (0.211 mL, 3.16 mmol) in ethanol (7 mL) was heated to reflux overnight.
The resulting dark solution was cooled to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. After filtration, the solution was concentrated to a yellow oil. This oil was subjected to column chromatography (silica gel, 3: 7
Purification by EtOAc / hexane) provided the title compound as a pale yellow solid (0.368 g, 58%). MP: 135.86 ° C .; Elemental analysis of C ₁₅ H ₁₂ N ₃ F · 0.1H ₂ O: Calculated: C, 70.63, H,
4.82, N, 16.47; Found: C, 70.45, H, 4.51, N, 16.42. Example 2:

[0145]

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Preparation of The title product was obtained according to the method of Example 1 by substituting 3-fluorophenylhydrazine.HCl for Step 2 of 4-fluorophenylhydrazine.HCl. MP: 131.11 ° C .; Elemental analysis of C ₁₅ H ₁₂ N ₃ F · 0.1H ₂ O: Calculated: C, 70.63, H
, 4.82, N, 16.47; Found: C, 70.64, H, 4.97, N, 16.09. Example 3

[0147]

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Preparation of The following product was obtained according to the method of Example 1 by substituting 3-methylphenylhydrazine.HCl for 4-fluorophenylhydrazine.HCl in Step 2: MP: 141.77 ° C .; Elemental analysis of C ₁₆ H ₁₅ N ₃ .0.05 H ₂ O: Calculated: C, 76.80, H,
6.08, N, 16.79; Found: C, 76.84, H, 6.27, N, 16.43. Example 4:

[0149]

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Preparation of The title product was obtained according to the method of Example 1 by substituting benzylhydrazine.HCl for 4-fluorophenylhydrazine.HCl in Step 2. Elemental analysis of C ₁₆ H ₁₅ N _3: Calculated: C, 77.08, H, 6.06 , N, 16.85; Found: C, 77.
03, H, 6.18, N, 16.72. Example 5:

[0151]

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Preparation of 2-Chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine (Example 41: 0.5 g, 2.53 mmol) and ethanolamine (15 mL) , 248.52 mmol) overnight
Heated to 105 ° C. (about 18 hours). The resulting solution was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The resulting yellow oil crystallized on standing. The crystals were washed with diethyl ether to give the title compound (0.475 g, 61%) as yellow-white crystals. _{MP: 148.20 ℃; C 18 H} 2 0 N 4 O Elemental analysis: Calculated: C, 70.11, H, 6.54 , N, 18.17; Found: C, 69.7
5, H, 6.71, N, 17.84. Example 6:

[0153]

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Preparation of 2-Chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine (Example 41; 0.5 g, 2.53 mmol) and 3- (amino Ethyl) pyridine (15mL, 147.3mmol
) Was heated to 180 ° C. overnight (about 18 hours). The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography of the obtained yellow oil (silica gel, EtOAc)
The title compound (0.378 g, 42%) was obtained as a yellowish white solid. MP: 108.94
° C.; Elemental analysis for C ₂₂ H ₂₁ N _5: Calculated: C, 73.97, H, 5.98 , N, 19.60; Found:
C, 73.86, H, 6.25, N, 19.39. Example 7:

[0155]

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Preparation of The title compound was obtained according to the method of Example 5 by substituting benzylamine for ethanolamine and changing the reaction temperature from 105 ° C. to 160 ° C. MP
_{: 102.10 ℃; C 23 H 22} N 4 Elemental analysis: Calculated: C, 77.94, H, 6.26 , N, 15.81;
Found: C, 77.82, H, 6.60, N, 15.69. Example 8:

[0157]

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Preparation of 2-Chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine (Example 41; 0.45 g, 2.3 mmol) and excess aqueous ethylamine (15 mL) in xylene at <200 psi to 160 ° C. overnight (about 18 hours). The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained yellow oil was purified by column chromatography [silica gel, ethyl acetate (EtOAc)] to give a white solid (0.372 g, 50%). M
P: 97.15 ° C .; Elemental analysis of C ₁₈ H ₂₀ N ₄ : Calculated: C, 73.94, H, 6.89, N, 19.16;
Found: C, 73.70, H, 6.83, N, 18.98. Example 9:

[0159]

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Preparation of 2-chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine (Example 41; 0.5 g, 2.53 mmol) and excess aqueous methyl The mixture with the amine (15 mL) was heated in xylene at <200 psi to 170 ° C. overnight (about 18 hours). The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained yellow oil was purified by column chromatography [silica gel, 3: 7 EtOAc / hexane] to give the title compound (0.218 g, 31%
)was gotten. MP: 126.34 ° C .; Elemental analysis of C ₁₇ H ₁₈ N ₄ : Calculated: C, 73.06, H, 6.
56, N, 19.81; Found: C, 73.06, H, 6.28, N, 19.43. Example 10:

[0161]

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Preparation of 2-Chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine (Example 41; 0.5 g, 2.53 mmol) and excess aqueous dimethyl The mixture with the amine (15 mL) was heated in xylene at 60-80 psi to 170 ° C. overnight (about 18 hours). The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography [silica gel, 3: 7 EtOAc / hexane] to give the title compound as a colorless oil (0.126 g, 1
7%). Elemental analysis of C ₁₈ H ₂₀ N _4: Calculated: C, 73.94, H, 6.89 , N, 19.1
6; Found: C, 74.04, H, 7.10, N, 19.03. Example 11:

[0163]

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Step 1: Preparation of 2-chloro-4- [1- (4-chlorophenyl) -3-methyl-1H-pyrazol-5-yl]
Preparation of pyridine 1- (2-chloro-4-pyridinyl) -1,3-butanedione (from Example 29, step 2) (2.5 g
, 12.69 mmol), a mixture of p-chlorophenylhydrazine.HCl (2.7 g, 15.11 mmol) and triethylamine (2.1 mL, 15.11 mmol) in ethanol (50 mL) overnight (about 18 hours)
Heated to reflux. The resulting dark solution was cooled to room temperature and extracted with ethyl acetate.
Wash the organic layer with saturated sodium bicarbonate and brine, dry over magnesium sulfate,
Filter and concentrate to an orange colored solid 2-chloro-4- [1- (4-chlorophenyl)
3-Methyl-1H-pyrazol-5-yl] pyridine (1.5 g, 39%) was obtained. MP: 110.05
° C. This product was used in the next step without further purification. Step 2: A mixture of 2-chloro-4- [1- (4-chlorophenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (0.6 g, 1.64 mmol) and ethanolamine (15 mL, 248.52 mmol) One night(
Heated to 105 ° C. (about 18 hours). The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained yellow oil was purified by column chromatography (silica gel, EtOAc) to give the title compound (0.253 g, 47%) as a white solid. _{MP: 137.57 ℃; C 17 H} 17 N 4 OCl Elemental analysis:
Calculated value: C, 62.10, H, 5.21, N, 17.04; Actual value: C, 62.09, H, 5.24, N
, 16.70. Example 12:

[0165]

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Preparation of The title compound was obtained according to Example 11 by substituting benzylamine for ethanolamine. MP: 105.53 ° C .; Elemental analysis of C ₂₂ H ₁₉ N ₄ Cl: Calculated: C, 69.95, H, 5.25, N, 14.44; Found: C, 70.24, H, 5.07, N, 14.19
. Example 13:

[0167]

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Preparation of A mixture of the compound from Step 1 of Example 11 (1 g, 3.29 mmol) and excess phenylethylamine (15 mL) was heated in xylene to 200 ° C. overnight (about 18 hours). The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, 1: 9 EtOAc / hexane) to give the title compound as a brown oil (0.5%).
(37 g, 42%). C ₂₃ H ₂₁ N ₄ Cl elemental analysis: Calculated: C, 71.03, H, 5.44 ,
N, 14.41; Found: C, 70.91, H, 5.43, N, 14.18. Example 14:

[0169]

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Step 1: Preparation of 1- (3-aminophenyl) -1,3-butanedione To a solution of methyl 3-aminobenzoate (7 g, 46.36 mmol) in THF (150 mL) was added acetone (7.5 g, 102 mmol) was added. The solution was warmed to 35 ° C., to which sodium methoxide (3 g, 55.63 mmol) was added continuously over 20 minutes. The mixture is stirred for 30 minutes,
Then refluxed for 3 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate. The resulting solution is washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1- (3-aminophenyl) as a brown oil.
-1,3-butanedione (3.1 g, 37%) was obtained. This oil was used in the next step without further purification. Step 2: 1- (3-aminophenyl) -1,3-butanedione (step 1) (0.5 g) in ethanol (7 mL)
, 2.82 mmol), p-tolylhydrazine HCl (0.533 g, 3.36 mmol) and triethylamine
(0.340 mL, 3.68 mmol) was heated to reflux overnight (about 18 hours). The resulting dark solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated to give a brown oil. The oil was purified by column chromatography (silica gel, 1: 1 EtOAc / hexane) to give the title compound (0.527 g, 65%) as a yellow solid. _{MP: 94.38 ℃; C 1 7} H 17 N 3 Elemental analysis: Calculated: C, 77.57, H, 6.46 , N, 15.97; Found: C, 77
.14, H, 6.56, N, 15.77. Example 15:

[0171]

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Preparation Step 1: Compound 1: A solution of LiHMDS (62.5 mL, 1.0 M in THF) was added at 0 ° C. to 4-acetylpyridine (6
.06 g, 0.05 mol) was added, and DMF (20 mL) was also added to dissolve the anion. To this mixture was added a solution of ethyl isothiocyanate (5.49 g, 0.0625 mol) in 30 mL of dry THF.
It was added dropwise in .5 hours. While warming to room temperature, the reaction mixture was stirred at room temperature (about 18 hours). After addition of 500 mL of a saturated NH ₄ Cl solution, the aqueous phase was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate / hexane, 3: 1).
2.3 g (24% yield) of the product was obtained as a yellow solid. MP: 130-132 ° C. Step 2: A mixture of compound 1 (0.4 g, 0.002 mol), 4-fluorophenylhydrazine hydrochloride (0.32 g, 0.002 mol) and triethylamine (0.20 g, 0.002 mol) in 10 mL of ethanol was heated under reflux for 24 hours. . After removal of the solvent, the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 8: 2) to give the title product as a yellow solid.
0.31 g (55% yield) was obtained. MP: 130-131 ° C; elemental analysis of C ₁₆ H ₁₅ FN ₄ , 0.25 H ₂ O:
Calculated value: C, 67.00, H, 5.95, N, 19.53; Actual value: C, 66.98, H, 5.13, N
, 19.07. Example 16: Preparation of 1- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole-4-carboxamide

[0173]

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Methyl 1- (4-fluorophenyl) -5- (in 10 mL of methanol in a sealed tube
A solution of 4-pyridinyl) -1H-pyrazole-4-carboxylate (0.90 g, 0.003 mol) was treated with excess liquid ammonia at low temperature. The reaction mixture was then heated at 80 C for 48 hours. The solvent was removed and the residue was triturated with ethyl acetate to afford the product as a yellow solid.
13 g (15% yield) were obtained. _{MP: 215~216 ℃; C 15 H} 11 FN 4 O Elemental analysis: Calculated: C,
, 63.38, H, 3.93, N, 19.85; found: C, 63.21, H, 3.98, N, 19.37. Example 17:

[0175]

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Preparation Step 1: Compound 3: To a solution of the carboxylic acid of Example 43 (0.16 g, 0.00056 mol) in DMF was added 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.12 g, 0.00062mo
l), followed by N-tert-butoxycarbonylpiperazine (0.10 g, 0.0056 mol)
Was added. The reaction mixture was stirred at room temperature for 16 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was recrystallized from ethyl acetate and hexane to give 0.14 g (55% yield) of the product as a pale yellow solid. _{MP: 223-234 ℃; C 24 H} 26 FN 5 O 3 Elemental analysis: Calculated: C, 63.85, H, 5.80 , N, 15.51; Found: C, 63.57, H, 6.1
2, N, 15.42. Step 2: To a solution of compound 3 (0.13 g, 0.00029 mol) in 5 mL of methylene chloride was added 2 mL of trifluoroacetic acid. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was basified with ammonium hydroxide. The aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by recrystallization from ethyl acetate and ether to give 0.07 g (64% yield) of the product as a pale yellow solid. _{MP: 184-186 ℃; C 19 H} 18 FN 5 O Elemental analysis: Calculated: C, 64.95, H, 5.16 , N, 19.93; Found: C, 64.50, H, 5.02 , N, 19.86
. Example 18:

[0177]

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Preparation Step 1: Compound 4: To a solution of 4-acetylpyridine (18.2 g, 0.15 mol) in 30 mL of 48% HBr,
A solution of Br ₂ (24.0 g, 0.15 mol) in 5 mL of 48% HBr was added dropwise at 70 ° C. After stirring at the same temperature for 3 hours, the suspension was cooled and filtered. The solid was washed with a mixture of methanol and petroleum ether to give 28.9 g (69% yield) of the product as a pale yellow solid.
mp: 210 ° C (decomposition). Step 2: Compound 5: Triethylamine (7.5 mL, 0.54 mol) was added to Compound 4 (7.8 g, 0.027 mol).
And N-tert-butoxycarbonylpiperazine (5.0 g, 0.027 mol) in DMF at room temperature. After heating at 80 ° C. for 16 hours, the reaction mixture was cooled and treated with water.
The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. Concentrate the filtrate and purify the crude product by chromatography on silica gel (ethyl acetate) to give the product as a yellow oil.
2.2 g (27% yield) were obtained. Step 3: To a solution of compound 5 (2.0 g, 0.065 mol) in THF was added N, N-dimethylformamide dimethyl acetal (7.8 g, 0.065 mol). After stirring at room temperature for 24 hours, the solvent was removed in vacuo to give 2.5 g of crude product as a dark brown oil. This crude product was dissolved in 50 mL of ethanol, treated with 4-fluorophenylhydrazine, and the mixture was heated under reflux overnight (about 18 hours). After removing the solvent, the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product (0.7 g) was dissolved in methylene chloride (5 mL) and TFA (2 mL)
Processed. After stirring at room temperature for 16 hours, the mixture was concentrated.

The concentrated residue was basified with 1N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and purified by chromatography on silica gel (methylene chloride / methanol, 9: 1) to give 0.25 g of the title compound as a yellow solid. _{MP: 150-151 ℃; C 18 H} 18 FN 5 · 2.0H 2 O Elemental analysis: Calculated: C, 60.15, H, 6.17 , N, 19.49; Found: C, 60.37, H, 5.74 ,
N, 19.98. Example 19: Preparation of 2- (benzylamino) -4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0180]

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A solution of 2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 45: 1.24 g, 0.0044 mol) and benzylamine (40 mL) Mix the mixture at 180 ° C for 2
Heated for 0 hours. Excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (ethyl acetate / hexane, 3: 7) to give 1.33 g (85% yield) of the title compound as a clear oil. When this was left, it solidified. _{MP: 73-75 ℃; C 23 H} 22 N 4 · 0.2H 2 O Elemental analysis: Calculated: C, 76.83, H, 6.39 , N, 15.06; Found: C, 76.88, H, 6.37
, N, 14.92. Example 20: Preparation of 2- (benzylamino) -4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0182]

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A solution of 2-chloro-4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 47: 1.11 g, 0.0039 mol) and benzylamine (30 mL) Mix overnight
Heated to 180 ° C. (about 18 hours). Excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (ethyl acetate / hexane, 2: 8) to give 1.24 g of the title compound as a clear oil (90%
Yield) was obtained. When this was left, it solidified. _{MP: 94-96 ℃; C 22 H} 19 FN 4 Elemental analysis: Calculated: C, 73.72, H, 5.34 , N, 15.63; Found: C, 73.62, H, 5.6
2, N, 15.34. Example 21: Preparation of 2-amino-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0184]

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2-Benzylamino-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine in acetic acid (Example 19: 1.03 g, 0.0029 mol) and hydroxylation Palladium (0.2
The mixture of g) was hydrogenated at 40 ° C. and 60 psi for 9 hours. The mixture was cooled and Celite (trademark)
) Filtered through the bed. The filtrate was concentrated and purified by silica gel chromatography (ethyl acetate / hexane, 1: 1) to give 0.43 g of the product as a white solid. MP: 12
_{4-125 ℃; C 16 H 16 N} 4 Elemental analysis: Calculated: C, 72.70, H, 6.10 , N, 21.20; Found: C, 72.41, H, 6.31 , N, 20.63. Example 22: 2-methoxy-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazole-5-
Production of [Il] pyridine

[0186]

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Step 1: Preparation of methyl 2-methoxyisonicotinate A mixture of methyl 2-chloroisonicotinate (5.23 g, 0.030 mol) and sodium methoxide (2.47 g, 0.045 mol) in 15 mL of dioxane is refluxed. Heated for 1.5 hours.
After cooling the reaction mixture, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give 3.76 g (75%) of the product as a yellow oil. Elemental analysis of C ₈ H ₉ NO _3: Calculated: C, 57.48, H, 5.43 , N, 8.38; Found: C, 57.07, H, 5.54 , N
, 8.34. Step 2: Preparation of 1- (2-methoxypyridyl) -1,3-butadione To a solution of methyl 2-methoxyisonicotinate (3.67 g, 0.022 mol) and acetone (4.85 mL, 0.066 mol) in 30 mL of THF was added sodium A solution of methoxide (1.25 g, 0.023 mol) was added in one portion. The reaction mixture was refluxed for 4 hours and then cooled to room temperature. Water was added and the solution was acidified with acetic acid to pH = 6. Extract the aqueous phase with ethyl acetate,
The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give 2.79 g (72%) of the product as a brown solid. It was used without further purification. Step 3: Preparation of 2-methoxy-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl ] pyridine: 1- (2-methoxypyridyl) -1, in 100 mL of ethanol. 3-butadione (2.7g, 0.014mo
Triethylamine (2.34 mL, 0.017 mol) was added dropwise to a suspension of l) and 3-methylphenylhydrazine hydrochloride (2.66 g, 0.017 mol). The reaction mixture was heated under reflux overnight (about 18 hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 2: 8) to give 2.8 g (72%) of the product as a yellow oil. C ₁₇ H ₁₇ N ₃ O Elemental analysis: Calculated: C,
, 73.10, H, 6.13, N, 15.04; Found: C, 72.81, H, 6.11, N, 14.68. Example 23: Preparation of 4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridone

[0188]

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2-Methoxy-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazole-5 in 5 mL of acetic acid
To a solution of [-yl] pyridine (Example 22; 0.56 g, 0.002 mol) was added 5 mL of hydrobromic acid. The reaction mixture was heated under reflux for 3 hours and cooled to room temperature. Water was added and the solution was basified with ammonium hydroxide. The aqueous phase was extracted with ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate is concentrated under vacuum,
0.45 g (85%) of the product was obtained as a white solid. MP: 182-183 ° C .; Elemental analysis of C ₁₆ H ₁₅ N ₃ O: Calculated: C, 72.43, H, 5.70, N, 15.84; Found: C, 72.37, H, 5.66,
N, 15.97. Example 24: 2- (phenylethylamino) -4- [1- (3-methylphenyl) -3-methyl-1H
Of [-Pyrazol-5-yl] pyridine

[0190]

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Mixture of 2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 45; 0.5 g, 0.0018 mol) and phenethylamine (15 mL) 200 ° C
For 24 hours. Excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered.
The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 1: 1) to give 0.48 g (74% yield) of the product as a yellow oil. When this was left, it solidified. _{MP: 86-87 ℃; C 24 H} 24 N 4 Elemental analysis: Calculated: C, 78.23,
H, 6.56, N, 15.20; Found: C, 78.07, H, 6.82, N, 14.71. Example 25: 2- (N-methylphenylethylamino) -4- [1- (3-methylphenyl) -3-
Preparation of [Methyl-1H-pyrazol-5-yl] pyridine

[0192]

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2-Chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 45; 0.5 g, 0.0018 mol) and N-methylphenethylamine (15 mL) )) Was heated to 200 ° C. for 24 hours. Excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 2: 8) to give 0.45 g (67% yield) of the product as a yellow oil. C ₂₅ H ₂₆ N ₄ Elemental analysis: Calculated: C, 78.50, H, 6.85 , N, 14.65; Found: C, 78.43, H, 6.87 , N, 14.30. Example 26: Preparation of 2- (2-hydroxyethylamino) -4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0194]

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Of 2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 45; 0.5 g, 0.0018 mol) and ethanolamine (15 mL) Mix at 100 ° C
Heated for 18 hours. The reaction mixture was cooled and treated with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate) to give 0.44 g (80% yield) of the product as a yellow oil. C ₁₈ H ₂₀ N ₄ O Elemental analysis: Calculated: C, 70.11, H
, 6.54, N, 18.17; Found: C, 69.89, H, 6.65, N, 18.35. Example 27: 2- (N-methylbenzylamino) -4- [1- (3-methylphenyl) -3-methyl-
Preparation of [1H-pyrazol-5-yl] pyridine

[0196]

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2-Chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 45; 1.0 g, 0.0036 mol) and N-methylbenzylamine ( 20 mL) was heated at 180 ° C. for 24 hours. Excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (ethyl acetate / hexane, 2: 8) to give 0.88 g (66% yield) of the product as a yellow oil. Elemental analysis of C ₂₄ H ₂₄ N _4: Calculated: C, 78.23, H, 6.56 , N, 15.20; Found: C
, 78.55, H, 6.51, N, 15.21. Example 28: Preparation of 2-benzyloxy-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0198]

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Potassium hydroxide (0.67 g, 0.012 mol) and potassium carbonate (0.41 g) in 30 mL of toluene
, 0.003 mol) was added to 2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (0.85 g, 0.003 mol). The reaction mixture was then charged with benzyl alcohol (0.49 g, 0.0045 mol), followed by the addition of tris [2- (2-methoxyethoxy) ethyl] -amine (0.1 g, 0.0003 mol) and the mixture was allowed to stand overnight (about (18 hours)
Heated under reflux. The toluene was removed under vacuum and the residue was partitioned between water and ethyl acetate.

The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (ethyl acetate / hexane 1: 9) to give 0.82 g (66% yield) of the product as a yellow oil. C ₂₃ H ₂₁ N ₃ O Elemental analysis: Calculated: C, 77.72, H, 5.96 , N, 11.82; Found: C, 77.42, H
, 5.90, N, 11.55. Example 29: 2- (benzylamino) -4- [1- (4-fluorophenyl) -1H-pyrazole-5
Of [-yl] pyridine

[0201]

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A mixture of 2-chloro-4- [1- (4-fluorophenyl) -1H-pyrazol-5-yl] pyridine (Example 46; 0.56 g, 0.002 mol) and benzylamine (20 mL) was added overnight. (About 18 hours)
Heated to 180 ° C. Excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 3: 7) to give 0.63 g (89% yield) of the product as a white solid. _{MP: 125-127 ℃; C 22 H} 17 FN 4 Elemental analysis: Calculated: C, 73.24, H, 4.98 , N
, 16.27; Found: C, 72.89, H, 4.69, N, 15.82. Example 30: Preparation of 2- (phenylethylamino) -4- [1- (4-fluorophenyl) -1H-pyrazol-5-yl] pyridine

[0203]

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A mixture of 2-chloro-4- [1- (4-fluorophenyl) -1H-pyrazol-5-yl] pyridine (Example 46; 0.6 g, 0.002 mol) and phenethylamine (20 mL) was added at 190 ° C. Heated for 24 hours. Excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate is concentrated and the crude product is chromatographed on silica gel (ethyl acetate / hexane, 2:
Purification in 8) gave 0.55 g (70% yield) of the product as a yellow oil. Elemental analysis of C ₂₂ H ₁₉ FN _4: Calculated: C, 73.72, H, 5.34 , N, 15.63; Found: C, 73.33, H, 5
.46, N, 15.22. Example 31: Preparation of 2-cyano-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0205]

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Step 1: Preparation of methyl isonicotinate N-oxide: To a solution of hydrogen peroxide (43 mL) in 250 mL of acetic acid was added methyl isonicotinate. The reaction mixture was stirred at 80 ° C. overnight (about 18 hours). The solution was concentrated to about 50 mL, water was added and the mixture was saturated with sodium carbonate. The aqueous phase was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and triturated with hexane. The resulting precipitate was filtered and air dried to give 24.5 g (65% yield) of the product as a white solid. mp: 118-120 ° C. Step 2: Preparation of 2-cyanoisonicotinate: methylisonicotinate N-oxide (20.0 g, 0.26 mol) in 200 mL of methylene chloride
In a solution of trimethylsilyl cyanide (16.1 g, 0.32 mol) followed by 50 ml of methylene chloride.
A solution of dimethylcarbamyl chloride (17.82 g, 0.32 mol) in mL was added at room temperature. The reaction mixture was stirred overnight (about 18 hours) and then treated with 500 mL of a 10% potassium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 15.2 g of crude product as a brown solid, which was used without further purification. Step 3: Preparation of 1- (2-cyanoisonicotinyl) -1,3-butanedione: To a solution of 2-cyanoisonicotinate (20.0 g, 0.126 mol) in 250 mL of THF, acetone (30.6 mL, 0.42 mol) Was added. Warm the solution to 35 ° C and add sodium methoxide (7.
(15 g, 0.132 mol) was added in small portions over 20 minutes. The mixture was heated under reflux for 16 hours. The solution was removed under vacuum, the residue was dissolved in water and acidified to pH = 6 with acetic acid. The aqueous phase was extracted with ethyl acetate, the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 13.0 g (58% yield) of the product as a brown solid. This was used in the next step without purification. Step 4: 2-cyano-4- [1- (3-methylphenyl-3-methyl -1H- pyrazol-5-yl] Pi lysine in producing ethanol 20mL of 1- (2-cyano isonicotinyloxycarbonyl) -1 , 3-butanedione (1.10 g, 0
.0058mol) and 3-methylphenylhydrazine hydrochloride (.097g, 0.0061mol) was added dropwise triethylamine (0.85mL, 0.0061mol). The reaction mixture is left overnight (about
Heated under reflux for 18 hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate is concentrated and the crude product is chromatographed on silica gel (ethyl acetate / hexane, 2:
Purification in 8) provided 1.30 g (87% yield) of the product as a yellow solid. MP: 128-130 ℃
; Elemental analysis for C ₁₇ H ₁₄ N _4: Calculated: C, 74.43, H, 5.14 , N, 20.42; Found: C
, 74.53, H, 5.22, N, 20.29. Example 32: 2-cyano-4- [1- (4-fluorophenyl) -3-methyl-1H-pyrazole-5-
Production of [Il] pyridine

[0207]

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Triethylamine (4.6 mL, 0.033 mol) was added to 1- (2-cyanoisonicotinyl) -1,3-butanedione (6.0 g, 0.032 mol) and 4-fluorophenylhydrazine hydrochloride (5.37) in 100 mL of ethanol. g, 0.033 mol). The reaction mixture is left overnight (about 18
H) Heated under reflux. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude product was purified by recrystallization from ether / hexane to give 4.7 g (53% yield) of the product as a yellow solid. _{MP: 94-95 ℃; C 16 H} 11 FN 4 Elemental analysis: Calculated:
C, 69.06, H, 3.98, N, 20.13; Found: C, 68.52, H, 3.89, N, 19.73.
Example 33: [4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl]]-2-
Production of pyridine-2-carboxamide

[0209]

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2-Cyano-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazole-5- in 5 mL of DMSO
Il] pyridine (Example 31; 0.16 g, 0.0006 mol) was added to a solution of hydrogen peroxide (0.072 mL).
, 0.0006 mol) and potassium carbonate (0.012 g, 0.00009 mol) at 0 ° C. The reaction mixture was warmed to room temperature for 30 minutes. Water was added and the mixture was stirred for 0.5 hours. The resulting precipitate was collected by filtration to give 0.12 g (70% yield) of the product as a pale yellow solid. MP
_{: 193-195 ℃; C 17 H 16} N 4 O Elemental analysis: Calculated: C, 69.85, H, 5.52 , N, 19.16
Found: C, 69.84, H, 5.40, N, 19.11. Example 34: [4- [1- (4-Fluorophenyl) -3-methyl-1H-pyrazol-5-yl]]-2
Of 2-pyridine-2-carboxamide

[0211]

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2-Cyano-4- [1- (4-fluorophenyl) -3-methyl-1H-pyrazole- in 25 mL of DMSO
To a solution of [5-yl] pyridine (Example 32; 1.0 g, 0.0036 mol) was added hydrogen peroxide (0.43 mL).
, 0.0036 mol) and potassium carbonate (0.072 g, 0.00051 mol) at 0 ° C. The reaction mixture was warmed to room temperature for 1 hour. Water was added and the mixture was stirred for 0.5 hours. The resulting precipitate was collected by filtration to give 0.95 g (98% yield) of the product as a pale yellow solid. MP: 168-170 ° C .; Elemental analysis of C ₁₆ H ₁₃ FN ₄ O: Calculated: C, 64.86, H, 4.42, N,
18.91; Found: C, 64.48, H, 4.27, N, 18.80. Example 35: Preparation of 2- (dimethylamino) -4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0213]

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2-Chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazole-5- in 20 mL DMF
A mixture of [yl] pyridine (Example 45; 0.91 g, 0.0032 mol) and 50 mL of liquid ammonia was stirred at 1800 psi in a sealed test tube at 180 ° C for 72 hours. After cooling the solution, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (ethyl acetate / hexane, 2: 8) to give 0.73 g (78% yield) of a yellow crystalline product. . MP:
_{84-85 ℃; C 18 H 20 N} 4 Elemental analysis: Calculated: C, 73.94, H, 6.89 , N, 19.16; Found: C, 73.68, H, 6.74 , N, 19.13. Example 36: Preparation of 2- (methylsulfonyl) -4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0215]

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2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazole-5- in 15 mL of DMF
Yl] pyridine (Example 45; 1.0 g, 0.0035 mol) and methanesulfonic acid sodium salt
(3.24 g, 0.021 mol) was heated at 140 ° C. for 24 hours. After cooling the mixture, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate is concentrated and the crude product is purified by chromatography on silica gel (ethyl acetate / hexane, 1: 1) to give 0.45 g of the product as a yellow solid (
(40% yield). _{MP: 140-142 ℃; C 17 H} 17 N 3 SO 2 Elemental analysis: Calculated: C, 62
.36, H, 5.23, N, 12.83, S, 9.79; found: C, 62.16, H, 5.31, N, 12.
74, S, 9.86. Example 37: Preparation of [4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl]] pyridine-2-azide

[0219]

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2-Chloro-4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazole-5 in 15 mL DMF
-Yl] pyridine (Example 47; 0.87 g, 0.003 mol) and sodium azide (0.59 g, 0.0
09mol) was heated at 100 ° C for 120 hours. After cooling the mixture, water is added,
The aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentrate the filtrate and purify the crude product by chromatography on silica gel (ethyl acetate / hexane, 1: 1) to give 0.13 g (15% yield) of the product as a yellow solid
was gotten. MP: 134-135 ° C .; Elemental analysis of C ₁₅ H ₁₁ FN ₆ : Calculated: C, 61.22, H, 3
.77, N, 28.56; Found: C, 61.44, H, 3.67, N, 28.00. Example 38: Preparation of 2- (3-pyridylmethylamino) -4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0219]

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2-Chloro-4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl] pyridine (Example 47; 0.48 g, 0.0017 mol) and 3- (aminomethyl) A mixture of pyridine (10 mL) was heated at 190 ° C. overnight (about 18 hours). The reaction mixture was cooled, treated with plenty of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / triethylamine, 99: 1) to give 0.35 g (60%) of the product as a yellow oil.
Yield) was obtained. Elemental analysis of C ₂₁ H ₁₈ FN ₅ : Calculated: C, 70.18, H, 5.05, N, 1
9.49; Found: C, 69.78, H, 5.35, N, 18.87. Example 39:

[0221]

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Production of 3-fluorophenylhydrazine in place of 4-fluorophenylhydrazine
Except for the replacement, 4-pentanoyl was used as starting material according to the method described in Example 1.
The title compound was synthesized using pyridine. 4-butanoylpyridine and 4-pen
Tanoylpyridines are both J. L. Born and S. Early J. Pharm. Sci., Vol. 69, 85.
It can be synthesized according to the method described on page 0-851 (1980). MP: 93-94 ° C; C₁₇H ₁₆ FN_ThreeElemental analysis of: calculated: C, 72.58, H, 5.73, N, 14.94; found: C, 72.
44, H, 5.81, N, 14.67. Example 40:

[0223]

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Preparation of The title compound was synthesized according to the method described in Example 25 using 4-butanoylpyridine as the starting material except that 4-fluorophenylhydrazine was replaced with 3-fluorophenylhydrazine. . 4-Butanoyl pyridine and 4-pentayl pyridine are both JLBorn and S. Early J. Pharm. Sci., 69, 85.
It can be synthesized according to the method described on page 0-851 (1980). _{MP: 109-110 ℃; C 1 6} H 14 FN 3 Elemental analysis: Calculated: C, 71.89, H, 5.28 , N, 15.72; Found: C, 7
1.58, H, 5.18, N, 15.61. Example 41: Preparation of 2-chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl] pyridine

[0225]

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Step 1: Preparation of methyl 2- chloroisonicotinate To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol) did. The solution was heated to reflux for 3 hours. The resulting brown solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was slowly added dropwise. The mixture was refluxed for 15 minutes and became clear. Cool the solution to room temperature, pour into water (150 mL), basify with 50% sodium hydroxide, and add ethyl acetate (2.
× 200 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown solid (11.93g, 73%).
This was used in the next step without further purification. Step 2: Preparation of 1- (2-chloro-4-pyridinyl) -1,3-butanedione To a solution of methyl-2-chloroisonicotinate (11.93 g, 69.53 mmol) in THF (200 mL) was added acetone (14.19). mL, 153 mmol) was added. The solution was warmed to 35 ° C., at which time sodium methoxide (94.13 g, 76.48 mmol) was added over the next 20 minutes. Mix 30
Stirred for minutes and then refluxed for 2.5 hours. The solvent was removed under reduced pressure and taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated to give a light brown solid, 1- (2-chloro-4-pyridinyl) -1,3-butanedione. (4.97 g, 76%) was obtained. This was used in the next step without further purification. Step 3: 2-chloro-4- [3-methyl-1- (4-methylphenyl) -1H-pyrazol-5-yl]
Preparation of pyridine 1- (2-chloro-4-pyridinyl) -1,3-butanedione (7 g, 35 mL) in methanol (100 mL)
.25 mmol), para-tolyl hydrazine HCl (6.13 g, 38.78 mmol) and triethylamine
(5.41 mL, 38.78 mmol) was heated to reflux overnight. The resulting dark solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After filtration, the solution was concentrated to give a brown solid. This solid was subjected to column chromatography (silica gel, 2: 8 Et
Purification by OAc / hexane) afforded the title compound as a crystalline light brown solid (3.6 g, 52%). MP: 100.07 ° C; Elemental analysis of C ₁₆ H ₁₄ N ₃ Cl: Calculated: C, 67.72, H, 4.97,
N, 14.81; Found: C, 67.40, H, 4.89, N, 14.59. Example 42: Preparation of 1- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole-4-carboxylate

[0227]

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Step 1: Preparation of Compound 6

[0229]

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Compound 6: To a solution of methyl isonicotinate (25.0 g, 0.182 mol) in 100 mL of methyl acetate was added NaOMe (10.8 g, 0.2 mol). The reaction mixture is heated under reflux for 3 hours,
Cooled to room temperature. Water was added and extracted with ethyl acetate. Wash the organic layer with brine,
Dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with hexane to give 14.0 g of the product as a pale yellow solid. Of this compound (13.0 g, 0.072 mol)
To a solution in THF, add N, N-dimethylformamide dimethyl acetal (51.9 g, 0.43 mol
) Was added and the mixture was stirred at room temperature for 36 hours. The solvent was removed and the residue was dissolved in water and saturated with sodium chloride. The aqueous phase was extracted with methylene chloride, the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 13.2 g of a crude product as a yellow oil. This was used in the next step without further purification. Step 2: Methyl 1- (4-fluorophenyl) -5- (4-pyridinyl)-1H-pyrazol-4-mosquito Rubokishireto manufacturing water and ethanol (1: 1) mixture 50mL crude compound in 6 (2.5 g , 0.011 mol) was added to 4-fluorophenylhydrazine hydrochloride (1.71 g, 0.011 mol), and the solution was cooled to 50%.
Stirred at C for 2 hours. After removing the solvent, the residue was basified with ammonium hydroxide. The resulting precipitate was filtered and air dried to give 2.05 g (64% yield) of the product as a yellow solid. MP: 119-120 ° C; Elemental analysis of C ₁₆ H ₁₂ FN ₃ O ₂ : Calculated: C, 64.64, H, 4
.07, N, 14.13; Found: C, 64.28, H, 3.87, N, 14.14. Example 43:

[0231]

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Preparation of a solution of methyl 1- (4-fluorophenyl) -5- (4-pyridinyl) -1H-pyrazole-4-carboxylate (Example 42; 0.6 g, 0.002 mol) in 20 mL of ethanol 1N NaO
4.0 mL of H solution was added. The reaction mixture was stirred at room temperature for 16 hours. After removing the solvent, the residue was acidified with 1N HCl. The precipitate was filtered and air dried to give 0.25 g (45% yield) of the product as a pale yellow solid. _{MP: 299-300 ℃; C 15 H} 02 FN 3 O 2 · H 2 O Elemental analysis:
Calculated value: C, 59.80, H, 4.01, N, 13.95; Actual value: C, 59.91, H, 3.52, N
, 13.63. Example 44: Preparation of 2-chloro-4- [1- (3-methylphenyl) -3-methyl-1H-pyrazol-5-yl] pyridine

[0233]

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1- (2-chloroisonicotinyl) -1,3-butanedione (1.35 g) in ethanol (40 mL)
, 0.068 mol) and ammonium hydroxide (0.96 mL, 0.0082 mol) were added dropwise to a solution of 3-methylphenylhydrazine hydrochloride (1.30 g, 0.0082 mol). The reaction mixture was heated under reflux overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 2: 8) to give 0.68 g (87% yield) of the product as a yellow oil. C ₁₆ H ₁₄ ClN ₃ Elemental analysis: Calculated: C, 67.72, H, 4.97 , N, 14.81, Cl, 12.49; Found: C, 67.91, H
, 5.08, N, 14.79, Cl, 12.40. Example 45: Preparation of 2-chloro-4- [1- (4-fluorophenyl-1H-pyrazol-5-yl] pyridine

[0235]

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Step 1: Preparation of 2-chloro-4- (N-methyl-N-methoxycarbamoyl) pyridine To a suspension of 2-chloroisonicotinic acid (18.0 g, 0.105 mol) in 250 mL of methylene chloride was added 1 , 1′-Carbonyldiimidazole (17.0 g, 0.105 mol) was added in small portions. The mixture was stirred for 0.5 hour and N, O-dimethylhydroxylamine hydrochloride (10.2 g, 0.105 mol)
Was added immediately. The reaction mixture was stirred overnight at room temperature. Ether was added and the organic layer was washed with water, dried, dried over magnesium sulfate and filtered. The filtrate was concentrated to yield 14.5 g (70%) of the product as a yellow oil. This was used in the next step without purification. Step 2: Preparation of 2-chloro-4-acetylpyridine To methylmagnesium bromide (30 mL of 3.0 M in HF) was added 2-chloro-4- (N-methyl-N-methoxycarbamoyl) pyridine (6.0 g) in 20 mL of THF. , 0.03 mol) at 0 ° C. The reaction mixture was stirred overnight at room temperature, during which time it was allowed to warm to room temperature. A solution of potassium hydrogen sulfate (12 g) in 300 mL of water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 4.0 g (86%) of the product as a yellow oil. This was used in the next step without purification. Step 3: 1- [2-chloroisonicotinyl) -2- (dimethylaminomethylene) ethanone
Preparation A mixture of 2-chloro-4-acetylpyridine (9.1 g, 0.058 mol) in 45 mL of N, N-dimethylformamide dimethyl acetal was heated under reflux for 3 hours. The dark solution was cooled and treated with 300 mL of hexane. The precipitate was collected by filtration and air dried to give 14.6 g (70%) of the product as a brownish solid. It was used without further purification.
Step 4: 2-Chloro-4- [1- (4-fluoroalkyl-phenyl)-1H-pyrazol-5-yl] pyridine in producing ethanol 50mL of 1- (4-pyridyl) -2- (dimethylamino-methylene) Etanon (2.
1 mL of water was added to a mixture of 1 g, 0.01 mol) and 4-fluorophenylhydrazine hydrochloride (1.63 g, 0.01 mol). The reaction mixture was heated at reflux for 1.5 hours. Remove the solvent,
The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentrate the filtrate and purify the crude product by column chromatography on silica gel (ethyl acetate / hexane, 2: 8) to give the product as a yellow oil.
2.5 g (93% yield) were obtained. Elemental analysis of C ₁₄ H ₉ ClFN _3: Calculated: C, 61.44, H, 3 .
31, N, 15.35; Found: C, 61.52, H, 3.27, N, 14.73. Example 46: 2-chloro-4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazole-5-
Production of [Il] pyridine

[0237]

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Step 1: Preparation of 2- chloroisonicotinic acid : Isonicotinic acid N-oxide (28.0 g, 0.2 mol) and phosphorus oxychloride (120.0 g, 0.8 mol)
)) Was heated under reflux for 7 hours. The reaction mixture was cooled and carefully poured into 600 mL of ice water. The precipitate was collected by filtration to give 20.6 g (65% yield) of the product as a pale yellow solid. mp: 248-249 ° C. (Literature value: 250-252 ° C). Step 2: Preparation of methyl 2- chloroisonicotinate: To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was taken up. Heated under reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature in 15 minutes. The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40% NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 8.2 g (83%) of the product as a brown oil. When this was left, it solidified. mp: 36
-37 ° C. Step 3: Preparation of 1- (2-chloroisonicotinyl) -1,3-butanedione: Methyl 2-chloroisonicotinate (12.0 g, 0.07 mol) and acetone (12.2 g, 0.21 mol) in 100 mL of dry THF To the solution was added sodium methoxide in small portions at 35 ° C. After heating the reaction mixture under reflux for 4 hours, the solvent was removed. The residue was diluted with 500 mL of water, acidified to pH = 6 with acetic acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to give 11.46 g (83% yield) of the product as a brown solid. Step 4: Preparation of 2-chloro-4- [1- (3-fluorophenyl) -3-methyl-1H-pyrazol-5-yl ] pyridine: 1- (2-chloroisonicotinyl in ethanol (40 mL) ) -1,3-butanedione (1.35g
, 0.068 mol) and ammonium hydroxide (0.96 mL, 0.0082 mol) were added dropwise to a solution of 3-fluorophenylhydrazine hydrochloride (1.33 g, 0.0082 mol). The reaction mixture was heated under reflux overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentrate the filtrate,
The crude product was purified by silica gel chromatography (acetic acid / hexane, 2: 8) to give 1.54 g (79% yield) of the product as a yellow oil. C ₁₅ H ₁₁ ClFN ₃ Elemental analysis: Calculated: C, 62.62, H, 3.85 , N, 14.60; Found: C, 62.34, H, 3.88 , N, 1
4.30. Biological evaluation p38 kinase assay Cloning of human p38: The coding region of the human p38a cDNA was isolated from the human monocyte cell line THP.1.
Obtained by PCR-amplification from RNA. The first strand cDNA has all R
Synthesized from NA: by heating to 70 ° C for 10 minutes followed by 2 minutes on ice,
2 μg of RNA was annealed to 100 ng of random hexamer primer in a 10 μl reaction. Then, 1 μl of RNAsin (Promega, Madison WI), 2 μl of 50 mM dN
TP, 4 μl of 5 × buffer, 2 μl of 100 mM DTT and 1 μl (200 U) of Superscript II (
CDNA was synthesized by adding (trademark) AMV reverse transcriptase. Random primers, dNTPs and Superscript ™ reagents are all available from Life-Technologies, Gaithersbu
rg, purchased from MA. The reaction was incubated at 42 ° C. for 1 hour. Amplification of the p38 cDNA was as follows: 80 μl dH ₂ O, 2 μl 50 mM dNTP, 1 μl each of forward and reverse primers (50 pmol / μl), 10 μl 10 × buffer and 1 μl Expand (
TM) polymerase (Boehringer Mannheim) in 5 μl of 100 μl PCR reaction
Performed by aliquoting 1 reverse transcriptase reaction. PCR primers contained Bam HI sites at the 5 'and 3' ends of the amplified fragment and were purchased from Genosys. The forward and reverse primers, respectively,

[0239]

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Was PCR amplification was performed in a DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles of 1 minute at 94 ° C, 1 minute at 60 ° C and 2 minutes at 68 ° C.
After amplification, excess primer and unincorporated dNTPs were combined with Wizard® PCR pre-
It was removed from the amplified fragment with p (Promega) and digested with Bam HI (New England Biolabs). The fragment digested with Bam HI was digested with T. Maniatis, Molecular Cloning
: As described in A Laboratory Manual, 2nd edition (1989), T-4 DNA ligase (New
England Biolabs) using BamHI digested pGEX 2T plasmid DNA (PharmaciaB
iotech). The ligation reaction was performed according to the manufacturer's instructions.
The cells were transformed into chemically competent E. coli DH10B cells purchased from ife-Technologies. Plasmid DNA was isolated from the resulting bacterial colonies using the Promega Wizard ™ miniprep kit. Plasmids containing the appropriate Bam HI fragment were transferred to a DNA Thermal using Prism ™ (Applied Biosystems Inc.).
Sequenced on a Cycler (Perkin Elmer). The cDNA clone is a human p38a isoform (Le
e et al., Nature 372, p. 739). Cloning site of pGEX 2T, cDN for p38a-2 (CSBP-2) inserted 3 'of GST coding region
One of the clones containing A is called pMON 35802. The sequence obtained for this clone is completely identical to the cDNA clone reported by Lee et al. With this expression plasmid, a GST-p38a fusion protein can be produced. Expression of human p38a: The GST / p38a fusion protein was expressed from plasmid pMON 35802 in E. coli, strain DH10B (Life Technologies, Gibco-BRL). L containing 100mg / ml ampicillin
Cultures were grown overnight in uria broth (LB). The next day, 10ml in a new 500ml LB
Overnight and cultured at 37 ° C. in a 2 liter flask with constant shaking until the culture reaches an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by the addition of isopropyl bD-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The culture was shaken at room temperature for 3 hours and cells were harvested by centrifugation. The cell pellet was stored frozen until protein purification. Purification of p38 kinase-α: All drugs were purchased from Sigma Chemical Co. unless stated. Five one
20 grams E.coli cell pellet recovered from L shake flask cultures, the predetermined volume PBS (140mM NaCl, 2.7mM KCl, 10mM Na 2 HPO 4, 1.8mM KH 2 PO 4, pH7.3) in the Resuspend to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2M DTT, then
It was aliquoted into two 50 mL Falcon conical tubes. The cells were sonicated (Ultrasonics model W375) (vibration) for 3 x 1 min on ice with a 1 cm probe. Lysed cellular material was removed by centrifugation (12,000 xg, 15 minutes) and the clarified supernatant was glutathione-
Applied to Sepharose resin (Pharmacia). Glutathione-Sepharose affinity chromatography: 12 ml of 50% glutathione-Sepharose-PBS suspension was added to 200 ml of clarified supernatant and incubated for 30 minutes at room temperature in batch mode. Centrifuge the resin (600 × g, 5
Min) and washed with 2 × 150 ml of PBS / 1% Triton X-100, followed by 4 × 40 ml of PBS. Glutathione to cleave p38 kinase from GST-p38 fusion protein
-Sepharose resin with 250 units of thrombin protease (Pharmacia, specific activity> 75)
(00 units / mg) was resuspended in 6 ml of PBS and mixed gently for 4 hours at room temperature.
Glutathione-Sepharose resin was removed by centrifugation (600 × g, 5 minutes),
Washed with 2 x 6 ml of PBS. The PBS wash fraction and the digestion supernatant containing the p38 kinase protein were pooled and adjusted to 0.3 mM PMSF. Mono-Q anion exchange chromatography: Thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved samples were prepared in buffer A (25 mM HEPES, pH 7.5, 25 mM
M-beta-glycerophosphate, 2 mM DTT, 5% glycerol) and diluted onto a mono-Q HR10 / 10 (Pharmacia) anion exchange column equilibrated with buffer A. The column was eluted with 160 ml of a 0.1 M to 0.6 NaCl / buffer A gradient (flow rate 2 ml / min). Two
The p38 kinase peak eluting with 00 mM NaCl was collected and collected on a Filtron 10 concentrator (Filtron 10
Corp.) to 3-4 ml. Sephacryl S100 gel filtration chromatography: Concentrate the purified mono-Q-p38 kinase purified sample with buffer B (50 mM HEPES, pH 7.5, 5
Purification was performed by gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 column) equilibrated with 0 mM NaCl, 2 mM DTT, 5% glycerol). The protein was eluted from the column with buffer B at a flow rate of 0.5 ml / min, and the protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at -80 ° C. A typical purified protein yield from a 5 L E. coli shake flask culture was 35 mg p38 kinase. In vitro assays The ability of a compound to inhibit human p38 kinase alpha was evaluated using two in vitro assays. In the first method, the presence of gamma ^{32 P-ATP (32 P-} ATP),
Activated human p38 kinase alpha phosphorylated a biotinylated substrate, PHAS-I (heat- and acid-stable protein-insulin inducible). PHAS-I before assay
To provide a means to obtain a substrate that is phosphorylated during the assay. p38 kinase was activated by MKK6. Compounds were made from 100 μM to 0.0
Tests were performed at 10-fold serial dilutions over a range of 01 μM. Each concentration of inhibitor was tested in triplicate.

All reactions were performed in 96-well polypropylene plates. Each reaction well contained 25 mM HEPES, pH 7.5, 10 mM magnesium acetate and 50 μM unlabeled ATP. P38 activity was required to obtain a sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μg per 50 μl reaction volume and the final concentration was 1.5 μM. Activated human p38 kinase alpha was used at 1 μg per 50 μl reaction volume, corresponding to a final concentration of 0.3 μM. Phosphorylation of PHAS-I was tracked using gamma ³² P-ATP. ³² P-ATP had a specific activity of 3000 Ci / mmol and was used at 1.2 μCi per 50 μl reaction volume. The reaction was allowed to proceed at 30 ° C. for 1 hour or overnight.

After the incubation, 20 μl of the reaction mixture was added to a high volume streptavidin-coated filter plate (SAM-
Streptavidin-matrix, Promega). Transfer the reaction mixture to Pro
The plate was contacted with a streptavidin membrane of a mega plate for 1-2 minutes. ³² P captured
After capturing biotinylated PHAS-I containing, each well was washed 3 times with 2M NaCl,
The unincorporated ³² P-ATP was removed by washing three times with 2M NaCl containing 1% phosphoric acid, three times with distilled water, and finally once with 95% ethanol. The filter plate was air dried and 20 μl of scintillant was added. The plate was sealed and measured. The results are shown in Table I.

[0243]³²In the presence of P-ATP, p38a of EGFRP (epidermal growth factor receptor peptide, 21 mer)
Also uses a second assay format based on kinase alpha-induced phosphorylation
Used. Compounds are tested in 10-fold serial dilutions ranging from 100 μM to 0.001 μM in 1% DMSO
did. Each concentration of inhibitor was tested in triplicate. The compound was 25 mM HEPES
PH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin
, 0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM) and 0.05 μCi gamma ³² Evaluated at 50 μM reaction volume in the presence of P-ATP. 0.09 μg of activated, purified human
The reaction was started by adding GST-p38 kinase alpha. Activation is 5
Performed using GST-MKK6 (5: 1, p38: MKK6) in the presence of 0 μM ATP. At room temperature
After incubation for 60 minutes, 150 μl in 900 mM sodium formate buffer, pH 3.0
The reaction was stopped by adding the AG 1X8 resin (1 volume resin to 2 volumes buffer).
Stopped. The mixture was mixed three times by pipetting to settle the resin. In all
The head volume of 50 μl of the clarification solution was transferred from the reaction well to a Microlite-2 plate
. Then add 150 μl of Microscint 40 to each well on the Microlite plate
Added, plates were sealed, mixed, and counted.

The results of these p38 kinase assays are shown in Table I.

[0245]

[Table 1]

[0246]

[Table 2]

TNF Cell Assay Method for Isolating Human Peripheral Blood Mononuclear Cells: Human whole blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. Blood samples (7 ml) were transferred to 5 ml of PMN cell isolation medium (Robbins Scienti in a 15 ml round bottom centrifuge tube).
fic) was carefully stacked. Sample at room temperature in swingout rotor
Centrifuged at 450-500 × g for 30-35 minutes. After centrifugation, the upper band of cells was removed and washed three times with PBS without calcium or magnesium. Cells were centrifuged at 400 xg for 10 minutes at room temperature. Macrophage at a concentration of 2 million cells / ml
Resuspended in Serum Free Medium (Gibco BRL). LPS stimulation of human PBM: PBM cells (0.1 ml, 2 million cells / ml) were placed in a flat-bottomed 96-well microtiter plate at 0.
Co-incubated with 1 ml compound (10-0.41 μM, final concentration) for 1 hour. Compounds were first dissolved in DMSO and then diluted in TCM to a final concentration of 0.1% DMSO. LPS (Calbiochem, 20 ng / ml, final concentration) was then added in a volume of 0.010 ml. 3 cultures
Incubated overnight at 7 ° C. The supernatant is then removed and ENF for TNF-a and ILI-b is removed.
Tested by LISA. Viability was analyzed using MTS. After collecting 0.1 ml of supernatant, 0.
020 ml of MTS was added to the remaining 0.1 ml of cells. The cells were incubated at 37 ° C for 2-4 hours, then the OD was measured at 490-650 nM.

The results of these TNF cell assays are shown in Table II.

[0249]

[Table 3]

[0250]

[Table 4]

Maintenance and differentiation of U937 human histiocytic lymphoma cell line: U937 cells (ATCC) contain 10% fetal bovine serum, 100 IU / ml penicillin, 100 μg / ml streptomycin, and 2 mM glutamine (Gibco) Grow in RPMI 1640. Terminal monocyte differentiation (terminal) was performed by incubating 50 million cells in 100 ml medium with 20 ng / ml phorbol 12-myristate 13-acetate (Sigma) for 24 hours.
monocytic differentiation). Cells were washed by centrifugation (200 × g for 5 minutes) and resuspended in 100 ml of fresh medium. After 24-48 hours, cells were harvested, centrifuged, and resuspended in medium at 2 million cells / ml. LPS stimulation of TNF production by U937 cells: U937 cells (0.1 ml, 2 million cells / ml in a 96-well microtiter plate) were incubated with 0.1 ml compound (0.004-50 μM, final concentration) for 1 hour Compounds in DMSO Ten
It was prepared as a mM stock solution and diluted in medium to a final DMSO concentration of 0.1% in the cell assay. LPS (E. coli, 100 ng / ml final concentration) was then added in a volume of 0.02 ml. After incubation at 37 ° C. for 4 hours, the amount of TNF-α released into the medium was quantified by ELISA. Inhibitory power is expressed as IC50 (μM).

The results of these U937 cell assays are shown in Table III.

[0253]

[Table 5]

[0254]

[Table 6]

All patent documents cited in this specification are incorporated by reference. Although the invention has been described with respect to particular embodiments, the details of these embodiments are not intended to limit the invention.

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] September 14, 1999 (September 14, 1999)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded imageWherein A is = N- or = CH-; Ar¹Is halogen, C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxy, d
Toro, cyano, perfluoro-C₁-C₁₂-Hydrocarbyl, trifluoromethyl-C ₁ -C₁₂-Hydrocarbyl, perfluoro-C₁-C₁₂-Hydrocarbyloxy, hydro
Xy, mercapto, hydroxycarbonyl, aryloxy, arylthio,
By one or more substituents selected from the group consisting of rufonyl or sulfoxide
An optionally substituted aryl group, wherein a substituent on said sulfur atom
Is C₁-C₁₂-Hydrocarbyl, sulfonylamide, wherein the substituent on the sulfonamide nitrogen atom is hydride or C₁-C₁₂-
Hydrocarbyl, arylamino, aryl-C₁-C₁₂-Hydrocarbyl, Ally
, Heteroaryloxy, heteroarylthio, heteroarylamino, hete
Loaryl-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxycarbonyl
-C₁-C₁₂-Hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C₁-C_{1 Two} -Hydrocarbyl, heterocyclothio, heterocycloamino, cyclo-C₁-C₁₂-
Hydrocarbyloxy, C_Three-C₁₂-Cyclohydrocarbylthio, heteroaryl-C ₁ -C₁₂-Hydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbylthio,
Heteroaryl-C₁-C₁₂-Hydrocarbylamino, aryl-C₁-C₁₂-Hydrocal
Biloxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-Hydro
Carbylamino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂-H
Drocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydro
Carbyloxy, C₁-C₁₂-Hydrocarbilloyl, arylcarbonyl, aryl-
 C₁-C₁₂-Hydrocarbilloyl, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-
C₁₂-Hydrocarbyloxy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy
C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hid
Locarbyloxy-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-H
Drocarbyloxycarbonyl-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarb
Lehydroxycarbonyl-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyl
Oxycarbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyl oki
Cicarbonyl-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbylcarbonyl
Amino, arylcarbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonyl
Amino, heterocyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C ₁ -C₁₂-Hydrocarbylcarbonylamino, heteroarylcarbonylamino, f
Teloaryl-C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C_{1 Two} -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbylsulfonylamino, aryl
Sulfonylamino, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, hete
Loarylsulfonylamino, heteroaryl-C₁-C₁₂-Hydrocarbyl sulfo
Nilamino, C_Three-C₁₂-Cyclohydrocarbylsulfonylamino, heterocyclo-C ₁ -C₁₂-Hydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted amino-C₁ -C₁₂-Hydrocarbyl group [wherein the amino-C₁-C₁₂-Hydrocarbyl nitrogen atom
The above substituent (s) is C₁-C₁₂-Hydrocarbyl, aryl, a
Reel-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Cyclohydrocarbyl, aryl-C₁ -C₁₂-Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxycarboni
And C₁-C₁₂-Selected from the group consisting of
Drocarbyl nitrogen and the two substituents attached thereto are a 5- to 8-membered heterocycle or heterocycle.
An aryl ring group], an amino, and an N-monosubstituted or N, N-disubstituted amino group [this
Wherein the substituent (s) on the amino nitrogen is hydride, C₁-C₁₂ -Hydrocarbyl, aryl, aryl-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Siku
Rohydrocarbyl, aryl-C₁-C₁₂-Hydrocarbyloxycarbonyl, C₁-C_{1 Two} -Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarboyl, arylsul
Honyl and C₁-C₁₂-Selected from the group consisting of hydrocarbylsulfonyl,
Or the amino nitrogen and the two substituents bonded thereto are a 5- to 8-membered heterocycle or
Z forms a heteroaryl ring group]; Z is hydride, C₁-C₁₂-Hydrocarbyl, halogen, carboxy, cyano, azide
C₁-C₁₂-Hydrocarbylsulfonyl, carbonyloxy-C₁-C₁₂-Hydrocal
Bil, carbonylamide, and -X-Y wherein -X is -O, -S or -NQ, -Y is hydride, C₁-C₁₂-Hydrocarbyl or C₁-C₁₂-Hydrocarbyl aryl
And Q is hydride, C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydrocarbyl
, 2-, 3-, or 4-pyridyl-C₁-C₁₂-Hydrocarbyl or aryl-C₁-
C₁₂-Hydrocarbyl]; R¹Is azide, hydride, C₁-C₁₂-Hydrocarbyl, amide, C₁-C₁₂-Hydrocal
Vilamino, Halo-C₁-C₁₂-Hydrocarbyl and halogen, C₁-C₁₂-Hydroca
Ruville, C₁-C₁₂-Hydrocarbyloxy, nitro, cyano, perfluoro-C₁-C_{1 Two} -Hydrocarbyl, trifluoromethyl-C₁-C₁₂-Hydrocarbyl, hydroxy
, Mercapto, hydroxycarbonyl, aryloxy, arylthio, aryl
Ruamino, aryl-C₁-C₁₂-Hydrocarbyl, aryl, heteroaryloxy
Si, heteroarylthio, heteroarylamino, heteroaryl-C₁-C₁₂-H
Drokarville, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydrocarb
, Heterocyclooxy, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyl, f
Telocyclothio, heterocycloamino, C_Three-C₁₂-Cyclohydrocarbyloxy, C _Three -C₁₂-Cyclohydrocarbylthio, C_Three-C₁₂-Cyclohydrocarbylamino, hete
Loarylhydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbirch
E, heteroaryl-C₁-C₁₂-Hydrocarbylamino, aryl-C₁-C₁₂-Hydro
Carbyloxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-H
Drocarbylamino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂ -Hydrocarbyloxy, C₁-C₁₂-Alkoxycarbonyl-C₁-C₁₂-Alkoxy, C ₁ -C₁₂-Hydrocarbilloyl, arylcarbonyl, aryl-C₁-C₁₂-Hydroca
Rubyloyl, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-C₁₂-Hydrocarbo
Iloxy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydro
Carbyloxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy-
C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl, hydro
Carbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycal
Bonil-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyl hydroxycarbonyl
-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C ₁₂ -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-
Hydrocarbylthio, amino, C₁-C₁₂-Hydrocarbylcarbonylamino, ant
Carbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonylamino, hete
Rocyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C₁-C₁₂-Hydro
Carbylcarbonylamino, heteroarylcarbonylamino, heteroaryl
-C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C₁₂-Hydrocal
Biloxy, C₁-C₁₂-Hydrocarbylsulfonylamino, arylsulfonylua
Mino, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, heteroaryls
Ruphonylamino, heteroaryl-C₁-C₁₂-Hydrocarbylsulfonylamino, C _Three -C₁₂-Cyclohydrocarbylsulfonylamino, hetero-C_Three-C₁₂-Cyclohydroca
Rubylsulfonylamino, and N-monosubstituted or N, N-disubstituted amino-C₁-C₁₂-Hid
Locarbyl group [wherein the aminohydrocarbyl nitrogen atom (s)
Substituents) are C₁-C₁₂-Hydrocarbyl, aryl, aryl-C₁-C₁₂-Hid
Locarville, C_Three-C₁₂-Cyclohydrocarbyl, aryl-C₁-C₁₂-Hydrocarbyl
Oxycarbonyl, C₁-C₁₂-Hydrocarbyloxycarbonyl, and C₁-C₁₂-Hid
Selected from the group consisting of locarboil or the amino-C₁-C₁₂-Hydrocarb
And the two substituents attached thereto are a 5- to 8-membered heterocycle or heteroaryl.
Form a ring).
Perhalo-C₁-C₁₂Independently from the group consisting of -hydrocarbyl substituents
Selected; and R^TwoIs azide, hydride, C₁-C₁₂-Hydrocarbyl, amide, halo-C₁-C₁₂-Hid
Localville, Perhalo-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and
Independently selected from the group consisting of aryl groups substituted with one or more substituents.
Wherein said one or more substituents are halogen, C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-
Hydrocarbyloxy, nitro, cyano, perfluoro-C₁-C₁₂-Hydrocarb
Trifluoromethyl-C₁-C₁₂-Hydrocarbyl, hydroxy, mercapto,
Hydroxycarbonyl, aryloxy, arylthio, arylamino, ant
RU-C₁-C₁₂-Hydrocarbyl, aryl, heteroaryloxy, heteroaryl
Thio, heteroarylamino, heteroaryl-C₁-C₁₂-Hydrocarbyl, C ₁ -C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydrocarbyl, heterocyclic
Rooxy, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyl, heterocyclothio
, Heterocycloamino, C_Three-C₁₂-Cyclohydrocarbyloxy, C_Three-C₁₂-Cyclohi
Drocarbirthio, C_Three-C₁₂-Cyclohydrocarbylamino, heteroaryl-C₁-
C₁₂-Hydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbylthio, f
Teloaryl-C₁-C₁₂-Hydrocarbyl-amino, aryl-C₁-C₁₂-Hydrocal
Biloxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-Hydro
Carbylamino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂-H
Drocarbyloxy, C₁-C₁₂-Alkoxycarbonyl-C₁-C₁₂-Alkoxy, C₁-C ₁₂ -Hydrocarbilloyl, arylcarbonyl, aryl-C₁-C₁₂-Hydrocarb
Royl, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-C₁₂-Hydrocarbyl
Oxy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydrocal
Biloxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy-C₁-C ₁₂ -Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl, hydroxy
Carbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycal
Bonil-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyl hydroxycarbonyl
-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C ₁₂ -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-
Hydrocarbylthio, amino, C₁-C₁₂-Hydrocarbylcarbonylamino, ant
Carbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonylamino, hete
Rocyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C₁-C₁₂-Hydro
Carbylcarbonylamino, heteroarylcarbonylamino, heteroaryl
-C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C₁₂-Hydrocal
Biloxy, C₁-C₁₂-Hydrocarbylsulfonylamino, arylsulfonylua
Mino, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, heteroaryls
Ruphonylamino, heteroaryl-C₁-C₁₂-Hydrocarbylsulfonylamino, C _Three -C₁₂-Cyclohydrocarbylsulfonylamino, heterocyclo-C₁-C₁₂-Hydro
Carbylsulfonylamino and N-monosubstituted or N, N-disubstituted amino-C₁-C₁₂-Hid
Selected from the group consisting of locarbyl groups, wherein said amino-C₁-C₁₂-Hydrocal
The substituent (s) on the building nitrogen is C₁-C₁₂-Hydrocarbyl, ant
, Aryl-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Cyclohydrocarbyl, ant
RU-C₁-C₁₂-Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, and C₁-C₁₂-Selected from the group consisting of hydrocarbyl or
Amino-C₁-C₁₂-Hydrocarbyl nitrogen and the two substituents attached thereto are 5- to 8-membered
Wherein A is = CH-, Z is hydride, C₁-C₁₂-Hydrocarbyl, halogen or C₁-C_{1 Two} -When hydrocarbyl: 1) Ar¹Is hydride, halogen, C₁-C₁₂-Alkoxy, C₁-C₁₂-Hydrocarbyl
, Perfluoro-C₁-C₁₂-Hydrocarbyloxy, nitro, perfluoro-C₁-C_{1 Two} -Hydrocarbyl, amino, aminosulfonyl, halo-C₁-C₁₂-Hydrocarbyl
Oxy-C₁-C₁₂-Hydrocarbyl, hydroxy, C₁-C₁₂-Hydrocarbyl sulfoni
Lumino, C₁-C₁₂-Hydrocarbylsulfonyl, acetylamino, carbonyl-C ₁ -C₁₂-Hydrocarbylamino, perfluoro-C₁-C₁₂-Hydrocarbyl sulfoni
, C₁-C₁₂-Hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, C₁-
C₁₂-Hydrocarbylthio, hydroxy-C₁-C₁₂-Hydrocarbyl, aryl-C₁-
C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxyhydrocarbyl, C₁-C₁₂-H
Drocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxyarylhydro
Carbyl, halo-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxy
A substituted with one or more substituents selected from the group consisting of hydrocarbyl.
Non-reel based; or 2) R¹Is a hydride, C₁-C₁₂-Hydrocarbyl, aryl, haloaryl, shea
Noaryl, hydroxyaryl, C₁-C₁₂-Hydrocarbylaryl, cyano,
Perfluoro-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydrocarbyl,
Aryl-C₁-C₁₂-Hydrocarbyl, carboxy, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, C₁-C₁₂-Hydrocarboylhydrocarbyl, aminocarbonyl,
Reel-C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarboyl-C₁-C₁₂-Hydroca
Rubil monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarb
Le-C₁-C₁₂-Hydrocarbyl monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl-
C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarboyl-C₁-C₁₂-Hydrocarbyl
Monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl-hydroxy-disubstituted amino acids
Rubonil-C₁-C₁₂-Hydrocarbyl, or a 6-membered
Is other than a teloaryl group; or 3) R^TwoIs hydride, carboxy, C₁-C₁₂-Hydrocarbyloxycarbonyl,
Other than halogen or aryl, wherein the heterocycle is a saturated atom whose heteroatom is selected from nitrogen, sulfur or oxygen,
Means a cyclic group containing partially unsaturated and aromatically unsaturated heteroatoms,
Heteroaryl means an unsaturated 5- to 10-membered heteromonocyclic group, and aryl is
, 1, 2 or 3 ring monocyclic aromatic systems].
Or a pharmaceutically acceptable salt thereof.

Embedded image Wherein R ³ is hydride or C ₁ -C ₆ hydrocarbyl; R ⁴ is hydride, C ₁ -C ₆ -hydrocarbyl, aryl-C ₁ -C ₆ -hydrocarbyl, hydroxyl-C ₁ -C ₆ -hydrocarbyl, and 2-pyridyl-C ₁ -C ₆ -hydrocarbyl,
Ar ¹ is independently selected from the group consisting of 3-pyridyl-C ₁ -C ₆ -hydrocarbyl or 4-pyridyl-C ₁ -C ₆ -hydrocarbyl; Ar ¹ is a halogen or halo group, C ₁ -C ₆ -hydrocarbyl, Or an aryl group substituted by a C ₁ -C ₁₂ -hydrocarbyloxy group; R ¹ is hydride or C ₁ -C ₆ -hydrocarbyl; and R ² is hydride or C ₁ -C ₆ -Hydrocarbyl], or a pharmaceutically acceptable salt thereof.

Embedded image Wherein R ⁵ is hydride, C ₁ -C ₆ -hydrocarbyl, or aryl-C ₁ -C ₆ -hydrocarbyl; Ar ¹ is halogen, C ₁ -C ₆ -hydrocarbyl, or C ₁ -C ₁₂ - independently a hydrocarbyloxy group substituted aryl group; R ¹ is an C ₁ -C ₆ hydrocarbyl; and R ² are as defined in claim 1 of the structure corresponding to a hydride] A compound or a pharmaceutically acceptable salt thereof.

Embedded image Wherein Ar ¹ is halogen, C ₁ -C ₆ -hydrocarbyl or an aryl group substituted by a C ₁ -C ₁₂ -hydrocarbyloxy group; R ¹ is C ₁ -C ₆ -hydrocarbyl; And R ² is hydride or C ₁ -C ₆ -hydrocarbyl].
Or a pharmaceutically acceptable salt thereof.

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image A compound having a structure corresponding to

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded image The compound according to claim 1, having a structure corresponding to:

Embedded imageWherein A is = N- or = CH-; Ar¹Is halogen, C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxy, d
Toro, cyano, perfluoro-C₁-C₁₂-Hydrocarbyl, trifluoromethyl-C ₁ -C₁₂-Hydrocarbyl, perfluoro-C₁-C₁₂-Hydrocarbyloxy, hydro
Xy, mercapto, hydroxycarbonyl, aryloxy, arylthio,
By one or more substituents selected from the group consisting of rufonyl or sulfoxide
An optionally substituted aryl group, wherein the substituent on the sulfur atom is C₁-C₁₂-Hydrocarbyl, sulfonylamide
Wherein the substituent on the sulfonamide nitrogen atom is hydride or C₁-C₁₂-
Hydrocarbyl, arylamino, aryl-C₁-C₁₂-Hydrocarbyl, Ally
, Heteroaryloxy, heteroarylthio, heteroarylamino, hete
Loaryl-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxycarbonyl
-C₁-C₁₂-Hydrocarbyl, heterocyclooxy, hydroxycarbonyl-C₁-C_{1 Two} -Hydrocarbyl, heterocyclothio, heterocycloamino, cyclo-C₁-C₁₂-
Hydrocarbyloxy, C_Three-C₁₂-Cyclohydrocarbylthio, heteroaryl-C ₁ -C₁₂-Hydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbylthio,
Heteroaryl-C₁-C₁₂-Hydrocarbylamino, aryl-C₁-C₁₂-Hydrocal
Biloxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-Hydro
Carbylamino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂-H
Drocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydro
Carbyloxy, C₁-C₁₂-Hydrocarbilloyl, arylcarbonyl, aryl-
 C₁-C₁₂-Hydrocarbilloyl, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-
C₁₂-Hydrocarbyloxy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy
C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hid
Locarbyloxy-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-H
Drocarbyloxycarbonyl-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarb
Lehydroxycarbonyl-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyl
Oxycarbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyl oki
Cicarbonyl-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbylcarbonyl
Amino, arylcarbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonyl
Amino, heterocyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C ₁ -C₁₂-Hydrocarbylcarbonylamino, heteroarylcarbonylamino, f
Teloaryl-C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C_{1 Two} -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbylsulfonylamino, aryl
Sulfonylamino, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, hete
Loarylsulfonylamino, heteroaryl-C₁-C₁₂-Hydrocarbyl sulfo
Nilamino, C_Three-C₁₂-Cyclohydrocarbylsulfonylamino, heterocyclo-C ₁ -C₁₂-Hydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted amino-C₁ -C₁₂-Hydrocarbyl group (wherein the amino-C₁-C₁₂-Hydrocarbyl nitrogen atom
The above substituent (s) is C₁-C₁₂-Hydrocarbyl, aryl, a
Reel-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Cyclohydrocarbyl, aryl-C₁ -C₁₂-Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxycarboni
And C₁-C₁₂Selected from the group consisting of -hydrocarboyl,
Drocarbyl nitrogen and the two substituents attached thereto are a 5- to 8-membered heterocycle or heterocycle.
To form a roaryl ring group), an amino, and an N-monosubstituted or N, N-disubstituted amino group [
Wherein the substituent (s) on the amino nitrogen is hydride, C₁-C ₁₂ -Hydrocarbyl, aryl, aryl-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-S
Chlohydrocarbyl, aryl-C₁-C₁₂-Hydrocarbyloxycarbonyl, C₁-
C₁₂-Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarboyl, aryls
Ruphonyl, and C₁-C₁₂Selected from the group consisting of -hydrocarbylsulfonyl
Or the amino nitrogen and the two substituents bonded thereto are a 5- to 8-membered heterocycle or
Forms a heteroaryl ring group]; Z is a hydride C₁-C₁₂-Hydrocarbyl, halogen, carboxy, cyano, azide
, C₁-C₁₂-Hydrocarbylsulfonyl, carbonyloxy-C₁-C₁₂-Hydrocarb
, Carbonylamide, and -X-Y wherein -X is -O, -S or -NQ, -Y is hydride, C₁-C₁₂-Hydrocarbyl or C₁-C₁₂-Hydrocarbyl aryl
And Q is hydride, C₁-C₁₂-Hydrocarbyl, hydroxyl-C₁-C₁₂-Hydrocarb
, 2-, 3-, or 4-pyridyl-C₁-C₁₂-Hydrocarbyl or aryl-C ₁ -C₁₂-Hydrocarbyl]; R¹Is azide, hydride, C₁-C₁₂-Hydrocarbyl, amide, C₁-C₁₂-Hydrocal
Vilamino, Halo-C₁-C₁₂-Hydrocarbyl and halogen, C₁-C₁₂-Hydroca
Ruville, C₁-C₁₂-Hydrocarbyloxy, nitro, cyano, perfluoro-C₁-C_{1 Two} -Hydrocarbyl, trifluoromethyl-C₁-C₁₂-Hydrocarbyl, hydroxy
, Mercapto, hydroxycarbonyl, aryloxy, arylthio, aryl
Ruamino, aryl-C₁-C₁₂-Hydrocarbyl, aryl, heteroaryloxy
Si, heteroarylthio, heteroarylamino, heteroaryl-C₁-C₁₂-H
Drokarville, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydrocarb
, Heterocyclooxy, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyl, f
Telocyclothio, heterocycloamino, C_Three-C₁₂-Cyclohydrocarbyloxy, C _Three -C₁₂-Cyclohydrocarbylthio, C_Three-C₁₂-Cyclohydrocarbylamino, hete
Loarylhydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbirch
E, heteroaryl-C₁-C₁₂-Hydrocarbylamino, aryl-C₁-C₁₂-Hydro
Carbyloxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-H
Drocarbylamino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂ -Hydrocarbyloxy, C₁-C₁₂-Alkoxycarbonyl-C₁-C₁₂-Alkoxy, C ₁ -C₁₂-Hydrocarbilloyl, arylcarbonyl, aryl-C₁-C₁₂-Hydroca
Rubyloyl, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-C₁₂-Hydrocarbo
Iloxy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydro
Carbyloxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy-
C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl, hydro
Carbonyl-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycal
Bonil-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyl hydroxycarbonyl
-C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C ₁₂ -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-
Hydrocarbylthio, amino, C₁-C₁₂-Hydrocarbylcarbonylamino, ant
Carbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonylamino, hete
Rocyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C₁-C₁₂-Hydro
Carbylcarbonylamino, heteroarylcarbonylamino, heteroaryl
-C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C₁₂-Hydrocal
Biloxy, C₁-C₁₂-Hydrocarbylsulfonylamino, arylsulfonylua
Mino, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, heteroaryls
Ruphonylamino, heteroaryl-C₁-C₁₂-Hydrocarbylsulfonylamino, C _Three -C₁₂-Cyclohydrocarbylsulfonylamino, hetero-C_Three-C₁₂-Cyclohydro
Carbylsulfonylamino, and N-monosubstituted or N, N-disubstituted amino-C₁-C₁₂-H
Drocarbyl group [wherein the amino-C₁-C₁₂-On the hydrocarbyl nitrogen atom
The substituent (s) is C₁-C₁₂-Hydrocarbyl, aryl, aryl-
C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Cyclohydrocarbyl, aryl-C₁-C₁₂-H
Drocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxycarbonyl, and
And C₁-C₁₂-Hydrocarboyl or the amino-C₁-C₁₂-Hydrocal
The bil nitrogen and the two substituents attached thereto are a 5- to 8-membered heterocycle or heteroaryl.
Form a ring) optionally with one or more substituents selected from the group consisting of
Perhalo-C being substituted₁-C₁₂-Independent from the group consisting of hydrocarbyl substituents
Selected; and R^TwoIs azide, hydride, C₁-C₁₂-Hydrocarbyl, amide, halo-C₁-C₁₂-Hid
Localville, Perhalo-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and
Independently selected from the group consisting of aryl groups substituted with one or more substituents.
Wherein said one or more substituents are halogen, C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-
Hydrocarbyloxy, nitro, cyano, perfluoro-C₁-C₁₂-Hydrocarb
Trifluoromethyl-C₁-C₁₂-Hydrocarbyl, hydroxy, mercapto,
Hydroxycarbonyl, aryloxy, arylthio, arylamino, ant
RU-C₁-C₁₂-Hydrocarbyl, aryl, heteroaryloxy, heteroaryl
Thio, heteroarylamino, heteroaryl-C₁-C₁₂-Hydrocarbyl, C ₁ -C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-Hydrocarbyl, heterocyclic
Rooxy, hydroxycarbonyl-C₁-C₁₂-Hydrocarbyl, heterocyclothio
, Heterocycloamino, C_Three-C₁₂-Cyclohydrocarbyloxy, C_Three-C₁₂-Cyclohi
Drocarbirthio, C_Three-C₁₂-Cyclohydrocarbylamino, heteroaryl-C₁-
C₁₂-Hydrocarbyloxy, heteroaryl-C₁-C₁₂-Hydrocarbylthio, f
Teloaryl-C₁-C₁₂-Hydrocarbylamino, aryl-C₁-C₁₂-Hydrocarb
Ruoxy, aryl-C₁-C₁₂-Hydrocarbylthio, aryl-C₁-C₁₂-Hydroca
Ruviramino, heterocycle, heteroaryl, hydroxycarbonyl-C₁-C₁₂-Hid
Locarbyloxy, C₁-C₁₂-Alkoxycarbonyl-C₁-C₁₂-Alkoxy, C₁-C₁₂ -Hydrocarbilloyl, arylcarbonyl, aryl-C₁-C₁₂-Hydrocarbiro
Il, C₁-C₁₂-Hydrocarbyloxy, aryl-C₁-C₁₂-Hydrocarboyl
Xy, hydroxy-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydrocarb
Luoxy, C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxy-C₁-C₁₂ -Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl, hydroxyca
Rubonil-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbo
Nil-C₁-C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyl hydroxycarbonyl-
C₁-C₁₂-Hydrocarbylthio, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂ -Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxycarbonyl-C₁-C₁₂-H
Drocarbylthio, amino, C₁-C₁₂-Hydrocarbylcarbonylamino, ally
Lecarbonylamino, C_Three-C₁₂-Cyclohydrocarbylcarbonylamino, hetero
Cyclo-C₁-C₁₂-Hydrocarbylcarbonylamino, aryl-C₁-C₁₂-Hydroca
Rubiylcarbonylamino, heteroarylcarbonylamino, heteroaryl-
C₁-C₁₂-Hydrocarbylcarbonylamino, heterocyclo-C₁-C₁₂-Hydrocarb
Luoxy, C₁-C₁₂-Hydrocarbylsulfonylamino, arylsulfonylamino
No, aryl-C₁-C₁₂-Hydrocarbylsulfonylamino, heteroarylsul
Honylamino, heteroaryl-C₁-C₁₂-Hydrocarbylsulfonylamino, C_Three-
C₁₂-Cyclohydrocarbylsulfonylamino, heterocyclo-C₁-C₁₂-Hydroca
Rubylsulfonylamino and N-monosubstituted or N, N-disubstituted amino-C₁-C₁₂-Hydro
Selected from the group consisting of carbyl groups, wherein said amino-C₁-C₁₂-Hydrocarb
The substituent (s) on the nitrogen is₁-C₁₂-Hydrocarbyl, Ally
Le, aryl-C₁-C₁₂-Hydrocarbyl, C_Three-C₁₂-Cyclohydrocarbyl, ally
Le-C₁-C₁₂-Hydrocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxyca
Rubonyl and C₁-C₁₂Selected from the group consisting of -hydrocarboyl, or
Mino-C₁-C₁₂The -hydrocarbyl nitrogen and the two substituents attached thereto are 5- to 8-membered
Forming a heterocyclic or heteroaryl ring group; and wherein A is = CH-, Z is hydride, C₁-C₁₂-Hydrocarbyl, halogen or C₁-C_{1 Two} -When hydrocarbyl: 1) Ar¹Is hydride, halogen, C₁-C₁₂-Alkoxy, C₁-C₁₂-Hydrocarbyl
, Perfluoro-C₁-C₁₂-Hydrocarbyloxy, nitro, perfluoro-C₁-C_{1 Two} -Hydrocarbyl, amino, aminosulfonyl, halo-C₁-C₁₂-Hydrocarbyl
Oxy-C₁-C₁₂-Hydrocarbyl, hydroxy, C₁-C₁₂-Hydrocarbyl sulfoni
Lumino, C₁-C₁₂-Hydrocarbylsulfonyl, acetylamino, carbonyl-C ₁ -C₁₂-Hydrocarbylamino, perfluoro-C₁-C₁₂-Hydrocarbyl sulfoni
, C₁-C₁₂-Hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, C₁-
C₁₂-Hydrocarbylthio, hydroxy-C₁-C₁₂-Hydrocarbyl, aryl-C₁-
C₁₂-Hydrocarbyl, C₁-C₁₂-Hydrocarbyloxyhydrocarbyl, C₁-C₁₂-H
Drocarbyloxycarbonyl, C₁-C₁₂-Hydrocarbyloxyarylhydro
Carbyl, halo-C₁-C₁₂-Hydrocarbyloxy, C₁-C₁₂-Hydrocarbyloxy
A substituted with one or more substituents selected from the group consisting of hydrocarbyl.
Non-reel based; or 2) R¹Is a hydride, C₁-C₁₂-Hydrocarbyl, aryl, haloaryl, shea
Noaryl, hydroxyaryl, C₁-C₁₂-Hydrocarbylaryl, cyano,
Perfluoro-C₁-C₁₂-Hydrocarbyl, hydroxy-C₁-C₁₂-Hydrocarbyl,
Aryl-C₁-C₁₂-Hydrocarbyl, carboxy, C₁-C₁₂-Hydrocarbyloxy
Carbonyl, C₁-C₁₂-Hydrocarboylhydrocarbyl, aminocarbonyl,
Reel-C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarboyl-C₁-C₁₂-Hydroca
Rubil monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarbo
Il-C₁-C₁₂-Hydrocarbyl monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl
-C₁-C₁₂-Hydrocarbyl-C₁-C₁₂-Hydrocarboyl-C₁-C₁₂-Hydrocarbyl
Monosubstituted aminocarbonyl, C₁-C₁₂-Hydrocarbyl-hydroxy-disubstituted amino acids
Rubonil-C₁-C₁₂-Hydrocarbyl, or a 6-membered
Is other than a teloaryl group; or 3) R^TwoIs hydride, carboxy, C₁-C₁₂-Hydrocarbyloxycarbonyl,
Other than halogen or aryl, wherein the heterocycle is a saturated atom whose heteroatom is selected from nitrogen, sulfur or oxygen,
Means a cyclic group containing partially unsaturated and aromatically unsaturated heteroatoms,
Heteroaryl means an unsaturated 5- to 10-membered heteromonocyclic group, and aryl is
, 1, 2 or 3 monocyclic aromatic systems].
Or a method of treating said host mammal, comprising administering a pharmaceutically acceptable salt thereof.
Law.

Embedded image Wherein R ³ is hydride or C ₁ -C ₆ -hydrocarbyl; R ⁴ is hydride, C ₁ -C ₆ -hydrocarbyl, aryl-C ₁ -C ₆ -hydrocarbyl, hydroxyl-C _1- C ₆ - hydrocarbyl, and 2-pyridyl - C ₁ -C ₆ - hydrocarbyl,
Ar ¹ is independently selected from the group consisting of 3-pyridyl-C ₁ -C ₆ -hydrocarbyl or 4-pyridyl-C ₁ -C ₆ -hydrocarbyl; Ar ¹ is a halogen or halo group, C ₁ -C ₆ -hydrocarbyl, Or an aryl group substituted by C ₁ -C ₁₂ -hydrocarbyloxy; R ¹ is hydride or C ₁ -C ₆ -hydrocarbyl; and R ² is hydride or C ₁ -C _6- Which is a hydrocarbyl], or a pharmaceutically acceptable salt thereof.

Embedded image Wherein R ⁵ is hydride, C ₁ -C ₆ hydrocarbyl, or aryl-C ₁ -C _6-
Ar ¹ is a halogen, a C ₁ -C ₆ -hydrocarbyl, or an aryl group independently substituted by a C ₁ -C ₁₂ -hydrocarbyloxy group; R ¹ is a C ₁ -C ₆ hydrocarbyl And R ² is hydride], or a pharmaceutically acceptable salt thereof.

Embedded image Wherein Ar ¹ is halogen, C ₁ -C ₆ -hydrocarbyl or an aryl group substituted by a C ₁ -C ₁₂ -hydrocarbyloxy group; R ¹ is C ₁ -C ₆ -hydrocarbyl; And R ² is hydride or C ₁ -C ₆ -hydrocarbyl];
Or a method of treating said host mammal, comprising administering a pharmaceutically acceptable salt thereof.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 1/16 A61P 1/16 3/10 3/10 7/02 7/02 9/00 9/00 9 / 02 9/02 9/04 9/04 9/10 9/10 11/00 11/00 11/06 11/06 13/12 13/12 17/00 17/00 17/02 17/02 17/06 17/06 19/02 19/02 19/10 19/10 27/02 27/02 29/00 29/00 101 101 31/04 31/04 31/12 31/12 31/18 31/18 33/06 33/06 35/00 35/00 43/00 111 43/00 111 C07D 231/12 C07D 231/12 C 401/14 401/14 403/04 403/04 (81) Designated countries EP (AT, BE, CH , CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN) , GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ , PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW Sue, Giandon 60202, Illinois, United States, Evanston, Hinman Avenue 85 5, Apartment 715 (72) Inventor Clitch, Joyce Zee Glenview, Illinois, United States of America, Glenview, Top Lane 1501 (72) Inventor Lao, Shasidhar 63141, Missouri, United States of America, Cent Lewis, Belllive Manor Dry 736 F term (reference) 4C063 AA01 AA03 BB01 BB09 CC22 DD12 EE01 4C086 AA01 AA02 AA03 BC36 GA07 GA08 MA01 MA04 NA14 ZB11 ZC02 ZC20

Claims (62)

[Claims] 1. A compound of the formula I: Wherein A is = N- or = CH-; Ar ¹ is halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano,
Aryl optionally substituted with one or more substituents selected from the group consisting of perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxide Group,
Here, the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,
Here, the substituent on the sulfonamide nitrogen atom is hydride or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy , Hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, hetero Ring, heteroaryl, hydroxycarbonyl hydroca Viroxy, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, Hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarb Nylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl Sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino,
N-monosubstituted or N, N-disubstituted aminohydrocarbyl group [wherein the substituent (s) on the aminohydrocarbyl nitrogen atom is hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl , Hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group] , Amino, and N-monosubstituted or N, N-disubstituted amino groups wherein the substituent (s) on the amino nitrogen are hydride, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, aryl Hydrocarbyloxycarbonyl, hydrocarbyloxycarb Wherein the amino nitrogen and two substituents attached thereto are selected from the group consisting of bonyl, hydrocarbyl, arylsulfonyl, and hydrocarbylsulfonyl, and the amino nitrogen and the two substituents are a 5- to 8-membered heterocyclic or heteroaryl ring group. Z is hydride, hydrocarbyl, halogen, carboxy, cyano, azide, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamide, and -XY, where -X is -O, -S, or -NQ , -Y is hydride, hydrocarbyl or hydrocarbylaryl; and Q is hydride, hydrocarbyl, hydroxyhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl, independently selected from the group consisting of: ; R ¹ is azido, hydride, hydrocarbyl, amido Hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl , Heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, Heteroarylhydrocarby Ruoxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbiroyl, arylcarbonyl, arylhydrocarbiroyl , Hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy,
Hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, hetero Arylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfo Amino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, and an N-monosubstituted or N, N-disubstituted aminohydrocarbyl group wherein the (single or plural) substituents on the aminohydrocarbyl nitrogen atom are The hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and the two substituents attached thereto are 5- to 8-membered. R ² is independently selected from the group consisting of aryl substituents optionally substituted by one or more substituents selected from the group consisting of: forming a heterocycle or heteroaryl ring; and R ² is azide, Hydride, hydrocarbyl, a Amide, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl, and independently selected from the group consisting of an aryl group substituted with one or more substituents, One or more substituents are
Halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroaryl Amino, heteroaryl hydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio , Heteroarylhydrocarbi- Mino, aryl hydrocarbyloxy, aryl hydrocarbylthio, aryl hydrocarbyl amino, heterocyclic, heteroaryl, hydroxycarbonyl hydrocarbyloxy, alkoxycarbonylalkoxy,
Hydrocarbyl, arylcarbonyl, arylhydrocarbyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonyl Hydrocarbyl, hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, Reel hydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, Heterocyclohydrocarbylsulfonylamino and N-
Selected from the group consisting of monosubstituted or N, N-disubstituted aminohydrocarbyl groups, wherein said substituent (s) on the aminohydrocarbyl nitrogen is hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyl Wherein the aminohydrocarbyl nitrogen and two substituents selected from the group consisting of oxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl form a 5- to 8-membered heterocyclic or heteroaryl ring group. And where A is = CH- and Z is hydride, hydrocarbyl, halogen or hydrocarbyl: 1) Ar ¹ is hydride, halogen, hydrocarbyl, perfluorohydrocarbyloxy, nitro, perfluorohydrocarbyl, Amino, aminosulfonyl,
Halohydrocarbyloxyhydrocarbyl, hydroxy, hydrocarbylsulfonylamino, hydrocarbylsulfonyl, acetylamino, carbonylhydrocarbylamino, perfluorohydrocarbylsulfonyl, hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, hydrocarbylthio, hydroxyhydrocarbyl, arylhydrocarbyl, hydrocarbyloxyhydrocarbyl,
2) R ¹ is other than an aryl group substituted with one or more substituents selected from the group consisting of hydrocarbyloxycarbonyl, hydrocarbyloxyarylhydrocarbyl, halohydrocarbyloxy, hydrocarbyloxyhydrocarbyl; or Hydride, hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, hydrocarbylaryl, cyano, perfluorohydrocarbyl, hydroxyhydrocarbyl, arylhydrocarbyl, carboxy, hydrocarbyloxycarbonyl, hydrocarbylhydrocarbyl, aminocarbonyl, arylhydrocarbyl-hydrocarboyl- Hydrocarbyl, monosubstituted aminocarbonyl, hydrocarbyl hydrocarbyl-hydrocarbyl monosubstituted aminocarb 3) R ² is other than bonyl, hydrocarbyl-hydrocarbyl hydrocarbyl-hydrocarbyl monosubstituted aminocarbonyl, hydrocarbyl-hydroxy-disubstituted aminocarbonyl hydrocarbyl, or a 6-membered heteroaryl group substituted by a nitrogen atom; or Is other than hydride, carboxy, hydrocarbyloxycarbonyl, halogen or aryl], or a pharmaceutically acceptable salt thereof. Wherein Ar ¹ is fluorine or an aryl group substituted by a group selected from lower hydrocarbyl; R ¹ is hydride or lower hydrocarbyl; R ² is hydride; Independently selected from the group consisting of lower hydrocarbyl and aminocarbonyl; Z is hydride or -XY; -X is -O or -NQ; Q is aryl lower hydrocarbyl; and -Y is The compound according to claim 1, which is a hydride or a lower hydrocarbyl, or a pharmaceutically acceptable salt thereof. Wherein Ar ¹ is lower hydrocarbyl or an aryl group substituted by one or more substituents which are halogen; R ¹ is hydride or lower hydrocarbyl; R ² is , Hydride, or lower hydrocarbyl; Z is hydride or -XY; -X is -NQ; Q is lower hydrocarbyl or hydroxyl lower hydrocarbyl; and
The compound of claim 1, wherein -Y is hydride or lower hydrocarbyl, or a pharmaceutically acceptable salt thereof. Wherein Ar ¹ is an aryl group substituted by one or more substituents which are lower hydrocarbyl or halogen; R ¹ is hydride or lower hydrocarbyl; R ² is Is hydride; Z is cyano or -XY; wherein -X is -O or -NQ; Q is hydride, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 3-pyridyl lower Or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of hydrocarbyl; and -Y is hydride, lower hydrocarbyl, or aryl lower hydrocarbyl. 5. A compound of formula II: Wherein R ³ is hydride or C ₁ -C ₆ hydrocarbyl; R ⁴ is hydride, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2-pyridyl lower hydrocarbyl, 3-pyridyl lower hydrocarbyl or Ar ¹ is independently selected from the group consisting of 4-pyridyl lower hydrocarbyl; Ar ¹ is a halogen or halo group, lower hydrocarbyl, or aryl group substituted by hydrocarbyloxy; R ¹ is hydride, or C _1- it is a C ₆ hydrocarbyl; and R ² is the compound or a pharmaceutically acceptable salt of the structure corresponding to the hydride, or a lower hydrocarbyl. 6. Ar ¹ is an aryl group substituted by a lower hydrocarbyl; R ¹ is a lower hydrocarbyl; R ² is a hydride; R ³ is a hydride or C ₁ it is -C ₆ hydrocarbyl; and R ^4, C ₁ -C ₆ hydrocarbyl or aryl-lower hydrocarbyl, compound, or a pharmaceutically acceptable salt thereof according to claim 5. 7. Ar ¹ is an aryl group substituted by lower hydrocarbyl; R ¹ is lower hydrocarbyl; R ² is hydride; R ³ is hydride or lower hydrocarbyl And R ⁴ is lower hydrocarbyl, or hydroxyl lower hydrocarbyl, or a pharmaceutically acceptable salt thereof. 8. In the formula, Ar ¹ is an aryl group substituted by a lower hydrocarbyl or a halogen group; R ¹ is a hydride or a lower hydrocarbyl; R ² is a hydride; R ³ is , Hydride, or lower hydrocarbyl; and R ⁴ is aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, or
The compound according to claim 5, which is 3-pyridyl lower hydrocarbyl, or a pharmaceutically acceptable salt thereof. 9. A compound of formula III: Wherein R ⁵ is hydride, C ₁ -C ₆ hydrocarbyl, or aryl lower hydrocarbyl; Ar ¹ is an aryl group independently substituted with halogen, lower hydrocarbyl, or hydrocarbyloxy group; ¹ is C ₁ -C ₆ hydrocarbyl; and R ² is hydride] or a pharmaceutically acceptable salt thereof. 10. wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl group; R ¹ is lower hydrocarbyl; R ² is hydride; and R ⁵ is lower hydrocarbyl or aryl. 10. A lower hydrocarbyl.
Or a pharmaceutically acceptable salt thereof. 11. A compound of formula IV: Wherein Ar ¹ is an aryl group substituted by a halogen, lower hydrocarbyl or hydrocarbyloxy group; R ¹ is lower hydrocarbyl; and R ² is hydride or lower hydrocarbyl. Or a pharmaceutically acceptable salt thereof. 12. The compound of claim 11, wherein Ar ¹ is an aryl group substituted by a lower hydrocarbyl group; R ¹ is lower hydrocarbyl; and R ² is hydride. Or a pharmaceutically acceptable salt thereof. 13. The formula: embedded image A compound having a structure corresponding to 14. The formula: embedded image A compound having a structure corresponding to 15. The formula: embedded image A compound having a structure corresponding to 16. The formula: embedded image A compound having a structure corresponding to 17. A compound of the formula: A compound having a structure corresponding to 18. The formula: embedded image A compound having a structure corresponding to 19. A compound of the formula: A compound having a structure corresponding to 20. The formula: A compound having a structure corresponding to 21. The formula: embedded image A compound having a structure corresponding to 22. The formula: A compound having a structure corresponding to 23. The formula: A compound having a structure corresponding to 24. The formula: embedded image A compound having a structure corresponding to 25. The formula: embedded image A compound having a structure corresponding to 26. The formula: embedded image A compound having a structure corresponding to 27. The formula: embedded image A compound having a structure corresponding to 28. The formula: A compound having a structure corresponding to 29. The formula: A compound having a structure corresponding to 30. The formula: A compound having a structure corresponding to 31. The formula: A compound having a structure corresponding to 32. The formula: embedded image A compound having a structure corresponding to 33. The formula: embedded image A compound having a structure corresponding to 34. The formula: A compound having a structure corresponding to 35. The formula: embedded image A compound having a structure corresponding to 36. The formula: embedded image A compound having a structure corresponding to 37. The formula: A compound having a structure corresponding to 38. The formula: A compound having a structure corresponding to 39. The formula: A compound having a structure corresponding to 40. The formula: A compound having a structure corresponding to 41. The formula: embedded image A compound having a structure corresponding to 42. The formula: A compound having a structure corresponding to 43. The formula: embedded image A compound having a structure corresponding to 44. The formula: embedded image A compound having a structure corresponding to 45. The formula: A compound having a structure corresponding to 46. The formula: A compound having a structure corresponding to 47. The formula: A compound having a structure corresponding to 48. The formula: A compound having a structure corresponding to 49. The formula: A compound having a structure corresponding to 50. The formula: A compound having a structure corresponding to 51. A host mammal having a condition associated with pathological p38 MAP kinase activity is treated with a p38 MAP kinase enzyme-inhibiting effective amount of a formula I: Wherein A is = N- or = CH-; Ar ¹ is halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano,
Aryl optionally substituted with one or more substituents selected from the group consisting of perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxide Group,
Here, the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,
Here, the substituent on the sulfonamide nitrogen atom is hydride or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy , Hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, hetero Ring, heteroaryl, hydroxycarbonyl hydroca Viroxy, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbylyl, arylcarbonyl, arylhydrocarbylyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, Hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarb Nylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbyl Sulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino,
N-monosubstituted or N, N-disubstituted aminohydrocarbyl group [wherein the substituent (s) on the aminohydrocarbyl nitrogen atom is hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl , Hydrocarbyloxycarbonyl, and hydrocarbonyl, wherein the aminohydrocarbyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring group] , Amino, and N-monosubstituted or N, N-disubstituted amino groups wherein the substituent (s) on the amino nitrogen are hydride, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, aryl Hydrocarbyloxycarbonyl, hydrocarbyloxy The amino nitrogen and the two substituents selected therefrom are selected from the group consisting of carbonyl, hydrocarbyl, arylsulfonyl, and hydrocarbylsulfonyl, and the amino nitrogen and the two substituents are a 5- to 8-membered heterocyclic or heteroaryl ring group. Z is hydride, hydrocarbyl, halogen, carboxy, cyano, azide, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamide, and -XY, where -X is -O, -S, or -NQ , -Y is hydride, hydrocarbyl or hydrocarbylaryl, and Q is hydride, hydrocarbyl, hydroxyhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl. It is; R ¹ is azido, hydride, hydrocarbyl, Mido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl , Aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbyl Amino, heteroaryl hydro Carbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbiroyl, arylcarbonyl, arylhydrocarbylyl , Hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydrocarbonylhydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbyl hydroxycarbonyl Locarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino , Heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfo Amino, and an N-monosubstituted or N, N-disubstituted aminohydrocarbyl group (wherein the substituent (s) on the aminohydrocarbyl nitrogen atom is hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, aryl Selected from hydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and the two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring] are independently selected from the group consisting of aryl substituents are optionally substituted by one or more substituents selected from the group consisting of; and R ^2, azido, hydride, hydrocarbyl, amido, halohydrocarbyl, perhalo Hydrocarbyl, hydrocarbyloxycarbonyl, N -Piperazinylcarbonyl, aminocarbonyl, piperazinyl, and independently selected from the group consisting of aryl groups substituted with one or more substituents, wherein the one or more substituents are
Halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroaryl Amino, heteroaryl hydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio , Heteroarylhydrocarbi- Mino, aryl hydrocarbyloxy, aryl hydrocarbylthio, aryl hydrocarbyl amino, heterocyclic, heteroaryl, hydroxycarbonyl hydrocarbyloxy, alkoxycarbonylalkoxy,
Hydrocarboyl, arylcarbonyl, arylhydrocarbiroyl, hydrocarbyloxy, arylhydrocarbyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl,
Hydrocarbyl hydroxycarbonyl hydrocarbylthio, hydrocarbyloxycarbonyl hydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, hetero Arylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino Selected from the group consisting of heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups, wherein the substituent (s) on the aminohydrocarbyl nitrogen is hydrocarbyl, aryl , An arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarbyl, or the aminohydrocarbyl nitrogen and the two substituents bonded thereto are 5- to 8-membered. Forming a heterocyclic or heteroaryl ring group; and wherein A is = CH- and Z is hydride, hydrocarbyl, halogen or hydrocarbyl: 1) Ar ¹ is hydride, halogen, hydrocarbyl, perfluoro Hydrocarbyloxy, nitro, par Fluorohydrocarbyl, amino, aminosulfonyl,
Halohydrocarbyloxyhydrocarbyl, hydroxy, hydrocarbylsulfonylamino, hydrocarbylsulfonyl, acetylamino, carbonylhydrocarbylamino, perfluorohydrocarbylsulfonyl, hydrocarbylamino, carbonyl monosubstituted amino, carbonyl, hydrocarbylthio, hydroxyhydrocarbyl, arylhydrocarbyl, hydrocarbyloxyhydrocarbyl,
2) R ¹ is other than an aryl group substituted with one or more substituents selected from the group consisting of hydrocarbyloxycarbonyl, hydrocarbyloxyarylhydrocarbyl, halohydrocarbyloxy, hydrocarbyloxyhydrocarbyl; or Hydride, hydrocarbyl, aryl, haloaryl, cyanoaryl, hydroxyaryl, hydrocarbylaryl, cyano, perfluorohydrocarbyl, hydroxyhydrocarbyl, arylhydrocarbyl, carboxy, hydrocarbyloxycarbonyl, hydrocarbylhydrocarbyl, aminocarbonyl, arylhydrocarbyl-hydrocarboyl- Hydrocarbyl, monosubstituted aminocarbonyl, hydrocarbyl hydrocarbyl-hydrocarbyl monosubstituted aminocarb 3) R ² is other than bonyl, hydrocarbyl-hydrocarbyl hydrocarbyl-hydrocarbyl monosubstituted aminocarbonyl, hydrocarbyl-hydroxyl-disubstituted aminocarbonyl hydrocarbyl, or a 6-membered heteroaryl group substituted by a nitrogen atom; or Is other than hydride, carboxy, hydrocarbyloxycarbonyl, halogen or aryl], or a pharmaceutically acceptable salt thereof. During 52. wherein it said Ar ¹ substituent is fluorine, or a lower hydrocarbyl aryl group substituted by a group, wherein R ¹ substituent is hydrido or lower hydrocarbyl, said R ² substituent The group is independently selected from the group consisting of hydride, lower hydrocarbyl and aminocarbonyl, and wherein the Z substituent is
52. The method of claim 51, wherein -X is -O or -NQ; Q is aryl lower hydrocarbyl; and -Y is hydride or lower hydrocarbyl. . 53. wherein the Ar ¹ substituent is a lower hydrocarbyl or an aryl group substituted with one or more substituents that are halogen, and the R ¹ substituent is a hydride or a lower hydrocarbyl. and the said R ² substituent is hydrido or lower hydrocarbyl, and the Z substituent is hydrido or -X-,
52. The method of claim 51, wherein -X is -NQ; Q is lower hydrocarbyl or hydroxyl lower hydrocarbyl; and -Y is hydride or lower hydrocarbyl. 54. wherein the Ar ¹ substituent is an aryl group substituted with one or more substituents that are lower hydrocarbyl or halogen; and the R ¹ substituent is hydride or lower hydrocarbyl. Wherein the R ² substituent is hydride and the Z substituent is selected from cyano or -XY; wherein -X is -O
Or -NQ; Q is selected from the group consisting of hydride, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 3-pyridyl lower hydrocarbyl; and -Y is hydride, lower hydrocarbyl, or aryl lower hydrocarbyl 52. The method of claim 51, wherein 55. A host mammal having a condition associated with pathological p38 MAP kinase activity is treated with a p38 MAP kinase enzyme-inhibitory effective amount of a compound of formula II: Wherein R ³ is hydride or C ₁ -C ₆ hydrocarbyl; R ⁴ is hydride, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2-pyridyl lower hydrocarbyl, 3-pyridyl lower hydrocarbyl or Ar ¹ is independently selected from the group consisting of 4-pyridyl lower hydrocarbyl; Ar ¹ is a halogen or halo group, lower hydrocarbyl, or aryl group substituted by hydrocarbyloxy; R ¹ is hydride, or C _1- C ₆ hydrocarbyl; and R ² is hydride or lower hydrocarbyl.
Or a method of treating said host mammal, comprising administering a pharmaceutically acceptable salt thereof. 56. wherein the Ar ¹ substituent is an aryl group substituted with a lower hydrocarbyl, the R ¹ substituent is a lower hydrocarbyl, and the R ² substituent is hydride; wherein R ³ substituent is hydrido or C ₁ -C ₆ hydrocarbyl, and wherein R ⁴ substituents is C ₁ -C ₆ hydrocarbyl or aryl lower hydrocarbyl the method of claim 55. 57. wherein the Ar ¹ substituent is an aryl group substituted with a lower hydrocarbyl, the R ¹ substituent is a lower hydrocarbyl, and the R ² substituent is hydride; wherein R ³ substituent is hydrido or lower hydrocarbyl, and the R ⁴ substituents are lower hydrocarbyl or hydroxyl lower hydrocarbyl, the method of claim 55. 58. wherein the Ar ¹ substituent is a lower hydrocarbyl or an aryl group substituted with a halogen group, the R ¹ substituent is hydride, or a lower hydrocarbyl, and the R ² substituent is Is a hydride, and the R ³ substituent is
It is hydrido or lower hydrocarbyl, and the R ⁴ substituent is aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, or 3-pyridyl lower hydrocarbyl The method of claim 55. 59. A method comprising administering to a host mammal a condition associated with pathological p38 MAP kinase activity a p38 MAP kinase enzyme-inhibiting effective amount of a compound of formula III: Wherein R ⁵ is hydride, C ₁ -C ₆ hydrocarbyl, or aryl lower hydrocarbyl; Ar ¹ is an aryl group independently substituted with halogen, lower hydrocarbyl, or hydrocarbyloxy group R ¹ is C ₁ -C ₆ hydrocarbyl; and R ² is hydride], or a pharmaceutically acceptable salt thereof. Treatment method. 60. wherein the Ar ¹ substituent is an aryl group substituted with a lower hydrocarbyl group, the R ¹ substituent is lower hydrocarbyl, and the R ² substituent is hydride , and wherein R ⁵ substituents are lower hydrocarbyl or aryl lower hydrocarbyl the method of claim 59. 61. A method comprising administering to a host mammal a condition associated with pathological p38 MAP kinase activity a p38 MAP kinase enzyme-inhibiting effective amount of a compound of formula IV: Wherein Ar ¹ is an aryl group substituted by a halogen, lower hydrocarbyl or hydrocarbyloxy group; R ¹ is lower hydrocarbyl; and R ² is hydride or lower hydrocarbyl. Or a pharmaceutically acceptable salt thereof, for treating the host mammal. 62. wherein the Ar ¹ substituent is an aryl group substituted by a lower hydrocarbyl group, the R ¹ substituent is a lower hydrocarbyl, and the R ² substituent is hydride. 62. The method of claim 61, wherein there is.