BG64313B1 - SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS - Google Patents

Abstract

The invention relates to a class of pyrazole derivatives designed for administration in treating p38 kinase mediated disorders. The compounds have the formula wherein R1, R2, R3 and R4 are described in the specification. 162 claims

Description

The present invention relates to a novel group of pyrazole compounds, pyrazole-based compositions, and methods for treating p38 kinase-induced disorders.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAPs) are a family of proline-mediated serine / threonine kinases that activate their substrates by double phosphorylation. Kinases are activated by a variety of signals, including nutritional and osmotic stress, ultraviolet light, growth factors, endotoxin and inflammatory cytokines. The mitogen-activated p38 protein kinase family is a family of mitogen-activated protein kinases of different isoforms, including ρ38α, ρ38β and ρ38γ, responsible for phosphorylation and activation of transcription factors (eg, ATF2, CHOP and MEF2C), as well as other kinases for example, MARCAR-2 and MARCAR-3). The p38 isoforms are activated by bacterial lipopolysaccharides, physical and chemical stress, and by inflammatory cytokines including tumor necrosis factor (TNF-α) and interleukin-1 (IL-1). The products of p38 phosphorylation mediate the production of inflammatory cytokines including TNF and IL-1 and cyclooxygenase-2.

TNF-a is a cytokine produced mainly by activated monocytes and macrophages. Unusual or unregulated TNF production is associated with the regulation of a number of diseases. Recent studies show that TNF is the cause of the pathogenesis of rheumatoid arthritis. Additional studies indicate that TNF suppression is widely used in the treatment of inflammation, inflammatory internal organs, multiple sclerosis, and asthma.

TNF is also associated with infections such as HIV, influenza virus, herpes virus, including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabis and rhyotracheitis.

IL-8 is a dut inflammatory cytokine that is produced by mononuclear cells, fibroblasts, endothelial cells and keratinocytes and binds to conditions including inflammation.

IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological reactions, including rheumatoid arthritis, fever, and bone tissue assimilation.

TNF, IL-1, and IL-8 affect a wide variety of cells and tissues and are important regulators of inflammation in a wide variety of conditions and conditions. Suppression of these cytokines by inhibition of p38 kinase is useful in controlling, reducing and ameliorating many of these disease states.

Different pyrazoles have been described so far. In the U.S. Patent No. 4,000,281, Beiler and Binon describe 4,5-aryl / heteroaryl substituted pyrazoles with antiviral activity against RNA and DNA viruses, such as myxoviruses, adenoviruses, rhinoviruses and various herpes viruses. In WO 92/19615, published November 12, 1992, pyrazoles are described as novel fungicides. In the U.S. Patent No. No. 3,984,431, Cueremy and Renault describe pyrazole-5-acetic acid derivatives as having anti-inflammatory activity. In particular, [1-isobutyl-3,4-diphenyl-1H-pyrazole-

5-yl] acetic acid. In the U.S. Patent No. No. 3,245,093 to Hinsgen et al. describe a method for preparing pyrazoles. WO 83/00330, published February 3, 1983, describes a novel process for the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO 95/06036, published March 2, 1995, describes a process for the preparation of pyrazole derivatives. In the U.S. Patent No.

No. 5,589,439 to T. Goto et al. describe tetrazole derivatives and their use as herbicides. EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel fungicides for agriculture. Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as acetylcholinesterase inhibitors.

Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 4,145,081 describes the synthesis of pyrazole derivatives acting as anti-inflammatory, anti-rheumatic, antibacterial and antiviral drugs. EP-115640, published December 30, 1983, discloses 4-imidazolylpyrazole derivatives as inhibitors of thromboxane synthesis. In particular, 3- (4-isopropyl-1-methylcyclohex-1-yl) -4- (imidazol-1-yl) -1H-pyrazole is described. WO 97/01551, published January 16, 1997, describes pyrazole compounds as adenosine antagonists. In particular, 4- (3-oxo-2,3-dihydropyridazin-6-yl) -3-phenylpyrazole is described. In the U.S. Patent No. No. 5,134,142 to Matsuo et al. describe 1,5-diarylpyrazoles having anti-inflammatory activity.

In the U.S. Patent No. No. 5,559,137 to Adams et al. describe novel pyrazoles (1,3,4-substituted) as cytokine inhibitors used in the treatment of cytokine diseases. In particular, 3- (4-fluorophenyl) -1 (4-methylsulfinylphenyl) -4- (4-pyridyl) -5H-pyrazole is described. WO 96/03385, published February 8, 1996, discloses 3,4-substituted pyrazoles having anti-inflammatory activity. In particular, 4- [1-ethyl-4- (4-pyridyl) -5-trifluoromethyl-1H-pyrazol-3-yl] benzenesulfonamide is described.

The pyrazolyl compounds of the present invention have been found to be effective as inhibitors of p38 kinase.

SUMMARY OF THE INVENTION

A class of substituted pyrazole compounds that are effective in treating p38 kinase-related disorders is defined by Formula !:

. R ¹ (D; as for R:

R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenyl-alkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkyloxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene. amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino. arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl. alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkilkarbonilalkilen, arilkarbonilalkilen, heterotsiklilkarbonilalkilen, alkilkarboniloksialkilen, arilkarboniloksialkilen and heterotsiklilkarboniloksialkilen; or

R ¹ corresponds to a structure of formula (II):

R ²⁵ 0 I II R ²⁶ 1 II / With N \ _R 27 L, 1 BC (N);

in which i is a number from 0 to 9;

R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamino;

as for R ²⁶ and R ²⁷ :

R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and

R ²⁷ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl. alkoxyarylene, alkoksiaralkil, alkoksiheterotsiklil, alkoksialkoksiarilen, ariloksiarilen, aralkoksiarilen, alkoksiheterotsiklilalkilen, ariloksialkoksiarilen, alkoxycarbonylalkyl, alkoksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonil7 aryl, aryl karbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen, wherein:

said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or

R ²⁷ is -CHR ²⁸ R ²⁹ or

R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle, such as:

said heterocyclic heterocyclic acid;

said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy;

R ²⁸ is alkoxycarbonyl;

R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where:

said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro;

as for R ² :

R ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylboxycarboxycarboxylcarboxy cycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbylamino;

said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl; or

R ² corresponds to a structure of formula (III):

9 '

R ³⁰

I ---- (CH2) j

R ³¹

\ _R 33 (W), wmR ² e-CR ⁴¹ R ⁴² ;

R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen;

j is a digit from 0 to 8;

y is selected from the group consisting of 0 and 1;

R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl;

R ³² is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocycloalkylaminoalkylamines;

R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ¹⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ;

R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl;

R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl;

R ⁴¹ is aryl;

R ⁴² is hydroxy;

R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl,

Λ

wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, allyloxy, allyloxy, allyloxy arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkylcarbonyloxycarbonyloxycarbonyl butoxycarbonyl, alkoxycarbonylamino, alkoksiaralkilamino, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilheterotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil and -NR ⁴⁴ !! ⁴⁵ ;

R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing 2 hydroxy substituent and when R ¹ is hydrogen;

R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl;

R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino:

R ⁴⁵ is selected from the group consisting of alkyl and aralkyl;

R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where:

alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl , alkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkyl, aryl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl alkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen.

The compounds of Formula I are effective, but without limitation, for the treatment of any disorder or disease in a human or other mammal that is exacerbated or caused by an excess or unregulated amount produced by the same mammalian TNF or p38 kinase. Therefore, the present invention relates to a method of treating disorders involving cytokines, which comprises administering an effective amount by cytokine intervention of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The compounds of Formula I are effective, but without limitation, for the treatment of inflammation and for use as antipyretics for the treatment of fever. The compounds of the present invention are effective in treating arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritis. These compounds may be effective in treating lung disease or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, and chronic pulmonary inflammation. The compounds of the present invention are also effective in the treatment of viral and bacterial infections, including sepsis, septic shock, gram-negative sepsis, malaria, meningitis, secondary cachexia to infection or malignancy, secondary cachexia to acquired syndrome (acquired immunity syndrome). AIDS), AIDS, ARC (pneumonia and herpes). The compounds of the present invention are also effective in treating diseases associated with bone resorption, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune diseases, including graft and rejection, cardiovascular, cardiovascular, including atherosclerosis, thrombosis, cardiac arrest, cardiac reperfusion injury, renal reperfusion injury, liver and nephritis and myalgia due to infection. The compounds of the present invention are also effective in treating influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), skin diseases such as psoriasis, eczema, burns, dermatitis, keloid formation, scarring and angiography. . The compounds of the present invention are also effective in the treatment of digestive disorders such as bowel inflammation, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds of the present invention are also effective in the treatment of ocular diseases such as retinitis, resolvapaps, uveitis, ocular photophobia, and acute damage to ocular tissue. The compounds of the present invention are also effective in the treatment of angiogenesis including neoplasia, metastases, ophthalmic conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization, including neovascularization due to injury or infection, diabetic disease, glaucoma; peptic ulcer diseases such as gastric ulcer, pathological but not malignant conditions such as hemaginoma, including invasive hemaginoma, nasopharyngeal angiofibroma, and avascular bone necrosis; diabetic nephropathy and cardiomyopathy and diseases of the female reproductive system such as endometriosis. The compounds of the present invention are also effective in preventing the release of cyclooxygenase-2.

Although effective in the treatment of humans, these compounds are also effective in the veterinary treatment of domestic animals, exotic animals and farm animals including mammals, rodents and the like. Preferred animals for treatment are horses, dogs and cats.

The compounds of the present invention may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory agents, such as, together with steroids, cyclooxygenase-2 inhibitors, DMARD, immunosuppressants, NSAIDs, 5 inhibitors -lipoxygenase, LTB ₄ antagonists and inhibitors of LTA4 hydrolase.

As used herein, the term "TNF involvement disorder" refers to disorders and conditions in which TNF plays a role either in controlling TNF itself or through TNF to induce the release of another monokine, such as, but not limited to , IL-1, IL-6, or IL-8. A disease state in which, for example, IL-1 is a major component and whose production or action is exacerbated or released in response to TNF, is considered to be a disorder involving TNF.

As used herein, the term "p38 involvement disorder" refers to disorders and conditions in which p38 plays a role either in controlling p38 itself or by causing p38 to secrete another factor, such as, but not limited to , IL-1, IL-6, or IL-8. A disease state in which, for example, IL-1 is a major component and whose production or action is impaired or secreted in response to p38, is considered a disorder involving p38.

Because TNF-β has close structural homology to TNF-α (also known as cachectin), and since each induces a similar biological response and binds to the same cellular receptor, the synthesis of TNF-α and TNF-β is inhibited by the compounds according to the present invention, and are therefore referred to in the present invention by the common name "TNF", unless explicitly mentioned otherwise.

A preferred class of compounds consists of those compounds of Formula I in which:

R ¹ is selected from hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkiltioalkilen, amino, lower alkylamino, lower arylamino lower alkylaminoalkylene and lower heterocyclylalkylene;

or

R ¹ has the formula

R ^{25 0} _n 26 · ιII /

- With - with snr - With - N

I ⁿ (II) in which i is 0, 1 or 2; and

R ²⁵ is selected from hydrogen, lower alkyl, lower phenylalkyl, lower hscherotsiklilalkil, lower alkoxyalkyl, lower fenoksialkilen, lower aminoalkyl, lower alkylaminoalkyl, lower fenoksiaminoalkil, lower alkilkarbonilalkilen, lower fenoksikarbonilalkilen and lower heterotsiklilkarbonilaminoalkilen; and

R ²⁶ is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkyl and lower alkylaminoalkyl; and

R ²⁷ is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower tsikloalkenilalkilen, lower tsikloalkilarilen, lower tsikloalkiltsikloalkil, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl , lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkyloxyxylene oxycycloxy l, lower alkoksialkoksifenilen, lower fenoksifenilen, lower fenilalkoksifenilen, lower alkoksiheterotsiklilalkilen, lower fenoksialkoksifenilen, lower alkoxycarbonylalkyl, lower alkoksikarbonilheterotsiklil, lower alkoksikarbonilheterotsiklilkarbonilalkilsn, lower aminoalkyl, lower alkylaminoalkyl, lower fenilaminokarbonilalkilen, lower alkoksifenilaminokarbonilalkilen, lower aminokarbonilalkilen, lower arilaminokarbonilalkilen, lower alkilaminokarbonilalkilen, lower fenilkarbonilalkilen, lower alkoxycarbonylphenylene, lower phenoxycarbo ilfenilen, lower alkilfenoksikarbonilfenilen, lower fenilkarbonilfenilen, lower alkilfenilkarbonilfenilen, lower alkoksikarbonilheterotsiklilfenilen, lower alkoksikarbonilalkoksifenilen, lower heterotsiklilkarbonilalkilfenilen, lower alkiltioalkilen, tsikloalkiltioalkilen, lower alkiltiofenilen, lower fenilalkiltiofinilen, lower heterotsikliltiofenilen, lower feniltioalkilfenilen, lower fenilsulfonilaminoalkilen, lower alkilsulfonilfenilen, lower alkilaminosulfonilfenilen; wherein said lower alkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower fenalkil, lower cycloalkylalkylene, lower alkilheterotsiklilfenilen, lower alkoxyphenyl, lower fenoksifenilen, lower fenilaminokarbonilalkilen, lower fenoksikarbonilfenilen, lower fenilkarbonilfenilen, lower alkiltiofenilen, lower heterotsikliltiofenilen , lower phenylthioalkylphenylene and lower alkylsulfonylphenylene are optionally substituted by one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, k it, amino, nitro and cyano; or

R ²⁷ is -CHR ⁴⁶ R ⁴⁷ wherein R ⁴⁶ is lower alkoxycarbonyl and R ⁴⁷ is selected from lower fenalkil, lower fenilalkoksialkilen, lower hetero cycles lalkilen, lower alkilheterotsiklilalkilen, lower alkoxycarbonylalkyl, lower alkiltioalkilen and lower fenilalkiltioalkilen; wherein said phenalkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from lower alkyl and nitro; or

R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form from a 4 to 8 membered heterocycle, said heterocycle being optionally substituted by one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl , heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenyloxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonylaminocarbonylaminocarbonylamino wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene are optionally substituted by one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and

R ² is selected from hydrido, halogen, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower haloalkyl, lower hydroxyalkyl, lower 5 or 6-membered heterocyclyl, lower alkylheterocyclyl, lower alkylnylamylcylamylcylaminylaminoalkylaminoalkylaminoalkylaminoalkylamino; heterocyclopaediate yl, lower alkoksikarbonilheterotsiklil, lower alkoksikarbonilheterotsiklilkarbonil, lower alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoksikarbonilaminoalkilamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl are optionally substituted by one or more radicals independently selected from halo, keto, lower alkyl, lower alkynyl, phenyl, 5- or

6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower keto, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkilaminoalkilamino, lower alkynylamino, lower amino (hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower al

xuulfonyl, lower phenylalkylsulfonyl and phenylsulfonyl; or

R ² has the formula:

R ³⁰

I - c-csn) IR ^{3 1} a which:

I is 0, 1 or 2; and πί is 0;

R ³⁰ and R ³¹ are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; and

R ³² is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkyl; and

R ³³ is selected from hydrogen, alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ , where

R ³⁵ is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, tsikloalkenilalkilen, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylaryl, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkyl, alkoksiaralkil, alkoxyarylene, aryloxyalkylene, aralkoksialkilen, tsikloalkiloksialkilen, alkoxycarbonyl , heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbo! schloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene and alkylthioalkylene; where said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkyl, cycloalkylcarbonyl and alkoxycarbonylheterocycloalkyl, alkyl or alkyloalkyl; cyano; or

R ³⁵ is CHR ⁴⁸ R ⁴⁹ where R ⁴⁸ is arylsulfonylamino or alkylarylsulfonylamino, and R ⁴⁹ is selected from aralkyl, amino, alkylamino and aralkylamino; or

R ³⁵ is -NR ⁵⁰ R ⁵¹ where R ⁵⁰ is alkyl and R ⁵¹ is aryl; and wherein R ³⁶ is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylaryl, arylaryl, aralkyl, aralkenyl, heterotsiklilheterotsiklil, karboksiarilen, alkoxyarylene, alkoksikarbonilarilen, alkilkarbonilaminoarilen, alkilkarbonilaminoheterotsiklil, arilkarbonilaminoalkilheterotsiklil, alkylaminoaryl, alkylamino, alkylaminoaryl, alkilsulfonilarilen, alkilsulfonilaralkil and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl and alkylsulfonylarylene are optionally substituted by one or more radicals independently selected from halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, haloalkoxy; and wherein R ³⁷ is selected from hydrogen and alkyl; and wherein R ³⁸ is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylaryl, cycloalkylalkylene, heterocyclylalkylene, alkilheterotsiklilalkilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, ariloksiarilen, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoksikarbonilarilen, alkilkarbonilkarbonilalkilen, alkylaminoalkyl , alkylamino aralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonyl aralkyl and aminosulfonyl aralkyl; wherein said aryl, heterocyclyl, aralkyl and heterocyclylalkylene are optionally substituted by one or more radicals independently selected from halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; or

R ³⁸ is -CR ⁵² R ⁵³ where R ⁵² is alkoxycarbonyl and R ⁵³ is alkylthioalkylene; or

R ³⁷ and R ³⁸ together with the nitrogen atom to which they are attached form a heterocycle; and

R ³⁹ and R ⁴⁰ have the same definitions as R ²⁶ and R ²⁷ in claim 1; or

R ² is -CR 4 R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; or

R ² is selected from the group consisting of

(VI) (VII) (VIII) where:

k is from 0 to 3; and

R ⁵⁶ is hydrogen or lower alkyl; and

R ⁵¹ is hydrogen or lower alkyl; or

R ⁵⁶ and R ⁵⁷ form a lower alkylene bridge; and

R ⁵⁸ is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C (O) R ⁵⁹ , -SO ₂ R ⁶⁰ , -C (O) NHR ⁶¹ ;

wherein R ⁵⁹ is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenyloxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaryl; wherein said aryl, heterocyclyl and aralkyl are optionally substituted by one or more radicals independently selected from halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶⁰ is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene and alkylsulfonylheterocyclyl; wherein said aryl, heterocyclyl and aralkyl are optionally substituted by one or more radicals independently selected from halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶¹ is selected from alkyl, aryl, alkylarylene and alkoxyarylene; wherein said aryl group is optionally substituted by one or more radicals independently selected from halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and

R ³ is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and (IV) wherein R ⁴³ is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkoxyalkyl and lower aryloxyalkyl; and wherein the R ³ radicals of pyridinyl, pyrimidinyl, quinolinyl, and puriyl are optionally substituted by one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower aralkyl, phenylalkylsilyl phenylsilylcylcylcylcylcylcylcylcylcylcylcylksilylcyllylcyllysilyl; , cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkynylamines, lower alkynylamines, lower alkynylamines, sulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoksifenilalkilamino, lower alkilaminoalkilamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterobifunctional rotsiklilalkilamino, lower fenilalkilheterotsiklilamino, lower alkylaminocarbonyl, lower alkoksifenilalkilamino, hydrazinyl, lower alkilhidrazinil or -NR ⁶² R ^63, where R ⁶² is lower alkylcarbonyl or amino, and R ⁶³ is lower alkyl or lower phenylalkyl; and

R ⁴ is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl and naphthyl, and a 5- or 6-membered heterocyclyl, wherein lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclic of R ⁴ is optionally substituted by one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclo, cycloalkyl, lower alkylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

A class of compounds of particular interest consists of those compounds of Formula I in which

R ¹ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl , ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, aminomethylthiomethyl ino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl; and

R ² is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoromethyl, pentafluoromethyl difluoroethyl, dichloroethylene, dichloromethane, dichloromethane, dichloromethane zinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N, N-dimethylamino, N-methyl-phenylamino, N-phenylamino, N-piperadinylamino benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, Ν, Ν-dimethylaminoethylamino, Ν, Ν-dimethylaminopropylamino, morfoliniletilamino, morfolinilpropilamino, carboxymethylamino, methoxyetes lamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylethoxycarbonylaminoethylamino, 1,1-dimethyloxycarbonylaminopropylamino, piperazinylcarbonyl and 1,1-dimethylethoxycarbonylpiperazinyl; wherein aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted by one or more radicals independently selected from chlorine, fluorine, bromine, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl and 1,1-dimethylethylcarbonyl; or

R ² is -CR 4 R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; and

R ³ is selected from pyridinyl, pyrimidinyl and purinyl; wherein R ³ is optionally substituted by one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, chlorine, fluorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonylcarbonylcarbonylcarbonyl fluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichlormethyl, hydroxy, fluorocarbon p-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitrol, chloropropylamino, nitrol, chloropropylamino, nitroyl, chloropropylamino ethoxycarbonylamino, methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylphenylmethylphenyl amino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, metoksifenilmetilamino, hydrazinyl, 1-methyl-hydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² is methylcarbonyl or amino, a R ⁶³ is methyl, ethyl or phenylmethyl; and

R ⁴ is selected from hydrogen ", cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tsiklopropilenil, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl and benzoyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R ⁴ are optionally substituted by one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, chlorine, fluorine, bromine, methyl, ethyl, isopropyl, tertbutyl, isobutyl, isobutyl, isobutyl, isoxy , ethoxy, phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula I wherein

R ¹ is selected from hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;

R ² is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N, N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl and piperazinylamino; wherein the phenyl, piperidinyl and pyridinyl groups are optionally substituted by one or more radicals independently selected from chlorine, fluorine, bromine, methyl, ethyl and trifluoromethyl;

R ³ is selected from pyridinyl, pyrimidinyl and quinolinyl; wherein R ³ is optionally substituted by one or more radicals independently selected from fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxide, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, aminoalkyl, hydroxycarbonyl ;

R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R ⁴ are optionally substituted by one or more radicals independently selected from methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino hydroxy;

or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula I wherein

R ¹ is hydrogen or methyl;

R ² is selected from hydrogen, methyl or ethyl;

R ³ is selected from pyridinyl, pyrimidinyl and quinolinyl; wherein R ³ is optionally substituted by one or more radicals independently selected from fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, aminoalkyl, hydroxy and hydroxy ;

R ⁴ is selected from phenyl which is optionally substituted by one or more radicals independently selected from methylthio, chloro, fluoro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula I in which

R ¹ is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl , ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methyloxymethyl mino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethyl aminostyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl and mercaptylmethyl; and

R ² has the formula:

(Iii) in which:

J is 0, I or 2; and πι is 0;

R ³⁰ and R ³¹ are independently selected from hydrogen and lower alkyl;

R ³² is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, aryloxyalkylene, aminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylenylalkenyl

R ³³ is selected from hydrogen, lower alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ , where

R ³⁵ is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower tsikloalkenilalkilen, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, fenilfenilen, lower phenylheterocyclyl, lower alkoxy, lower alkoxy, lower alkoxyalkylene, lower alkoxyphenyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkyl, alkyloalkyl, alkyloxyalkyl, alkyloxyalkyl boniloksialkilen, lower alkilkarboniloksifenilen, lower alkoxycarbonylalkyl, lower alkoksikarbonilfeni flax, lower fenilalkoksikarbonilheterotsiklil, lower alkilkarbonilheterotsiklil, lower fenilkarboniloksialkilfenilen and lower alkiltioalkilen; wherever aryl is selected from phenyl, biphenyl and naphthyl, lower heterocyclic, lower phenylhexyl, lower alkyloxycarbonyl; from halo, alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or

R ³⁵ is CHR ⁴⁸ R ⁴⁹ where R ⁴⁸ is phenylsulfonylamino or lower alkylphenylsulfonylamino and R ⁴⁹ is selected from lower phenylalkyl, amino, lower alkylamino and lower phenylalkylamino; or

R ³⁵ is -NR ⁵⁰ R ⁵¹ where R ⁵⁰ is lower alkyl and R ⁵¹ is aryl selected from phenyl, biphenyl and naphthyl; and wherein R ³⁶ is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenilfenilen, fenilfenilen, lower fenalkil, lower phenylalkenyl, lower heterotsiklilheterotsiklil, karboksifenilen, lower alkoxyphenyl , lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylsulfonylphenylalkenylphenylalkylphenylene ilsulfonilfenilalkil and lower fenilsulfonilheterotsiklil; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl and lower alkylsulfonylphenylene groups is optionally substituted by one or more hydroxyalkyls, hydroxyl, alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ is selected from hydrogen and lower alkyl; and wherein R ³⁸ is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, fenilfenilen, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkilheterotsiklilalkilen, lower fenilalkilheterotsiklil , lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkyl, alkylene alkylene, alkylene alkylene nofenilalkil, lower alkilkarbonilamipoalkilen, lower alkiltiofenilen, lower alkileulfonilfenilalkil and lower aminosulfonilfenilalkil; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl and lower heterocyclylalkylene are optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower haloalkyl, lower alkoxy, lower alkoxy, lower haloalkyl, lower alkoxy amino, nitro and cyano; or R ³⁸ is -CR ⁵² R ⁵³ where R ⁵² is lower alkoxycarbonyl and R ⁵³ is lower alkylglyoalkylene; or

R and R together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle; and

R ³⁹ and R ⁴⁰ have the same definitions as R ²⁶ and R ²⁷ in claim 2; or R is selected from the group consisting of

N

(VI) (VII) (VIII) where:

k is 0 to 2; and

R ⁵⁶ is hydrogen or lower alkyl; and

R ⁵⁷ is hydrogen or lower alkyl; and

R ⁵⁸ is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C (O) R ^59, - SO ₂ R ⁶⁰ , -C (O) NHR ⁶¹ ;

wherein R ⁵⁹ is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkyloxyalkyl, lower alkyloxyalkyl, lower alkyloxy alkoxyphenylene, lower alkoxyphenyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower haloalkoxy, and cyano; and wherein R ⁶⁰ is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower heterotsiklilheterotsiklil, lower alkoxyphenyl, lower alkylamino, lower alkilaminofenilen, lower alkilsulfonilfenilen and lower fenilsulfonilheterotsiklil; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl groups is optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower haloalkoxy, lower haloalkoxy, lower haloalkoxy nitro and cyano; and wherein R ⁶¹ is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower alkylphenylene and lower alkoxyphenylene; wherein said aryl group is optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and

R ³ is selected from pyridinyl, pyrimidinyl, quinolinyl and purinyl; wherein R ³ is optionally substituted by one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonylcarbonylcarbonylcarbonyl fluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichlormethyl, hydroxy, fluorocarbon p-butyl, ethylamino, dimethylamino, diethylamino, propylamino, aminomethyl, n-methyl-phenylamino, phenylamino, pentylamine methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylpiperidinylamino, phenylmethylpiperidinylamino amino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, metoksifenilmetilamino, hydrazinyl, 1-metilhidrazinil or -NR ⁶² R ⁶³ wherein R ⁶² is methylcarbonyl or amino, a R ⁶³ is methyl, ethyl or phenylmethyl; and

R ⁴ is selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, piperidinyl, piperidinyl , pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenziofuryl and benzyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R ⁴ are optionally substituted by one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, chlorine, fluorine, bromine, methyl, ethyl, isopropyl, tertbutyl, isobutyl, isobutyl, isobutyl, isobutyl, isoxy ethoxy, phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula I in which

R ¹ is selected from Hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimegylaminoethyl, diethylaminoethyl and morpholinylethyl;

R has the formula:

pZ ° g n “IR ³²

I I /

L ^R (III) in which:

j is 0, 1 or 2; and m is 0;

R ³⁰ is hydrogen; and

R ³¹ is selected from hydrogen and lower alkyl; and

R is selected from hydrogen and lower alkyl;

R ³³ is selected from lower alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO ₂ R ³⁶ ,

-C (O) NR ³⁷ R ³⁸ and -SO ₂ NR ³⁹ R ⁴⁰ ;

wherein R ³⁵ is selected from lower alkyl, lower cycloalkyl, phenyl, lower xherocyclyl, lower alkylphenylene, lower alkoxy, lower alkoxy, lower alkoxyalkylene, lower phenoxyalkylene and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl and lower haloalkyl; and wherein R ³⁶ is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and where R ³⁷ is hydrogen; and wherein R ³⁸ is selected from lower alkyl, phenyl and lower alkylphenylene;

R ³⁹ and R ⁴⁰ have the same definitions as R ²⁶ and R ²⁷ in claim 2; or

R ² is selected from the group consisting of

I

С С н ₂ } _k _ (VII) where:

k is 0 or 1; and

R ⁵⁶ is hydrogen; and

R ⁵⁷ is hydrogen; and (VIII)

R ⁵⁸ is selected from -C (O) R ⁵⁹ and -SO 2 R ⁶⁰ ;

wherein R ⁵⁹ is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene and lower alkoxyalkylene; wherein said phenyl group is optionally substituted by one or more radicals independently selected from halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶⁰ is selected from lower alkyl; and

R is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R is optionally substituted by one or more radicals independently selected from fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy and hydroxy; and

R ⁴ is selected from phenyl, quinolyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R ⁴ are optionally substituted by one or more radicals independently selected from methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula I in which

R ¹ is selected from hydrogen or methyl; and

R is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R is optionally substituted by one or more radicals independently selected from fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy and hydroxy; and

R ⁴ is selected from phenyl which is optionally substituted by one or more radicals independently selected from methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

In one aspect of the present invention, the compounds of Formula I satisfy one or more of the following conditions:

R ¹ is hydrido or lower alkyl; preferably R ¹ is hydrido or methyl; and more preferably R ¹ is hydrido;

R ² is hydrido or lower alkyl; preferably R ² is hydrido or methyl; and more preferably R ² is hydrido;

R ³ is substituted or unsubstituted pyridinyl; preferably pyridinyl is 4-pyridinyl;

R ⁴ is substituted or unsubstituted phenyl; preferably R ⁴ is phenyl substituted with halo.

In addition, when R ³ is substituted pyrimidinyl, at least one of the R ³ substituents is preferably bonded to a carbon atom at a position between two nitrogen atoms of the pyrimidinyl ring.

A family of specific compounds of particular interest of Formula I consists of compounds, tautomers and pharmaceutically acceptable salts thereof, as follows:

4- [5- (3-Fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

4- [5-methyl-3- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [5-methyl-3- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [5-methyl-3- [4- (methylthio) phenyl] -1H-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- (5- (2,5-dimethylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- (5- (1,3-benzodioxol-5-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -1H-pyrazole -4-yl] pyridine;

4- (5- (1,1'-biphenyl) -4-yl] -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- [3- (phenoxyphenyl)] -1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- [3- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- [2- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine;

2- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol;

3- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol;

-hydroxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridinium;

5- (4-fluorophenyl) -N> 1-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

5- (4-fluorophenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

4- [5- (4-Fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] pyridine; 4- (5-cyclohexyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-Fluoro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-methylphenyl) -3-propyl-1H-pyrazol-4-yl] pyridine; 4 - [(3-methyl-5-phenyl-1H-pyrazol-4-yl) methyl] pyridine;

4- (3,5-bis (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [4-methyl-2- (2-trifluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (2-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [5-methyl-3- (2,4-dimethylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [5- (4-Chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-fluoro-2-methylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- (3- (3,5-dimethylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- (3- (3,5-dimethoxyphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [5-methyl-3- (3-nitrophenyl) -1H-pyrazol-4-yl] pyridine;

N, N-dimethyl-4- [5-methyl-4- (4-pyridinyl) -1H-pyrazol-3-yl] benzenamine;

4- (3- (2,3-dihydrobenzofuran-5-yl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-bromophenyl) -5-methyl-1H-pyrazole -4-yl] pyridine;

4- [3- (2-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- (3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine;

4- (3-ethyl-4-phenyl-1H-pyrazol-4-yl) pyridine;

4- [5- (3-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-ethyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- (5- (3,4-difluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-Ethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine;

4- [3-methyl-5- (3-thienyl) -1H-pyrazol-4-yl] pyridine;

4- (5- (2,4-dichlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Chloro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

ethyl 3- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazole-5-propanoate,

4- [3- (4-fluorophenyl> 1-methyl-pyrazol-4-yl] pyridine;

5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine;

5- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyrimidin-2-amine;

5- [3-methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyrimidin-2-amine;

5- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine;

5- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine;

5- (5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine,

5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

4- (5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine;

5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

2-methoxy-5- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

2-methoxy-5- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

2-methoxy-4- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

2-methoxy-4- [3-methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

4- [5- (4-fluorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

2-methoxy-4- [3-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine;

5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol;

4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol;

5- [5- (3-Chlorophenyl} -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (3-chlorophenyl) -3-methyl-1H-pyrazole- 4-yl] pyridin-2-methanamine; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (4-chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide;

4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (3-Fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (4-Fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (4-Chloro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- (5- (2,3-dihydrobenzofuran-6-yl) -3-methyl> 1H-pyrazol-4-yl] pyridine; 4- (5- (benzofuran-6-yl) -3-methyl-1H- pyrazol-4-yl] pyridine; 4- [5- (3-fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-chloro-5- methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- (5- (1-cyclohexylene-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine;

4- (5- (1,3-cyclohexadien-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- (5- (5,6-dihydro-2H-pyran-4- yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl) pyridine;

4- [5- (4-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Methoxy-5-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine ·, 4- [5- (3-furyl) -3-methyl-1H-pyrazole- 4-yl] pyridine;

2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

2-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2-carboxylate; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2-carboxylate;

- [4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-2-yl] ethanone; H1-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-2-amine;

3-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

3-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3-carboxylate;

4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3-carboxamide;

- [4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-3-yl] ethanone;

3-bromo-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

N, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-3-amine;

2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine;

4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine;

2-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine;

4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine; N, 14-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine; 4- (5,6-dihydro-2H-pyran-4-yl) -3-methyl-5-phenyl-1H-pyrazole;

3-methyl-5-phenyl-4- (3-thienyl) -1H-pyrazole;

4- (3-furyl) -3-methyl-5-phenyl-1H-pyrazole;

3-methyl-5-phenyl-4- (2-thienyl) -1H-pyrazole;

4- (2-furyl) -3-methyl-5-phenyl-1H-pyrazole;

4- (3-Isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole;

4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole;

4- (5-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole;

4- (5-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole;

3-methyl-5-phenyl-4- (5-thiazolyl) -1H-pyrazole;

3-methyl-4- (5-oxazolyl) -5-phenyl-1H-pyrazole;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine;

2-methyl-4- [3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- (1-methyl-3-phenyl-1H-pyrazol-4-yl) pyridine;

4- (3-phenyl-1H-pyrazol-4-yl) pyridine;

2-methyl-4- (3-phenyl-1H-pyrazol-4-yl) pyridine;

4- [3- (3-chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine;

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] 2-methylpyridine;

4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (3-chlorophenyl) -1-methyl-pyrazol-4-yl] -2-methylpyridine;

5- (4-chlorophenyl) -1H-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

5- (4-chlorophenyl) -14-methyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

5- (4-chlorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazole-3-amine dihydrate;

5- (3-fluorophenyl) -NK-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

14, N-dimethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine;

N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine;

N-ethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N, N-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine;

5- (4-chlorophenyl) -H, N-diethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] morpholine;

5- (4-chlorophenyl) -H-propyl-4- (4-pyridinyl) -1H-pyrazole-3-amine;

5- (4-chlorophenyl) -14- (phenylmethyl) ~ 4- (4-pyridinyl) -1H-pyrazol-3-amine hydrate (2: 1);

5- (4-chlorophenyl) -N- (2-methoxyethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine monohydrate;

1,1-dimethylethyl 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1 piperazinecarboxylate;

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine trihydrochloride;

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methylpiperazine;

1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 42

-piperazinecarboxylate;

- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine trihydrochloride;

N- [5- (4-chlorophenyl) -4- [2- (phenylmethyl) amino] -4-pyridinyl] -1H-pyrazol3-yl] -1,3-propanediamine trihydrochloride;

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4- (phenylmethyl) piperazine;

4- [3- (4-fluorophenyl) 5- (1-piperazinyl) -1H-pyrazol-4-yl] pyrimidine dihydrochloride;

1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate;

N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1,3-propanediamine trihydrochloride monohydrate;

1,1-dimethylethyl [2 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] amino] ethyl] carbamate;

1,1-dimethylethyl 4- [5- (4-chlorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -

N-pyrazol-3-yl] -1-piperazinecarboxylate;

1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-Zyl] -1-piperazinecarboxylate,

1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (2-fluoro-4-pyridinyl) -1Hpyrazol-3-yl] amino] propyl] carbamate;

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-ethylpiperazine;

14- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1,2-ethanediamine;

4- (3- (2,6-difluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-ethylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine;

4- [3-ethyl-5- (3-ethylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -5- (1-methylethyl) -1H-pyrazol-4-yl] pyridine;

4- [3-cyclopropyl-5- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4 ~ fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine;

4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine);

5- cyclopropyl-3- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol;

3- (4- (fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol;

4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone;

-acetyl-4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1Hpyrazol-5-yl] -2 (1H) -pyridinone;

ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1Hpyrazol-5-yl] cyclopropanecarboxylate;

2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylic acid;

3- (4- (fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol;

4- [3- (4-chloro-3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

5- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-carboxylic acid;

5- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-methanol;

- [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] piperazine;

1,1-dimethylethyl 4 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3yl] carbonyl] -1-piperazinecarboxylate,

4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine;

4- (1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

4- [3- (4-chlorophenyl) -1,5-dimethyl-1H-pyrazol-4-yl] pyridine;

4- [5- (4-Chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine;

4- [5-ethyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- [3-ethyl-1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -2-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (2-chlorophenyl) -1H-pyrazol-4-yl] pyridine;

3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol;

3- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-1-ethanol;

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

2- [[4- [3- (4-fluorophenyl> 1H-pyrazol-4-yl] -2-pyridinyl] amino] -1-butanol;

4- [5-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile; 4- [2- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-yl] ethyl] morpholine;

3- (4-fluorophenyl) -1-methyl-α-phenyl-4- (4-pyrimidinyl) -1H-pyrazole-5-methanol;

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinethane amine;

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyridinamine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -1H- (phenylethyl) -2-pyridinamine; 4- [3- (3-chlorophenyl> 1H-pyrazol-4-yl] -N-ethyl-2-pyridinamine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide; methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate; 4- [3- (4-fluorophenyl) -N-pyrazol-4-yl] -14-methyl-2-pyridinecarboxamide; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylic acid; 4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- (3- (1,3-benzodioxol-5-yl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4- yl] pyridine;

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyridine;

4- (3- (1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine;

4- [5- (3-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine;

4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [5- (3-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

2-methyl-4- [1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

2-methyl-4- [1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

4- (3-phenyl-1H-pyrazol-4-yl) pyridine;

4- [3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine;

4- [1-methyl-3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine,

4- (3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine;

4- [3- (4-bromophenyl) -1H-pyrazol-4-yl] pyridine;

4- (3- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

(E) -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-phenylethenyl) pyridine;

(c) -4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -14- (2-methylbutyl) -2-pyridinamine;

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N [(4-methoxyphenyl) methyl] -2pyridinamine;

N1-4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridinomethane amine;

N4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridinmethane amine;

2-fluoro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-iodophenyl) -1H-pyrazol-4-yl] pyridine;

4- [3- (4-iodophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [1-methyl-3- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine;

N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine;

N - [(3-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine;

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2- (1-methylhydrazino) pyridine;

2- fluoro-4- [3- (4-fluorophenyl> 1-methyl-1H-pyrazol-4-yl] pyridine; 4- (3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine;

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -3-methylpyridine;

4- (3- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-fluoropyridine;

3- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-1-ethanamine;

2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H- [1- (phenylmethyl) -4-piperidinyl] -2-pyridinamine;

N '- [4- [3- (4-fluorophenyl> 1H-pyrazol-4-yl] -2-pyridinyl] N, N-dimethyl-

1,2-ethanediamine;

2,4-bis [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -4-morpholinethanamine;

3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-1-ethanol;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol-1-yl) ethyl] -2-pyridinamine;

4- [2- [3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl> 1H-pyrazol-1-yl] ethyl] morpholine;

(E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] -4-pyridinyl] -1H-pyrazole-1-ethanol;

3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) ethenyl] -4-pyridinyl] -N, 4-dimethyl-1H-pyrazol-1-ethanamine;

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -1H-pyrazole-

1-ethanol;

4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H, N-dimethyl-2-pyridinamine;

4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1 H [(4-fluorophenyl) methyl] -2-pyridinamine;

3- (4-fluorophenyl) ~ 4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -NH-dimethyl-1H-pyrazol-1-ethanamine;

N - [(4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1 - [[2- (4-morpholinyl) ethyl] -1H-pyrazol-4-yl] -2- pyridinamine;

4- [3- (4-fluorophenyl> 1H-pyrazol-4-yl] -H-4-piperadinyl-2-pyridinamine;

N, N-diets 1- 3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1 ethanamine;

4- [1- [2- (diethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -L1 - [(4-fluorophenyl) methyl] -2-pyridinamine;

2 - [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol;

2- [[4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol;

3- [[4- [3- (4-fluorophenyl} -1H-pyrazol-4-yl] -2-pyridinyl] amino] 1-propanol;

3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] 4-pyridinyl] -1H-pyrazole-1-ethanol;

5- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazol-1-ethanol;

N, N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanamine;

N - [(4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4-morpholinyl) ethyl] 1H-pyrazol-4-yl] -2-pyridinamine;

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholine propanamine;

N '- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1H, 1H-dimethyl-

1,3-propandiamine;

5- (4-fluorophenyl) -1H-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine;

3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazo-1-ethanol;

5- (4-fluorophenyl) ~ 4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazole-1-ethanol;

4- [3 - [(4-fluorophenyl) -1H-pyrazol-4-yl] quinoline;

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-glycine methyl ester;

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-1H -razol-3-yl] -4-glycine;

4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine;

4- [5- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine;

4,4 '- (1H-pyrazole-3,4-diyl) bis [pyridine];

4- (3- (3,4-dichlorophenyl) -1H-pyrazol-4-yl] pyridine; No. [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] N -) -piperidinamine;

2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -4-pyrimidine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyrimidinone hydrazone;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N, N-dimethyl-2-pyrimidinamine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1 H -methyl-2-pyrimidinamine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H- (phenylmethyl) -2-pyrimidine amine;

N-cyclopropyl-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidine amine;

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -14 - [(4-methoxyphenyl) methyl] -2-pyrimidine amine;

LH4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -N- (phenylmethyl) acetamide;

ethyl [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] carbamate; 4- [3- (3-methoxyphenyl) -1H-pyrazol-4-yl] pyrimidine;

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyrimidine;

4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine; and

-13- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine.

Within Formula I, there is a subclass of compounds of high interest represented by Formula IX:

R ¹ (IX) in which:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocyclyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrogen, lower alkyl, aryl, selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkylalkylalkylalkylalkylalkyloxyalkyl lower amp; amp; mino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl; or

R ² is -CR ^M R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; and

R ⁴ is selected from hydrogen, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl and aryl selected from phenyl, biphenyl and naphthyl; wherein R ⁴ is optionally substituted at the appropriate position by one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R ⁵ is selected from hydrogen, halo, amino, cyano, lower aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl , carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyalkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylnylamines, nyl and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ , wherein R ⁶² is lower alkylcarbonyl or amino, and R ⁶³ is lower alkyl or lower phenylal 51 kilos; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of those compounds of formula IX in which:

R ¹ is selected from: hydrogen, methyl, ethyl, hydroxyethyl and propargyl; and

R ² is selected from hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, Nmethylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-π-phenylamino, N-phenylamino, N-phenylamino, N , aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethyl, methyloxymethyl 1,1-smoke methyl) etilkarbonilaminoetilamino, piperazinylcarbonyl, 1,1-dimetiletilpiperazinilkarbonil; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted by one or more radicals independently selected from fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl , 1-dimethyl) ethoxycarbonyl; and

R ⁴ is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted at the appropriate position by one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl and hydroxy; and

R ⁵ is selected from hydrogen, fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylaminoethylamino, 2-dimethylaminoethylamino, 2-dimethylaminoethylamino, , imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpyridinylmethylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, ino, phenylmethylamino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1 -metilhidrazinil, or -NR ⁶² R ⁶³ wherein R ⁶² is methylcarbonyl or amino, a R ⁶³ is methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

Within Formula I, there is a subclass of compounds of high interest represented by Formula X:

R '

A ¹ (X) in which:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl. lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrogen, lower alkyl, aryl, selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl alkoxyalkyl lower alkaline lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl; or

R ² is -CR 4 R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; and

R ⁴ is selected from 5- or 6-membered heteroaryl and aryl selected from phenyl, biphenyl and naphthyl; wherein R ⁴ is optionally substituted by one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R ⁵ is selected from hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carbohydrates, carbohydrates, carbohydrates, carbohydrates, carbohydrates lower alkylhydrazinyl, or -NR ⁶² R ⁶³ , wherein R ⁶² is lower alkylcarbonyl or amino, and R ⁶³ is lower alkyl or lower phenylal 54 kilos; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of those compounds of Formula X in which:

R ¹ is selected from methyl, ethyl, hydroxyethyl and propargyl, and R ² is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N-ethylamino, N-ethylamino, N-ethylamino Diethylamino, dimethylammonium hydroxyamide, polyethylene boxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl and 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted by one or more radicals independently selected from fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl , 1-dimethyl) ethoxycarbonyl; and

R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted at the appropriate position by one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; and

R ⁵ is selected from hydrogen, fluorine, chlorine, bromine, methyl, flubrfenileshil, fluorfsniletenil, fluorfenilpirazolil, cyano, methoxycarbonyl, aminokarbopil, acetyl, hydroxy, carboxy, methoxy, methylamino, dimetilamipo, 2-megilbutilamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino , propargylamino, imidazolylamino, morphol) ϋ schlethylamino, (1-ethyl-2-hydroxy) ethylamino, pipercinylamino, nyridinylmethylamino, phenylmegylpyridinylmethylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonylmethylcarbonyl oxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ where R ⁶² is methylcarbonyl or amino, and R ⁶³ is methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

Within Formula I, there is a subclass of compounds of high interest represented by Formula XI:

R

R (XI) in which:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from Hydrogen, lower alkyl, aryl, selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, hydroxyalkyl lower, lower lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl; or

R ² is -CR ^M R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; and • R ⁴ is selected from 5- or 6-membered heteroaryl and aryl selected from phenyl, biphenyl and naphthyl; wherein R ⁴ is optionally substituted by one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R ⁵ is selected from hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carbohydrates, carbohydrates, carbohydrates, carbohydrates, carbohydrates lower alkylhydrazinyl, or -NR ⁶² R ⁶³ , wherein R ⁶² is lower alkylcarbonyl or amino, and R ⁶³ is lower alkyl or lower phenylal 57 kilos; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of those compounds of Formula XI in which:

R ¹ is selected from methyl, ethyl, hydroxyethyl and propargyl; and

R ² is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-phenylethylamino, N-phenylethylamino, N-phenylamino ,, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxymethylmethyl, (1,1-dimethylmethyl), (1,1-dimethylmethyl), (1,1-dimethylmethyl), (1,1-dimethylmethyl), 1-dimethyl) ethyl arbonylaminoethylamino, piperazinylcarbonyl and 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted by one or more radicals independently selected from fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl , 1-dimethyl) ethoxycarbonyl;

R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted at the appropriate position by one or more radicals independently selected from methylglyo, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; and

R ⁵ is selected from hydrogen, fluorine, chlorine, bromine, mesyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylaminoethylamino, 2-dimethylaminoylamino, 2-dimethylaminoamines, 2-methyl hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxymethylcarbonyl o, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ where R ⁶² is methylcarbonyl or amino and R ⁶³ is methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of those compounds of Formula IX in which:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrogen; lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkylaminoalkylaminoalkylamboxycarbonyl lower aralkin, lower thoracic y alkoxyalkylamino, lower alkoksikarbonilaminoalkilamino, lower heterocyclylcarbonyl, lower alkoksikarbonilheterotsiklil and lower alkoksikarbonilheterotsiklilkarbonil; wherein the aryl and heteroaryl groups are optionally substituted by one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl; or

R ² is -CR ^M R ⁵⁵ where R ⁵⁴ is phenyl and R ⁵⁵ is hydroxy; and

R ⁴ is phenyl optionally substituted by one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R ⁵ is selected from hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carbohydrates, carbohydrates, carbohydrates, carbohydrates, carbohydrates lower alkylhydrazinyl or -NR ⁶² R ⁶³ where R ⁶² is lower alkylcarbonyl or amino and R ⁶³ is lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof.

A class of compounds of particular interest consists of those compounds of Formula IX in which:

R ¹ is selected from hydrogen, methyl, ethyl, hydroxyethyl and propargyl; and

R ² is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-phenylamino, N-phenylamino, N aminotylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholine ethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxylic acid , 1-dimethyl) ethyl arbonilaminoetilamino, piperazinylcarbonyl, and 1,1-dimetiletilpiperazinilkarbonil; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted by one or more radicals independently selected from fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl , 1-dimethyl) ethoxycarbonyl;

R ⁴ is phenyl optionally substituted by one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; and

R ⁵ is selected from hydrogen, fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2 , imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxycarbonylamino, methoxycarbonylamino , Phenylmethylamino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-metilhidrazinil, or -NR ⁶² R ⁶³ wherein R ⁶² is methylcarbonyl or amino, a R ⁶³ is methyl or benzyl; or

a pharmaceutically acceptable salt or tautomer thereof. A tautomer or salt compound of the present invention, wherein the compound is selected from the group consisting of

ίl

NH — NH

N — NH

N — NH

Another class of compounds of particular interest consists of those compounds of Formula IX in which:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from hydrogen, lower alkyl, lower hydroxyalkyl and lower alkynyl; and

A

R is selected from hydrogen) and lower alkyl; and

R ⁴ is selected from phenyl and benzodioxolyl; wherein the phenyl is optionally substituted by one or more halo radicals; and

R ⁵ is selected from hydrogen, halo and alkylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of those compounds of Formula IX in which.

Z represents a carbon atom; and

R ¹ is selected from hydrogen, methyl, hydroxyethyl and propargyl; and

R ² is hydrido; and

R ⁴ is selected from phenyl and benzodioxolyl; wherein the phenyl is optionally substituted by one or more radicals independently selected from chlorine, fluorine and bromine; and

R ⁵ is selected from hydrogen, fluorine and 1-methylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof. A preferred class of compounds of particular interest consists of those compounds of Formula IX in which:

Z represents a carbon atom; and

R ¹ is selected from hydrogen and methyl; and

R ² is hydrido; and

R ⁴ is selected from phenyl, optionally substituted by one or more radicals independently selected from chlorine, fluorine and bromine; and

R ⁵ is selected from hydrogen and fluorine; or a pharmaceutically acceptable salt or tautomer thereof.

The term "hydrido" means a single hydrogen atom (H). This hydrido radical may be bonded to, for example, an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be bonded to a carbon atom to form a methylene (-CH2) radical.

When used, whether alone or with other terms, such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", "cyanoalkyl" and "mercaptoalkyl", the term "alkyl" includes linear or branched radicals having 1 or 2 radicals having up to about 20 carbon atoms, or preferably from 1 to about 12 carbon atoms. More preferably, the alkyl radicals are "lower alkyl" radicals having from 1 to about 10 carbon atoms. Most preferably, lower alkyl radicals have from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.

The term "alkenyl" includes linear or branched radicals having at least one carbon-carbon double bond of 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferably, alkenyl radicals are "lower alkenyl" radicals having from 2 to about 6 carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" include radicals having a "cis" and "trans" orientation, or else an "E" and "Z" orientation.

The term "alkynyl" includes linear or branched radicals having at least one carbon-carbon triple bond of 2 to about carbon atoms, or, preferably, 2 to about 12 carbon atoms. More preferably alkynyl radicals are " lower alkynyl " radicals having from 2 to about 6 carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-bouginyl, 1-pentynyl.

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

The term "cycloalkylalkylene" includes alkyl radicals substituted with a cycloalkyl radical. More preferably, the cycloalkylalkylene radicals are " lower cycloalkylalkylene " radicals that include lower alkyl radicals substituted with a lower cycloalkyl radical, as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term "cycloalkenyl" includes partially unsaturated carbocyclic radicals having from 3 to about 12 carbon atoms. Cycloalkenyl radicals, which are partially unsaturated carbocyclic radicals containing two double bonds (which may or may not be conjugated) may be called "cycloalkyldienyl". More preferably, cycloalkenyl radicals are "lower cycloalkenyl" radicals having from 4 to about 8 carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term "halo" means halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" includes radicals in which one or more alkyl70 carbon atoms are substituted with halo as defined above. In particular, monohaloalkyl dihaloalkyl and polyhaloalkyl radicals are included. For example, a monohaloalkyl radical may include an iodine, bromine, chlorine or fluorine atom in the radical. Respiratory and polyhaloalkyl radicals may include two or more identical halogen atoms or combinations of different halo radicals. The term "lower haloalkyl" includes radicals having from 1 to 6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, difluoroethyl, difluoroethyl,

The term "hydroxyalkyl" includes linear or branched alkyl radicals having from 1 to about 10 carbon atoms, each of which may be substituted by one or more hydroxyl radicals. More preferably, the hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having from 1 to about 6 carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The terms "alkoxy" and "alkyloxy" include linear or branched oxy-containing radicals, each having an alkyl moiety of from 1 to about 10 carbon atoms. More preferably, alkoxy radicals are "lower alkoxy" radicals having from 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" includes alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, i.e. monoalkoxyalkyl and dialkoxyalkyl radicals are formed. "Alkoxy" radicals may also be substituted by one or more halogen atoms, such as fluorine, chlorine or bromine, to form haloalkoxy radicals.

The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings in which each ring may be attached to the other or may be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aryl moieties may also be substituted, at a suitable substitution position, with one or more substituents independently selected from halo, alkyl, alkenyl, alkenyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfonyl alkylsulfuric acid minoalkilen, arylaminoalkylene, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminokarbonilalkilen, acyl, carboxy, and aralkoxycarbonyl.

The term "heterocyclyl" includes saturated, partially unsaturated and unsaturated heteroatom-containing ring radicals, which may also be referred to as "heterocyclyl", "heterocyclylalkenyl" and "heteroaryl", respectively, where heteroatoms may be selected from nitrogen. Examples of saturated heterocyclyl radicals include a saturated 3 to 6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); a saturated 3 to 6 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.); a saturated 3 to 6 membered heteromonocyclic group containing στ 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include petivalent nitrogen such as in tetrazolium and pyridinium radicals.

The term "heteroaryl" includes unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include an unsaturated 3 to 6 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, e.g. triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; an unsaturated fused heterocyclyl group containing from 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolpyridazinyl (e.g., 1,5-tetrazolyl) triazolyl] etc.; an unsaturated 3 to 6 membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc .; an unsaturated 3 to 6 membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc .; an unsaturated 3 to 6 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2,5-oxadiazolyl, etc.), etc .; an unsaturated fused heterocyclyl group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.); an unsaturated 3 to 6 membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-diadiazolyl, etc.), etc .; an unsaturated fused heterocyclyl group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term "heterocycle" also includes radicals where the heterocyclyl radicals are fused to aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl group" may have from 1 to 3 substituents such as alkyl, hydroxide, halo, alkoxy, oxo, amino, alkylthio and alkylamino.

The term "heterocyclylalkylene" includes heterocyclyl-substituted alkyl radicals. More preferably, heterocyclylalkylene radicals are " lower heterocyclylalkylene " radicals having from 1 to 6 carbon atoms and heterocyclyl radicals.

The term "alkylthio" includes radicals containing a linear or branched alkyl radical of from 1 to about 10 carbon atoms bonded to a divalent sulfur atom. More preferably, alkylthio radicals are "lower alkylthio" radicals having alkyl radicals having from 1 to 6 carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylgly and hexylthio.

The term "alkylthioalkylene" includes radicals containing an alkylthio radical bonded via a divalent sulfur atom to an alkyl radical having from 1 to about 10 carbon atoms. More preferably, alkylthioalkylene radicals are "lower alkylthioalkylene" radicals having alkyl radicals of from 1 to 6 carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl.

The term "alkylsulfinyl" includes radicals containing a linear or branched alkyl radical having from 1 to about 10 carbon atoms bonded to a divalent -S (= O) radical. More preferably, alkylsulfinyl radicals are "lower alkylsulfinyl" radicals containing alkyl radicals of from 1 to 6 carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.

The term "sulfonyl", used alone or in conjunction with other terms such as "alkylsulfonyl" and "halosulfonyl", means a divalent radical -SO ₂ -. The term "alkylsulfonyl" includes alkyl radicals attached to a sulfonyl radical, where alkyl is as defined above. More preferably, the alkylsulfonyl radicals are "lower alkylsulfonyl" radicals containing from 1 to 6 carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The "alkylsulfonyl" radicals may be substituted by one or more halogen atoms, such as fluorine, chlorine or bromine, to form haloalkylsulfoyl radicals. The term "halosulfonyl" includes halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl and bromosulfonyl.

The terms "sulfamide", "aminosulfonyl" and "sulfonamidyl" mean NH ₂ O ₂ S-.

The term "acyl" means a radical obtained as a residue after removal of hydroxide from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals derived from succinic, glucolic, gluconic, milky, malic, aurobic, citric, pyrogrodenic, almond, pantothenic, β-hydroxybutyric, galactaric and galacturonic acids.

The term "carbonyl", used alone or in conjunction with other terms such as "alkoxycarbonyl", means - (C = O) -.

The term "carboxy" or "carboxyl" used alone or in conjunction with other terms such as "carboxyalkyl" means -CO ₂ H. The term "carboxyalkyl" includes alkyl radicals substituted with a carboxy radical. More preferred is "lower carboxyalkyl" which includes lower alkyl radicals as defined above and may be further substituted on the halo alkyl radical. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.

The term "alkoxycarbonyl" means a radical containing an alkoxy radical as defined above bonded through an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals, with alkyl moieties having from 1 to 6 carbon atoms. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.

The term "alkoxycarbonylalkyl" includes alkyl radicals substituted with an alkoxycarbonyl radical as defined above. "Lower alkoxycarbonylalkyl" radicals with alkyl moieties having from 1 to 6 carbon atoms are preferred. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl.

The term "alkylcarbonyl" includes radicals having alkyl and hydroxyalkyl radicals as defined above, bonded to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl and hydroxyethylcarbonyl.

The term "aralkyl" includes aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may be further substituted by one or more substituents independently selected from halo, alkyl, alkoxy, haloalkyl, haloalkoxy, amino and nitro. The terms benzyl and phenylmethyl cover each other.

The term "heterocyclylalkylene" includes saturated and partially unsaturated heterocyclyl-substituted alkyl radicals (may also be referred to as heterocycloalkylalkylene and heterocycloalkenylalkylene) such as pyrrolidinylmethyl and heteroaryl-substituted alkylaryl pyridyl harylarylcarbonyl; , furylethyl and quinolylethyl. The heteroaryl in said heteroaralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "aryloxy" includes aryl radicals bonded through an oxygen atom to other radicals. The term "aralkoxy" includes aralkyl radicals bonded through an oxygen atom to other radicals.

The term "aminoalkyl" includes alkyl radicals substituted with amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl and the like.

The term "alkylamino" includes amino groups substituted by one or two alkyl radicals. Preferred "lower alkylamino" radicals having alkyl moieties having from 1 to 6 carbon atoms. Suitable lower alkylamino radicals may be monosubstituted N-alkylamino or disubstituted N, N-alkylamino, such as N-methylamino, N-ethylamino, Ν, мети dimethylamino, Ν, Ν-diethylamino and the like.

The term "arylamino" includes amino groups substituted by one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be substituted on the aryl ring of the radical.

The term "aminocarbonyl" includes an amide group of formula -C (= O) NH ₂ . The term "alkylaminocarbonyl" includes an aminocarbonyl group which is substituted by one or two alkyl radicals at the amine nitrogen atom. "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" are preferred. More preferred are "lower N-alkylaminocarbonyl" and "lower N, N-dialkylaminocarbonyl" with lower alkyl moieties defined above.

The term "alkylcarbonylamino" includes amino groups substituted by one alkylcarbonyl radical. More preferred alkylcarbonylamino radicals are " lower alkylcarbonylamino " having lower alkylcarbonyl radicals as defined above, related to amino radicals.

The term "alkylaminoalkylene" includes radicals having one or more alkyl radicals attached to an aminoalkyl radical.

The "hydrocarbon" moieties described in the present invention are organic compounds or radicals consisting mainly of carbon and hydrogen elements. These moieties include alkyl, alkenyl, alkynyl and aryl. These moieties also include alkyl, alkenyl, alkynyl and aryl substituted with other aliphatic or cyclic hydrocarbon groups such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties contain from 1 to 20 carbon atoms.

The hetero substituted hydrocarbon groups described in the present invention are hydrocarbon groups which are substituted by at least one non-carbon atom, including groups in which a carbon atom in the chain is substituted by a heteroatom such as nitrogen, oxygen, sulfur or a halogen atom. These moieties include lower alkoxy such as methoxy, ethoxy, butoxy; halogen, such as chlorine or fluorine, ethers, acetals, ketals, esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino and amido.

The additional terms used to describe pyrazole ring substituents and not specifically defined herein are defined in the same way in the definitions described above. As above, preferred substituents are those containing "lower" radicals. Unless otherwise defined, the term "lower" as used herein means that each alkyl radical as a substituent in the pyrazole ring containing one or more alkyl radicals has from 1 to about 6 carbon atoms; each alkenyl radical as a substituent in the pyrazole ring containing one or more alkenyl radicals has from 2 to about 6 carbon atoms; each alkynyl radical as a substituent in the pyrazole ring containing one or more alkynyl radicals has from 2 to about 6 carbon atoms; each cycloalkyl or cycloalkenyl radical as a substituent in the pyrazole ring containing one or more cycloalkyl and / or cycloalkenyl radicals is, respectively, a 3 to 8 membered cycloalkyl or cycloalkenyl radical; each aryl radical as a substituent in the pyrazole ring containing one or more aryl radicals is a monocyclic aryl radical; and each heterocyclyl radical as a substituent in the pyrazole ring containing one or more heterocyclyl radicals is a 4-8 membered ring heterocyclyl.

The present invention includes tautomeric forms of the compounds of Formulas I and IX. As shown below, the pyrazoles of Formulas I and D are magnetically and structurally equivalent to the prototropic tautomeric nature of hydrogen:

(D)

The present invention also includes compounds of Formulas I, IX, X and XI having one or more asymmetric carbon agoms. It is known to those skilled in the art that these pyrazoles of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic or optically active forms. All heme forms are contemplated within the scope of the present invention. In particular, the present invention includes enantiomers, diastereomers, racemic mixtures and other mixtures thereof.

The present invention relates to a pharmaceutical composition for the treatment of TNF-related disorders, disorders of p38 kinase, inflammation and / or arthritis, and includes a therapeutically active amount of a compound of Formula I, or a therapeutically acceptable salt or tautomer thereof, together with at least one pharmaceutically acceptable carrier, additive or diluent.

The present invention also relates to substituted pyrazoles that specifically bind to the ATP binding site of the p38 kinase. Without adhering to any theory, the claimants of the present invention hypothesize that these substituted pyrazoles interact! with p38 kinase, as noted below. As the substituent of the 3rd position of the pyrazole ring approaches the ATP binding site of the p38 kinase, a hydrophobic cavity is formed in the p38 kinase around the third position of the substitution of the binding site. A gaseous hydrophobic cavity is thought to be formed as the substituent at the 3-position binds to a specific peptide sequence of the enzyme. In particular, it is believed that the connection is made to the side chains of Lys _52, Glu _69, Leu _73, lie _82, Leu ^, Leu ₁₀ i and the methyl group of TYgyuz sidechain of p38 kinase at the ATP binding site (wherein the pattern the numbering corresponds to the commonly used ERK-2 numbering scheme). When the substituent at the 3-position is aryl or heteroaryl, such aryl or heteroaryl may be substituted. It has been hypothesized that such ring substituents may be useful in preventing hydroxylation or further ring metabolism.

The substituent at the 4-position of the pyrazole ring is such that it partially resembles the ATP adenine ring, although it may then be complicated. It is preferred that it be a planar substituent terminated with a suitable hydrogen bond acceptor. It has been hypothesized that this hydrogen acceptor binds to the basic N-H of the Met _W 6 moiety while one edge of this substituent is in contact with a solvent.

The 5th position substituent on the pyrazole ring is well selected and can provide increased potential and selectivity. It has been hypothesized that such substituents appear to be out of the solvent direction and that a suitable polar group positioned at this end may interact with the side chain of Asp ₁₀₉ , leading to increased potential and selectivity.

Similarly, the substitution at the nitrogen atom of the 1- or 2-position of the pyrazole ring is well selected and may provide increased potential. It has been hypothesized that a hydrogen substituent attached to one of the nitrogen atoms of the ring binds to a hydrogen bond to Aspi ₆₅ . Preferably, the nitrogen atom at the 2-position is bonded to the carbon atom at the 3-position of the pyrazole, while the nitrogen atom at the 1-position is free to replace with hydrogen or other substituents.

The 5th position substituent and the 1 or 2 position pyrazole substituent can be selected to improve the physical characteristics of the substituted pyrazole, especially water solubility and drug delivery capability. However, it is preferred that each of these substituents has a molecular weight of less than about 360 atomic mass per unit. More preferably, each of these substituents has a molecular weight of less than about 250 atomic mass per unit. And most preferably, each of these substituents has a molecular weight of less than about 360 atomic mass per unit.

A class of substituted pyrazoles of particular interest consists of those compounds having the formula:

R (XII) in which:

R ¹ is hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl radical having a molecular weight of less than about 360 atomic mass per unit; and

R is hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl radical which binds to the p38 kinase at said ATP binding site of the p38 kinase; and

R is hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor; and

R ⁴ is hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl radical having a molecular weight of less than about 360 atomic mass per unit;

provided that R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2-hydroxy substituent and when R ¹ is hydrido; and provided that R is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R ⁴ is hydrido; and provided that R ⁴ is not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof.

A class of substituted pyrazoles of particular interest consists of those compounds of formula XI in which:

R ¹ is hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl radical having a molecular weight of less than about 360 atomic mass per unit; and

R is hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical, wherein said radical binds to Lys ₅₂ , Glu ₆₉ , Leu ₇₃ , lie ₈ g, Leug4, Leuioi and the side chains of said ATP binding site of the p38 kinase, such as said p38 kinase, to a large extent in the hydrophobic cavity formed during said binding of the p38 kinase to the ATP binding site; and

R ³ is hydrocarbyl, hetero-substituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor such that hydrogen binds to the basic N-H of Met ₁₀₆ of p38 kinase; and

R ⁴ is hydrocarbyl, hetero substituted hydrocarbyl, or heterocyclyl radical having a molecular weight of less than about 360 atomic mass per unit.

The present invention also relates to a therapeutic method for the treatment of TNF-related disorders, disorders of p38 kinase, inflammation and / or arthritis, the method comprising treating a patient suffering from or predisposed to such disorder or condition83. with a therapeutically effective amount of a compound of Formula I,

R

R

R (I)

IN WHICH

R ¹ is selected from hydrido, alkyl, cycloalkyl, alkenyl, tsikloalksnil, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, tsikloalkenilalkilen, heterocyclylalkylene, haloayalkil, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralksnil, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl , alkoxyalkyl, alkyoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocycloxyalkyl, alkoxyalkyloxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylaminoalkyl, alkylamino methanesulfonylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenilsulfinil, alkylsulfinyl, arylsulfinyl, heterotsiklilsulfinil, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, heterotsikliloksikarbonilarilen, alkilkarbonilalkilen, arilkarbonilalkilen, heterocyclylcarbonylalkylene, alkylcarbonylaryl H arilkarbonilarilen, heterotsiklilkarbonilarilen, alkilkarboniloksialkilen, arilkarboniloksialkilen, heterotsiklilkarboniloksialkilen, alkilkarboniloksiarilen, arilkarboniloksiarilen and heterotsiklilkarboniloksiarilen; or

R ¹ has the formula in which i is from 0 to 9;

R ²⁵ is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkyl; and

R ²⁶ is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and

R is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoksiarilsn, alkoksiaralkil, alkoksiheterotsiklil, alkoksialkoksiarilen, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocytes Lille alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilep, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbo! ιilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarils11, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiliyualkilsn, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, hsgerotsikliltioarilen, ariltioalkilarilen, arylsulfonylamino alkylene alkilsulfonilarilen, alkilaminosulfonilarilen; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl , alkoxy, keto, amino, nitro and cyano; or

R ²⁷ is -CHR ^ R ²⁹ where R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from alkyl and nitro; or

R and R together with the nitrogen atom to which they are attached form a heterocycle, said heterocycle being optionally substituted by one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkyl, aryloxyalkylalkyl, alkyloxyalkylene, alkyloxyalkylene, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, alkylene , aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene are optionally substituted by one or more radicals independently selected from halogen, alkyl and alkoxy; and

Λ

R is selected from hydrido, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylgio, heherocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkyl, carboxycycloalkyl oalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylyl and heterocycloalkylamino; wherein said aryl, hex 1 erocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl are optionally substituted by one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkylalkyl (hydroxyalkyl) hydroxyalkyl (hydroxyalkyl) hydroxyalkyl carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or

R ² has the formula:

C-CHC, JI and ³¹

(III) in which:

j is 0 to 8; and m is 0 or 1; and

R ³⁰ and R ³¹ are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, amiocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; and

R ³² is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylamyloalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkyl;

R ³³ is selected from hydrogen, alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO ₂ R ³⁶ ,

-C (O) NR ”R ³⁸ and -SO ₂ NR ³⁹ R ^{4 <>} , where R ³⁵ , R ³⁶ , R ³ ', R ³⁸ , R ³ ' and R ⁴⁰ are independently selected from hydrocarbon, hetero substituted hydrocarbon and heterocyclyl ; and

R ³⁴ is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or

R ² is -CR ⁴¹ R ⁴² where R ⁴¹ is aryl and R ⁴² is hydroxy; and

R ³ is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,

(IV) (V) wherein R ⁴³ is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; and wherein the R ³ radicals of pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted by one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthiol, thiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiolthiol alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxycarboxyl, hydroxycarboxyl rotsikliloksikarbonil, alkoxycarbonylamino, alkoksiaralkilamino, aminosulfinyl, aminosulfonyl, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilhetsrotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfopil, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ is alkylcarbonyl or amino, and R ⁴⁵ is alkyl or aralkyl; and

R ⁴ is selected from Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where R ⁴ is optionally substituted by one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, alkylthio arylthio, alkiltioalkilen, ariltioalkilen, alkylsulfinyl, alkilsulfinilalkilen, arilsulfinilalkilen, alkylsulfonyl, alkilsulfonilalkilen, arilsulfonilalkilen, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, o, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy;

provided that R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2-hydroxy substituent and when R ¹ is hydrogen; also, provided that R is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R ⁴ is hydrogen; also, provided that R ⁴ is not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof.

BASIC SYNTHESIS METHODS

The compounds of the present invention can be prepared according to the methods described in Schemes I - XVIII, in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above for compounds of Formulas I, IX, X and XI, unless otherwise stated.

Scheme I

Scheme I shows the synthesis of pyrazole 5 in two ways. Condensation of pyridylmethylketone 1 with aldehyde 2 in the presence of a base such as piperidine, in a solvent such as nude or benzene, or in the absence or presence of acetic acid, upon boiling, yields α, β-unsaturated ketone 3. method 1, ketone 3 is first converted to epoxide 4 by treatment with a solution of hydrogen peroxide at room temperature in the presence of a base such as sodium hydroxide. By treating epoxide 4 with hydrazine in ethanol or another suitable solvent at reflux temperature, pyrazole 5 is obtained. By method 2, ketone 3 is directly condensed with tosylhydrazide in the presence of an acid, such as acetic acid, at reflux temperature. to obtain pyrazole 5. Alternatively, intermediate tosylhydrazone 6 can be isolated, converting it to pyrazole 5 by treatment with a base such as potassium hydroxide in a suitable solvent, such as ethylene glycol, in the temperature range from 25 ° C to 150 ° C.

Scheme II

2

Scheme II shows the synthesis of pyrazole 12 according to the present invention. Reaction of pyridine derivative 7 with ester 8 in the presence of a base such as sodium (trimethylsilyl) amide, in a suitable solvent such as tetrahydrofuran, ketone 9 is obtained. By treating ketone 9 or a ketone hydrohalide salt 9 with a halogenating agent such as bromine, N-bromosuccinimide or N-chlorosuccinimide, in suitable solvents such as acetic acid, methylene chloride, methanol or mixtures thereof, yields α-halogenated ketone 10 (in which X is halo). Examples of suitable hydrohalide salts include hydrochloride and hydrobromide salts. By reacting haloketone 10 with thiosemicarbazide 11 (in which R and R may be hydrido, lower alkyl, phenyl, heterocyclyl and the like, or in which R and R form a heterocyclyl ring which may contain an additional heteroatom), pyrazole is obtained 12. Examples of suitable solvents for this reaction are ethanol and dimethylformamide. The reaction may be carried out in the presence or absence of a base or an acid, in the temperature range from room temperature to 100 ° C.

Non-commercially available thiosemicarbazides can be successfully obtained by any person skilled in the art, first of all, a suitable amine is reacted with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide. Treatment of the resulting alkyldithiocarbamag with hydrazine yields the desired alkylthiosemicarbazide. This chemism has been described by E. Lieber and R.

S. Orlowski, J. Org. Chem., Vol. 22, ρ. 88 (1957). An alternative method is to add hydrazine to suitably substituted thiocyanates, as described by Y. Nomoto et al., Chem. Pharm. Bull., Vol. 39, p. 86 (1991). Lieber and Nomoto's publications are given for comparison.

Scheme III

A

R ⁴

N \

N.

heating (180-200 ° C)

Scheme III shows the synthesis of pyrazole 19 in a more basic form by three methods. According to method 1, ketone 13 is condensed with hydrazine 14 to give92 to substituted hydrazide 16, which is then reacted with alkyl halide or anhydride 17 at room temperature to form acylhydrazone 18. Upon heating to 200 ° C, acylhydrazone 18 is converted in pyrazole 19. By method 2, acylhydrazone 18 is obtained directly by reaction of ketone 13 with acylhydrazide 15, obtained by reacting hydrazine with a carboxylic acid ester at room temperature. By heating acylhydrazone 18 as above, pyrazole 19 is obtained. According to method 3, ketone 13 is treated with acylhydrazide 15 at a suitable temperature, in the range of room temperature to about 200 ° C, to directly produce pyrazole 19. Or however, this condensation may be carried out in an acidic solvent, such as acetic acid, or in a solvent containing acetic acid.

NHR ¹ NH, heating

Scheme IV

Synthesis Scheme IV describes the preparation of pyrazole 19.

X = halyl, alkyl

R ¹ = Me, CH ₂ CH ₂ OH

R ⁴ = cyclopropyl, 4-pyridyl, 4-imidazolyl

Scheme V shows two-step synthesis of 3-substituted 4-pyridyl-

5-arylpyrazoles 33 according to the present invention by cyclization of hydrazone dianions with carboxylates. In step 1, reacting substituted pyridyl methyl ketones 31 (prepared, for example, as described later in Scheme IX) with hydrazines in the presence of solvents such as ethanol, ketohydrazones 32 are obtained. Examples of suitable hydrazines include, but without is restriction, phenylhydrazine and p-methoxyphenylhydrazine. In step 2, the hydrazones 32 are treated with two equivalents of base, such as sodium bis (trimethylsilyl) amide in a suitable solvent, such as tetrahydrofuran, to give dianions. This reaction can be carried out at temperatures of about 0 ° C or lower. In the same step, the dianions are then condensed with esters such as methylisonicotinate and methylcyclopropanecarboxylate to give the desired pyrazoles 33. In some cases, it may be necessary to treat the product at this stage with a dehydrating agent such as mineral acid to obtain the desired pyrazole .

Scheme VI base

R ³

Fr.

RR., NHNH _a

R ³ = heteroaryl

R ⁴ = substituted or unsubstituted phenyl

X = lower alkyl, lower alkenyl or aryl

DMF dimethyl acetal

and

7

Scheme VI shows an alternative method for the synthesis of pyrazoles which are unsubstituted at the 5-position of the ring. According to this method, heteroarylmethylketone 34 is first synthesized by treating a strong base heteroarylmethane such as lithium hexamethyldisilazide or lithium diisopropylamide. Examples of suitable heteroarylmethane are 4-methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine. The resulting heteroarylmethyl lithium samples are then reacted with suitable benzoate to give ketone 34. Examples of suitable benzoates are methyl and ethyl p-fluorobenzoate and ethyl and methyl p-chlorobenzoate. Ketone 34 is converted to an aminomethylene derivative 35 by reaction with an aminomethylene agent such as dimethylformamide dimethylacetal or tertbutoxybis (dimethylamino) methane. Ketone 35 is converted to pyrazole 36 by reaction with hydrazine.

By modifying this synthetic method, pyrazole 38, which contains substituted nitrogen at position 1 of the ring, is selectively synthesized. First, ketone 34 is converted to hydrazone 37 by reaction with a suitable substituted hydrazine. Examples of suitable hydrazines are N-megylhydrazine and b1- (2-hydroxyethyl) hydrazine. By reacting hydrazone 37 with an aminomethylene agent, pyrazole 38 is obtained. Examples of suitable aminomethylene agents include dimethylformamide dimethylacetal and tert-butoxybis (dimethylamino) methane.

In the case where the substituent R ³ of pyrazoles 36 and 38 gives leaving groups such as halogen, the subsequent reaction with an amine results in an amino substituted heteroaromatic derivative. Examples of such amines include benzylamine, cyclopropylamine and ammonia. The leaving groups may also be replaced by other nucleophiles, such as mercaptides and alkoxides. Examples of substituent R ³ groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl.

Scheme VII shows the preparation of pyrazole 5 derivatives (prepared according to Scheme I) when R ² = CH ₃ . Oxidation of pyrazole 5 yields carboxylic acid 39, which is then reduced to hydroxymethyl compound 40, or linked to an amine NR ¹⁰ R ⁿ (where R ¹⁰ and R ¹¹ are independently selected, for example, from hydrogen, alkyl and aryl) , or together with the nitrogen atom to which they are attached, form a 4-8 membered ring, which may further comprise one or more heteroatoms selected from oxygen, nitrogen or sulfur) to afford amide 41, followed by reduction to give an amine derivative 42.

Scheme VII

II

C \ J

X / //

1L

Scheme VIII

Scheme VIII shows the synthesis of pyrazoles 44 and 45 from pyrazole 43. The alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished by conventional methods. Reaction of pyrazole 43 with a suitable base (e.g., sodium hydride) followed by reaction with an alkyl halide (e.g. methyl iodide) yields a mixture of isomers 44 and 45.

Scheme IX shows the synthesis of 3-aryl-4-pyridylpyrazoles according to the present invention. Benzoate 46 is reacted with pyridine 47 in the presence of a strong base, such as an alkali metal hexamethyldisilazide (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give deoxybenzoin 48p. by reaction with an excess of dimethylformamide dimethyl acetal. The ketone 49 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to form pyrazole 50. In Scheme IX, R ¹² represents one or more radicals independently selected from the possible

Scheme IX rn Et

Li Hesamethyldisilazide tetrahydrofuran room temperature

“Deoxybenzoin”

DMF dimethyl acetal (4-fold excess) tetrahydrofuran (1 volume) room temperature m

hydrazine hydrate ethanol

CH ₃

substituents defined above for R ⁴ . Preferably, R ¹² is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy.

The 3-aryl-4-pyrimidinylpyrazoles of the present invention can be synthesized by the method shown in Scheme IX by replacing pyridine 47 with the corresponding pyrimidine. Similarly, Schemes X to XVII can be used to synthesize the 3-aryl-4-pyrimidinylpyrimidines corresponding to the 3-aryl-4-pyrimidinylpyrazoles shown in these schemes.

Scheme X

Scheme X shows one embodiment of Scheme IX that can be used to synthesize 3-aryl-4-pyridylpyrazoles, which are then replaced at the nitrogen atom at position 1 of the pyrazole ring. If, first, deoxybenzoin 48 (obtained according to Scheme IX) is converted to hydrazone 51 by treatment with hydrazine and hydrazone 51 then reacted with dimethylformamide dimethylacetal, the product obtained is pyrazole 52.

100

Schemes XI to XVIII show modifications that can be made to Scheme IX to synthesize other 3-aryl-4-pyridylpyrazoles having possible substituents.

Scheme XI

ethanol

9

NH ,. NHR ¹

quantity

Scheme XII

5B

ιοί

In Scheme XII, X is chlorine, fluorine or bromine; R ¹³ is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino; and R ²⁰ is, for example, hydrogen or alkyl.

Scheme XIII

bromine

DMF acetic acid

Scheme XIV

2

102

Scheme XV

In Scheme XV, η is 1, 2, 3, 4 or 5; and R ¹⁴ and R ¹⁵ are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached, form a 4-7 membered ring which may further comprise one or more heteroatoms selected from oxygen, nitrogen or sulfur.

Scheme XVI

7

103

In Scheme XVI, R ¹⁴ is selected, for example, from hydrogen, alkyl or phenyl.

Scheme XVII

R ¹² · R ¹² ί | \ Ί N-CHLOROSUCCINIMIDE 'χ /' '' ' Υ ⁰ \ dimethylformamide | l With ι '/% R ⁵ R ⁵ 65 with e

In Scheme XVII, R ¹⁷ is selected, for example, from alkyl, phenylalkyl or heterocyclylalkyl.

104

Scheme XVIII

B9 [0]

T M S C N

Me j N CO CI

N Η Η, 0 -

CN

Β

1

Compounds in which the second position of the pyridine ring is substituted by a carboxyl group or a carboxyl derivative can be synthesized according to the methods shown in Scheme XVIII. The starting pyridylpyrazole 67 is converted to a 2-cyan derivative 68, first,

105 by conversion to its pyridine N-oxide by reaction with an oxidizing agent such as m-chloroperoxybenzoic acid. Reaction of pyridine N-oxide with trimethylsilyl cyanide followed by dimethylcarbamoyl chloride yields 2-cyan compound 68. Compound 68 is converted to its carboxamide 69 by reaction with hydrogen peroxide in the presence of a suitable base. Examples of suitable bases include potassium carbonate and potassium bicarbonate. Carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethylacetal in methanol. The ester 70 is converted to its carboxylic acid 71 by saponification. Typical saponification conditions include reaction with a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent such as ethanol or ethanol and water or methanol and water, or the like. The ester 70 is converted to a suitable amide 72 by reaction with a desired amine, such as methylamine, at a suitable temperature. Temperatures can range from room temperature to 180 ° C. In Scheme XVIII, R ¹⁸ h R ¹⁹ ca independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached, form a 4-8 membered ring which may further comprise one or more heteroatoms selected from oxygen, nitrogen or sulfur.

Examples of carrying out the invention

The following examples describe in detail the methods for preparing compounds of Formulas I, XI, X and XI. These detailed descriptions fall within the scope of the present invention and serve only as examples of the basic synthesis methods described above that are part of the present invention. These detailed descriptions are for illustrative purposes only and do not limit the scope of the present invention. All parts are tagged

106 hunting parts, and temperatures are given in degrees Celsius, unless otherwise noted. The NMR spectra of all compounds are consistent with their structures shown. In some cases, the structures shown are confirmed by Nuclear Overhauser Effect (NOE).

The following abbreviations are used:

HCl - hydrochloric acid

MgSO ₄ - magnesium sulfate

Na ₂ SO ₄ - sodium sulfate

NaIO ₄ - Sodium periodate

NaHSO ₃ - sodium bisulfite

NaOH - sodium hydroxide

KOH - potassium base

P2O5 - Biphosphorus pentoxide

Methyl

Et - ethyl

MeOH - methanol

EtOH - ethanol

HOAc (or AcOH) - acetic acid

EtOAc - ethyl acetate

H ₂ O- water

H ₂ O ₂ - hydrogen peroxide

CH ₂ Cl ₂ - methylene chloride

K ₂ CO ₃ - potassium carbonate

KMPO ₄ is potassium permanganate

NaHMDS is sodium hexamethyldisilazide

DMF - dimethylformamide

EDC - 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBT - 1-hydroxybenzotriazole

107 mCPBA - 3-chloroperoxybenzoic acid

Ts - so-called

TMSCN - Grimethylsilyl cyanide

Mc ₂ NCOC1 - N, N-dimethylcarbamoyl chloride

SI'M-Cl - 2- (Grimethylsilyl) ethoxymethyl chloride h - hr hr - hr min - min

THE - i ci Rihydrofuran

TI - thin layer chromatography

DSC - differential scanning calorimetry

b.p. - boiling point

years - melting point eq - equivalent

RT - with secret temperature

Example A-1

4- [5- (3-Fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine

Step 1: Preparation of 4- (3-fluoro-4-methoxyphenyl) -3-pyridyl-3-butene-2one

A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol) and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was added.

108 is heated to reflux. After 18 hours, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate / hexane) to give 4 (3-fluoro-4-methoxyphenyl) -3-pyridyl-3-buten-2-one as a pale yellow solid substance (1.60 g, 80%).

Step 2: Preparation of 4- [5- (3-fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine

To a solution of 4- (3-fluoro-4-methoxyphenyl) -3-pyridyl-3-butene-2one (Step 1) (0.99 g, 3.65 mmol) in acetic acid (25 ml) was added p-toluenesulfonyl hydrazide (0.68 g , 3.65 mmol). The reaction solution was heated to reflux for 6 hours. Acetic acid was separated from the reaction solution by distillation. The resulting residue was diluted with methylene chloride (150 ml), washed with water (2x100 ml), dried over sodium sulfate, filtered and concentrated. The crude product (1.5 g) was purified by chromatography (silica gel, ethyl acetate) to give 4- [5- (3-fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine as a pale yellow solid (213 mg, 20.7%). Elemental analysis: Calculated for Ci ₆ Hi ₄ N ₃ OF.0.1 H ₂ O: C = 67.41; H = 5.02; N = 14.74. Found: C = 67.37; H, 4.88; N = 14.35.

Example A-2

4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine

109

Step 1: Preparation of 4-pyridylacetone

4-Pyridylacetone is prepared according to the method of Ippolito et al., U.S. Pat. Patent 4,681,944.

Step 2: Preparation of 4-phenyl-3- (4-pyridyl) -3-butene-2-one

In the procedure described in Example A-1, Step 1, 4-Pyridylacetone (Step 1) (1 g, 7.4 mmol), was heated under reflux with benzaldehyde (790 mg, 7.4 mmol) in benzene ( 15 ml) containing piperidine (50 mg). The desired 4-phenyl-3- (4-pyridyl) -3-buten-2-one (1.3 g, 78%) was obtained as a crystalline solid, m.p. 101-103 ° C. Elemental analysis: Calculated for C15H13NO (223.28): C = 80.69; H, 5.87; N = 6.27. Found: C = 80.59; H = 5.79; N, 6.18.

Step 3: Preparation of 4-phenyl-3- (4-pyridyl) -3,4-epoxy-2-butanone

In the method described in Example A-1, Step 2, a solution of 4-phenyl-3- (4-pyridyl) -3-buten-2-one (Step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was obtained. treated with 30% aqueous hydrogen peroxide (1 ml) in the presence of sodium hydroxide (230 mg, 5.7 mmol). The crude product was purified by chromatography (silica gel, 1: 1 ethyl acetate / hexane) to give 4-phenyl-3- (4-pyridyl) -3,4-epoxy-2-butanone (270 mg, 20%).

Step 4: Preparation of 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine

In the method described in Example A-1, Step 3, a solution of 4-phenyl-3- (4-pyridyl) -3,4-epoxy-2-butanone) (Step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and refluxed for 4 hours. The crude product was purified by chromatography (silica gel, 1: 1 acetone / hexane). The product was recrystallized from ethyl acetate and hexane to give 4 (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine (81 mg, 35%) as a crystalline solid, m.p. 212-214 ° C. Elemental analysis: Calculated for Ci ₅ Hi ₃ N ₃ (235.29): C, 76.57; H = 5.57; N = 17.86. Found: C = 76.49; H = 5.42; N, 17.39.

110

Example A-3

-15-meth-3- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine

Step 1: Preparation of 4- (2-methylphenyl) -3- (4-pyridyl) -3-buten-2-one

A solution of 4-pyridylacetone (Example A-5, Step 1) (0.75 g, 5.56 mmol), o-tolualdehyde (0.73 g, 5.56 mmol) and piperidine (100 mg) in toluene (50 ml) was heated to reflux. refrigerator. The water obtained during the reaction was recovered by a Dean-Stark trap. After refluxing for 5 hours, the reaction mixture was stirred at room temperature for 1 5 hours. The mixture was concentrated to give a residue as an orange colored oil. The crude ketone was purified by chromatography to give 4- (2-methylphenyl) -3- (4-pyridyl) -3-buten-2-one. Elemental analysis: Calculated for C ₆ H ₅ NO ₅ (237.30): C = 80.98; H, 6.37; N, 5.90. Found: C = 80.78; H, 6.61; N = 5.85.

Ethane 2: Preparation of 4- (2-methylphenyl) -3- (4-pyridyl) -3,4-epoxy-2-butanone

To a solution of 4- (2-methylphenyl) -3- (4-pyridyl) -3-buten-2-one (Step 1) (1.0 g, 4.2 mmol) in methanol (18 ml) was added a solution of hydrogen peroxide ( 30 wt.%) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g, 4.6 mmol) in water (4 ml). The reaction mixture was stirred at room temperature for 70 hours. After the methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two-phase mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was washed with ethyl acetate (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give an oil. 4- (2-Methylphenyl) -3- (4-pyridyl) -3,4-epoxy-2-butanone was isolated from the oily residue by chromatography.

Ethane 3: I moiety of 4- [5-methyl-3- (2-methylphenyl) -1H-pyrazol-4yl] iridinium 4- (2-methylphenyl) -3- (4-pyridyl) -3,4- epoxy-2-butanone (Step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in methanol (50 ml) were heated at reflux for 20 hours. The solvent was removed and the resulting residue was purified by chromatography to give 4- [5-methyl-3- (2-methylphenyl) -111-pyrazol-4-yl] pyridine. Elemental analysis: Calculated for C24H26F3 (249.32): C 77.08; H, 6.06; N, 16.85. Found: C = 76.66; H, 5.91; N, 16.84.

Example A-4

4- [5-methyl-3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine

The title compound was prepared by the method of Example

A-3 and when o-tolualdehyde is replaced by p-fluorobenzaldehyde. Elemental analysis: Calculated for Ci ₅ H _{2 and} N ₃ F + 0.1 H ₂ O: (249.32): C = 70.63; H, 4.82;

N, 16.47. Found: C = 70.63; H = 4.78; N = 16.40.

112

Example A-5

- [5-methyl-3- (4-methyl-phenyl) -1H-pyrazo-4-yl] pyridine

The title compound was isolated by the method of Example A-3 (a slight change: in Step 2, the preparation of the intermediate epoxide was carried out at 0-10 ° C for 1 hour and the reaction was stopped by separation with water, containing 2 equivalents of sodium bisulfite and ethyl acetate) and by substituting o-toluene dehydrate with p-tolualdehyde. Elemental analysis: Calculated for Ci ₆ Hi ₅ N ₃ (249.32): 077.08; H, 6.06; N16.85. Found: 076.97; H = 6.09; N16.90.

llpHMCp .'A-6

4- [5-methyl-3- [4- (methylthio) phenyl] -1H-pyrazol-4-yl] pyridine

The title compound was prepared by the method of Example

A-5 and by substituting p-tolualdehyde with 4- (methylthio) benzaldehyde.

Elemental analysis: Calculated for C ₆ H ₅ N ₃ S (281.38): 068.30; H = 5.37;

N, 14.93. Found: 068.34; H = 5.09; N = 14.78.

113

Example A-7

4- [3- (4-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine

The title compound was prepared by the method of Example A-5 and iri substituted p-tolualdehyde with p-chlorobenzaldehyde. Elemental analysis: Calculated for C ₅ H ₂ N ₂ C ₃ (269.77): C = 66.79; H, 4.48; N, 15.58. 11 Found: 0 = 66.43; H, 4.44; N, 15.78.

Example A-8

4- | 3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine

The title compound was prepared by the method of Example A-5 and substitution of p-tolualdehyde with m-tolualdehyde. Elemental analysis: Calculated for C ₆ H ₅ H ₅ N ₃ + 0.2 H ₂ O: C = 75.98; H, 6.14; N = 16.61. Found: C = 76.06; H, 6.05; N, 16.38.

Example A-9

4- [5- (2,5-dimethylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine

114

The title chant is obtained by the method of Example

A-5 and by substituting p-tolualdehyde with 2,5-dimethylbenzaldehyde.

Elemental analysis: Calculated 3aCi ₇ Hi ₇ N ₃ + 0.1 H ₂ O: C = 77.01; H, 6.54;

N = 15.85. Found: 0 = 76.96; H, 6.81; N, 15.51.

Example A-10

4- [5- (1,3-Benzodioxol-5-yl) -3-methyl-1H-pyrazol-4-yl] pyridine

4-N-iridylacetone (1.5 g, 12 mmol), piperronal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.2 mmol) and piperidine (110 mg, 1.3 mmol) were dissolved in toluene (30 ml) and heated in refluxed in a flask equipped with a Dean-Stark trap for 2 hours. The solution was cooled to room temperature and ethyl acetate was added to precipitate a solid, which was collected on a filter plate (1.25 g). A sample (500 mg) of this solid was heated with p-toluenesulfonylhydrazide (348 mg, 1.81 mmol) in acetic acid (5 ml) at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous potassium carbonate and water. The organic layer was dried over magnesium sulfate, filtered and evaporated to give a yellow solid. This solid was triturated with methylene chloride to give 4- [5- (1,3-benzodioxol-5-yl) -3-methyl-1H-pyrazol-4-yl] pyridine, which was collected on a filter plate (220 mg yields 42%). Elemental analysis: Calculated for Ci ₆ Hi ₃ N ₃ O _2: C, 68.81; H = 4.69; N = 15.04.

115

Found: C = 68.02; H, 4.54; N = 14.76. MS (M + H): 280 (peak).

Example A-11

4- | 3-methyl-5- (4-phenoxyphenyl) -1H-pyrazol-4-yl] pyridine

4-Pyridylacetone (1.5 g, 12 mmol), 4-phenoxybenzaldehyde (92.1 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol) and piperidine (110 mg,

1.3 mmol) were dissolved in toluene (30 ml) and heated at reflux for 2 hours in a flask equipped with a DeanStark trap. The solution was cooled to room temperature and ethyl acetate was added to precipitate a solid which collected on a filter plate. A sample (223 nig) of this solid was heated with p-toluenesulfonylhydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium base (77 mg) at 1 10 ° C for 0.5 h. The method is then the same as in Example A-10. 4- [3-Methyl-5- (4-phenoxyphenyl) -1H-pyrazol4-yl] pyridine (100 mg, yield 66%) was obtained. Elemental analysis: Calculated for C ₂₁ H ₁₇ N ₃ O + 0.1 H ₂ O: C = 76.62; H = 5.27; N, 12.76. Found: C = 76.37; H = 5.19; N, 12.64. MS (M + H): 328 (base peak).

Example A-12

4- (5 - ((1,1'-biphenyl) -4-yl] -3-methyl-1H-pyrazol-4-yl] pyridine

116

The same method as in Example A-10 was used using 4formylbiphenyl instead of piperronal to give 4- [5 - [(1,1'-biphenyl) -4-yl] -3-methyl-1H-pyrazol-4 -yl] pyridine as a white solid: MS (M + H): 312 (base peak).

Example A-13

4- | 3-methyl-5- [3- (phenoxyphenyl) -1H-pyrazol-4-yl] pyridine

The same method as in Example A-10 was used using 3-phenoxybenzaldehyde instead of piperronal to give 4- [3-methyl-5- [3 (phenoxy-phenyl) -1H-pyrazol-4-yl] pyridine as a white solid.

Example A-14

4- | 3-Methyl-5- [3- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine

The same method as in Example A-10 was used using 3-benzyloxybenzaldehyde instead of piperronal to give 4- [3-methyl-5 [3- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine as a white solid substance: MS (M + H): 342 (base peak).

117

Example A-15

4- [3-megyl-5- [2- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine

The same method as in Example A-10 was used using 2-benzyloxybenzaldehyde instead of piperronal to give 4- [3-methyl-5 | 2- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine. MS (M + H): 342 (peak).

Example A-16

2- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol

The same method as in Example A-10 was used using 2-hydroxybenzaldehyde instead of piperronal to give 2- [3-methyl-4 (4-nidiidyl) -1H-pyrazol-4-yl] phenol. MS (M + H): 252 (base peak).

3- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol

118

The same method as in Example A-10 was used using 3hydroxybenzaldehyde instead of piperronal to give 3- [3-methyl-4 (4-pyridinyl) -1H-pyrazol-4-yl] phenol: MS (M + H) ): 252 (base peak).

Example A-18

-hydroxy-4- [3-methyl-5-phenyl-1H-pyrazol-4-yl] pyridinium

To a solution of 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine (Example A-2) (2.06 g, 8.76 mmol) in a mixture of methylene chloride (10 ml) and methanol (20 ml) 3-Chloroperoxybenzoic acid (57-86%) (2.65 g,

8.76 mmol). The reaction mixture was stirred at room temperature for 2 hours, fixed with potassium carbonate solution (25%, 15 ml) and concentrated. The resulting residue was partitioned between ethyl acetate (2.0 L) and water (500 ml). The organic layer was separated, washed with water (500 ml), dried over magnesium sulfate, filtered and concentrated to give 1-hydroxy-4- [3-methyl-5-phenyl-1H-pyrazol-4- yl] pyridinium (1.12 g, 54.5%): MS (M + H): 252 (base peak).

Example A-19

5- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

119

Step 1: Preparation of 1-fluoro-4- (4′-pyridylacetyl) benzene

To a solution of sodium bis (trimethylsilyl) amide (200 ml, 1.0 M in tetrahydrofuran) at 0 ° C was added a solution of 4-picoline (18.6 g, 0.20 mol) in dry tetrahydrofuran (200 ml) for 30 minutes. The reaction mixture was stirred at 0-10 ° C for a further 30 minutes, then added to a solution of ethyl 4-fluorobenzoate (16.8 g, 0.10 mol) in dry THF (200 ml) at such a rate that the internal temperature was does not exceed 15 ° C. After the addition, the resulting yellow suspension was stirred at room temperature for 3 hours. Water (600 ml) was added and the aqueous phase was extracted with ethyl acetate (3x 200 ml). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-fluoro-4- (4'-pyridylacetyl) benzene (19.9 g, 92%) as an oil which solidified upon standing: m.p. 90-91 ° C. Elemental analysis: Calculated for Ci ₃ Hi ₀ FNO: C = 72.55; H, 4.68; N, 6.51. Found: C = 72.07; H, 4.66; N = 6.62.

Step 2: Preparation of 1-fluoro-4- (4'-pyridyl bromoacetyl) benzene

To a solution of 1-fluoro-4- (4'-pyridylacetyl) benzene (Step 1) (10.0 g, 0.046 mol) in acetic acid (200 ml) was added dropwise a solution of bromine (8.2 g, 0.052 mol) in acetic acid acid (20 ml). The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was triturated with ethyl acetate. A yellow solid was obtained which was filtered and air-dried to give 1-fluoro-4- (4'-pyridylbromoacetyl) benzene (14.5 g). The compound was used in the next step without further purification. Step 3: Preparation of 5- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) 1H-pyrazol-3-amine

A mixture of 1-fluoro-4- (4'-pyridylbromoacetyl) benzene (Step 2) (3.8 g,

120

0.01 mol) and 4,4-dimethylamino-3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 ml) were refluxed for 30 minutes. The dark green solution was cooled and poured into water (100 ml). The phase was immediately extracted with methylene chloride (100 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by chromatography (silica gel, ethyl acetate) to give 0.3 g of 5- (4-fluorophenyl) -NP-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine (0.3 g, 11%) as light yellow solid: m.p. 245-247 ° C. Elemental analysis: Calculated for C ₁₆ H ₁₅ FN ₄ : C = 68.07; H = 5.36; N, 19.84. Found: C = 68.00; 11 = 5.37; N, 19.61.

Example A-20

5- (4-fluorophenyl) -H-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

5 (4-Fluorophenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine was prepared but the method described in Example A-19: mp. 218-219 ° C. Elemental analysis: Calculated for C ₂ oHi ₅ FN ₄ + 0.1 H ₂ O: C = 72.33; H, 4.61; N = 16.87. Found: 072.16; H, 4.56; N, 16.77.

Example Λ-21

- [5- (4-fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine

121

Step 1: Preparation of 1-fluoro-4- (4′-pyridylacetyl) benzene N-benzoylhydrazone

To a solution of benzoic hydrazide (1.36 g, 0.01 mol) in tetrahydrofuran (20 ml) was added at once 1-fluoro-4- (4'-pyridylacetyl) benzene (2.15 g, 0.011 mol), followed by a drop of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature overnight. A white precipitate formed which was filtered, washed with ether and air-dried to give 1-fluoro-4- (4'-pyridylacetyl) benzene Nbenzoylhydrazone (2.90 g, 79%) as a mixture of cis and trans (1 ratio) : 9) isomers.

Step 2: Preparation of 4- [5- (4-fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine

-Fluoro-4- (4'-pyridylacetyl) benzene N-benzoylhydrazone (Step 1) (0.50 g, 1.5 mol) was heated at 180 ° C under nitrogen for 15 minutes, then cooled. The resulting solid was purified by chromatography (silica gel, 1: 1 ethyl acetate / hexane) to give 4- [5- (4-fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine (0.25 g, 53% ) as a pale yellow solid: m.p. 265-267 ° C. Elemental analysis: Calculated for C ₂ oH 14FN3 + 0.25 H ₂ O: 0 = 75.10; H = 4.57; N, 13.14. Found: C 74.98: N 4.49; N12.87.

Example A-22

-15- (3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine

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Step 1: Preparation of 3- (4′-pyridylacetyl) toluene

3- (4-Pyridylacetyl) toluene was prepared by the method described in Example A-19, Step 1 in 70% yield.

Step 2: Preparation of Trifluoroacetylhydrazide

A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 ml) was refluxed for 6 hours. The solvent was removed and the resulting residue was dried in vacuo to give trifluoroacetylhydrazide (12.3 g, 96%) as a clear oil which solidified on standing. Step 3: Preparation of 4- [5- (3-methylphenyl) -3- (trifluoromethyl) -1Hpyrazol-4-yl] pyridine

A mixture of 3- (4'-pyridylacetyl) toluene (2.11 g, 0.01 mol) and trifluoroacetylhydrazide (Step 2) (1.0 g, 0.01 mol) was heated at 200 ° C under nitrogen for 15 minutes. The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate / hexane) to give 4 [5- (3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine (0.56 g) as white solid: m.p. 237-239 ° C. Elemental analysis: Calculated for C _{16 J} II _{) 2} F ₃ N ₃ : C 63.36; H, 3.99; N13.85. Found: C = 63.6; H = 4.00;

N 13.70.

Example A-23

~ [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] pyridine

123

A mixture of 1-fluoro-4- (4'-pyridylacetyl) benzene (1.0 g, 4.6 mmol) and isopicotinhydrazide (0.63 g, 4.6 mmol) in tetrahydrofuran (25 ml) was heated to dissolve and then evaporated to dryness. . The solid obtained is first heated to 140 ° C, during which phase separation occurs, and then melts with further heating to 180 ° C. The reaction mixture was immediately cooled, diluted with 10% hydrochloric acid (50 ml) and washed with chloroform. The aqueous layer was neutralized with bicarbonate to give a tan solid. The solid was purified by treatment with activated carbon (Darco®) in boiling methanol (100 ml), followed by filtration and concentration to give 4- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H -pyrazol-5-yl] pyridine (1.05 g, 69%) as a shiny reddish-brown solid, m.p. 304 ° C (DSC). MS (MH ⁺ ) 137 (100%). Elemental analysis: Calculated for C19H13N4F. 1/4 H ₂ O: 071.13; H, 4.24; N, 17.46. Found: 070.88; H, 3.87; N, 17.38.

Example A-24

4- (5-cyclohexyl) -3-methyl-1H-pyrazol-4-yl] pyridine

Ethane 1: Preparation of 4-cyclohexyl-3-pyridyl-3-butene-2-one

4-Cyclohexyl-3-pyridyl-3-butene-2-one was prepared according to the procedure described in Example A-1, Step 1, by replacing 3-fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde.

Step 2: Preparation of 4- (5-cyclohexyl) -3-methyl-1H-pyrazol-4-yl] nyridine

124

4- (5-Cyclohexyl) -3-methyl-1H-pyrazol-4-yl] pyridine was prepared according to the method described in Example A-1, Step 2, by substituting 4- (3-fluoro-4-methoxyphenyl) -3 -pyridyl-3-buten-2-one with 4-cyclohexyl-3-pyridyl-3-buten-2-one (Step 1): Elemental analysis: Calculated for C15H19N3: C = 73.56; H = 7.98; N = 17.16. Found: C = 73.72; H = 7.91; N, 19.98.

Example A-25

4- [5- (3-Fluoro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine

4- [5- (3-Fluoro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine was prepared according to the method described in Example A-1, Steps 1 and 2, by substituting 3 -fluoro-p-anisaldehyde with 3-fluoro-t-anisaldehyde: Elemental analysis: Calculated for C ₆ H ₁₆ N ₃ OF: C = 67.83; H, 4.98; N, 14.83. Found: C = 67.68; H = 4.92; N = 14.92.

The following Examples (No 26-55) shown in Table 1 are prepared by the methods described above:

No R ¹ R ² R ³ R ⁴ m.p. or DSC (° C ' Anal.Calc'd Formula Anal. Calc'd (calcd / found) C H N 26 N. n-> n- • | Q 185-186 C _I8 H ₁₉ N ₃ 77.95 / 77.51 6.90 / 6.93 .. 15.15 / 14.73 27 N. • | dream ₃ · «□> 142-144 C and ₆ H 15 N ₃ 75.71 / 75.69 6.16 / 6.11 16.55 / 16.49 28 n ί <£> 240-242 ε _Ώ Η _{! 9} Ν ₃ .0.25H, O 80.09 / 79.74 5.96 / 5.90 12.74 / 13.01 29 n i-Q F.C 4ch ₃ 228.8 c ₁₆ h _I2 n ₃ f ₃ 63.36 / 63.28 3.99 / 3.73 13.85 / 13.69 30 n • | CH3 • i £> 189.6 CjjHpNjC: 66.13 / 4: 55 / 15.42 / N .0.15Η-Ό 6,5.98 4.31 15.74

125

3 1 Η -ί CH ₃ 171.6 c ₁₇ h _i7 n ₃ .0.2H, O 76.49 / 76.69 6.57 / 6.53 15.74 / 15.61 3 2 6 CH3 '<, N '& a 88.6 C ₁₆ H ₁₄ N ₃ C1 67.72 / 67.35 4.97 / 5.29 14.81 / 15.02 ν! - -Ί 1 Η • icHj '<N • 'I 188.8 c ₁₆ h ₁₄ n ₃ f 71.89 / 71.72 5.28 / 5.45 15.72 / 15.77 3-4 in 4 CH3 7r ^ * <, n 215.7 Ci ₇ H _i7 N ₃ 77.54 / 77.24 6.51 / 6.80 15.96 / 15.71 35 in • ί CH3 7j ^ '<, N <· 201.4 .0.25H, O 68.10 / 67.92 5.88 / 5.65 14.01 / 13.65 36 Η η ** _x <£ Nz ! <N ! © NO 210.7 Ci ₅ H ₁₂ N ₄ O _; .0.25H, O 63.26 / 63.59 4.42 / 4.39 19.67 / 19.31 37 Η | dream ₃ '© H 252.5 C17H _u N ₄ 73.35 / 72.61 6.52 / 6.79 20.13 / 19.59 38 Η 1 <N | ch ₃ 196.3 Ci ₇ H ₁₃ N ₃ C 73.63 / 73.43 5.45 / 5.46 15.15 / 15.19 39 Η 7 ^ ! <, N • | ch ₃ 252.8 Ci ₅ H ₁₂ N ₃ Art 57.34 / 57.09 3.85 / 3 79 13.37 / 13.06 40 Η 7 ^ * <i, N • | dream ₃ 198.5 Ci ₅ H ₁₂ N ₃ F 71.13 / 71.23 4.78 / 5.01 16.59 / 16.76 41 Η • | ch ₃ 7 ^ l ^ N - «Q> F 225.6 ^ 15 ^ 12 ^ 3 ^ 3 71.13 / 70.74 4.78 / 4.66 16.59 / 16.44 42 Η • | ch ₃ 7r ^> · <, N -ιφ CFi 219.5 Ci6H ₁₂ F ₃ N ₃ 63.36 / 63.19 3.99 / 4.07 13.85 / 13.38 43 Η dsc ₂ dream ₃ * <N · «□> 227.7 Ci ₆ H ₁₅ N ₃ .Ο.ΙΗ, Ο 76.53 / 76.53 6.10 / 6.20 16.73 / 16.49 44 Η • bcH3 V ' 175.6 c ₁₆ h _I5 n ₃ o .0.15H ₂ O 71.70 / 71.92 5.75 / 5.76 15.68 / 15.29 45 Η Vch ₂ ch ₃ 7 ^ '<N -iQ - Ci ₇ H ₁₉ N ₃ 77.54 / 77.13 6.51 / 6.28 15.96 / 15.69 46 Η i'CH ₃ N 412.1 c ₁₅ h _h n ₃ f ₂ 66.42 / 66.12 4.09 / 3.86 15.49 / 15.25 47 Η • Vch ₃ 7 ^ ^With CV 168.5 C-17H17N3O .0.15H ₂ O 72.40 / 72.39 6.18 / 5.87 14.90 / 14.50 48 Η • i'CH ₃ in. 211.2 C ₁₆ H ₁₂ N ₃ F ₃ .0.2H, O 62.62 / 62.64 4.07 / 4.06 13.69 / 13.35 49 Η i'CH ₃ 7 "<i> l ^ N - C ₁₃ H _U N ₃ S 64.71 / 64.44 4.59 / 4.58 17.41 / 17.27 50 Η • Vch ₃ 7] ^! kt.N ^c, T2r7 189.2 CijHh ^ CIj 59.23 / 59.22 3.65 / 3.24 13.81 / 13.81 51 Η • Vch ₃ 7 ^ '<> N 'V 211.7 CjjHpNjCl .0.15H ₂ O 66.13 / 66.33 4.55 / 4.62 15.42 / 15.05 52 Η + ch ₃ 7 ^ Ε, ν 219.8 c ₁₆ h ₁₄ n ₃ ci 64.11 / 63.85 4.71 / 4.69 14.02 / 13.93 j 3 Η 7r <b ^y a _c , 163.4 C ₁₉ H ₁₇ N ₃ OC1 64.32 / 63.98 4.83 / 5.08 11.84 / 11.80 54 + dream ₃ in '<N H c ₁₅ h ₁₂ n ₃ f .0.2H, O 70.15 / 70.18 4.86 / 4.60 16.35 / 16.47 55 Η EsN H - c ₁₄ h ₁₀ n ₃ f 70.28 / 69.97 4.21 / 3.84 17.56 / 17.53

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The following pyrazoles can be prepared by the methods described above:

Example A-56: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin2-amine;

Example A-57: 5- [3-Methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyrimidin2-amine;

Example A-58: 5- [3-Methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyrimidin2-amine;

Example A-59: 5- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin2-amine;

Example A-60: 5- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin2-amine;

Example A-61: 5- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine;

Example A-62: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-63: 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-64: 4- [5- (3-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-65: 4- [5- (2-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-66: 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-67: 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2amine;

Example A-68: 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin2-amine;

127

Example A-69: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

Example A-70: 2-Methoxy-5- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

Example A-71: 2-Methoxy-5- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4yl] pyridine;

Example A-72: 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

Example A-73: 2-Methoxy-4- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

Example A-74: 2-Methoxy-4- [3-methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine;

Example A-75: 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

Example A-76: 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine;

Example A-77: 2-Methoxy-4- [3-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine;

Example A-78: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

Example A-79: 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

Example A-80: 4- [5- (3-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

Example A-81: 4- [5- (2-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

Example A-82: 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

128

Example A-83: 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2ol;

Example A-84: 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin2-ol;

Example A-85: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-methanamine;

Example A-86: 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-methanamine;

Example A-87: 4- [5- (3-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

Example A-88: 4- [5- (2-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

Example A-89: 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

Example A-90: 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine;

Example A-91: 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine2-methanamine;

Example A-92: 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

Example A-93: 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

Example A-94: 4- [5- (3-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

Example A-95: 4- [5- (2-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

Example A-96: 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

129

Example A-97: 4- (5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2carboxamide;

Example A-98: 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine2-carboxamide;

Example A-99: 4- [5- (3-Fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-100: 4- [5- (4-Fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-101: 4- [5- (4-Chloro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-102: 4- (5- (2,3-Dihydrobenzofuran-6-yl) -3-methyl-1H-pyrazol4-yl] pyridine;

Example A-103: 4- (5- (Benzofuran-6-yl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-104: 4- (5- (3-Fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-105: 4- [5- (3-Chloro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-106: 4- [5- (1-Cyclohexylene-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-107: 4- (5- (1,3-cyclohexadien-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-108: 4- (5- (5,6-Dihydro-2H-pyran-4-yl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-109: 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl) pyridine;

Example A-110: 4- (5- (4-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-111: 4- (5- (3-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl]

130 pyridine;

Example A-112: 4- [5- (3-Methoxy-5-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-113: 4- [5- (3-furyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-114: 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-115: 2-Methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-116: Methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2carboxylate;

Example A-117: 4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2-carboxamide;

Example A-118: 1- [4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-2-yl] ethanone;

Example A-119: N, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-2-amine;

Example A-120: 3-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-121: 3-Methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-122: Methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3carboxylate;

Example A-123: 4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3-carboxamide;

Example A-124: 1- [4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-3-yl] ethanone;

Example A-125: 3-Bromo-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-126: b1, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-3-amine;

Example A-127: 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine;

Example A-128: 4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine;

Example A-129: 2-Methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimines

131 din;

Example A-130: 4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine,

Example A-131: N, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine;

Example A-132: 4- (5,6-Dihydro-2H-pyran-4-yl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-133: 3-Methyl-5-phenyl-4- (3-thienyl) -1H-pyrazole;

Example A-134: 4- (3-furyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-135: 3-methyl-5-phenyl-4- (2-thienyl) -1H-pyrazole;

Example A-136: 4- (2-furyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-137: 4- (3-Isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-138: 4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-139: 4- (5-Isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-140: 4- (5-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole;

Example A-141: 3-Methyl-5-phenyl-4- (5-thiazolyl) -1H-pyrazole;

Example A-142: 3-methyl-4- (5-oxazolyl) -5-phenyl-1H-pyrazole;

Example A-143: 2-methyl-4- [3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine;

Example A-144: 4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] pyridine;

Example A-145: 4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] pyridine;

Example A-146: 2-methyl-4- (3-phenyl-1H-pyrazol-4-yl) pyridine;

Example A-147: 4- [3- (3-Chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine;

Example A-148: 4- [3- (4-Chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine;

Example A-149: 4- [3- (3-Chlorophenyl) -1H-pyrazol-4-yl] pyridine;

Example A-150: 4- [3- (4-Chlorophenyl) -1H-pyrazol-4-yl] pyridine;

Example A-151: 4- [3- (3-Chlorophenyl) -1H-pyrazol-4-yl] 2-methylpyridine;

Example A-152: 4- [3- (3-Fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine;

Example A-153: 4- [3- (3-Fluorophenyl) -1H-pyrazol-4-yl] pyridine; and

Example A-154: 4- [3- (3-Chlorophenyl) -1-methyl-pyrazol-4-yl] -2-methylpyridine

132 din.

The compounds of Examples A-155 to A-172 were synthesized according to the chemistry described above (in particular Scheme II) and illustrated in the moto above examples by selecting the appropriate starting materials:

Example A-155

5- (4-chlorophenyl) -H-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

DSC 261 ° C. Elemental analysis: Calculated for C ₂ oHi ₅ C1N4 + 0.25 H ₂ O (molecular weight 351.32): C, 68.38; H, 4.30; N = 15.95. Found: C = 68.25;

11 = 4.41; N15.74.

Example A-156

5- (4-Chlorophenyl) -1H-methyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

DSC 260 ° C. Elemental analysis: Calculated for Ci ₅ Hi ₃ C1N ₄ + 0.125 H ₂ O (molecular weight 287.00): C, 62.77; H = 4.57; N, 19.52. Found: C = 62.78;

11 = 4.33; N19.22.

133

Example A-.157

5- (4-chlorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazole-3-amine dihydrate

DSC 230 ° C. Elemental analysis: Calculated for C ₆ H ₁₅ ClN 4 + 2 H ₂ O (molecular weight 334.81): 057.40; H, 4.52; N, 16.73. Found: 057.72;

4.85: N16.54.

Example A-158

- (3-fluorophenyl) -I, dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

DSC 227 ° C. Elemental analysis: Calculated for Ci ₆ Hi ₅ FN ₄ + 0.125 H ₂ O (molecular weight 284.57): 067.53; 11 = 5.31; N = 19.69. Found: 067.60;

05.20; 019.84.

Example A-159

N, N-dimethyl ethyl 5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine

134

DSC 222 ° C. Elemental analysis: Calculated for CпH ^Clд + 0.25 H ₂ O (molecular weight 282.86): 0 = 72.19; H, 6.41; N, 19.81. Found: 0 = 71.99;

H, 6.46; N = 19.90.

Example A-160

N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine

DSC 226 ° C. Elemental analysis: Calculated for C 22 H 26 Cl ₂ O + 0.125 H ₂ O (molecular bed 266.58): 0 = 72.09; H, 6.05; N = 21.02. Found: 0 = 72.12;

H, 6.12; N, 20.83.

Example A-161

N-ei yl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine

DSC 227 ° C. Elemental analysis: Calculated for Ο ₁₇ Ηι ₈ Ν ₄ + 0.125 H ₂ O (molecular weight 280.61): C 72.77; H, 6.47; N, 19.97. Found: 0 = 72.63;

H = 6.40; N, 19.73.

135

Example A-162

HH-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine i) SC 234 ° C. Elemental analysis: Calculated for C 19 H 22 N 4 (molecular weight 306.41): 074.48; H, 7.24; N = 18.29. Found: 074.12; H = 7.18; N = 18.13.

Example A-163

5- (4-chlorophenyl) -H, N-diethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

Mp 260-261 ° C. Elemental analysis: Calculated for Ci ₈ H ₁₉ C1N4 (molecular weight 326.83): 066.15; H = 5.86; N = 17.14. Found: 066.03; 11 = 5.72; N17.23.

Example A-164

4- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] morpholine

136

DSC 279 ° C. Elemental analysis: Calculated for C 18 H ₁₇ ClN ₄ O + 0.25 H ₂ O (molecular weight 345.32): C = 62.61; H, 4.96; N, 16.23. Found: C = 62.52;

And 4.77: N = 16.52.

Example A-165

5- (4-chlorophenyl) -H-propyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

i) SC 244 ° C. Elemental analysis: Calculated for C 25 H 25 Cl 2 + 0.125 H ₂ O (molecular weight 315.06): C = 64.81; H = 5.44; N, 17.78. Found: C = 64.94;

H = 5.43; N, 17.78.

Example A-166

Isolated as 5- (4-chlorophenyl) -1H- (phenylmethyl) -4- (4-pyridinyl) 1H-pyrazole-3-amine hydrate (2: 1): DSC 237 ° C. Elemental analysis:

Calculated for C21H17CIN4 + 0.5 H ₂ O (molecular weight 369.86): C = 68.20;

11 = 1. () 3. N 1 5.15. Found: C = 68.09; H = 4.55; N = 15.15.

137

Example A-167

Isolated as 5- (4-chlorophenyl) -N- (2-methoxyethyl) -4- (4-pyridinyl) 1H-pyrazole-3-amine monohydrate: DSC 223 ° C. Elemental analysis:

Calculated for C ₁₇ HitC1N ₄ O + H ₂ O (molecular weight 346.82): C = 58.87;

H = 4.94 ·; N = 16.15. Found: C = 58.59; H, 4.79; N = 16.02.

Example A-168

1,1-dimethylethyl 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -

-piperazinecarboxylate

DSC 251 ° C. Elemental analysis: Calculated for C ₂ H _{2 6} OCH ₅ O (molecular weight 439.95): C = 62.79; H = 5.96; N, 15.92. Found: C = 62.40; H = 5.82; N, 15.82.

138

Example A-169

Isolated as 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3yl] piperazine trihydrochloride: DSC 99 ° C. Elemental analysis: Calculated for C ₁₈ H ₁₈ ClN ₄ + 3 H ₂ O (molecular weight 449.21): C = 48.13; H = 4.71;

N, 15.59. Found: C = 47.76; H = 5.07; N, 15.51.

Example A-170

1- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methylpiperazine

1'l. Mp 247-249 ° C. Elemental analysis: Calculated for Ci ₉ H ₂ oC1N ₅ + 0.75

H ₂ O (molecular weight 367.33): C = 62.12; H = 5.49; N = 19.06. Found:

62.45; H, 5.86; N, 19.32.

Example A-171

139

1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -

-piperazinecarboxylate

M.P. Mp 243-244 ° C. Elemental analysis: Calculated for C23H26FN5O2 + 0.5

CH3CH2CO2CH2CH3 (molecular weight 467.55): C-64.22; H, 6.47; N-14.98.

Found: 0 63.90; H, 6.61; N, 14.88.

Example A-172

- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine trihydrochloride

1.1. Mp 204-206 ° C. Elemental analysis: Calculated for C ₁₈ Hi8FN ₅ + 3 H 2 O (molecular weight 441.77): C, 48.94; H, 4.79; N = 15.85. Found: C = 48.66;

II 4.88: N = 15.50.

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine

M.P. Mp 264-265 ° C. Elemental analysis: Calculated for Ci ₈ Hi ₈ C1N ₅ + 0.125

H ₂ O (molecular weight 342.08): C = 63.20; H = 5.30; N, 20.47. Found:

O-63.04; 11 = 5.36; N, 20.33.

Other compounds that have been synthesized according to the chemistry described in Scheme II when selecting the appropriate starting compounds include the compounds described in Table 2.

140 pts

ο o MS o Midrange oo Γ- ο MS ο Q ο o C /) OJ oo mx · - MS rX MS r ** MS ο hey Ό MS MS MS MS Midrange Ζ MS MS 40 c oo - TG τΓ Γ * · tg Γ- Γ * 40 rx • S ' 40 MS rx 40 ΓΧ ττ ΓΧ oo £ '' T 40 © ' 40 MX 40 ΤΓ ex νχ G- ' Z ech _o 40 o MS Γ- οο GC σ \ _ 40 C5 MS ο GC ex ΟΟ ΤΓ ΓΧ Γ rx ° TG 40 ο 40 νχ 40 '' Τ οχ νχ OO z MS -σι rx 40 40 τΓ r- - VX MX XT Tf Oh MX οο Ο oo ΟΟ MS MS MX 40 G- * s <x vx vx ΤΓ 40 rf MX 40 40 MX MX 1 X Mr Rücker υ δ * w 40 o 40 MS MX Μ νχ MX r * x Pi o o · 40 MX 40 ΟΟ Midrange 00 40 00 MX • 5 X 'T MX ΤΓ 40 TG MX 40 VX MX MX TG • o c oo CX VX Mr- 40 «Μ 40 40 oo r- G- * Z3 mx rx ΤΓ MX 04 MX Γ ' 00 04 Ox rx £ o CX οο - ^ r Ο Ο 00 * MS MX Oh mx 40 '' Τ 40 40 40 40 MX 40 TT _υ GC Γ- ΤΓ MX MX __ 40 Ό oo Π5 40 40 G- * 00 40 ο ΟΧ MS ex • 4 © ex οο - TG ό MS ό ox MS MX o MX 40 '' Τ 40 40 40 40 MX 40 TG o Ο MS IT * o MS ο About MS 112 20 o 1 3HC1-1.5 X MX MS Oh MX MS MX MS 40 C1N5O2 y ex 02 * 0.125 C1N5O3 502 * 0.511 C1FN5O2 mx D * o MX y rx MX with TG t 40 z (1 z in H · 17FN 2Η26 z o oo sn ζ Ο 51130 Ζ U-. νχ MX MS X z u Midrange I19C1 C24H25I C25II2 C17H C2 C17II1 C21H24 MS C22H2 C22 X o midrange Oh 5 Mr ) bg etod X X X ₌ II 4 X h. Il X X ₌ X Q (J υ Q Q υ Ο ο <_> (J CJ C / 2 GO 00 00 GO C / 2 GO GO CZ) 00 GO fl. rx xr MX 40 r- οο 04 Ο MS ex • Mr Γ * · Γ * · D * Γ- r- Γ- * Mr- 00 00 OO OO s < 1 < 1 < < < 1 I < 1 < I < < t < < I * <

141

Example A-173

N- [5- (4-chlorophenyl) -4- [2- (phenylmethyl) amino] -4-pyridinyl] -1H-pyrazole-

3-yl] -1,3-propandiamine trihydrochloride

Example A-174

- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4- (phenylmethyl) piperazine

Example A-175

Isolated as 4- [3- (4-fluorophenyl) -5- (1-piperazinyl) -1H-pyrazole-

4-yl | ishrimidine dihydrochloride

142

Example A-176

1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate

Example A-177

Isolated as N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3yl] -1,3-propandiamine trihydrochloride monohydrate.

Example A-178

1,1-dimethylethyl [2 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] amino] ethyl] carbamate

143

Example A-179

1,1-dimsgilsgyl 4- [5- (4-chlorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl)

N-pyrazol-3-yl] -1-piperazinecarboxylate

Example A-180

1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-3-yl] -1-piperazinecarboxylate

Example A-181

1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate

144

Example A-182

- | 5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-ethylpiperazine

Example A-183

N - [5- (4-lophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1,2-ethanediamine

The compounds of Examples A-184 to A-189 were synthesized according to the chemistry described above (in particular in Schemes I and IV) and illustrated in the aforementioned examples when selecting the corresponding starting compounds:

Example A-184

4- (3- (2,6-difluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for C15H11F2N3: C = 66.42; H = 4.09;

N I 5.49. Found: C = 66.20; H, 3.94; N = 15.16. M.P. 236.67 ° C.

145

Example A-185

4- [3- (3-ethylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for C ₇ H ₁₇ N ₃ : C = 77.54; H = 6.51; N, 15.96. Found: C = 77.16; H, 6.27; N, 15.69. M.P. (DSC) 189.25 ° C.

Example A-186

4- | 3- (3-chlorophenyl) -5-ethyl-1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for C ₆ H ₄ Cl ₄ N ₃ · 0.1 mol H ₂ O: C = 67.15; II 4.91, N-14.33. Found: C = 66.95; H = 5.00; N, 14.36. M.P. (DSC)! 76.1ZT.

Example A-187

4- [3-ethyl-5- (3-ethylphenyl) -1H-pyrazol-4-yl] pyridine

146

Elemental analysis: Calculated for C ₁₈ H ₉ N ₃ O · 0.1 mol H ₂ O: 077.44;

06.93; N = 15.05. Found: 077.39; H = 6.94; N, 14.93. M.P. (DSC) 192.66 ° C.

Example A-188

4- [3- (4-chlorophenyl) -5- (1-methylethyl) -1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for C ₇ H ₆ ClN ₂ · 0.4 M EtOAc: 067.08;

11 = 5.81; N12.62. Found: 067.40; H = 6.15; N = 12.34.

Example A-189

4- [3-cyclopropyl-5- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for Ci ₇ Hi4FN _3: 073.1; H = 5.05; N = 15.04. Found: 073.23; H, 4.89; N, 14.63. M.P. 239-240 ° C.

The compound of Example A-190 was synthesized according to the chemistry described above (in particular in Scheme III) and illustrated in the said example when selecting the appropriate starting compounds:

147

Example A-190

4- (3- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine

This compound was prepared by the method described for Example A-22 by replacing 3- (4'-pyridylacetyl) toluene with 1-fluoro-4- (4'-pyridylacetyl) benzene (prepared according to Example A-19). Elemental analysis: Calculated for C ₁₅ H ₉ F ₄ N ₃ ; C, 58.64; H = 2.95; N, 13.68. Found: C = 58.57; H = 3.07;

N, 13.31. M.P. (DSC) 281.94 ° C.

The compounds of Examples A-191 to A-198 were synthesized according to the chemistry described above (in particular in Scheme V) when selecting the corresponding starting compounds:

Example A-191

4- (5- (cyclopropyl-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine)

Ethane 1: Preparation of 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone methylhydrazole

148

- (4-fluorophenyl) -2- (4-pyridinyl) ethanone methylhydrazone

To a solution of 4-fluorobenzoyl-4'-pyridinylmethane (8.60 g, 0.04 mol) and methyl hydrazine (2.14 g, 0.044 mol) in 50 ml of ethanol were added two drops of concentrated sulfuric acid. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium carbonate solution, washed with brine and dried over magnesium sulfate. The filtrate was concentrated and the crude product was recrystallized from diethyl ether and hexane to give 7.5 g of a yellow solid (yield 77%), 1- (4-fluorophenyl) -2- (4-pyridyl) ylpropion methylhydrazone.

Ethane 2: Preparation of 4- [5- (cyclopropyl-3- (4-fluorophenyl) -1-methyl-1H1 chrazol-4-yl] pyridine

To a solution of sodium hexamethyldisilazide (5.5 ml, 1.0M in tetrahydrofuran) at 0 ° C was added dropwise a solution of the compound obtained in Eian 1 (0.67 g, 0.0028 mol) in 10 ml of dry tetrahydrofuran. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methylcyclopropanecarboxylate (0.34 g, 0.0034 mol) in 5 ml of dry tetrahydrofuran was then added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. Organic! the layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography

149 raffia over silica gel (ethyl acetate / hexane / acetone, 10: 9: 1) to give 0.45 g of product 4- [5- (cyclopropyl-3- (4-fluorophenyl) -1-methyl-1H-pyrazol4-yl] nyridine) as light yellow solid (yield 55%), mp 129130 ° C; ΪΙ NMR (CDCl ₃ ): δ 8.53 (m, 2H), 7.32 (m, 2H), 7.14 (m, 2H), 6.97 (m , 2H), 4.00 (s, 3H), 1.83 (m, 1H), 0.95 (m, 2H), 0.36 (m, 2H) Elemental analysis: Calculated 3aC ₁₈ H ₁₆ FN ₃ : C = 73.70; H = 5.50 N = 14.32 Found: C = 73.63; H = 5.57; N = 14.08.

Example Λ-192

OH

5-cyclopropyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol

Step J: Preparation of 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone (2-hydroxy) hydroxy

! - (Effluorophenyl) -2- (4-pyridinyl) ethanone (2-hydroxyethyl) hydrazone

To a flask containing hydroxyethylhydrazine (3.4 g, 0.04 mol) at 80 ° C was added portionwise 4-fluorobenzoyl-4'-pyridinylmethane (8.6 g, 0.01 mol). The yellow oil was stirred at this temperature for one hour. The cooled reaction mixture was dissolved in hot ethyl acetate and then sprayed with hexane to give 8.9 g of προ

1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone (2-hydroxyethyl) hydrazone as yellow crystals (81%), m.p. 122-123 ° C.

Step 2: Preparation of 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] hydrazone

- (4-fluorophenyl) -2- (4-pyridinyl) ethanone [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] hydrazone

To a solution of 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone (2-hydroxyethyl) hydrazone obtained in Step 1 (2.73 g, 0.01 mol) and (1,1-dimethylethyl) dimethylsilyl chloride (1.5 g, 0.01 mol) in 25 ml of dimethylformamide imidazole is added portionwise. The reaction mixture was stirred at room temperature overnight. 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 3.8 g of the crude product 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone | 2- [| (1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] hydrazone, as a yellow oil, which is used in the next step without further purification.

Step 3: Preparation of 5-cyclopropyl-1- [2 - [[(1D-dimethylethyl) dimethylsilyl (oxy | with til] -3,4-diphenyl-1H-pyrazole

151

5-cyclopropyl-1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

3,4-diphenyl-1H-pyrazole

A solution of the compound obtained in Step 2 (0.78 g, 0.002 mol) in 10 ml of dry tetrahydrofuran was added dropwise to a solution of sodium hexamethyldisilazide (4.2 ml, 1.0 M in tetrahydrofuran) at 0 ° C. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methylcyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 ml of dry tetrahydrofuran was then added. The reaction mixture was allowed to warm to room temperature and stirred for 3 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 purified by chromatography over silica gel (ethyl acetate / hexane, 3: 7) to give 0.30 g of product 5-cyclopropyl-1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3 , 4-diphenyl-1H-pyrazole as a light yellow oil (35% yield). ^! H NMR (CDCl ₃ ): δ 8.53 (m, 2H), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97 (m, 2H), 4.47 (t, J = 4.8 Hz. 2H), 4.14 (t, J = 4.8 Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H), 0.41 (m, 2H). Elemental analysis: Calculated for C 25 H ₃₂ FN ₃ OSi: C = 68.61; H, 7.37; N = 9.60. Found: C = 68.39; H = 7.81; N, 9.23.

Step 4: Preparation of 5-cyclopropyl-3- (4-fluorophenyl) -4- (4-pyridinyl) 1H-pyrazol-1-ethanol

To a solution of the compound obtained in Step 3 (0.27 g, 0.00062 mol) in 5 ml of tetrahydrofuran at room temperature was added tetrabutylammonium fluoride (1.9 ml, 1.0 Mv tetrahydrofuran). After one hour, 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 purified by chromatography over

152 silica (ci ilacetate / hexane, 9: 1) to give 0.30 g of product 5µl! N-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol as a pale yellow solid, m.p. Mp 155-157 ° C. 1 H NMR (CDCl ₃ ): δ 8.53 (br s.2II), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97 (m, 2H), 4.42 (t, J = 4.8) 11z, 2H), 4.14 (t, J = 4.8 Hz, 2H), 1.83 (m, 1H), 0.93 (m, 2H), 0.35 (m, 2H). Elemental analysis: Calculated for C ₉ H ₁₈ FN ₃ O: C = 70.57; H = 5.61; N, 12.99. Found: C -70.46; H = 5.87; N, 12.84.

Example A-193

3- (4-fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol

To a solution of sodium hexamethyldisilazide (7.4 ml, 1.0 M in tetrahydrofuran) at 0 ° C was added dropwise a solution of the compound obtained in Step 2 of Example A-192 (1.25 g, 0.0034 mol) in 15 ml of dry tetrahydrofuran. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methyl 4- (2methoxy) pyridinecarboxylate (0.0.59 g, 0.0035 mol) in 5 ml of dry tetrahydrofuran was then added. The reaction mixture was allowed to warm to room temperature and stirred for 3 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 purified by chromatography over silica gel (ethyl acetate / hexane, 1: 1).

153 to give 0.28 g of 3- (4-fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol as a yellow solid. mp Mp 168-169 ° C. ¹ H NMR (CDCl ₃ ): δ 8.42 (m, 2H), 8.20 (dd, J = 0.7.5.2 IIzJII), 7.37 (m, 2H), 7.02 (m, 2H), 6.95 (m, 2H), 6.71 (dd, J = 1.4,5.2 Ηζ, ΙΗ), 6.66 (t, J 0.7 Ηζ, ΙΗ), 4.20 (m, 2H), 4.14 (m, 2H), 3.95 (s, 3H). Elemental analysis: Calculated for C22H19FN4O2: C = 67.86; H, 4.91; N = 14.35. Found: C = 67.46; H = 5.08; N = 14.03.

4- | 1- {2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4-fluorophenyl4- (4-pyridinyl) -1H-pyrazol-5-yl] -2-methoxypyridine

A second compound, 4- [1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4) can also be isolated from the reaction mixture by chromatography. -fluorophenyl-4- (4-pyridinyl) -1H-pyrazol-5-yl] -2-methoxypyridine as a yellow oil Ή NMR (CDCl ₃ ): δ 8.45 (m, 2H) 8.20 (m, 1H), 7.40 (m, 2H), 7.04 (m, 2H), 6.93 (m, 2H), 6.81 (m, 2H), 4.24 (ni, 2Il), 4.14 (m, 2H), 3.98 (s, 3H), 0.83 (s, 9H), 0.02 (s, 6H).

Example A-194

154

4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone

To a solution of 3- (4-fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-nitridinyl) -1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 ml of acetic acid was added 3 ml of 48% hydrobromic acid. The reaction mixture was refluxed for 3 hours. After cooling, the cooled mixture was treated with water, basified with ammonium hydroxide 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 over silica gel (methanol / methylene chloride / ammonium hydroxide, 5: 94: 1) to give 0.07 g of product 4- [3 (4-fluorophenyl) -1- (2-hydroxyethyl) -4- ( 4-Pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone as a yellow solid (yield 32%), m.p. 250-251 ° C. 1 H NMR (DMSO-d ₆ ): δ 11.74 (s, 1H), 8.45 (d, J = 5.0 Hz, 2H), 7.35 (m, 3H).

7.16 (m, 2H), 7.03 (d, J = 5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J = 5.2 Ηζ, ΙΗ), 5.0 (m, 11-l), 4.13 (m , 2H), 3.81 (m, 2H). Elemental analysis: Calculated for C ₂₁ 11 ₁₇ ΕΝ ₄ Ο ₂ · 0.2 Η ₂ Ο: C = 66.06; H = 4.65; N = 14.67. Found: C = 66.31;

N = 4.49; N, 14.27.

Example A-195

1-Listyl-1- | 3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1Hpyrazol-5-yl] -2 (1H) -pyridinone

155

-Ai is mp-4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -N-nrazol-5-yl] -2 (1H) -pyridinone is obtained as the reaction by-product of Example A-194 as a yellow solid (yield 38%), m.p. 220-221 ° C. Ή NMR (CDCl ₃ ): δ 8.50 (m, 2H), 7.39 (ηι, 3Π), 7.02 (m, 4H), 6.59 (m, 1H), 6.08 (dd, J = 1.4,5.2 Ηζ, ΙΗ). 4.52 (t, J = 6.0 Hz, 21 -I), 4.43 (t, J = 6.0 Hz, 2H), 2.04 (s, 3H). Elemental analysis: Calculated for C ₂₃ H _{1 S} 1% O ₃ · 0-3 H ₂ O: C = 65.46; H, 4.63; N, 13.28. Found: C = 65.09;

And! ! .6 · | ·. N, 12.99.

Example A-196

is til 2- | 3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylate

To a solution of sodium hexamethyldisilazide (17.0 ml, 1.0 M in tetrahydrofuran) at 0 ° C was added dropwise a solution of the compound obtained in Step 1 of Example A-192 (1.37 g, 0.005 mol) in 20 ml of dry tetrahydrofuran. The dark brown solution was stirred at this temperature for 30 minutes. A solution of diethyl was then added

1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 ml of dry tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 2 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 concentrated

Chromatography over silica gel (ethyl acetate / hexane, 8: 2) to give 0.18 g of ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxystyl) -144-pyridinyl) -1H-pyrazole- 5-yl] cyclopropanecarboxylate as a light yellow oil (35% yield). 1 H NMR (CDCl ₃ ): δ 8.55 (m, 2H), 7.32 (m, 211), 7.1 1 (m, 2H), 6.97 (m, 2H), 4.38 (m, 2H), 4.16 (m, 4H) , 2.47 (m, 1H), 1.53 (rn, 211), 1.26 (t, J = 7.0 Hz, 3H), (m, 2H), 0.90 (m, 2H). Elemental analysis: Calculated for C ₂₂ H ₂₂ FN ₃ O ₃ · 0.25 H ₂ O: 066.07; H = 5.67; N, 10.51. Found: 065.89; H = 5.80; N = 9.95.

Example A-197

2-13- (4-Fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1Hnirazol-5-yl] cyclopropanecarboxylic acid

To a solution of ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylate prepared according to Example A-196 (0.21 g, 0.00045 mol) in 10 ml of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 1 ml of water. The reaction mixture was stirred at reflux for 6 hours. After removal of the solvent, the residue was dissolved in 10 ml of 1N hydrochloric acid and stirred for 30 minutes. The pH was then adjusted to 5-6 by the addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and crude

The 157 product was purified by recrystallization from ethanol and ether to give 0.1 g of 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -! N-pyrazol-5-yl] cyclopropanecarboxylic acid as a white solid (60% yield), m.p. Mp 253-255 ° C; 1 H NMR (CD ₃ OD): δ 8.46 (m, 211). 7.32 (m, 2Η), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J = 5.0 Hz, 2H), 4.03 (no, 211), 2.60 (m, 1H), 1.51 (m , 2H), 0.97 (m, 2H). Elemental analysis: Calculated for C ₂₀ Hi ₈ FN ₃ O _3: 0 = 65.39; H, 4.94; N, 11.44. Found:

64.92; 11 1.77; N, 11.20.

Example Λ-198

3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol

Step 1: Preparation of methyl 1 - [[2- (trimethylsilyl) ethoxy] methoxy] -1H pyro-3-carboxylic acid

TMS methyl 1 - [[2- (trimethylsilyl) ethoxy | methoxy] -1H-pyrrole-3-carboxylate

To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 ml of dimethylformamide, methyl 4imidazolecarboxylate (2.95 g, 0.023 mol) was added portionwise at room temperature. The mixture was stirred at room temperature for 0.5 h. Then, drop by drop, over

158 we at 5 minutes, SEM-C1 (4.17 g, 0.025 mol) was added. The reaction mixture was stirred for 4 hours and fixed by the addition of water. The aqueous phase was extracted with ethyl acetate and 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 over silica gel (ethyl acetate / hexane, 8: 2) to give 4.0 g of the main regioisomer as a clear oil.

Step 2: Preparation of 4- [1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4-fluorophenyl-5- [1 - [[(2-trimethylsilyl) ethoxy] methyl-1Nimidizol-4-yl] -1H-pyrazol-4-yl] pyridine

TMS

4- [I - [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4-fluorophenyl-

5- [1 | (2-trimethylsilyl) ethoxy] methyl-1H-imidizol-4-yl] -1H-pyrazole-

4-yl] pyridine

A solution of the compound obtained in Step 2 of Example A-192 (0.8 g, 0.002 mol) in 10 ml was added dropwise to a solution of sodium hexamethyldisilazide (4.4 ml, 1 OM in tetrahydrofuran) at 0 ° C. dry tetrahydrofuran. The dark brown solution was stirred at this temperature for 30 minutes. A solution of the compound obtained in Step 1 of the present example (0.54 g, 0.0021 mol) in 5 ml of dry tetrahydrofuran was then added. The reaction mixture was allowed to warm to

159 room temperature and stirred for 1 hour. 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 purified by chromatography over silica gel (ethyl acetate / hexane, 8: 2) to give 0.98 g of product as a pale yellow oil which solidified on standing (91% yield), m.p. 79-80 ° C;

ΉNMR (CDCl ₃ ): δ 8.48 (d, J = 6.0 Hz, 2H), 7.68 (d, J = 1.3 Ηζ, ΙΗ), 7.38 (d, J = 6.0 Hz, 2H), 7.10 (m, 2H). 7.00 (m, 2H), 6.93 (d, J = 1.3 Ηζ, ΙΗ), 5.25 (s, 2H), 4.53 (t, J = 6.0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H). 3.84 (t, J = 8.0 Hz, 2H), 0.92 (t, J = 8.0 Hz, 2H), 0.84 (s, 9H), 0.021 (s, 18H). Elemental analysis: Calculated for C ₃₁ H44FN ₅ O ₂ Si _2: C, 62.70; H, 7.47; N = 11.79. Found: C = 62.98; H = 7.74; N, 11.88.

Step 3: Preparation of 3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol

To a solution of the compound obtained in Ethane 2 of the present example (0.54 g, 0.001 mol) in 10 ml of tetrahydrofuran was added a solution of tetrabutylammonium fluoride (1. OM in tetrahydrofuran). After the mixture was refluxed for 3 hours, the solvent was removed and the residue partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography over silica gel (methylene chloride / methanol, 95: 5) to give 0.22 g of product 3- (4-fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H -pyrazole-1-ethanol as a white solid (yield 63%), m.p. 227-228'C; 1 H NMR (DMSOd,): δ 8.45 (m, 2H), 7.83 (s, 1H), 7.35 (m, 2H),

7.15 (m, 4H), 7.09 (s, 1H), 5.20 (br S.1H), 4.32 (s, 2H), 3.81 (m, 2H). Elemental analysis: Calculated for C 19 H 16 FN 5 O: C = 65.32; H, 4.62; N = 20.05. Found: C = 64.98; H = 4.55; N, 19.79.

160

The compound of Example A-199 was synthesized according to the chemistry described above (especially Scheme VI) when selecting the appropriate starting materials:

4- [3- (4-Chloro-3-methylphenyl) -1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for Ci ₅ H ₁₂ N ₃ C1 (269.74): C = 66.79; H, 4.48; N, 15.58. Found: C = 66.57; H, 4.15; N, 15.54. M.P. (DSC): 198.17 ° C.

The compounds of Examples A-200 to A-202 were synthesized according to the chemistry described above (in particular Scheme VII) when selecting the appropriate starting materials:

Example A-200

5- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-carboxylic acid

Mixture of 4- [3- (4-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine,

161 obtained according to Example A-4 (5.83 g, 24.0909 mmol) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 ml) and tert-butanol (10 ml) was heated at reflux for 6 hours. hours (or until all the potassium permanganate is consumed). The mixture was then stirred at room temperature overnight and then diluted with water (150 ml). Magnesium dioxide is separated from the mixture by filtration. The filtrate was extracted with ethyl acetate to remove the unreacted starting material. The aqueous layer was acidified with 1N hydrochloric acid until the pH increased to about 6. A white precipitate was obtained which was filtered off, washed with water and dried in a vacuum oven to give 5- (4-fluorophenyl) -4- ( 4-Pyridinyl) -1H-pyrazole-3-carboxylic acid (isolated as monohydrate) (2.9777 g, 43.7%). Elemental analysis: Calculated for C ₁₅ H ₁₀ N ₃ FO ₂ . H ₂ O (283 + 18): C = 59.80; H = 4.01; N, 13.95. Found: 0 = 59.48; H, 3.26; N, 13.65. MS (ΜΗ *): 284 (base peak).

Example A-201

5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-methanol

To a suspension of 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3carboxylic acid, the monohydrate obtained according to Example A-200 (0.526 g, 2.0 mmol) in dry tetrahydrofuran (15 ml) at boiling under reflux under nitrogen for 15 minutes, add a solution

162 of 1 L lithium aluminum hydride in tetrahydrofuran (4.0 ml, 4.0 mmol). A precipitate is obtained. The mixture is allowed to boil for another hour. The excess lithium aluminum hydride was then decomposed by the careful addition of a solution of 4N potassium hydroxide in water (0.5 ml). White salt precipitates during hydrolysis. After the addition is complete, the mixture is heated at reflux for 15 minutes. The hot solution was filtered by suction through a Buchner funnel and the remaining product was extracted from the precipitate by boiling in tetrahydrofuran (15 ml) for 1 hour, followed by filtration again with a water pump. The collected filtrates were concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate to give the crude product (0.45 g). Recrystallization of the crude product from methanol gave 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-methanol (0.2808 g, 56.5%). DSC: 260.26 ° C. Elemental analysis: Calculated for C15H12N3FO (269): 0 = 66.91; H, 4.49; N = 15.60. Found: C = 66.07; H, 4.63; N = 15.20. MS (MH ⁺ ): 270 (base peak).

Example A-202

- [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] piperazine

163

Step 1: Preparation of 1,1-dimethylethyl 4 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] -1-piperazinecarboxylate

To a solution of 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3carboxylic acid, the monohydrate obtained according to Example A-200 (0.9905 g, 3.5 mmol) and 1-hydroxybenzotriazole (0.4824 g, 3.57 mmol) in dimethylformamide (20 ml) at 0 ° C under nitrogen, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.6984 g, 3.57 mmol, Aldrich Chemical Co.) was added. The solution was stirred at 0 ° C under nitrogen for 1 hour, then 1-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) was added followed by N-methylmorpholine (0.40 ml, 3.6 mmol). The reaction mixture was stirred from 0 ° C to room temperature overnight. After 19 hours, the solvent was removed under reduced pressure and the resulting residue was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine and dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure to give the crude product (1.7595 g). 1,1-Dimethylethyl 4 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] -1-piperazinecarboxylate (1.2372 g, 78.4%) was obtained by chromatography . Elemental analysis: Calculated for C 25 H 25 N 5 O 5 F (451): C = 63.85; H = 5.80; N, 15.51. Found: C = 63.75; H, 5.71; N = 15.16. MS (MH +): 452 (base peak).

164

Step 2: Preparation of 1 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-

3-yl] carbonyl] piperazine bis (trifluoroacetate) monohydrate

A solution of the compound obtained according to Step 1 (0.1804 g, 0.4 mmol) in methylene chloride (1.0 ml) and trifluoroacetic acid (0.3 ml) was stirred at room temperature under nitrogen for 2 hours. The solvent was removed under reduced pressure and the trifluoroacetic acid was expelled using methylene chloride and methanol. The resulting colorless oily residue was dried in a vacuum oven overnight to give 1 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1Hpyrazol-3-yl] carbonyl] piperazine (isolated as bis ( trifluoroacetate) monohydrate (0.2400 g, 100%) as a white solid. Elemental analysis. Calculated for Ci ₉ H ₁₈ N ₅ OF. CF ₃ COOH (351 + 228 + 18): C = 46.24; H, 3.71; N, 11.72. Found: C = 45.87; H = 3.43; N, 11.45. MS (MH *): 352 (base peak).

The compounds of Examples A-203 to A-206 were synthesized according to the chemistry described above (in particular, Scheme VIII) when selecting the appropriate starting materials:

Example A-203

4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine

165

4- (1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl) pyridine% Dispersion of sodium hydride (14 mg, 0.00172 mol) (previously washed with hexane) in mineral oil (69 mg) was added with stirring, together with 5 ml of dioxane, to a solution of 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine (200 mg, 0.00086 mol) (obtained according to Example A-2) in 50 ml dioxane. After 3 hours, a solution of methyl iodide (122 mg, 0.00086 mol) in 10 ml of dioxane was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated to a solid. The products were partitioned between water (15 ml) and ethyl acetate (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to a solid. The products were purified and separated by radial chromatography. NMR data (NOE experiments) indicate that the first component exiting the column (in a minimum amount) is 4- (1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl) pyridine and the second component which leaving the column is 4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine.

The main component 4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine: m.p. 94-99 ° C. Elemental analysis: Calculated for C16H15N3.0.1M H2O: C = 77.08; H, 6.06; N, 16.85. Found: C = 76.59; H = 5.70; N, 16.62.

Example A-204

N

166

4- [3- (4-Chlorophenyl) -1,5-dimethyl-1H-pyazol-4-yl] pyridine

4- [5- (4-Chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine (The compound of Example A-32)

4- [3- (4-Chlorophenyl) -1,5-dimethyl-1H-pyrazol-4-yl] pyridine and 4- [5 (4-chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl ] Pyridine was prepared by the same method as described in Example A-203 by substituting 4- (3-methyl-

5-Phenyl-1H-pyrazol-4-yl) pyridine with 4- [3- (4-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine (prepared according to Example A-7).

Main Isomer 4- [3- (4-Chlorophenyl) -1,5-dimethyl-1H-pyrazol-4-yl] pyridine: Elemental Analysis: Calculated for C ₆ H ₄ N ₃ C 1 (283.76): C = 67.72; H, 4.97; N, 14.81. Found: C = 67.45; H = 4.71; N, 14.63. mp (DSC): 190.67 ° C.

Minimal isomer: 4- [5- (4-chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine; 82-88 ° C. Elemental analysis: Calculated for C ₁₆ H ₁₄ N ₃ C1: C = 67.72; H, 4.97; N, 14.81. Found: C = 67.56; H, 4.96; N, 14.73.

Example A-205

4- [5-ethyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine

167

4- [3-ethyl-1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine

4- [5-Egyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine and 4 [3-ethyl-1-methyl-5- (3-methylphenyl) -1H- Pyrazol-4-yl] pyridine was prepared by the same method as described in Example A-203 by replacing 4- (3methyl-5-phenyl-1H-pyrazol-4-yl) pyridine by 4- (3- (4 -methylphenyl) -5-ethyl-1H-pyrazol-4-yl] pyridine (prepared according to Example A-45).

Main Isomer: 4- [5-ethyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4yl] pyridine. Elemental analysis: Calculated for C18H19NO3.0.45M H ₂ O: C = 75.73; H = 7.03; N = 14.77. Found: C = 76.03; H, 6.87; N, 14.28.

Isomer in minimum amount: 4- [3-ethyl-1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine. Elemental analysis: Calculated for C ₁₈ H ₁₉ NO ₃ . O.ZOM H ₂ O: C = 76.46; H = 6.99; N = 14.86. Found; C = 76.58; H = 6.98; N, 14.63.

Example A-206

4- [3- (4-Chlorophenyl) -1-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine

168

Elemental analysis: Calculated for C ₁₇ Hi ₆ N ₃ C1 (297.79): C = 68.57; H = 5.42; N = 14.11. Found: C = 68.33; H = 5.27; N = 14.08. mp (DSC): 164.36 ° C.

Example A-207

4- [3- (4-Chlorophenyl) -2-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine

Elemental analysis: Calculated for C ₇ H ₁₆ N ₃ Cl (297.79): C-68.57;

H = 5.42; N = 14.11. Found: C = 68.25; H = 5.36; N, 13.74. mp (DSC): 153.46 ° C.

The compounds of Examples A-208 to A-209 were synthesized according to the chemistry described above (in particular, Scheme IX).

Example A-208

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine

Step 1: Preparation of 4-fluorobenzoyl-4'-pyridylmethane

169

To a mixture of 4-picoline (32.6 g, 0.35 mol) and ethyl-4-fluorobenzoate (50.45 g, 0.3 mol) at 20 ° C was added lithium bis (trimethylsilylamide) (600 ml, 1M) in a steady rapid stream, so as to maintain room temperature. Initially, the yellow solution was converted into a suspension which was stirred for a further 2 hours. Toluene (250 ml) was added and the mixture was cooled to 0 ° C. The reaction mixture was fixed with concentrated hydrochloric acid at 0 ° C until the pH was lowered to about 7. The organic layer was separated and the aqueous layer was again extracted with toluene (100 ml). The organic layer was dried over sodium sulfate and concentrated to give a yellow solid which was triturated with hexanes (200 ml) to give pure deoxybenzoin, 4-fluorobenzoyl-4'-pyridylmethane in 90% yield (58 g). ^! H NMR confirmed the proposed structure.

Stage 2:

To a suspension of deoxybenzoin obtained in Step 1 (30 g, 0.14 mol) in THF (50 ml) was added dimethylformamide dimethyl acetal (50 ml) and the mixture was stirred at room temperature for two days. The solution was then concentrated to dryness and the resulting solid paste was sprayed with hexanes (150 ml) to give a yellow solid that was sufficiently pure (NMR data) and used in the next step without further purification. Yield: 33.9 g (90%). ^! H NMR confirmed the proposed structure.

Stage 3:

The vinylamine obtained in Step 2 (33.9 g, 0.1255 mol) was dissolved in 125 ml of ethanol and cooled to 0 ° C. Hydrazine hydrate (8.0 g anhydrous or 16.0 g hydrate, 0.25 mol) was then added in one go. The mixture was stirred well and allowed to warm to room temperature for a total of 3 hours. The mixture was concentrated and placed in 200 ml of chloroform. After washing with water (100 ml), the organic layer was extracted with 150

170 ml of 10% hydrochloric acid. The aqueous layer was then treated with 0.5 g of charcoal at 70 ° C for 10 minutes, filtered through Celite and neutralized cautiously to pH 7-8 with vigorous stirring and cooling (using 20% sodium hydroxide). The fine off-white precipitate was filtered off and dried to give 4- [3- (4-fluorophenyl) 1H-pyrazol-4-yl] pyridine. Yield: 27.3 g (91%). MS: m / z = 240. ^! HNMR confirms the proposed structure. Elemental analysis: Calculated for

C, ₄ H ₁₀ FN ₃ : 070.28; H, 4.21; N, 17.56. Found: C = 70.11; H, 4.33;

N, 17.61.

Example A-209

4- [3- (2-Chlorophenyl) -1H-pyrazol-4-yl] pyridine

This compound was prepared by the method described in Example A-208 using the appropriate starting materials. Elemental analysis: Calculated for Ci ₄ H ₁₀ C1N _3: C = 65.76; H, 3.94; N, 16.43. Found: C = 65.22; H, 3.91; N = 16.50. M.P. (DSC): 208.46 ° C.

The compounds of Examples A-210 and A-211 were synthesized according to the chemistry described above (in particular, Scheme X).

Example A-210

171

3- (4-fluorophenyl) -4- (4-piperidinyl) -1H-pyrazole-1-ethanol

The deoxybenzoin obtained in Step 1 of Example A-208 and 4-fluorobenzoyl-4'-pyridylmethane (12.7 g, 0.059 mol) were mixed with 90% hydroxyethyl hydrazine (5.3 g, 0.062 mol) in 30 ml ethanol containing 0.5 ml acetic acid. into a 500 ml Erlenmeyer flask. After moderate reflux for 1 hour, under high vacuum, a small sample was taken and examined by &lt; 1 &gt; H NMR to determine hydrazone formation. Upon cooling to room temperature, the reaction mixture solidified to a yellow mass. Dimethylformamide dimethylacetal (36 ml, 0.27 mol) was then added and the mixture heated to 80 ° C for 10 minutes, at which temperature the whole solid dissolved to give a clear, yellow, viscous solution. The reaction mixture was immediately allowed to cool to 25 ° C and water (20 ml) was added dropwise and stirred to give a cloudy yellow oil suspension. The solution was heated to approximately 50-60 ° C, whereby the solution turned a clear yellow. Slow cooling to room temperature with stirring (crystalline nuclei appear as the process accelerates) results in abundant crystals. Filtration by suction, followed by washing with 10% ethanol-water (50 ml) followed by drying, yielded

3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol as a light yellow crystalline solid. Reheating the filtrate to clarify as above, followed by cooling, yields more from the product. The third and fourth development of the mother liquor after standing overnight gave more 3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol. Total yield: (12.3 + 3.3 + 0.4 + 0.4) = 16.4 g (97.6%). MS: m / z = 284. ¹ H NMR confirms the proposed structure. Elemental analysis: Calculated for Ci ₆ H _M FN ₃ O + H ₂ O: C = 63.78; H = 5.35; N, 13.95.

172

Found: 0 63.55; H = 5.07; N-13.69.

Example A-211

The 3- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-1-ethanol compound was prepared by the method described in Example A-210, except that it was used in the synthesis of deoxybenzoin, 4-picoline was replaced by 4-methylpyrimidine.

The compound of Example A-212 was prepared according to the chemistry shown in Scheme XI.

Example A-212

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

The vinylamine obtained in Step 2 of Example A-208 (5.0 g, 0.0185 mol) was taken up in ethanol (75 ml) and cooled to 0 ° C. Methyl hydrazine (1.7 g, 0.037 mol) in ethanol (75 ml) was added at once while maintaining the temperature between 0 and 10 ° C. After three hours, at room temperature, dissolve

173 Bed was removed and the residue was taken up in methylene chloride (150 ml) and water (100 ml). The organic layer was separated, dried and concentrated to give a crude regio-isomer mixture as a light reddish-brown solid (80:20 according to NMR data to give the title compound predominantly). The crude isomer mixture was added to 10% hydrochloric acid (100 ml) and washed with methylene chloride (100 ml) and the aqueous layer treated with activated carbon (0.5 g). After filtration through Celite, the solution was neutralized with sodium hydroxide (20%) to pH 8 with good stirring and cooling. The cream precipitate was filtered off, washed with water and dried. The solid (5 g) was dissolved in hot 10% heptane / toluene (70 ml) and allowed to cool slowly, first to room temperature and then to 15 ° C. Scratching the walls of the flask begins the crystallization process. After standing for 2 hours, the resulting solid was filtered off, washed with cold 50% toluene / heptane (25 ml) followed by hexane (25 ml) and dried to give the pure title compound. Ή NMR confirmed the structure (including regiochemistry using HaNOE experiments). Yield: 2.1 g (45%). MS: m / z = 254 (base peak). Elemental analysis: Calculated for C ₁₅ II ₁₂ FN ₃ + 0.2 H ₂ O: C = 70.15; H = 4.86; N = 16.4. Found: C = 70.18; H = 4.6; N, 16.47.

The compound of Example A-213 was prepared according to the chemistry shown in Scheme XII.

Example A-213

N

^S ' ^S N ---- H

174

2 - [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] -1-butanol

Mixture of 2-fluoropyridinylpyrazole (0.2 g) (prepared by the method described for Example A-210, except that the 4-picoline used for the synthesis of deoxybeisoin is replaced by 2-fluoro-4-methylpyridine) and (R, S ) -2 amino-1-butanol (quadruple molar excess) was heated to 210220 ° C in a closed vessel for 1.5 hours. After cooling to 100 ° C, the vessel was opened cautiously, 5 ml of toluene and 5 ml of water were added and stirred well for 1 hour. The resulting solid, 2- [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] -1-butanol was filtered by suction and washed once more with 5 ml of water followed by toluene and dried. Yield: 190 mg (71%). MS: m / z = 343. ^! H NMR confirmed the proposed structure.

The compound of Example A-214 was prepared according to the chemistry shown in Scheme XIII.

Example A-214

4- [5-Bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

To a solution of 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine (2.7 g, 10.67 mmol) (prepared according to Example A-212) in acetic acid (30 ml) and dimethylformamide (13 ml) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80 ° C overnight. Thin

175 layer chromatography indicated the reaction was complete. The mixture was slowly fixed with potassium carbonate (25 g). When the pH is about 5, a precipitate forms. The precipitate was washed with water (50 ml x 5) to give 4- [5bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine (1.24 g, 35%). M.p .: 174.38 ° C. MS: m / z = 332, 334. 1 INMR confirms the proposed structure. Elemental analysis: Calculated for C 23 H ₂₅ N ₂ O ₂ Br + 0.2 H ₂ O: 0 = 53.66; H, 3.42; N, 12.51. Found: C = 53.58; H, 3.12; N, 12.43.

The compound of Example A-215 was prepared according to the chemistry shown in Scheme XIV.

Example A-215

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile

Stage 1:

To a solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine (4.3 g, 17.97 mmol) (prepared according to Example A-208) in methanol (100 ml) was added 3-chloroperoxybenzoic acid. (5.44 g, 57% purity, 17.97 mmol). The solution was stirred at 25 ° C overnight. The mixture was concentrated. Potassium carbonate (10%, 100 ml) was added to the residue. A precipitate was obtained which was filtered and washed with water (30 ml x 3) to give the corresponding N-oxide. (3.764 g, 81.66%).

Stage 2:

To a suspension of the HaN-oxide obtained in Step 1 (0.40 g, 1.567 mmol) in

176 Dimethylformamide (5 ml) was added trimethylsilyl cyanide (0.3 ml, 2.25 mmol). The mixture was stirred for 15 minutes at 25 ° C. Dimethylcarbamyl chloride (0.8 ml, 8.69 mmol) was added. The mixture was stirred for 2 hours at 25 ° C. Thin layer chromatography shows that the starting materials are depleted. The mixture was partitioned into ethyl acetate: water (100 ml: 20 ml). The organic layer was washed with potassium carbonate (10%, 20 ml), water (50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and concentrated to give 4- [3- (4-fluorophenyl) 1 H-Pyrazol-4-yl] -2-pyridinecarbonitrile (0.23 g, yield 56%). M.p .: 209.22 ° C. MS (chemical ionization): m / z = 265. * H NMR confirms the proposed structure. Elemental analysis: Calculated for C15H9N4F + 0.2 H2O: C = 67.26; II = 3.54, N = 20.92. Found: C = 67.44; H, 3.40; N, 20.69.

The compound of Example A-216 was prepared according to the chemistry shown in Scheme XV.

Example A-216

4- (2- (3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-yl] ethyl] morpholine

Stage 1:

3- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol (10.0 g, 0.0353 mol) (prepared according to Example A-210) was suspended in pyridine (100 ml) and cooled to 0 ° C. Methanesulfonyl chloride (4.4 g, 0.0388 mol) was slowly added while maintaining the temperature at 0 ° C. After stirring in

177 overnight at 10 ° C cold water (100 ml) and methylene chloride (150 ml) were added, and the two layers were separated. The aqueous layer was again extracted with 100 ml of methylene chloride and the organic layer was dried and concentrated to a paste. Drying under high vacuum gave a light reddish brown mass which was triturated with ether (75 ml), filtered and dried to give a cream solid in 79% yield (10.1 g). ^X H NMR confirmed the proposed structure. The compound is used directly in Step 2.

Stage 2:

The mesylate obtained in Step 1 (5.0 g, 0.0138 mol) was dissolved in eight-fold excess morpholine (9.6 g, 0.011 mol) in methanol (50 ml) and refluxed for 3 to 4 hours. After the NMR data indicated that the reaction was complete, the mixture was concentrated and placed in methylene chloride (150 ml) and washed with water (100 ml) and then with 75 ml of 5% hydrochloric acid. The aqueous layer was neutralized to pH 8 and extracted with methylene chloride (100 ml). Drying and concentration gave a light yellow paste solid which was sprayed with 25 ml of ether to give a solid. Recrystallization from toluene / hexane gave 4- [2- [3- (4-fluorophenyl) -

4- (4-Pyridinyl) -1H-pyrazol-1-yl] ethyl] morpholine as a solid. Yield: 4.5 g (86%). MS: m / z = 353. ^X H NMR confirmed the proposed structure. Elemental analysis: Calculated for C2oH ₂ iN ₄ FO: C = 68.16; H = 6.01; N, 15.90. Found: C = 68.20; H, 6.21; N = 15.80.

The compound of Example A-217 was prepared according to the chemistry shown in Scheme XVI.

178

Example A-217

3- (4-fluorophenyl) -1-methyl-a-phenyl-4- (4-pyridinyl) -1H-pyrazole-

5-methanol

To a solid magnesium (60 mg, 5 mmol) solution under nitrogen was added

4- [5-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine (450 mg,

1.35 mmol) (prepared according to Example A-214) in tetrahydrofuran (7 ml). The mixture was heated at 40 ° C for 2 hours. Benzaldehyde (1 ml) was added. The mixture was heated at 45 ° C for 2 hours. It was fixed with hydrochloric acid (10 ml, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give a residue. The residue was purified through a column of silica gel to give the title compound (59 mg, yield 12%). MS: m / z = 360 (M + 1). &Lt; 1 &gt; H NMR confirms the proposed structure. Elemental analysis: Calculated for C22Hi ₈ N ₂ FO. 0.6 EtOAc: 071.1; H, 5.6; N = 10.2. Found: 070.9; H = 5.47; N = 10.2.

The compound of Example A-218 was prepared according to the chemistry shown in Scheme XVII.

Example A-218

179

N- [5- (4-fluoro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinethanamine

The starting deoxybenzoin obtained in Step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridylmethane, (1.0 g, 0.0046 mol) was dissolved in 10 ml of dimethylformamide and cooled to -10 ° C (dry ice-water isopropanol) N-chlorosuccinimide (0.62 g, 0.0046 mol) was added at one time while maintaining the temperature at -10 ° C. After 5 minutes, at 0 ° C, thiosemicarbazide (0.0046 mol) was added and allowed to warm slowly to room temperature for 1 hour. After stirring overnight, the solvent was removed under high vacuum, water and toluene (25 ml each) were added and stirred well. The toluene layer was separated and the aqueous layer (initial pH 5.5) was treated with bicarbonate to pH 8. The fine precipitate formed was filtered off and washed with water, toluene and ether. Spraying with ether (25 ml) gave an off-white solid, N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinethanamine, which was filtered again and sushi. Yield: 0.95 g (56%).

MS: m / z = 368 (base peak). Elemental analysis: Calculated for C20H22FN5O: 065.38; H = 6.04; N49.06. Found: C = 64.90; H = 5.92; N = 18.67.

Example A-219

180

Η ^ ΝΗΝ

C I

H

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone

Step 1: Preparation of (E) -2- (2-bromo-4-pyridinyl) -1H, E1-dimethylethenamine

4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and Ebutoxybis (dimethylamino) methane (5 ml) were heated to 150 ° C for 16 hours. 4-Methyl-2-bromopyridine is prepared according to Adger et al. J. Chem. Soc., Perkin Trans. 1, pp. 2791-2796 (1988) given for comparison. The contents were evaporated and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 1.0 g of (E) -2- (2-bromo-4-pyridinyl) -L 1 D 4 dimethylethenamine as an oil suitable for use in Step 2. Step 2: Preparation of (S) -2- (2-Bromo-4-pyridinyl) -1- (3-chlorophenyl) -3 (dimegylamino) -2-propen-1-one

The product of Step 1 (1.0 g, 4.4 mmol) was dissolved in methylene chloride

181 (15 ml). Triethylamine (900 mg, 8.8 mmol) was added at 0 ° C, followed by the addition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol). The mixture was stirred under nitrogen for 16 hours. The solvent was removed in vacuo and the residue dissolved in ether (25 ml), stirred with magnesium sulfate (500 mg) and silica gel (500 mg) and filtered. The ether was evaporated and axis I chromatographed over silica gel using a mixture of acetone and methylene chloride as eluent to afford 670 mg of product ((S) - 2- (2-bromo-4-pyridinyl) -1- (3 -chlorophenyl) -3- (dimethylamino) -2-propen-one, such as glass, which is used in Step 3 without further purification.

Step 3: Preparation of 2-bromo-4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] pyrene

A solution of the product from Step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was heated at reflux for 24 hours. The solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] pyridine (190 mg, 31%) as an oil. Elemental analysis: Calculated for C14H26FN3O3: C = 50.25; H = 2.71; N, 12.56. Found: C = 50.10; H = 2.60; N = 12.40.

Subsequent elution with mixtures of ethyl acetate and methanol gave 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone (190 mg, 36%) as a crystalline solid: mp Mp 163-164 ° C. MS (Mi 11) = 286. Elemental analysis: Calculated for C14H12N5CI: C = 58.85; H, 4.23; N, 24.51. Found: C = 58.53; H = 4.28; N, 24.87.

182

Example A-220

n

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyridinamine

A solution of the bromopyridine compound obtained in Step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 ml) was heated at 175 ° C for 6 hours. After cooling, excess benzylamine was removed by distillation under high vacuum and ethacetate was added to the residue. After washing the organic phase with water and drying over magnesium sulfate, the solvent is removed in vacuo and the residue is chromatographed over silica gel using mixtures of ethyl acetate and toluene to give 4- [3- (3-chlorophenyl) -1H-pyrazole- 4-yl] -N (phenylmethyl) -2-pyridinamine (110 mg, 61%) as a solid, m.p.

179-180 ° C. Elemental analysis: Calculated for C21H17CIN4: C = 69.90; H = 4.75;

N, 15.53. Found: C = 69.69; H, 4.81; N = 15.11.

Example A-221 n

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -14- (phenylethyl) -2-pyridinamine

183

A solution of the bromopyridine compound obtained in Step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175 ° C for 6 hours under a nitrogen atmosphere. The excess amine was removed by distillation under high vacuum and the residue was dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate and removing the solvent, the residue was chromatographed over silica gel using mixtures of ethyl acetate and toluene to give 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- ( phenylethyl) -2-pyridinamine (230 nig, 81%) as a solid, m.p. 185-186 ° C. Elemental analysis: Calculated for C ₂₂ H ₁₉ ClN ₄ : C = 70.49; H, 5.11; N = 14.95. Found: C = 70.29; 115.15; N, 14.66.

Example A-222 n

4- (3- (3-chlorophenyl) -1H-pyrazol-4-yl] -1H-ethyl-2-pyridinamine

A solution of the bromopyridine compound obtained in Step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine (3.5 ml) and ethanol (5 ml) was heated at 150 ° C in a welded tube for 9 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel using 70 ethyl acetate / 30 toluene to give 4 | 3- (3-chlorophenyl) -] N-pyrazol-4-yl] -L-ethyl-2-pyridinamine ( 125 mg, 46%) as a solid, m.p. 186-187 ° C. Elemental analysis: Calculated for C ₁₆ H ₁₅ ClN ₄ : C = 64.32; H, 7.06; N = 18.75. Found: C = 64.42; H = 7.01; N = 18.45.

184

Compounds according to Examples A-223 to A-226 are synthesized according to the chemistry described above (in particular, Scheme XVIII) when selecting the appropriate starting materials.

Example A-223

NH

I

N

- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide

Stage 1:

To a suspension of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridine (prepared according to Example A-208) (8.8 g, 0.037 mol) in methylene chloride at one, at room temperature, was m-Chloroperoxybenzoic acid (mCBA) was added. After stirring for 16 hours, the solvent was removed and the residue was treated with saturated sodium bicarbonate solution. The precipitate was filtered off, air-dried to afford

8.2 g of product as a white solid (87%), m.p. 207-209 ° C.

Step 2: Preparation of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile

To a solution of the product of Step 1 (5.1 g, 0.02 mol) in 20 ml of dimethylformamide was added trimethylsilyl cyanide (2.5 g, 0.025 mol) followed by a solution of N, N-dimethylcarbamoyl chloride (2.7 g, 0.025 mol) in 5 ml of dimethylformamide. room temperature. After stirring overnight, the reaction mixture was basified with 200 ml of 10% solution

185 thallium in potassium carbonate water. 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 triturated with hexane and filtered to give 4.3 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile (90%) as a pale yellow solid. , so. 238-239 ° C.

Step 3: Preparation of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide

To a solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile from Step 2 (0.45 g, 0.0017 mol) in 10 ml of dimethyl sulfoxide was added hydrogen peroxide (0.24 ml of 30% - aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0 ° C. The mixture was stirred for 1 hour until warmed to room temperature. Water was added and the precipitate was removed by filtration and air drying to give 0.32 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide as a white solid (yield 67%) , so. Mp 230-231 ° C. Elemental analysis: Calculated for Ci ₅ HnFN ₄ O: C = 63.83; H, 3.93; N, 19.85. Found: C = 63.42; H, 3.66; N, 19.58.

Example A-224

methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate

186

To a suspension of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide prepared according to Example A-223 (2.9 g, 0.01 mol) in 50 ml of methanol was added dropwise Ν, Ν dimethylformamide dimethylacetal (3.67 g, 0.03 mol). The reaction mixture was stirred at room temperature overnight and refluxed for 4 hours. After cooling, the precipitate was removed by filtration and air drying to give 2.0 g of methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate as a white solid (yield 69% ), m.p. 239-241 ° C. Elemental analysis: Calculated for Ci ₆ Hi ₂ FN ₃ O ₂ : 0 = 64.64; H = 4.07; N = 14.13. Found: C = 64.36; H, 4.10; N, 14.27.

Example A-225

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H-methyl-2-pyridinecarboxamide

Mixture of methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate prepared according to Example A-224 (0.45 g, 1.5 mmol) and 20 ml of methylamine (40%) aqueous solution) was heated in a welded tube at 120 ° C for 16 hours. After cooling, 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 0.4 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] N-methyl-2-pyridinecarboxamide as a white solid, m.p. 88-89 ° C. Elemental analysis: Calculated for C ₆ H ₁₃ FN ₄ O + 0.4 H ₂ O: C = 63.32; H, 4.58;

187

N, 18.46. Found: C = 63.10; H, 4.62; N, 18.35.

Example A-226

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylic acid

To a solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate prepared according to Example A-224 (0.90 g, 0.003 mol) in 10 ml of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 ml of water. The reaction mixture was refluxed for 10 hours. After removal of the solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. The aqueous phase was then extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by treatment with ether to give 0.62 g of 4- [3- (4-fluorophenyl) 1,11-pyrazol-4-yl] -2-pyridinecarboxylic acid as a white solid (yield 73%), m.p. . 245 ° C (dec.). Elemental analysis: Calculated for C ₁₅ H ₁₀ FN ₃ O + 0.2 H ₂ O: C = 62.80; H, 3.65; N, 14.65. Found: C = 62.77; 11 = 3.42; N, 14.58.

Other compounds of the present invention obtainable! according to one or more of the reaction schemes shown above (especially Schemes ωτ IX to XVHI) are shown in Table 3. Reaction schemes as well as mass spectroscopy and elemental analysis results for each compound are also shown in Table 3.

188

Table 3

EtOAc added Microanalysis H D 4J added 0.25 0.2 CN Oh 0.1 r-4 o 0.25 0.6 and o 0.6 0.1 N found 16.8 14.98 16.3 -------------------------------------------------- -------------------------------------------------- ------------------ 1 16.52 13.90 15.32 14.9 15.4 15.7 19 14. 32 13.83 16.31 14.95 14.01 15.32 13.27 12.05 15.82 12.26 18.65 15.98 N calc rhh 15.32 16.5; -------------------------------------------------- -------------------------------------------------- -1 16.43 13.86 15.58 14.6 15.4 15.8 18.84 14.35 in co ro t-4 16.33 15.35 14.00 15.49 13. 37 12.31 15.93 14.01 18.79 16.22 H found 4.6 4.33 4.5 3.78 4.31 4.24 1P 40 6.5 5.1 3.51 3.91 3.52 3.01 40 (N m o 3.68 4. 51 6.17 40 in and m 3.63 Η calc 4.3 4.41 CD 3.94 4.39 CO., LTD and 4.6 6.5 40 Oh and 3.58 CTt σ. n 3.53 3.31 3.36 60 · ϊ 3. 85 4.81 40 m 40 5.04 4.65 3.58 C found 69 65.69 40 Oh 65.48 63.95 66.79 66.8 9'59 76.7 75.44 61.67 63.28 65.39 61.14 55.99 66.41 CN CN > in 40 r-4 40 r * and 40 40 66.18 64.16 co 40 With calc 69 65.69 70.6 65.76 64.18 66.79 66.9 65.9 77 F co and 61.52 40 m cn 40 65.37 61.44 56.02 66.42 m r * in 76.39 64.89 66.08 64.46 r4 CD 40 MS rh + 3 240 266 254 256 280 271 284 270 264 221 290 304 1 258 274 300 272 314 342 341 391 362 1 258 General method Ί XI IX IX XI XI XI XI XI IX IX IX XI IX XI IX XI XI IX XII XII XII IIX I I Example Ί A-227 A-228 A-229 A-230 A-231 A-232 A-233 A-234 A-235 A-236 A-237 A-238 A-239 A-240 A-241 A-242 A-243 A-244 A-245 A-246 A-247 A-249

189

rd rd (N Oh Oh o VD and — 1 CM .25 rd . 25 . 75 . 75 rd rd 75 rd .25 and CM CM Oh o o Oh o o o o o o o o rd rd LD CM CD m rd σ σ co and m LD m and c- and co 89 ο and CO., LTD m co r * CD m co σ o co and and rd rd CM 1—1 CO., LTD o CM m and Γ ο and o and r n 22 Oh LD σ co rd rd f — '1 rd rd CM rd rd rd rd rd rd rd CM rd rd rd rd rd rn rn CO., LTD and m ΟΊ tn ΟΛ fN tN m W VD ω LD co OJ m D “1 VD co and o and σ Oh CO., LTD LO r- rd xr rd rd rd 12 11. 13. 14. 14. 20 m CM 15. 15. 15. 14. rd 11. 15. 20. 16. 18. 13 22 14. 10 17 10. 19 14 CM rd LD rd rd XT 1—1 VO CO., LTD co and CO., LTD and σ m and • 4 * co st ¹ rd LD co LD 00 co and Ch CO., LTD CM rd CM CM σ o CM m CM LD CM CM m CO., LTD xr m and m and co LD LD ID xr LD and rf and and LD LD CT * • 35 66 m r * and CM . 09 . 06 .28 J_____________________________1 .48 CN ¹⁷ .28 , 39 rd .28 CM .71 CM 00 and 35 σ CO., LTD CM CO., LTD rn m W cn and m VO and ID LD xT ID and and and and LD LD 07 68 L 34 ______________________1 17 CM rd VO 58 63 rd CM and 59 76 77 38 tn CO., LTD CM co CO., LTD 13 CM rd CO., LTD 63. 68. 66. G VO 64. 66. 60 rd 62. 69 72 70. 63. 66. 62. 62. 63 61. 70 65 70. 67 63 XT co ld rd m m CN rd σι CD 10 rd rd σι co Midrange ID σ and ID 00 and σ LD co m CM CO., LTD VO rd CO., LTD CN CM r- CO., LTD r- rd n LO CO., LTD LO cn co SL m CO., LTD LO VO LD Oh rd CM cn CM Oh m LD CM CM (N ID rd Oh 65 σι 66 63 VO LD ID LD VO ID VD LD ID ID LO ID ID ID co CM > m and CO., LTD CM LD co Oh rd LO co LD o co CM σ rd σ> LD GG LD o D * vo ID σ r O ' and VO σ rd Γ » C4 CM o LD o 4 * t o CM o and m m co m m m CM CN CM CM CM CM OJ m n 'Φ m m m CO., LTD m m m X, XV > > > hd IX H-l X IX XII IIX XIV XII XI IX XI IX X IX XII XII IX XII XI XII X hd X M X · »Bd XI XI M X> X X X X bd X o rd CM rn 4 * Yu and Yu r> 00 σ o rd CM m and LD r- co σ o rd CM co TJ * and and and LO and rd and and and tn and ID LD LD VD ID LD ID ID ID Yu t- r> t- CM CM CM CM CM CM CM CM CM ΟΪ CM CM CM CM CM CM CM CM N CM <N Midrange CM CM CM < 4 rt! << > < << 4 4 < 4 4

190

and and o o VO 1P vo 05 Xia m 25 25 25 and r * rd 4 « 00 co Ο o o o o o o o CM Oh rd o rd rd 05 VO 61 co r> 21 48 38 CM CM vo 65 27 60 and and 97 37 Cn r- and CM »—1 13 16. rd co rd 17. 17. 17. 13 in rd L22 16. 17. 19. 13 12 14 16. 16. rd 13 25 14 . 64 _________________________________________________________________________________________________________1 m .75 and vo .73 CO., LTD vo m and .21 . 05 co m and CO., LTD .25 QA QA and 1 12. m rd 18. rd 13 17. 17. 17. 13 16 114 16 17. 19. 13 rd 14 16 16. 15 rd and QA 14 ΓΩ rd σ \ m M3 CM | W ⁶³ 43 cm o> CM 56J rd VO and 05 CM 53 02 CM CO., LTD 05 V0 VO vo vo tn and and and vo vo ID t 'T «A * 'T CM 18 rd 48 and r * 37 55 55 and 05 r ~ 81 31 52 and co CM 77 85 <n and rd V0 VO VO vo vo and tn and vo and VO t tn • <3 < 4 * «A * CO., LTD CM 02 co rd 47 94 81 r- co and 05 VO 26 and W 05 46 86 QA 4 · r- ο 66 63. 63 r * vo 61. vo vo vo 70 co vo 59. 56. 69 67 64 61. 55. 73 67 70 r * in 44 ί cn 11 CM CM co vo 63 CM o CM LL o 42 CO., LTD r- CM CM and Γ » VO 05 m 05 70. 65 61. vo r · vo rd VO 64. vo > vo Γ 68 05 in 56. 05 VO 10 ID γ- 61. 55. 73 67 70 > in GP vo co r- m σι co m r- σι VO GY o CO., LTD r- Γ- o ID CO., LTD co co m co and vo 05 rd rd o m CO., LTD 4 * cn o Oh 05 CM rd r- m co CM CO., LTD CO., LTD co co m QA CM co n n CM XV hd hd X> l-d XV XII, V hd hd hd IIX XV xil, > II II II XII XII X II II hd hd X X nights X X hd X X X X hd X XV XV XV hd XV XV X X hd hd X XI X XI X X X X and u> co 05 o rd eq CO., LTD • ύ * and vo t CO., LTD σι o rd QA CO., LTD 'T tn ID r * r * r * Mr Γ ' CD GO GO co CO., LTD co co 00 co GO 05 05 05 05 05 05 σι 05 see see cm CM Xia QA eq eq eq CM CM CS CM CM QA QA QA CM QA CM CM Xia CM d d d d d d d d d < «4 d * 4 d d d d d d d

191

Example A-227

4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyridine

Example A-228

4- (3- (1,3-benzodioxol-5-yl) -1H-pyrazol-4-yl] pyridine

Example A-229

4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-230

4- [3- (4-Chlorophenyl) -1H-pyrazol-4-yl] pyridine

192

Example A-231

4- (3- (1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-232

4- [3- (4-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-233

4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine and

4- [5- (3-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine

Example A-234

+ isomer

193

4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine and

4- [5- (3-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-235

2-megyl-4- [1-methyl-3 (or 5) - (3-methylphenyl) -1H-pyrazol-4-yl] pyridine

Example A-236

4- (3-phenyl-1H-pyrazol-4-yl) pyridine

Example A-237

4- [3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine

194

Example A-238

4- [1-methyl-3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine

Example A-239

4- (3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] pyridine

Example A-240

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine

Example A-241

4- [3- (4-Bromophenyl) -1H-pyrazol-4-yl] pyridine

195

Example A-242

4- (3- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-243

4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-244

(E) -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-phenylethenyl) pyridine

196

Example A-245

s (S) 4- [3- (4-Chlorophenyl) -1H-pyrazol-4-yl] -B [- (2-methylbutyl) -2-pyridinamine

Example A-246

- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N - [(4-methoxyphenyl) methyl] -2-pyridinamine

Example A-247

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine methanamine

197

Example A-248

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine methanamine

Elemental analysis: Calculated: C = 41.12; H, 3.58; N = 9.22. Found:

C = 41.74; H = 5.05; N = 11.11.

Example A-249

2-fluoro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine

Example A-250

4- [3- (4-iodophenyl) -1H-pyrazol-4-yl] pyridine

198

Example A-251

4- [3- (4-iodophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-252

4- [1-methyl-3- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine

Example A-253

L. η ₃

N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine

Example A-254

199

N - [(3-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine

Example A-255

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2- (1-methylhydrazino) pyridine

Example A-256

2-Fluoro-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-257

4- [3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine

200

Example A-258

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine

Example A-259

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -3-methylpyridine

Example A-261

dream,

201

3- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-1-ethanamine

Example A-262

2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

Example A-263

4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -N- [1- (phenylmethyl) -4-piperidinyl] -2-pyridinamine

Example A-264

202

N- [3- (4-fluorophenyl> 1H-pyrazol-1-yl] -2-pyridinyl] -H, N-dimethyl-1,2-ethanediamine

Example A-265

2,4-bis [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine

Example A-266

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -4-morpholinethanamine

Example A-267

203

3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1-ethanol

Example A-268

4- [3 < 4 &gt; -fluorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol-1-yl) ethyl] -2-pyridinamine

Example A-269

4- [2- [3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-1 Example A-270 yl] ethyl] morpholine

he

204 ^ Eu3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] -4-pyricinyl] -1Hpyrazo-1-ethanol

Example A-271

3 <4-fluorophenyl-N2-fluoro-4-1Shridinyl) -No-dimethyl-1H-pyrazol-1 ezhanamine

Example A-272

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -1H-pyrazole-

1-ethanol

205

Example A-273

4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H, N-dimethyl-2-pyridinamine

Example A-274

4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-1razol-4-yl] -N - [(4fluorophenyl) methyl] -2-pyridinamine

Example A-275

206

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -NH-dimethyl-1H-pyrazo-1-ethanamine

Example A-276

N - [(4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1 - [[2- (4-morpholinyl) ethyl] -1H-pyrazol-4-yl] -2- pyridinamine

Example A-277

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -H-4-piperadinyl-2-pyridinamine

207

Example A-278

NK-Distyl-3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1 ethanamine

Example A-279

4- [1- (2- (diethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] - N - [(4fluorophenyl) methyl] -2-pyridinamine

Example A-280

2 - [[4- [3- (4- (fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol

208

Example A-281

2 - [[4- [3- (4- (fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol

Example A-282

3 - [[4- [3- (4- (fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl} amino] -1 propanol

Example A-283

(or 5) - (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazol-1-ethanol

209

Example A-284

N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanamine

Example A-285

N - [(4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4-morpholinyl) ethyl] 1H-pyrazol-4-yl] -2-pyridinamine

Example A-286

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinopropanamine

210

Example A-287

N '- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -H, N-dimethyl-

1,3-propandiamine

Example A-288 *

5- (4-fluorophenyl) -1H-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine

Example A-289

3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazole-1-ethanol

211

Example A-290

5- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazol-1-ethanol

Example A-291

4- [3 -: [(4-fluorophenyl) -1H-schrazol-4-yl] quinoline

Example A-292

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -glycine methyl ester

Example A-293

212

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] glycine

Example A-294

4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine

Example A-295

4- [5- (4-Fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine

Example A-296

213

4,4 '- (1H-pyrazole-3,4-diyl) bis [pyridine]

Example A-297

4- (3- (3,4-dichlorophenyl) -1H-pyrazol-4-yl] pyridine

Example A-298

N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1-piperidinamine

The pyrimidine substituted compounds prepared according to Examples A-299 to A-312 were synthesized according to the chemistry described in Schemes IXVIII when selecting the appropriate starting materials.

Example A-299

With I

214 s

2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine

Stage 1:

NMe ₂

A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g, 0.031 mol), triethyl · amine (6.23 g, 0.062 mol) and a catalytic amount of 5% palladium on charcoal in 100 ml of tetrahydrofuran was hydrogenated in a Parr apparatus at 40 psi at room temperature. After 0.5 hours, the catalyst was filtered off and the filtrate was concentrated. The crude product was purified by chromatography over silica gel (ethyl acetate / hexane, 3: 7) to give 2.36 g of the product as pale yellow crystals (yield 50%), m.p. 47-49 ° C.

Step 2: Preparation of 2- (2-chloro-4-pyrimidinyl) -1- (4-fluorophenyl) ethone

With I

2- (2-chloro-4-pyrimidinyl) -1- (4-fluorophenyl) ethanone

To a solution of lithium diisopropylamide (obtained from butyllithium (0.045 mol) and diisopropylamine (0.048 mol) in tetrahydrofuran, at -78 ° C was added a solution of the compound obtained in Step 1 (5.5 g, 0.037 mol) in tetrahydrofuran, slowly over After 30 minutes, a solution of ethyl 4-fluorobenzoate (7.62 g, 0.045 mol) in tetrahydrofuran was added and the reaction mixture was stirred overnight and stirred overnight.

215 allowed to warm to room temperature. 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 purified by chromatography over silica gel (ethyl acetate / hexane, 3: 7) to give 4.78 g of a yellow solid (yield 51%), m.p. 112-113 ° C.

Step 3: Preparation of (E) -2- (2-chloro-4-pyrimidinyl) -3- (dimethylamino) 1- (4-fluorophenyl) -2-propen-1-one

(E) -2- (2-Chloro-4-pyrimidinyl) -3 ~ (dimethylamino) -1- (4-fluorophenyl) -2-tropen-1-one

A mixture of the compound obtained in Step 2 (4.7 g, 0.017 mol) in 100 ml dimegilformamide dimethylacetal was stirred at room temperature overnight. Excess dimegilformamide dimethylacetal was removed in vacuo to give 4.5 g of crude product as a thick brown oil, which was used through an additional purification ai ί e.

Step / 1: Preparation of 2-chloro-4- [3- (4-fluorophen (yl) -1H-pyrazol-4-yl] pyrimidine

A solution of the compound obtained in Ethane 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirred at room temperature for 6 hours. The yellow precipitate was filtered off and dried in air to give 1.85 g of 2-chloro-4- [3- (4-fluorophenyl) -1H.chrazol4-yl] -pyrimidine as a yellow solid, m.p. Mp 204-205 ° C.

216

Calculated for C ₁₃ H ₈ ClFN ₄ : C = 56.84; H = 2.94; N = 20.40; C1 “12.§1, Found:

C = 56.43; H = 2.76; N = 20.02; 01 = 12.97. '_; Mr

Example A-300

NHNHj

4- (3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyrimidinone hydrazone

A solution of the compound obtained in Step 3 of Example A-299 (1.5

g) and hydrazine hydrate (5 ml) in ethanol was refluxed overnight. After cooling the reaction mixture, the solvent was separated. The residue was partitioned between ethyl acetate and water. The organic phase 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 hexane to give 0.5 g of product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyrimidinone hydrazone, such as pale yellow solid (38% yield), m.p. 149-150 ° C. Elemental analysis: Calculated for C13H15N3O: C = 57.77; H, 4.10; N31.10. Found: 0 = 57.70; H, 4.31; N, 30.73.

Example A-301% N

217

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -NK-dimethyl-2-pyrimidinamine

Stage 1: Obtaining

NMe ₂

A solution of the compound obtained in Step 2 of Example A-299 (3.0 g, 0.02 mol) and N, 1-butylbis (dimethylamino) methane (10.45 g, 0.06 mol) in 40 ml of dimethylformamide was stirred at 110 ° C for 10 h. one night. After the solvent was removed in vacuo, water was added 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 recrystallization from ethyl acetate and hexane to give 1.23 g of product as a yellow solid (yield 32%), m.p. 7677 ° C. Elemental analysis: Calculated for C = 62.47; H = 8.39;

N29.14. Found: C = 62.19; H = 8.58; N = 29.02.

Step 2: Preparation of 4- [3- (4-fluorophenyl) -N-pyrazol-4-yl] -H, Idimethyl-2-pyrimidinamine

To a solution of the compound obtained in Step 1 of this Example (1.2 g, 0.0064 mol) and triethylamine (0.65 g, 0.0064 mol) in 10 ml of toluene was added dropwise 4-fluorobenzoyl chloride. The mixture was heated at reflux for 10 hours and the solvent was removed. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product (1.6 g) was dissolved in 50 ml of ethanol. The solution was treated with hydrazine hydrate (0.36 g, 0.006 mol) and the mixture was refluxed for 2 hours. After ethanol separation, the residue was partitioned between ethyl acetate and water. Organic

The 218 phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography over silica gel (ethyl acetate / hexane, 1: 1) to give 0.6 g of product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -H. N-dimethyl-2-pyrimidinamine as a yellow solid (yield 33%), m.p. 155-156 C. Elemental Analysis: Calculated for Ci _{5 4} Hi FN _5: C = 63.59; H, 4.98; N, 24.72. Found: C = 63.32; H = 4.92; N, 24.31.

Example A-302

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H-methyl-2-pyrimidinamine

A suspension of 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to Example A-299 (0.3 g, 0.0011 mol) in 10 ml of methylamine (40% aqueous) solution) was heated in a sealed tube at 100 ° C overnight. The mixture was then cooled to room temperature and the precipitate filtered and air-dried to give 0.2 g of product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N-methyl-2- pyrimidinamine as a white solid (yield 68%), m.p. 217-218 ° C. Elemental analysis: Calculated for C14H12FN5: C = 62.45; H, 4.49; N = 26.01. Found: C = 62.58; H, 4.36; N = 25.90.

Example A-303

219

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidinamine

This compound was synthesized by refluxing 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to Example A-299 in benzylamine overnight. . The product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -14- (phenylmethyl) -2-pyrimidinamine, was obtained as a white solid (yield 95%), m.p. 216-217 ° C. Elemental analysis: Calculated for C2oHi ₆ FN _5: C = 69.55; H = 4.67; N, 20.28. Found: C = 69.73; H = 4.69; N = 19.90.

Example A-304

HN

N-cyclopropyl-4 ~ [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine

This compound was synthesized by stirring 2-chloro 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to Example A-299 with excess cyclopropylamine at 50 ° C for 12 hours. The product, N-cyclopropyl-4- [3- (4-fluorophenyl) -1H-pyrazole220

4-yl] -2-pyrimidinamine, obtained as a white solid (yield 26%), m.p. 203-204 ° C. Elemental analysis: Calculated for Ci ₆ Hi ₄ FN ₅ : 0 = 65.07; H, 4.78; N, 23.71. Found: C = 64.42; H, 4.82; N, 23.58.

Example A-305

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H - [(4-methoxyphenyl) methyl] -2-pyrimidinamine

This compound was synthesized by refluxing 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine, obtained according to Example A-299, in 4-methoxybenzylamine for 4 hours. one night. The product 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -LT [(4-methoxyphenyl) methyl] -2-pyrimidinamine, was obtained as an off-white solid (yield 80%), m. t. 183-185 ° C. Elemental analysis: Calculated for C ₂ H ₁₈ FN ₅ O: O = 67.19; H, 4.83; N, 18.66. Found: 0 = 67.01; H, 5.11; N, 18.93.

Example A-306

221

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine

A solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -14 - [(4-methoxyphenyl) methyl] -2-pyrimidinamine, prepared according to Example A-305 (0.35 g, 0.00093 mol) in 15 ml of trifluoroacetic acid was heated at reflux for 16 hours. The solvent was separated and the residue partitioned between ethyl acetate and 1N ammonium hydroxide. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography over silica gel (ethyl acetate) to give 0.14 g of product, 4- (3- (4fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine as a pale yellow solid (59% yield) mp 273-274 ° C. Elemental analysis: Calculated for C ₁₃ H ₁₀ FN ₅ .0.25 H ₂ O: C = 60.11; H = 4.07; N = 26.96. Found: C = 60.15; H = 3.82; N, 26.38.

Example A-307

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -N (phenylmethyl) acetamide

To a mixture of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidinamine prepared according to Example A-303 (0.35 g, 0.00093 mol), dimethylaminopyridine (0.027 g , 0.00022 mol) and acetic anhydride

222 (0.066 g, 0.00066 mol) in 10 ml of tetrahydrofuran was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N- [4- [3- (4fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -N- (phenylmethyl) acetamide such as white solid (60% yield), m.p. 176-178 ° C. Elemental analysis: Calculated for C22H18FN5: C = 68.21; 11 = 4.68; N = 18.08. Found: C = 67.67; H = 4.85; N, 17.79.

*

Example A-308

Fr.

Ethyl [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] carbamate

To a suspension of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine prepared according to Example A-306 (0.26 g, 0.001 mol) in 5 ml of pyridine was added dropwise ethyl chloroformate. After the addition, the clear solution was stirred at room temperature for 6 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 triturated with ether to

223 to give 0.15 g of product, ethyl [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] carbamate as a white solid (yield 46%), m.p. Mp 163-165 ° C. Elemental analysis: Calculated for C ₁₆ Hi ₄ FN ₅ O _2: C, 58.71; H, 4.31; N = 21.04. Found: C = 59.22; H, 4.51; N, 21.66.

Example A-309

*

4- [3- (3-methylphenyl) -1H-pyrazol-4-yl] pyrimidine

This compound was prepared by the same method as described in Example A-208, except that 1-methyl-3- (4'-pyrimidinylacetyl) benzene (obtained according to Step 1 of Example A-19 from 4-methylpyrimidine and methyl-

3-methylbenzoate) is used in place of 4-fluorobenzoyl-4-pyridinylmethane. Elemental analysis: Calculated for Ci ₄ Hi ₂ N ₄ (236.27): C, 71.17; H, 5.12; N, 23.71. Found: C = 70.67; H = 5.26; N, 23.53. M.P. (DSC): 151.67 ° C.

Example A-310

4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyrimidine

224

This compound is prepared according to the chemistry described in Schemes VI and IX when selecting the corresponding pyrimidine starting material instead of the pyridine starting material. Elemental analysis: Calculated for C ₁₃ H ₉ N ₄ C1 · 0.25M H ₂ O: C = 59.78; H, 3.67; N, 21.45. Found: C = 59.89; H, 3.32; N, 21.56. M.P. (DSC): 218.17 ° C.

Example A-311

F

4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine

This compound is prepared according to the chemistry described in Schemes VI and IX when selecting the corresponding pyrimidine starting material instead of the pyridine starting material. Elemental analysis: Calculated for C ₁₃ H ₉ N ₄ F (240.24): C = 64.99; H, 3.78; N = 23.22. Found: C = 64.78; H, 3.75; N, 23.31. M.P. (DSC): 168.58 ° C.

Example A-312

4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine

225

This compound is prepared according to the chemistry described in Schemes VI and IX when selecting the corresponding pyrimidine starting material instead of the pyridine starting material. Elemental analysis: Calculated for C ₁₃ H ₉ N ₄ F (240.24): C = 64.99; H, 3.78; N = 23.22. Found: C = 64.94; H, 3.56; N, 23.44. M.P. (DSC): 191.47 ° C.

Other compounds of the present invention that can be prepared using one or more of the schemes included in this specification, but without limitation, are the following:

4- [3- (4-chlorophenyl) -5- (1-piperazinyl) -! N-pyrazol-4-yl] pyrimidine

- [5- (4-bromophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine

226

- [4- (4-pyridinyl) -5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3yl] piperazine

4- (5- (1-piperazinyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] benzonitrile

1- [5- (4-Ethylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine

227

5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-3-pyrrolidinyl-1H-pyrazol-3-amine

5- (4-chlorophenyl) -4- (4-pyridinyl) -H-3-pyrrolidinyl-1H-pyrazol-3-amine

74_ [5_ (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-piperidinamine

3- (4-fluorophenyl) -5- (1-piperazinyl) -4- (4-pyridinyl) -1H-pyrazole-1 ethanol

228

4- (2-aminoethyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydro-3- (4-pyridinyl) pyrazolo- [1,5-a] pyrimidin-6-ol

4- (2-aminoethyl) -2- (4-chlorophenyl) -4,5,6,7-tetrahydro-3- (4-pyridinyl) pyrazolo- [1,5-a] pyrimidin-6-ol

he

3- (4-chlorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-1-ethanol

229

5- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-3-ethanamine

5- (4-chlorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-3-ethanamine

4_ [3_ (4-fluorophenyl) -5- (4-piperidinyl) -1H-pyrazol-4-yl] pyrimidine

4- [3- (4-chlorophenyl) -5- (4-piperidinyl) -1H-pyrazol-4-yl] pyrimidine

230

NHCOMe] N- [4_ [3_ (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] acetamide

NHCOMe

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] acetamide

NHCOEt

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] propanamide

NHCOEt

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] propanamide

231

6- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H-purine

6- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -1H-purine

NCOMe

Bn ^Z

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -H (phenylmethyl) acetamide

NCOEt

Bn

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -1H (phenylmethyl) propanamide

232

NCOct

BrX

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] N (phenylmethyl) propanamide

BIOLOGICAL ASSESSMENT

Analysis of p38 kinase

Human p38a cloning:

The coding interval of human p38a cDNA was obtained by PCR-elongation from ribonucleic acid isolated from the THP line. 1 per human monocyte cell. The first strand of cDNA was synthesized from whole ribonucleic acid as follows: 2 pg of ribonucleic acid was heated to 100 ng of precursor statistical hexamer in 10 μΐ reaction medium by heating to 70 ° C for 10 minutes, followed by 2 minutes on ice. The cDNA was then synthesized by adding 1 pl RNAsin (Promega, Madison WI), 2 μ 2 50 mM dNTP, 4 μΐ 5X buffer, 2 μΐ 100 mM DTT, and 1 μ 200 (200 U) Superscript II ™ AMV reversible transcriptase. Statistical precursor, dNTP and Superscript II ™ reagents were supplied by Life-Technologies, Gaithersburg, MA. The reaction medium was incubated at 42 ° C for 1 hour.

Extension of p38 cDNA is accomplished by aliquot mixing 5 μΐ reversible transcriptase in 100 μΐ PCR reaction medium, containing

233 reaped the following components: 80 μΐ distilled water, 2 μΐ 50 mM dNTP, 1 μΐ straight and reversible precursors (50 pmol / μΐ), 10 μΐ 10X buffer, and 1 μΐ Expand TM polymerase (Boehringer Mannheim). PCR precursors include Bam HI sites at the 5 'and 3' ends of the elongate fragment and were supplied by Genosys. The sequences of the straight and reversible precursors are 5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 'and 5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3', respectively. PCR elongation was performed in DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles at 94 ° C for 1 minute, at 60 ° C for 1 minute, and at 68 ° C for 2 minutes. After extension, excess precursors and non-introduced dNTPs were removed from the elongate fragment using Wizard ™ PCR prep (Promega) and bound to Bam HI (New England Biolabs). The Bam HI-linked fragment binds to the Bam HI-bound pGEX 2T plasmid DNA (PharmaciaBiotech) using DNA ligase (New England Biolabs), as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2 ^nd ed. (1989). The binding was transformed into chemically competitive E. coli DH10B cells supplied by Life-Technologies following the manufacturer's instructions. Plasmid DNA was isolated from the bacterial colonies obtained using a Promega Wizard ™ mimiprep kit. Plasmids containing the appropriate Bam HI fragment were sequenced in DNA Thermal Cycler (Perkin Elmer) with Prism ™ (Applied Biosystems Inc.). cDNA clones were identified to be encoded for both human p38α isoforms (Lee et al., Nature 372, 739). One clone containing the p38a-2 cDNA (CSBP-2) inserted at the cloning site of pGEX 2T, 3 'of the GST coding region is designated as pMON 35802. The sequence obtained for this clone is an exact copy of the cDNA clone described by Lee et al. This plasmid produces a GST-p38a fused protein.

234

Preparation of human p38a:

GST / p38a fusion protein was obtained from plasmid ρΜΟΝ 35802 in E. coli dye DH10B (Life-Technologies, Gibco-BRL). The cultures were grown overnight in Luria Broth (LB) containing 100 mg / ml ampicillin. The next day, 10 ml of the overnight culture was mixed with 500 ml of fresh LB and the growth continued in a 2 liter flask at 37 ° C and shaking continuously until the culture reached an absorption of 0.8 at 600 nm. The production of condensed protein is induced by the addition of isopropyl b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for 3 hours at room temperature and the cells were removed by centrifugation. The cell pellets were stored frozen until the protein was purified.

P38 Kinase Purification:

All chemicals are supplied by Sigma Chemical Co. unless otherwise noted. Twenty grams of E. coli cell pellets separated by 5 fermentations with shaking in a 1 liter flask were resuspended in PBS (140 mM sodium chloride, 2.7 mM potassium chloride, 10 mM disodium hydrophosphate, 1.8 mM potassium dihydrophosphate, pH 7.3) ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then divided equally into five 50 ml conical Falcon tubes. Cells were sonicated (Ultrasonics model W375) with a 1 cm sample for 3 x 1 minutes (pulse) on ice. The Lys cell material was removed by centrifugation (12,000 x g, 15 minutes) and the clarified supernatant was placed in resin glutathione Sepharose (Pharmacia).

235

Chromatography for affinity for glutathione-sepharose:

ml of 50% glutathione-Sepharose-PBS suspension were added to 200 ml of clear supernatant and incubated for 30 minutes at room temperature. The resin was separated by centrifugation (600 x g, 5 minutes) and washed with 2 x 150 ml PBS / 1% Triton X-100, followed by 4 x 40 ml PBS. For cleavage of the p38 kinase from the GST-p38 fused protein, the glutathione-sepharose resin was resuspended in 6 ml of PBS containing 250 units of thrombin protease (Pharmacia, specific activity> 7500 units / mg, and stirred gently for 4 hours at The glutathione-Sepharose resin was separated by centrifugation (600 x g, 5 minutes) and washed with 2 x 6 ml with PBS The PBS fractions and the extracted supernatant containing p38 kinase protein were bound and adjusted to 0.3 mM PMSF.

Mono O anion exchange chromatography:

Thrombin-cleaved p38 kinase was then purified by FPLC anion exchange chromatography. The thrombin-split sample was diluted twice with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected into a Mono Q HR 10/10 (Pharmacia) anion exchange column, equilibrated with Buffer A. The column was eluted with 160 ml of 0.1 M-0.6 M sodium chloride / Buffer A gradient (2 ml / minute flow rate). The p38 kinase eluted at 200 mM sodium chloride was separated and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl SI00 gel filtration chromatography:

The concentrated Mono Q p38 kinase purified sample was purified by gel filtration chromatography (Pharmacia HiPrep 26/60

236

Sephacryl S100 column equalized with Buffer B (50 mM HEPES, pH 7.5, 50 mM sodium chloride, 2 mM DTT, 5% glycerol). The protein was eluted from the Buffer B column at 0.5 ml / min flow rate and the protein was detected by ingestion at 280 shi. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were collected and frozen at -80 ° C. Usually 35 mg of p38 kinase are obtained from purified protein by shaking fermentations in 5 liter flasks with E. coli.

In vitro analysis

The ability of the compounds to inhibit human p38 kinase alpha was evaluated using two in vitro assays. In the first method, activated human p38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I (phosphorylation heat and acid-resistant protein-insulin), in the presence of ³² P-ATP ( ³² P-ATP) gamma. PHAS-I is biotinylated prior to analysis and provides destruction of the substrate, which is phosphorylated during analysis. p38 kinase is activated by MCC6. The compounds were tested at 10x dilution as a series in the range of 100 μΜ to 0.001 μΜ using 1% dimethyl sulfoxide. Each inhibitor concentration was tested three times.

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 μΜ unlabeled ATP. When p38 is activated, a significant signal is obtained in the assay. Biotinylated PHAS-I was used at 1-2 pg per 50 μΐ reaction volume with a final concentration of 1.5 μΜ. Activated human p38 kinase alpha was used at 1 pg per 50 μΐ reaction volume at a final concentration of 0.3 μΜ. For phosphorylation of

237

PHAS-Ι uses a range of ³² P-ATP. ³² P-ATP has a specific activity of 3000 Ci / mmol and is used at 1.2 μθί per 50 μΐ reaction volume. The reaction was carried out from 1 hour to overnight at 30 ° C.

After incubation, 20 μΐ of the reaction mixture was transferred onto a high capacity filter plate coated with streptavidin (SAM-streptavidin, Promega) pre-moistened with phosphate buffered saline. The transferred reaction mixture can come into contact with the strepavidin membrane of the Promega plate for 1-2 minutes. After coupling the biotinylated PHAS-Ι with the ³² P introduced, each well was washed three times with 2 M sodium chloride, three times with 2 M sodium chloride with 1% phosphoric acid, three times with distilled water, and finally once with 95% ethanol , to separate unbound ³² P-ATP. The filter plates were air-dried and 20 μΐ scintillant was added. The plates are closed and calculations are made. The results are shown in Table 4.

The second assay used is based on p38 kinase induced alpha phosphorylation of EGFRP (epidermal growth factor receptor peptide, 21 mer) in the presence of P-ATP. The compounds were tested at 10x dilution as a series in the range of 100 μΜ to 0.001 μΜ using 1% dimethyl sulfoxide. Each inhibitor concentration was tested three times. Compounds were evaluated in 50 μΐ reaction volumes in the presence of 25 mM HEPES, pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4 mM DTT, 50 μΜ unlabeled ATP, 25 pg EGFRP (200 μΜ) and 0.05 uCi gamma ³² P-ATP. The reaction is initiated by the addition of 0.09 pg of activated purified human GST-p38 kinase alpha. Activation was performed using GST-MKK6 (5: 1, p38: MKK6) for 1 hour at 30 ° C in the presence of 50 μΜ ATP. After incubation for 60 minutes at

238 room temperature, the reaction was stopped by the addition of 150 μ 150 AG 1X8 resin in 900 mM sodium formate buffer, pH 3.0 (1 volume of resin per 2 volumes of buffer). The mixture is formed by pipetting three times and the resin is allowed to precipitate. A total of 50 μΐ volume of purified solution was transferred from the reaction wells to Microlite-2 plates. Then, 150 μΐ of Microscint 40 was added to each well of the Microlite-2 plate and the plate was closed, mixed, and calculations were made.

TABLE 4

Example p38 kinase IC50 (μΜ) 1 4.6 2 1.5 8 <0.1 16 3.8 23 1.5 25 2.6 26 0.7 28 0.3 33 2.5 34 8.0 36 12.1 38 0.8 39 1.1 40 1.3 42 0.3 43 <0.1 44 <0.1 45 <0.1 46 <0.1 47 3.2 48 1.8 50 2.3 51 <0.1 52 0.1 53 0.9 54 0.7 55 6.4 143 <0.1

239

TNF cell assays

Method for isolating human peripheral blood mononuclear cells:

Human blood is collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully placed over 5 ml of PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round-bottomed centrifuge tube. The sample was centrifuged at 450-500 x g for 30-35 minutes on a rotating rotor at room temperature. After centrifugation, the upper band of cells was separated and washed three times with PBS w / o calcium or magnesium. The cells were centrifuged at 400 x g for 10 minutes at room temperature. The cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells / ml.

LPS stimulation of PBM:

PBM cells (0.1 ml, 2 million cells / ml) were incubated with 0.1 ml of compound (final concentration 10-0.41 μΜ) for 1 hour in 96-well flat-bottom microtiter plates. The compounds were first dissolved in dimethyl sulfoxide and dissolved in SCI at a final concentration of 0.1% dimethyl sulfoxide. Then, in a volume of 0.010 ml, LPS (Calbiochem, 20 ng / ml final concentration) was added. The cultures were incubated overnight at 37 ° C. The supernatants were then separated and tested by ELISA for TNF-α and IL1-b. Viability was analyzed using MTS. After removal of 0.1 ml of the supernatant, 0.020 ml of MTS was added to leave 0.1 ml of cells. The cells were incubated at 37 ° C for 2-4 hours, after which O.D. was measured. at 490-650 nM.

240

Maintenance and differentiation of U937 human histiocytic lymphoma cell line:

U937 cells were propagated in RPMI1640 containing 10% fetal bovine serum, 100 IU / ml penicillin, 100 pg / ml streptomycin and 2 µM glutamine (Gibco). Fifty million cells in 100 ml of medium were induced for final monocytic differentiation by 24 h incubation with 20 ng / ml phorbol 12-myristate 13-acetate (Sigma). The cells were washed by centrifugation (200 x g for 5 minutes) and resuspended in 100 ml of fresh medium. After 24-48 hours, the cells were separated, centrifuged and resuspended in culture medium at 2 million cells / ml.

LPS stimulation of TNF production by U937 cells:

U937 cells (0.1 ml, 2 million / ml) were incubated with 0.1 ml of compound (0.004-50 μΜ final concentration) for 1 hour in 96-well microtiter plates. The compounds were prepared as 10 µM stock solutions in dimethyl sulfoxide and dissolved in the culture medium to give a final concentration in dimethyl sulfoxide 0.1% for cellular analysis. LPS (E.coli, 100 ng / ml final concentration) was then added in a volume of 0.02 ml. After incubation for 4 hours at 37 ° C, the amount of TNF-α released in the culture medium was quantified by ELISA. The inhibitory potential is expressed as IC50 (μΜ). The results of these TNF cell assays are shown in Table 5.

241

Table 5 Example Human PBM U937 cell analysis IC50 (μΜ) IC50 (μΜ)

1 0.5 2 1.6 0.578 e 0.1 0.222 5 0.274 7 0.2 0.201 8 <0.1 9 0.4 10 0.7 1.687 12 8 .. 5 13 4.8 14 1.2 17 1.1 19 0.3 0.484 20 1,089 21 ♦ 0.077 22 3.2 24 8.2 26 <0.1 0.029 27 2.7 28 0.1 29 2.2 30 2.6 31 0.8 1,053 32 2.696 33 0.4 34 0.5. 35 0.7 36 1.4 37 1.5 0.099 38 0.2 0.208 39 0.7 0.244 4.0 0.4 41 1.0 42 0.7 43 <0.1 0.243 44 0.4 0.477 45 <0.1 0.04 46 0.329 47 2,359 48 2.2 0.522 49 6.8 50 0.9 51 0.074 54 0.2 0.13 55 <0.1 0.228 143 0.301

.242

Analysis in rats

The efficacy of new compounds for blocking TNF secretion was also evaluated using a model based on LPS-induced rats. This model uses male rats of the Harlen Lewis breed [Sprague Dawley Co.]. Each rat weighing approximately 300 g was fed overnight before testing. Administration of the compound is usually performed orally via a tube (although in some cases peritoneal, subcutaneous, and intravenous administration may also be administered) from 1 to 24 hours prior to LPS administration. Rats were administered intravenously 30 pg / kg of LPS [salmonella typosa, Sigma Co.] via the tail vein. Blood was collected via a puncture of the heart 1 hour after LPS placement. Serum samples were stored at -20 ° C until quantitative analysis of TNF-α was performed using Enzyme Linked-Immuno-Sorbent Assay ("ELISA") [Biosource]. B Perretti, M., et al., No. J. Pharmacol. (1993) 110, 868-874 given for comparison in the present description, further details of the analysis are provided.

Analysis in mice

LPS-induced mouse model of TNF-α production:

TNF-α was induced in BALB / c female mice at 10-12 weeks by injection into the tail vein with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline. One hour later, retro-orbital sinus blood was released to the mice and TNF concentrations in the clotting serum were quantified by ELISA. Typically, peak243 levels of serum TNF range from 2-6 ng / ml one hour after injection of LPS.

The test compounds were administered to fed mice via an oral tube in suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 in water 1 hour or 6 hours before injection of LPS. The one-hour protocol makes it possible to evaluate the strength of a compound at Cmax plasma levels, while the six-hour protocol allows an estimate to be made of the duration of the compound. Efficacy is defined at each time point as a percentage inhibition of serum TNF levels with respect to LPS-injected mice receiving solvent only.

*

Further results obtained using the analyzes described above are given in Table 6 below. The results of the p38 and U937 cell analysis were expressed as IC50 (μΜ). The results of the mouse-LPS analysis are expressed as percentage inhibition.

-l ·.

Table 6

Example p38 ^J p38 ² U937 mL PS mL PS mL PS

4. 6 4. Dose 1 hour, 30 mpk

A-212 0.49 0.74 0.0967 20 10 ----- Gz ----- A-208 0.104 0.049 0.1896 98 30 97 A-227 0.06 96 A-228 0.76 0.339 0.4173 32 30 92 A-229 1.4 0.4622 76 91 A-230 0.42 0.178 96 A-231 0.174 0.3225 86 30 94 A-232 0.048 96 A-233 0.044 53 A-234 0.103 A-235 0.104 56

244

Example p38 * p38 ² U937 mL PS mL PS mL PS

4. 6 h. Dose 1 h., 30 mpk

A-236 0.237 94 A-237 0.093 0.087 60 A-238 0.177 0.4016 A-239 0. 034 51 30 87 A-240 0.961 78 30 - A-241 0.338 79 30 87 A-242 0.047 95 30 87 A-243 0.729 82 A-244 0.099 A-245 <. 001 0.0337 6 5 A-246 0.403 0.592 0.4952 A-247 <0.01 0.166 A-249 0.432 73 30 86 A-250 2.873 A-251 0.637 . 32 87 A-252 0.774 1.197 '48 30 75 A-253 <. 001 0.0044 61 A-254 0.081 0.1411 A-215 2.34 0.2976 38 30 80 A-256 0.813 0.4562 A-257 1,081 <. 01 0.51.67 A-213 0.22 57 A-258 0.48 1.2083 68 A-259 0.17 0.7574 62 A-210 0.16 0.1983 85 30 93 A-260 0.23 1.2821 47 30 79 A-214 0.06 1.4006 70 A-261 0.008 0.2542 48 30 92 A-216 0.018 1.8287 27 30 91 A-262 <0.1 0.3267 45 A-263 <0.01 <0.1 0.5434 49 A-264 0.2594 61 i A-265. <0.1 0.6016 ³² L 1 A-266 0.5393 0! A-267 | 0.43 2.6681 80 j A-268 <0.01 0.0074 11! A-217 0.697 0.3486 9 i A-269 > 10 μM ⁵¹ A-270 0.015 0.3466 ⁵³ A-271 0.216 4.2144 I 68 I A-272 0.073 0.583 -8 A-273 6.98 > 10 43 A-274 <0.1 0.92 21 30

245

Example p38 ^{'p38 z U937 mL PS mL PS} mL PS

4. 6 4. Dose 1 hour, 30 mpk

A-275 10.14 2 > 10 A-276 0.176 0.45 -24 ' 30 A-277 0.026 33 30 A-278 0.285 2 .3 62 30 A-279 0.005 0.7 64 30 A-280 0.134 15 30 A-2S1 0.053 22 30 A-21S 0.044 18 30 A-282 0.045 0.0973 30 30 A-283 <0.1 0.7998 -20 30 A-284 0.98 0.5088 -1 A-285 <0.1 0.1795 11 30 A-286 0.057 0.09 29 30 A-287 0.041 0.27 '' -24 30 A-288 0.017 0.3 40 30 A-289 <0.1 0.14 44 30 A-290 6.0191 l * 1 30 A-291 0.388 1.1309 36 30 A-292 1.15 > 10 A-293 0.73 A-294 0.015 0.5 61 30 A-295 7.66 > 10 94 30 A-296 26 A-297 0.52 0.17 89 30

¹ Results of in vitro ρ38α analysis based on the assay method

PHAS-I.

² Results of in vitro analysis of p38a based on the assay method

EGFRP.

246

Induction and evaluation of collagen-induced arthritis in mice:

Arthritis in mice was induced according to the method given by J. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. 2. Immunol. 2: 199 (1984), presented for comparison. In particular, arthritis was induced in DBA / 1 male mice at 8-12 weeks by injection at the base of the tail of 50 pg chicken type II collagen (SP) (provided by Dr. Marie Griffiths, Univ, of Utah, Salt Lake City , UT) together with the Freund (Sigma) additive on day zero. The injection volume is 100 pl. On the 21st vein, the animals were amplified with 50 pg SI together with Freund supplement (100 pl volume). Animals were examined several times each week for signs of arthritis. Any animal with a red or swollen paw is considered to be suffering from arthritis. The arthritis paw study was performed according to the method given by Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectability and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15: 180 (1983). The severity of the disease is assessed with 1-3 scores for each paw (maximum score 12 per mouse). Animals with red or swollen paws are evaluated by 1. Strong swelling of the entire paw or deformity is evaluated by 2. Ankylosis of the joints is evaluated by 3. Animals are examined for 8 weeks. 8 to 10 animals per group are used.

Preparation and administration of compounds:

Compounds tested on collagen-induced arthritis mice were prepared as a suspension in 0.5% methylcellulose (Sigma, St. Louis, MO), 0.025% Tween 20 (Sigma). The suspensions of the compounds were administered via an oral tube in a volume of 0.1 ml b.i.d. Admins

247 stripping commences on the 20th day after collagen injection and continues daily until the final study on the 56th day. The arthritic paw study is performed as described above. The results of the analysis are presented in Table 7.

Table 7

Compound % Arthritis Suppression A-210 58.5 @ 15 mpk A-172 49.3 @ 100 mpk A-189 51.6 @ 30 mpk A-208 97.5 @ 60 mpk A-208 75.0 @ 60 mpk

An object of the present invention is also a class of pharmaceutical compositions comprising the active compounds of the present invention, together with one or more non-toxic, pharmaceutically acceptable carriers and / or diluents and / or additives (commonly referred to as "carriers") and, if other active ingredients are needed. The active compounds of the present invention may be appropriately administered, preferably in the form of a pharmaceutical composition adapted to the chosen route of administration, and at a dose effective for the intended treatment. The active compounds and compositions may, for example, be administered orally, intravascularly (IV), peritoneally, subcutaneously, intramuscularly (IM) or topically. For topical administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, dragees, powders, suspensions or liquids. The pharmaceutical composition is preferably formulated in a single form

248 per dose containing a separate amount of active ingredient. Examples of such dosage units are tablets and capsules. The active ingredient may also be administered by injection (IV, IM, subcutaneously or by injection) as a composition in which saline, dextrose or water can be used as a suitable carrier. The pH of the composition is adjusted, if necessary, with a suitable acid, base or buffer. Suitable bulk, dispersing, wetting or suspending agents, including mannitol and polyethylene glycol 400, may also be incorporated into the composition. A suitable parenteral formulation may include, in injection ampoules, a compound in the form of a sterile solid substance comprising a lyophilized powder. An aqueous solution may be added to dissolve the compound prior to injection. The amount of the therapeutically active compounds administered and the dosage for treating the disease state with the compounds and / or compositions according to the present invention depends on various factors including the age, weight, sex and medical condition of the patient, the severity of the inflammation or disorder associated with inflammation, mode and frequency of administration, and the particular compound used, and may therefore vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg / kg body weight, preferably between about 0.1 and about 50 mg / kg body weight, and most preferably between about 0.5 and 30 mg / kg body weight, may be appropriate. The daily dose can be administered from one to four times a day. In the case of skin disease, it may be preferable to administer the compounds according to the present invention locally to the damaged site two to four times daily. In case of eye or other external disorders

249 invitations, for example, mouth or skin, preferably, the compositions are administered as a topical gel, spray, ointment or cream, or as a suppository comprising the active ingredients in a total amount, for example, from 0.075 to 30% w / w, for preferably, from 0.2 to 20% w / w. and especially from 0.4 to 15% w / w. When the composition is in the form of an ointment, the active ingredients may be administered either with a paraffin base or with a water-miscible ointment base. Alternatively, the active ingredients may be incorporated into an oil-in-water cream. If desired, the aqueous phase based on the cream may include, for example, at least 30% w / w. polyvalent alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical composition may optionally include a compound that enhances the absorption or penetration of the active ingredient through the skin or through other damaged areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

The compounds of the present invention may also be administered transdermally. Preferred local administration can be accomplished using a patch, either tank type and porous membrane, or as a solid matrix. In some cases, the active compound is delivered continuously from a reservoir or microcapsules through a membrane into an adhesive that passes the active ingredient in contact with the skin or mucous membrane of the recipient. If the active substance is absorbed through the skin, a controlled and predetermined flow of the active substance is administered to the recipient. In the case of microcapsules, the encapsulating agent may also serve as a membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion and a polyester patch.

250

The oil phase of the emulsions according to the present invention can be made up of known ingredients in a known manner. As long as the phase may contain only an emulsifier, it may include a mixture of at least one emulsifier with fat or oil, or both fat and oil at the same time. It is preferable to include the hydrophilic emulsifier together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include oil and fat. Together, the emulsifier (s), with or without stabilizer (s), form so-called emulsifying wax, and the wax, together with the oil and grease, form the so-called ointment base which forms the oil-dispersed phase of the compositions in the form of a cream. Emulsifiers and emulsion stabilizers suitable for use in the compositions of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The choice of suitable oils or fats for the compositions is based on achieving the desired cosmetic properties since the solubility of the active compound in most oils used in pharmaceutical emulsion compositions is very poor. Therefore, the cream should not be greasy, stain or washable, with a suitable consistency to prevent leakage from tubes and other packaging. Straight- or branched-chain mono- and di-basic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyloleate, isopropyl palmitate, butyl stearate, 2-ethylarylate, 2-ethyl-stearyl, 2-ethyl ester, can be used. They can be used alone or in combination depending on the desired properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

251

Formulations suitable for topical administration to the eye include eye drops in which the active ingredients are dissolved or suspended in a suitable carrier, in particular, an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are present in such compositions at concentrations of 0.5 to 20%, preferably 0.5 to 10%, and in particular about 1.5% w / w.

For therapeutic purposes, the active compounds of the present invention are typically combined with one or more additives suitable for the chosen route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and phosphate salts. , gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and then be tableted or encapsulated for convenient administration. Such capsules or tablets may contain controlled release formulations which may be in the form of a dispersion of the active compound in hydroxypropyl methylcellulose.

The compositions for parenteral administration may be in the form of aqueous or non-aqueous, isotonic, sterile, injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules and one or more of the carriers or diluents mentioned in the description of oral administration. The compounds may 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 add-ons and administration methods are good and wide-ranging

252 newspapers in the pharmaceutical field.

All patent documents cited in the present invention are provided for comparison.

Although the present invention is described in relation to individual aspects, the details of these aspects should not be construed as limiting the present invention.

Description of a parallel systemic synthetic method used to prepare the compounds according to Examples B-i, B-ii and B-iii

Scheme B-1 describes parallel acting systemic reaction blocks that are used to prepare compounds according to Examples B-0001 to B-1574 and, similarly, can be used to prepare compounds according to Examples B- 1575 to B-2269. Parallel reactions take place in multi-chamber reaction blocks. In a simple reaction block, 48 parallel reactions can take place, and it is possible to produce a different compound in each reaction vessel B1. Each reaction vessel B1 is made of either polypropylene or glass rug and includes a frit B2 above the base of the vessel. Each reaction vessel is connected to a valve system B3 of the reaction block with a special lock system (leur-lock) or threaded. Each valve B4 is either opened or closed by controlling the locking position or by opening or closing the B5 levers in a row in the valve system. The solutions may flow through or hold over the fryers of the vessels leaving the valves in the open position and controlling the pressure below the valve system by controlling the flow of inert gas through the inlet valve for inert gas B6. The parallel reactions that take place in these reaction blocks

253 are allowed to develop upon incubation in a temperature controlled shaking position. The temperature control of the reaction chambers is accomplished by passing hot liquid through the aluminum cladding plates that make contact with the cladding of the reaction block B7. The mixing is carried out in a shaking position, either vertically orbital upward of the reaction block or horizontally, with the reaction block tilted to one side.

During the reaction or after completion of the reaction, functionalized resins are added to each reaction vessel B1. These functionalized resins are capable of rapidly purifying the product in any reaction vessel. When vacuum filtered on the reaction block when the B8 vacuum valve is opened, the purified products are separated from the resin-derived by-products. The valve B8 is located at the bottom of the chamber of the reaction unit B10, which houses rectangular bottles B1. The desired products are obtained as filtrates into the bottles B9. Removal of the solvent from these bottles yields the desired products.

Scheme B-2 illustrates various applications of functionalized resins for the purification of products from reaction vessels B22 prior to filtration from F1 vessels in B9 bottles. Said functionalized resins are expressed as 1) resin bound B12 reagents which increase the by-products of the resin bound B13 reagents; 2) binders B14 or B15 of excess reagents from the solution phase, respectively. B16 or B17. The reagents from the solution phase B16 and B17 contain the reactive functionality -rf'i and -rf ₂ , which enables them to be chemically selectively linked by the additional reactive functionality -Crfi and -Crf ₂ of the resins B14 and B15; 3) B18 by-products of by-products

254

B6: inert gas inlet

B8: Vacuum valve

B9 is a possible collection of glass shelves

Bl 1 are mounted at the bottom of the chamber of the reaction unit B10

Scheme B-2

255 from the solution Bl9. Byproducts B19 comprise a functionality of the molecule referred to as -mr ₂ that can be chemically selectively linked by the additional functionality -Cr ₂ associated with the resin B18; resins that inhibit the B20 reaction which pass into extinguished B21 resins. The B20 resin contains the -Q functionality that quenches the reaction (e.g., proton transfer) of product B22 to obtain the desired insulating form of product B22. Upon termination of the reaction, resin B20 is converted to resin B21, in which -q represents the exhausted functionality of resin B21; 5) binders B23 of chemically labeled reagents B24 and their corresponding by-products B25. The soluble B24 reagent includes a bifunctional chemical group, -tag, which is inert in the reaction conditions but is used to provide the binding of B24 after the reaction of the additional -Ctag functionality associated with resin B23. In addition, the soluble byproducts B25 obtained during the reaction contain the same chemical functionality -tag, which also enables the binding of resin B23. Moreover, some B16 reagents, in particular, ethereally cross-linked reagents and / or electron-poor nucleophiles, have binding functionality (-rfi in this case is a weak binding functionality). These weak B16 binding reagents can be transformed in situ to stronger B27 binding species by their interaction with the B26 binding reagents. B26 includes highly reactive additional functionality -Crf _b which reacts with B16 to stimulate B27 in situ. The bifunctional functionality of the molecule, designated -mr included in B26, is also present in the resulting in situ B27. Both B26 and B27 bind to the additional molecular functionality attached to the B28 resin. Similarly, some reactions produce byproducts that bind! weakly B19, in which case, mo

256 lecular functionality of mr ₂ cannot directly bind B19 to the additional functionality associated with resin B18. With such use of the bifunctional binder B29, B19 is transformed into a more easily bindable BST. The resulting molecular functionality, mr present in the WHO, is easily coupled by the additional functionality, Cmr, associated with the B31 resin. In some reactions, multi-linking resins are used which simultaneously purify the reaction product. Even resins containing incompatible functional groups can be used simultaneously, since these resins purify further functionalized dissolved reagents, reagents or by-products from the aqueous phase faster than neutralizing resins. Similarly, resins containing general reactive and cessation reaction functionality are capable of affecting the reagents, products or by-products of the solution faster than the neutralizing resins.

Scheme B-3 shows the modules of the robotic laboratory equipment used in the preparation of the compounds of Examples B0001 to Vxxxx. The chemicals used in the automated laboratory are weighed and then dissolved or suspended in solvents at Position # 1 (Automated Chemistry Prep Station). Therefore, solutions or suspensions with known molarity are used in other robotic positions. In position # 1, the labels of each chemical solution are also encoded so that its identity is recognized by the code scanned at that or other positions.

The reactions are initialized to modular Positions 42 and # 2 DUP. Item 42 DUP is defined as duplicate to Item # 2 and used to increase the capacity of a robotic laboratory. A reaction block is mounted on Item 42 or 42 DUP, Item 42 or on the DUP

257 # 2 DUPs are also installed, which include reactants, reagents, solvents and resin suspensions. In controlling the chemical information file, reactions are initialized by transferring reactant solutions, reagent solutions, solvents and / or gums into each vessel of the reaction block. The transfer of known volumes of solutions, suspensions or solvents is by syringes that control the single penetration through the barrier / passage of argon through the cannula, the passage of the resin slurry through the cannula, or through six cannulas, which provided simultaneous delivery of volumes of the six reaction vessels in a row. The reaction block and / or the chemical solution shelves may be cooled to room temperature during the transfer of the chemical solution. After transferring the chemical solutions and solvents carried out at Position # 2 or 42 DUP, incubation of the reaction block can be carried out while the reaction block is mounted on the robotic position. However, it is preferred to remove the reaction block when complete volume transfer is complete and the reaction block is warmed to room temperature. The reaction block is transferred along the line of vertical or horizontal shaking in incubator position # 5.

The automatic weighing / archiving item 43 presents the functions of weighing empty receptacles (to obtain the tare of the weight of the receptacles) and the functions of weighing the receptacles containing filtered, purified products (to obtain the total weight of the receptacles) ). After the bottles containing the product have been weighed (determination of total weight) in 11 # 3, it is possible to reconstitute the glassware in an organic solvent of Item # 3. Solvent transfer is performed by single-syringe syringes

258 ηοίό penetration through mounted barrier / argon leakage through cannula. A solution of known molarity, prepared and recorded by the chemical information system, is prepared in each flask containing the product. These product solutions may then be in Item # 2 or # 2 DUP for use in the next reaction steps, or go to Item # 7 or # 7 DUP for analytical development.

Rapid evaporation of the solvent from the product containing bottles is accomplished by mounting the Savant Automated Solvent Evaporation collecting racks Item # 4, # 4 DUP or # 4 TRIP, where # 4 DUP and # 4 TRIP are defined as double and triple copies of Item # 4 for Increasing the Solvent Release Capacity in a Robotic Laboratory. Commercially available solvent separation equipment is supplied by Savant Company (model # SC21OA speedvac, equipped with model # RVT4104 vapor trap and model # VN100 vapornet cryopump).

Positions # 1 and # 7 DUP play analytical functions. Position # 7 DUP is a copy of Position # 7 to increase the capacity of the robotic laboratory. Shelves containing a product are mounted in these positions. A solution of known molarity was prepared in each flask containing the product indicated and recorded by the chemical information file. It is possible that the gaseous dissolution function may be accomplished in the previous development of the Bottle Shelf of Item # 3 as described above. In heading # 7 or # 7 of the DUP, under control of the chemical information file, aliquots of the flask product are transferred to single and recognizable microtiter plate slots for analytical determinations. Such a microtiter plate is prepared in the # 7 or # 7 DUP positions for further use in Automated IIPLC / Mass Spectrometer Items # 8 or # 8 DUP. Position # 8 DUP is co

259 is drinking at Position # 7 for Robotics Laboratory Capacity Building. Item # 8 or # 8 DUP are commercially available LC / MS instruments manufactured by Hewlett Packard (HP 1100 HPLC model coupled to HP1100 MSD (G1946A) mass spectrometer; this apparatus is also provided with a solvent degasser, model # G1322A, double pump, model # G1312A, column heater, model # G1316A, diode system detector, model # G1315A The chromatograph is equipped with an automatic sample collection (Gilson Company # 215 autosampler) Item # 8 or # 8 DUP are used to determine purity and identification by means of liquid pressure chromatography (HPLC) of the product and co-chemical ionization at atm Fields pressure (APCI) or electrospray masspektromegriya to determine the molecular weight.

Another microtiter plate is prepared in Heading # 7 or # 7 DUP for later use in a commercially available Varian NMR Liquid Spectrometer in Heading # 10 (Varian Instruments flow probe NMR, 300 MIL ·: equipped with a commercially available Gilson 215 automatic sample collection) . This position # 10 defines 1 H, ¹³ C and / or ¹⁹ F NMR spectra.

Other microtiter plates may be mounted on Item # 7 or # 7 DUP for the preparation of plates containing biological analysis product. Aliquots of the product in the bottles are transferred to these microtiter plates for biological analysis under the control of the chemical information file. The identity and quantity of each transferred product are recorded by the chemical information system for use by biologists who perform the biological analysis of the products.

Fourier Transform InfraRed (FT-IR) spectrometric Item # 11 is used to analyze resins to identify organic functional groups chemically bonded to these resins. Resins as noted

260 above, they contain chemical functionality and use kayu reagents, selective complexing agents or a stop medium during the development and purification of the mixtures of the crude product present in the vessels of the reaction block. The robotic laboratory includes a commercially available i'T-IR spectrometer manufactured by HaNicolet Instruments (Model 7 MagnaIR 560, equipped with an Inspect IR microscope for resin placement and positioning).

Scheme B-C

The lines connecting the modular positions mean the movement of chemical racks, reaction blocks and / or shelves with prefabricated bottles from one modular position to another.

Automated Chemistry Prep Station # 1

Automated weighing / archival

Station # 3

Automated Solvent Evap. Station # 4 Automated Solvent Evap. Station # 4 DUP Automated Solvent Evap. Station # 4 TRIP Automated Automated Automated HPLC / Analytical Prep. Station # 7 Analytical Prep. Station # 7 DUP Mass Spec Station # 8 \ 1 X FT-IR Station # 11 NMR Flow Probe Station # 10 Automated HPLC / Mass Spec Station # 8 DUP

261

The ChemLib IT system is a collection of client-side software and server-side software.

The ChemLib IT system is an application of client / server software designed to maintain and document flow data in the robotics lab described above. This IT system integrates the chemistry of the robotic synthesis laboratory and manages the data obtained.

The server-side software (software) stores all electronic data about the robotic chemical device. This server. Silicon Graphics IRIX station v6.2. works with Oracle 7 v7.3.3.5.0 software database. who stores the data. The connection between the client computer and the server is via Oracle's TCP / IP Adapter v2.2.2.1.0 and SQL * Net v2.2.2.1,0D. SQL * Net is an Oracle network that allows data from the client's computer to be processed in the Oracle database. The client computer is loaded with Microsoft Windows 95. The client software, ChemLib IT system, is composed of Omnis7 v3.5 and Microsoft Visual C v5.0. This composition by the client is such that it is referred to as ChemLib. ChemLib communicates with the server for its data through Oracle's PL / SQL v2.3.3.4.0. These PL / SQL signals in ChemLib create a panel network connection with Oracle's SQL * Net driver and TCP / IP adapter, allowing the server to process data.

A "library" is defined as a series of nests, where each nest defines a separate connection. ChemLib stands for Library in a module called Electronic Spreadsheet. After the meal. The Electronic Spreadsheet consists of a n-number of wells containing the components that are required to synthesize the compound in each of the helical wells.

The chemist is beginning to fill Electronic Spreadsheet with these components. which are required for the synthesis of the compound. The identity of

262 lyric of 1'SRI components defined! in the Building Hlock Catalog module in CliemLib. The Building Block Catalog is a catalog of all reagents. solvents and auxiliaries located in the robotic laboratory. When selecting components for each compound, we also guarantee the quantity of each component used. The amount of each component can be determined by its molarity and by volume (ul) or solid (mg). Therefore. socket in Electronic Spreadsheet means a compound that is identified by its components and the amount of each of these components.

Component synthesis for each compound in Electronic Spreadsheet is defined in the ChemLib WS Sequence module. The WS Define Sequence module defines the stages of synthesis that take place in robotic positions and activities that are performed manually in the robotic position. With this module, we determine the components of the Electronic Spreadsheet and the activity that must be performed with that component in the robotics laboratory. In the Define WS Sequence module, the chemist selects from the list of activities to be performed in the robotic laboratory and arranges them in the order in which they are performed. The ChemLib system takes this set of activities and component data into Electronic Spreadsheet and reformatts these instructions in terminology for use in the robotic position. This robotic terminology is stored in a "sequential" file in a simple server that is associated with the robotic position.

The robotic position represents the synthesis in the apparatus of the reaction block as described above. Each socket in Electronic Spreadsheet is placed and displayed in a specific position in the apparatus of the reaction block of the robotic position. The compound or product, synthesis

263 wounds in the robotic position in the reaction block are then transferred to the collecting flasks.

First, the beakers are charred and then weighed to the robotic position after taking the products from the reaction block. These weights (station and gross) are recorded on the ChemLib system with the Tare / Gross Session module. The Tare / Gross Session module then calculates the yield and final mass of the product or compound.

The receipt of the analyte and screening compound is determined by the Analytical WS Setup module in the ChemLib system. The Analytical WS Setup module determines the dissolution factor for each Electronic Spreadsheet well based on the compound yield and the desired molar concentration. It determines the amount, in uL, that is transferred from the robotic position to a specific microtiter plate (MTP) location for analysis and / or biological analysis. Mass spectrometry and pressure chromatography results for each well were recorded and stored in the ChemLib system.

The Dilute / Archive WS module determines the position of each connection slot by means of an Electronic Spreadsheet hatch to a specific MX location in the continuous storage and archiving unit as part of the registration process.

All links between ChemLib and robot iziranige positions are via ASCII files. These files are located on the ChemLib system server, which is accessible to the robotic positions. The server also contains the results obtained in robotic positions, where the ChemLib system can read these files and save the received data. Each robotic item consists of hardware from Bohdan Automation, Inc. Mundelein, Illinois and PC uploaded Microsoft Windows for Workgroup v3.11 and Ethernet software. The personal computer is connected to

264 unidirectional communication network that allows only access to server files.

General scheme B-4

The skeleton C1 with a primary amino group included in the substituent R ⁴ interacts in parallel in spatially placed vessels of the reaction block with excess electrophiles R ^J -Q, wherein Q is chlorine, bromine or an acidic activating group, including, but not limited to, N hydroxysuccinimide. R ¹ -Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated carboxylic acid esters, activated carbamates and isocyanates. The reaction of Ci with R ¹ -Q is carried out in the presence of a tertiary amine at room temperature in a mixture of a polar aprotic solvent and / or halogenated solvent. As shown in Scheme B-4, the products of general formulas Bi were isolated in purified form by the addition of carbonyl functionalized resin B32, which covalently binds the unreacted skeleton Ci. containing a primary amine as a resin bound adduct B35 and also by the addition of a functionalized primary amine resin B3 which covalently binds any remaining electrophile R ^J -Q to any reaction mixture as a resin bound adduct B34. The BZ3 resin also binds the IIQ by-product of the reaction mixture by transferring a proton from the Base-HQ solution phase. After incubation at room temperature, filtration, washing of the resinous filter residue and concentration of the filtrates, the purified B-1 products are obtained, which are filtered off by the resin-bound adducts B32, B3, B34, B35 and B36.

Scheme B-5 shows the preparation of the desired amine skeleton C-i of the desired products B-i by parallel systemic synthesis. In the parallel systemic synthetic reaction block, the individual psak265

266 cepic products are prepared in each of the reaction vessel vessels in a spatially arranged format. A solution of the desired containing primary amine skeleton Ci (limited amount) in dimethylformamide was added to the reaction vessels, followed by a four-fold stoichiometric excess of a solution of N-methylmorpholine in dimethylformamide. The electrophiles are then added to each reaction vessel: either a two-fold stoichiometric excess when R ^J -Q is acid chloride or alkyl chloroformate, or a 1.5-fold stoichiometric excess when R ^J -Q is sulfonyl chloride, or 1.25-fold stoichiometric excess when R ^J -Q is isocyanate. Excess electrophiles and N-methylmorpholine are required for the faster and / or more complete conversion of the skeleton Ci into products B-0001 to B-0048, compared to reactions that do not use stoichiometric excess electrophiles and N- methylmorpholine. The reaction mixtures were incubated at room temperature for 2-3 hours. With ice, each reaction vessel was charged with a large excess (15-20-fold stoichiometric excess) of functionalized amine resin B3 and functionalized with aldehyde resin B32. The resin-filled reaction block was shaken vertically for 14-20 hours in an orbital shaker at room temperature to achieve optimum stirring of the mixtures in the resin-containing vessels. Excess electrophiles R ^J -Q and unreacted scaffold amine Ci are separated from the reaction medium as insoluble adducts, respectively, B34 and B37. In addition, the N-methylmorpholine hydrochloride formed during the reaction is neutralized to the corresponding free base by a proton transfer reaction of an amine resin functionalized B3. Filtration of the insoluble resin adducts B32, BZ3, B34, B36 and B37, washed with dichloroethane and evaporation of the filtrates gave the desired Bi products in pure state.

267

Scheme B-6 shows a general synthetic method involving a parallel systemic reaction of the C-ii skeleton containing a secondary amino group in the R ¹ substituent. Each reaction vessel was charged with a secondary amine skeleton C-ii, followed by the introduction of a stoichiometric excess of a separate electrophile R ^J -Q into each vessel, where Q is chlorine, bromine or an acid activating group including, but not limited to, N-hydroxysuccinimide. R ¹ -Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated carboxylic acid esters, activated carbamages and isocyanates. The interaction of the C-ii skeleton with R ^J -Q is carried out in the presence of a tertiary amine at room temperature or elevated temperature in a mixture of polar aprotic solvent and / or halogenated solvent. After reconstitution, the reaction is continued until a crude product is obtained in the form of a mixture in each vessel. Products B-ii are isolated in pure state by the addition of isocyanate functionalized resin B38, which covalently binds it to the remaining secondary amine skeleton C-ii as a resin bound adduct B39 and also by the addition of functionalized with primary amine resin B3 , which covalently binds any remaining electrophile R ^J -Q from each reaction vessel as a resin bound adduct B40. The VZ3 resin also binds the HQ by-product in each vessel such as B36 obtained by proton transfer from the Base-HQ solution phase. Incubation with these resins, either simultaneously or sequentially, followed by filtration, washing and concentration of the filtrates, yields the purified B-ii products, which are filtered off by the resin-bound adducts B3, B36, B38, B39 and B40.

Scheme B-7 illustrates the conversion of the secondary amine-containing skeleton C-2 into the desired products B-ii. In a parallel systemic synthetic reaction block, the individual reaction products are obtained in

268 each of the 48 vessels of the reaction block. A solution of the C-2 skeleton (limited amount) in dimethylformamide was added to the reaction vessels. followed by a four-fold stoichiometric excess of a solution of N-methylmorpholine in dimethylformamide. To each reaction vessel was then added electrophilic R ¹ -Q in dichloroethane solution: either a double stoichiometric excess was used when R ¹ -Q was an acid chloride or alkyl chloroformiag, or a 1.5-fold stoichiometric excess when it was. R ^J -Q is sulfonyl chloride, or a 1,25-fold stoichiometric excess, when R ^J -Q is isocyanate. The reaction mixtures were incubated at room temperature for 2-6 hours. Subsequently, each reaction vessel was charged with a large excess (15-20-fold stoichiometric excess) of an amine functionalized resin B3Z and of a functionalized with isocyanate resin B32. Charges! with resin, the reaction block is shaken vertically for 14-20 hours in an orbital shaker at room temperature to achieve optimal stirring of the mixtures in the resin containing vessels. Excess electrophiles R ^J -Q and unreacted scaffold amine C-2 are removed from the reaction medium as the undiluted-soluble adducts, relevant, B40 and B39. The VZ3 resin also binds the HQ by-product in each vessel as B36 prepared by the proton transfer reaction of dissolved Base-HQ. Incubation of these resins, followed by filtration and washing with solvent mixtures of dimethylformamide and / or DCE, results in pure solutions of the products in the collecting bottles, which are filtered by the resin adducts BZ3, B36, B38, B39 and B40. Concentration of the filtrates results in pure B-ii products.

Scheme B-8 illustrates another common synthetic method involving a parallel systemic reaction of the C-ii skeleton containing a secondary amino group in the substituent R ⁴ . Each reaction vessel is charged with a container containing

270 binary amine of C'-ii skeletons. as a result _of introducing a stoichiometric excess of a separate electrophile R ^J -Q into each vessel. The interaction of the scaffold C-n with R ^{, J} -Q is carried out in the presence of a tertiary amine at room temperature or elevated temperature in a mixture of polar aprotic solvent and / or halogenated solvent. Excess electrophiles and N-methylmorpholine is required for the faster and / or more complete conversion of the C-n skeleton into products B-ii, compared to reactions that do not use stoichiometric excess electrophiles and N-methylmorpholine . The reaction mixtures were incubated at room temperature for 2-8 hours. Each reaction vessel is then charged with phenylsulfonyl isocyanate capable of complexing B41. This reagent B41 interacts with the remaining skeleton C-ii, converting C-n into an in situ-produced compound B42. Upon subsequent incubation of mixtures of these with adove with a large excess (15-20 fold stoichiometric excess) of functionalized with amine resin VZZ bind R ^J -Q, HQ, B41, and B42 as the resin-bound adducts. respectively, B40, B36, B44 and B43. The resin-loaded reaction block was shaken vertically for 14-20 hours in an orbital shaker at room temperature to achieve optimum agitation of the mixtures in the resin containing vessels. Filtration of the insoluble resin adducts BZ3, B36, B40, B43 and B44 and subsequent washing of the resin vessel with dimethylformamide and / or DCE results in filtrates containing pure B-ii products. Concentration of the filtrates gave the products B-ii in pure state.

Scheme B-9 shows the method of Scheme B-8 using the C-2 skeleton. A solution of the C-2 skeleton (limited amount) in dimethylformamide was added to the reaction vessels, followed by a four-fold stoichiometric excess of a solution of N-methylmorpholine in dimethyl271

formamide. An electrophile R ^J -Q in dichlorostane solution is then added to each reaction vessel: either a double stoichiometric excess is used when R ^J -Q is acid chloride or alkyl chloroformate, or a 1.5-fold stoichiometric excess when R ^J - Q is sulfonyl chloride. or a 1.25-fold stoichiometric excess when R ^J -Q is isocyanate. The reaction mixtures were incubated at room temp

272

2-6 hours. After reconstitution, reactions continue! to obtain mixtures of the crude product, after which each reaction vessel was charged with a solution in dichloroethane of phenylsulfonylisocyanate. capable of complexing B41. This reagent B41 interacts with the remaining C-2 skeleton, converting C-2 into an in situ prepared compound B45. Subsequent incubation of mixtures of these vessels with high excess (15-20-fold stoichio213

274 metric an excess) of (Yunk! 1i <Una: 1 and h i pa of amine resin VZZ cc bind soluble R ^J -Q, HQ, B41, and B45 as the resin-bound Aluk. Respectively. B40, B36, B44 and B46. The resin-loaded reaction block was shaken vertically for 20 hours in an orbital shaker at room temperature to achieve optimal stirring of the mixtures in the resin-containing vessels.In filtering insoluble resin alloys BZ3, B36, B40, B44 and B46 and further washing the vessel with a resin layer with dimegilformamide and / or dichloroethane yielded filtrates containing Pure B-ii products Concentration of the filtrate results in the B-ii products in pure state.

Another common method for parallel systemic block synthesis is shown in Scheme B-10 for the preparation of a carboxylic acid-containing skeleton C-iii. The free-carboxyl group C-iii skeleton is reacted in spatially parallel vessels of a reaction block with an excess of possibly different bovine or secondary amines B47 in the presence of a polymer-bound carbodiimide reagent B48 and a tertiary amine base in a mixture of polar aprotic solvent and / or halogenated solvent. After filtering the mixture of crude products from each separating vessel from resins B48 and B49. each reaction mixture is purified by treatment is a reagent capable of complexing B50 (GFA). The B50 reagent reacts with the remaining excess of amine B47 to obtain in situ B51 intermediates that contain carboxylic acid functionality. Further incubation of each reaction mixture with a 15-20-fold stoichiometric excess of functionalized with primary amine resin BZ3 produced B51, B52 and the remaining acid skeleton C-iii. as resin-bound adducts. respectively. B52, B53 and B54. By filtering the soluble product and B-iii from these resin-related adducts and flushing the resin layer with the fields

275 Aprotoic solvent and / or halogenated solvent, filtrates were obtained containing pure B-iii products. Concentration of the filtrates gave the B-iii products in pure state.

Scheme B-11 shows the conversion of the acid-containing skeleton C-49 to the desired amide products B-iii in parallel synthesis. An amount of C-49 was added in the form of a solution in dimegilformamide in each reaction vessel. containing polymer-bound carbodiimide reagent B48 (five-fold stoichiometric excess). To this suspension was added a solution of pyridine (four-fold stoichiometric excess) in dichloromethane, followed by the addition of an excess amount of a solution of single amine B47 in dimethylformamide (1.5-fold stoichiometric excess) in each vessel. The parallel reaction block was then stirred vertically on an orbital shaker for 16-1 8 hours at room temperature and filtered to separate the product mixture in solution from the resin-bound reagent B48 and the resin-bound by-product of reagent B49. The resulting solutions (filtrates) containing a mixture of the desired amide products B-iii. excess of amines B47 and unreacted acid-containing skeleton C-49 are treated with tetrafluoroftal anhydride B50. B50 converts the excess amines B47 from the filtrate into each vessel into their corresponding B51 half-acids. After 2 hours of incubation time, an excess of amine functionalized resin B3 3 and dichloromethane as solvent was added to each reaction vessel. The amine-containing resin BZ3 converts B51. each remaining B50 and each remaining C-49 in their resin-containing adducts, respectively. B52, B53 and B55. The resin-loaded reaction block was shaken vertically on an orbital shaker for 16 hours at room temperature to achieve optimal stirring of the resin-containing mixture in the reaction vessel. Filtration of insoluble resins

276

Scheme B-11

C-49 (remaining) / X

Q55

277 alkhti 1H, B52. B53 and B55 and the subsequent washing of the resin layer in a dimethylformamide vessel were filtered off. containing pure B-iii products. Concentration of the filtrates gave the B-iii products in pure state.

Although Schemes B-Ι to B-11 illustrate the use of concurrent systemic chemical technology for the preparation of compounds, the general formulas B-i, B-ii and B-iii. it is noted that those skilled in the art of classical synthetic organic chemistry can obtain Bi, B-ii and B-iii by conventional methods (the compound is obtained in a glass vessel; and for a certain time, it is purified by conventional means, such as chromatography and / or crystallization).

The synthesis of the pyridylpyrazole skeletons C-i, C-ii and C-iii is shown in Scheme C-1.

Step A: Picolin is treated with a base selected from, but without limitation. p-Butyl Illithium (n-BuLi). lithium diisopropylamide (IJ) A), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide (tBuOK) or sodium hydride (Nall) in an organic solvent such as tetrahydrofuran. diethyl ether. 1-butylmethyl ether, t-BuOH or dioxane from -78 ° C to 50 ° C for 10 minutes to 3 hours. Then, to the solution of ester B56 is added a solution of megalithic picoline. The reaction mixture was allowed to stir for 30 minutes to 48 hours, during which time the temperature could range from -20 ° C to 120 ° C. The mixture was then poured into water and extracted with an organic solvent. After drying and removal of the solvent, pyridyl mono-ketone B57 is isolated as a crude solid which can be purified by crystallization and or chromatography.

278 l-Butyl alcohol or dioxane is added to a base selected from, but not limited to, n-butyllithium (n-BuLi) or seam diisopronylamide (LDA). lithium hexamegildisilazide (LiHMDS), potassium t-oxide (tBuOK) or sodium hydride; (NaH) in hexane. tetrahydrofuran. diethyl ether, t-butylmethyl ether or t-BuOH from -78 ° C to 50 ° C for 10 minutes to 3 hours. A suitably substituted activated ester or acid halide derived from R ⁴ -CO ₂ H. after cooking is added in the form of a solution in tetrahydrofuran. diethyl ether or dioxane to the B57 anion monoketone. while the gauge gum is maintained between -50 ° C and 50 ° C. The resulting mixture was stirred at a specified temperature for 5 minutes to 3 hours. The resulting intermediate pyridyldiketone B58 was used in Step B without further purification.

Step B: A solution containing pyridyldiketone B58 is fixed with water and the pH is adjusted between 4 and 8 using an inorganic or organic acid selected from acetic, sulfuric, hydrochloric or nitric acid. The temperature is maintained between -20 ° C and room temperature during the step. Hydrazine or hydrazium hydrate is then added to the mixture while maintaining the temperature between -20 ° C and 40 ° C for 30 minutes to 3 hours. The mixture was then poured into water and extracted with an organic solvent. The pyridylpyrazole C-i or C-ii is obtained as a crude solid, which is purified by chromium or crystallization.

Step D: In some cases has piridilpirazolat Ci or C-ii is alkylated with (FS (E ^A) - (CII _{2) n} SS) 2 alkyl. where Q is halogen. Ci or C-ii is treated with a base selected from sodium hydride, sodium ethylate, potassium t-butylate or ΝΕΐ ₃ in an organic solvent such as tetrahydrofuran. methylene chloride. dioxane or dimethylformamide at temperatures between -20 ° C and 150 ° C for 30 minutes to 12 hours, the resulting alkylated pyrid and l

The pyrazole ester is then hydrolyzed to acid by treatment with sodium or lithium hydroxide in a solvent mixture of water, alcohol, or heterohydrofuran / water. Or. The ester functionality is eliminated by treatment with organic or inorganic acid if the alkyl residue is t-butyl. Acidification, followed by extraction with an organic solvent, yields C-iii, which can be purified by purification by chromatography or crystallography. In some cases, regioisomeric alkylated C-iv products are also obtained. The desired C-iii can be separated from C-iv by chromatographic purification or fractional crystallization.

The synthesis of pyridylpyrazole skeletons C-1 is shown in Scheme C-2.

Step A: Picolin was added to a solution of lithium hexamethyldisilazide in tetrahydrofuran at room temperature for 30 minutes to 1 hour. The resulting solution was stirred for a further 30 minutes to 1 hour at room temperature. This solution was then added to pure ethyl p-fluorobenzoate B60 at room temperature for 1-2 hours. The reaction mixture was then allowed to stir at room temperature for 16-24 hours. Equal amounts of water and ethacene were then added to the reaction mixture and the mixture separated in an extraction funnel. The organic layer was dried, filtered and evaporated to give an oily solid. Hexanes are then added and the solid is filtered and washed with cold hexanes to give pyridyl monoketone B61 for use in Et aB.

Step B: The pyridyl monoketone B61 is placed as a solution in tetrahydrofuran in a flask at room temperature, which contains IBOC in a mixture or solvents of tegrahydrofuran / t-BuOK. Yellow280 is obtained

Scheme C-l

Stage A o

Q56

StageB

1) Base

2) XCOR ⁴

Stage B

this precipitate and stirring at room temperature continued for 1-3 hours. After this time, N-Cbz-protected glycine N-hydroxysuccinimide B62 was added dropwise at room temperature as a solution in tegrahydrofuran for 1-3 hours. This solution containing crude diketone B63 is used directly in Step B.

Step B: The solution from Step B is treated with water and the pH is adjusted to between 6 and 7 with acetic acid. Hydrazine hydrate is then added dropwise to the mixture as a solution in water for 30 hours.

281 minutes lOh at room temp. Water and ethyl acetate were then added to the flask and the mixture separated into a separatory funnel. The organic layer was dried, filtered and evaporated to give an oil which was purified by chromatography over silica gel to give pure C-ICbz.

282

Etan D: Cbz protecting group. found in compound C1 Cbz. is cleaved by hydrogen gas under pressure and palladium on charcoal in methanol. The amine C-1 is obtained after filtration and concentration.

A number of pyridylpyrazole skeletons of gina C-v were prepared as shown in Scheme C-3.

Step A: Picolin is treated with a base selected from, but not limited to, n-butyllithium (n-BuLi), lithium diisopropylamide (LDA). lithium hexamegyldisilazide (LiHMDS), potassium t-butoxide (tBuOK) or sodium hydride (Nall) in an organic solvent such as tetrahydrofuran, diethyl ether, t-butylmethyl ether, t-BuOH or dioxane from -78 ° C to 50 ° C from 10 minutes to 3 hours. The solution of megalised picoline is then added to a solution of a suitably activated carboxylic acid ester analog of CbzNR ^H - (CH2) nCR ^f '(R ^Cl ) -CO2H or BocNR ^H - (CH2) n. CR ^b ( ^RG ) -CO2H, preferably, but not limited to, hydroxysuccinimide B64. The reaction mixture was left stirring for 30 minutes to 48 hours, during which time temperature a could range from -20 ° C to 120 ° C. The mixture was then poured into water and extracted with an organic solvent. After drying and removing the solvent. Pyridyl monoketone B65 is isolated as a crude solid which can be purified by crystallization and / or chromatography.

Step B: Solution of pyridyl monoketone B65 in eger, tetrahydrofuran. t-butyl alcohol or dioxane is added to a base selected from, but not limited to, n-butyl lithium (n-BuLi), lithium diisopropylamide (LDA). lithium hexamegildysilazide (LiHMDS). potassium t-butoxide (tBuOK) or sodium hydride (Nall) in hexane. tetrahydrofuran, diethyl ether, t-butyl283

Scheme C-3

Stage A

And Base

Step ¹ > Base

° B66

Boc or Cbz

284 methyl ether or t-ΒιιΟΙΊ from -78'C to 50C for 10 minutes to 3 hours. Sometimes the anion precipitates as a yellow solid. A suitably substituted activated ester such as N-hydroxylsuccinimide is then added in the form of a solution of ft tetrahydrofuran. diethyl ether or dioxane to the monocetone anion. as long as the temperature is maintained between -50 ° C and 50 ° C. The resulting mixture was stirred at a specified temperature for 5 minutes to 3 hours. The resultant intermediate was pyridyldigone B67 cc used in Step B without further purification.

Step B: A solution containing pyridyldiconegone B67 is fixed with water and the pH is adjusted to between 4 and 8 using an inorganic or organic acid selected from acetic, sulfuric, hydrochloric or nitric acid. The temperature is maintained between -20 ° C and room gempsugura during the step. Hydrazine or hydrazine hydrate is then added to the mixture. while maintaining the temperature between -20 ° C and 40 ° C for 30 minutes to 3 hours. The mixture was then poured into water and extracted with organic solvents. The pyridylpyrazole C-vBoc or C-vCbz was obtained as a crude solid, which was purified by chromatography or crystallization.

Step E: Carbamide protecting carcasses of C-vBoc or C-vCbz are further added to form 1 skeleton (s) containing either a free primary amine (R ^H is hydrogen) or a free secondary amine (R ^H is not hydrogen The carbamate protecting groups are cleaved using I: i glyfluorocept acid methylene chloride at room temperature for several hours Cbz the protecting carbamate groups are cleaved using hydrogen gas under pressure and palladium on charcoal in an alcoholic solvent. it is possible to crystallize or and be purified by .hromatografiya.

285

E1 an L: Boc protected pyridylpyrazole B68 is treated with oenzaltehide in methylene chloride at room temperature in the presence of dry conditions for 1 to 24 hours. The solvent was then evaporated and the resulting amine B69 was used in Step b3 further further.

Step B: The iridylpyrazolimine B69 was dissolved in icipaxyl chloride and stirred under nitrogen at temperatures between -78 ° C and -2 (GS. A base such as n-butyllithium (n-BuLi), lithium diisotronylamide (L) was added dropwise. or lithium hexamethyldisilazide (IJIMDS) and the mixture was stirred for at least 10 minutes to 3 hours, 2-5 equivalents of the alkylating agent R ^h -Q were then added to the mixture and stirring continued for several hours. quench is acid and allow to warm to room temperature and stir for several hours until the cleavage of Boc is complete and the imine tresses are adjusted to pH 12 and the mixture is extracted with an organic solvent which is dried and evaporated, then the crude pyridylpyridol is crystallized and chromatographed to give C-vi.

Scheme C -?> Shows the synthesis of maleimide-containing skeletons C-vii:

Maleimidpyrazole skeletons C-vii are synthesized; as is the C-5 floorboard. The condensation reaction of primary amine 1 IJM-R with maleic anhydride B70 which is substituted at position 3 by a bromine, chlorine or triflate group yields compound B71. Thereafter, the learned malimide derivative B71 is reacted with the acheophenone B72 derivative in the presence of a NaD (O) catalyst and base until the overnight preparation of Compound B73. The methyl position of B73 is then triturated with acid anhydride B74 or activated acid ester B75.

286

287 to obtain a dikegop B76 derivative. The D76 is condensed

Scheme C-6 illustrates the synthesis of a maleimidnirazole skeleton (-63. In which R ⁴ is hydrogen. Synthesis starts a condensation reaction of bromomaleic anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride to give intermediate. B78 The maleimide B78 is then treated with 4'-fluorocystophenone in the presence of a catalytic amount of Pd ₂ (dba) ₃ and sodium t-butoxide to give fluoroacetophenone substituted maleimide B79. B79 is treated with tert-butoxybisane (dimethylamino) dimethylamine to obtain α-xgonamine B80. α-Ketonamine B80 condensed with the hydrazine to give the maleimide pyrazole skeleton B81. The protecting 2,4-dimethoxybenzyl carcass can be removed with cerium-amopium nitrate (CAN) to give compound C-63.

288

Scheme C-7 illustrates the synthesis of maleimide-containing skeletons C-64 and C-65. The corresponding C-49 and C-50 skeletons were synthesized according to the methods illustrated in Scheme C-5 and used the N-hydroxysuccinimides B82 and B-83 to obtain maleimide-containing schrazoles, respectively, B86 and B87. With the possible removal of the 2,4-dimethoxybenzyl group is a cerium-ammonium moiety and subsequent removal of the trifluoroacetic acid protecting groups, the C-64 and C-65 skeletons are obtained.

289

Below, more fully described various functionalized resins and complexing agents used to prepare and purify parallel reaction mixtures using commercial sources or literature to obtain them.

functionalized with 4-benzyloxybenz · aldehyde polystyrene

Novabiochem cat. # 01-64-0182

OZZ

Obtained as described in D.L.Flyim et al., J. Am. Chem. Soc. (1997) 119, 4874-4881.

B38 O-A Functionalized with methylisocyanate N - C = O polystyrene Novabiochem cat. # 01-64-0169

B48

B41

Polymer-bound EDC prepared as described in MS Desai et al., Tetrahedron Letters (1993) 34. 7685.

Benzenesulfonyl isocyanate supplied by

Aldrich Chemical Company, cat. # 23,229-7

B50

F

F

Oh

Tetrafluoroftalic anhydride supplied by Aldrich Chemical Company, cat. # 33,901-6

290 ί photocopy. and · »me» n sa ya'a u-.n-i ong on sept amidz. carbamate urea and su. typhoons w from B-1HY1 to B-H048 from the skeleton (1

Examples B 0001 to B-0048

200 µl were added to each reaction vessel (polypropylene syringes, foam flange, closed at the bottom) of the parallel reaction apparatus. dimethylformamide. Stock solution of scaffold gene amine <-1 in dimethylformamide (0.1 M, 500 µL) was added to each reaction vessel. followed by the addition of a stock solution of N-megilmorph · dimethylformamide (1.0 M. 200 ul.). A stock solution of each electrophile was then added to the respective reaction vessels: a) 500 µl. p? VI acid chloride solution in dichloroethane or b) 500 µl. 0.2 M solution of dichloroethane in dichloroethane or c) 313 µL 0.2 M solution of dichloroethane drunk and d) 375 µL 0.2 M solution of dichloroethane sulfonic chloride. The parallel reaction apparatus was then shaken non-circularly (Labline Benchtop orbital shaker) at 200 RPM at room temperature (23-30 ° C) for 2-3 hours in a low flow >> m azo !. During this time, each reaction vessel was treated with approximately 2 × 0 mg B3.3 polyamine resin (4.0 meq N g resin) and approximately 100 mg B32 iolialdehyde resin (2.0 mmol g resin). Each reaction vessel was diluted with 1 ml of dimethylformamide and 1 ml of dichloroethane and shaking was continued at 200 RPM for 14-20 hours at room temperature. Each reaction vessel is then opened and the desired products from the solution phase are separated from the insoluble ie oranite products by filtration and collection into separate conical bottles. Each is washed with two ml of dichloroethane (1 ml). and washing water

291 are also collected. The resulting solutions were then evaporated to dryness in a Savaiit apparatus (ml. Centrifuge. Equipped with a vacuum vacuum device.

for measuring temperature ' era and solvent tap for condensation of volatile solution money? crushed amides, carbamates, urea-

you and cva <b <. 'find then they are weighed and characterized. The product and product analytics are obtained by the method shown below.

Example % Yield Calc. Obs. - * + vols MS MS

(M + H)

B-0001 I 85 397 398  I Il I B-0002 94 412 413 Mr. OC r-TO B-0003 91 340 341 and ^F ~ CH  0 i B-0004 79 368 369 and ^F ~ CH B-0005 92 498 499 J ____I

292

Est.

Нал.

Example

293

Example '' Home Naol.

_: * MS MS

294

Example% Add Calc. Obs.

- 'MS MS

295

Example ^of Extraction Calc.

XIS

Obs.

MS (\ '!!)

296

In analogy to the method shown above for the preparation of Examples B-0001 to B-0048, Examples B-0049 to B-157.V are obtained.

297

298

299

300

301

B-0096 410 411 r ~ CH ^: is cf ^ i h ^ o I I Ο: B-0097 and ^F <H 0 '· | : (ο i li 14 486 487 B-0098 • -LQ— ί - n 8 465 - B-0099 -Sch o / \ j, o I! 75 464 465 B-0100 -He c / / H i ο I 72 388 389 B-0101 23 408 409 o 0 B-0102 : UN μκο ⁰ 37 487 488 in-union Mr • -nf 11 492 493

302

303

304

305

306

307

308

309

310

311

312

B-0200 78 373 374 B-0201 I I V-r! 0 I 95 352 353 'B-0202 -it | L ° ^: 0 100 416 417 B-0203 ! ^F <H <rVi Bh: 0 69 354 355 B-0204 '<n N / I 93 340 341 B-0205 S L 0 94 354 355 B-0206 to I I \\ N 0 | 79 424 425 B-0207 ! 'OC m 82 326 327 B-0208 --CH ι 88 378 379 B-0209 and ^F <H - <h O i 83 362 363

313

B-0210 100 364 365 ! ^F Oi hv ^CF1 ! 0 £ 3-0211 60 325 326 | <I. 5 w '>. nh; X j o / 1 B-0212 'Och Oh, oh 79 339 340 B-0213 71 353 354 $ / X. ^{ΝΗ ΝΗ} 0 B-0214 77 311 312 0 B-0215 24 353 354 > 1 4Ί ο! B-0216 339 340 / Oi Hr 0 ί B-0217 F ¹ 0: 381 382 B-0218 365 366 >, o B-0219 ⁰ ; Ύ 401 402

314

315

316

317

318

319

320

321

322

323

324

B-0312

B-0313

B-0314

B-0315

B-0316

B-0317

B-0318

B-0319

B-0320

B-0321

342

356

370

384

368

366

388

424

424

442

343

357

325

326

327

328

/

329

330

331

332 at

333

334

335

B-0412 IS Η I  0 91 365 366 _ B-0413 K ^H ο I 79 367 368 B-0414 85 429 430 B-0415 khz 82 401 402 B-0416 ¹ b ¹ 93 429 430 B-0417 • Όη ^ γ = γθ 97 429 430 B-0418 ι · ^ utd * t 1 100 419 420 B-0419 1 100 431 432 B-0420 'ΤΊ 36 381 382 B-0421 l ^F <H hrk 96 353 354

336

B-0422 ⁰ \ 100 461 462 B-0423 and 100 406 407 B-0424 n ~ n 0 76 366 367 * B-0425 21 368 369 B-0426 I 100 354 355 B-0427 100 379 380 '-See ΗΝ --- \ PM 0 B-0428 100 379 380 B-0429 86 368 369 km

337

338

339

340

341

342

343

B-0487 > II with ίΐ \ | ο! 32 389 390 B-0488 100 568 569 B-0489 / - = - 0: 91 500 501 B-0490 HS ~ ΧΖ! 0 I 40 473 474 B-0491 Η-0Ί 73 514 515

344 ./

345

346

347

348

349

350

351

352

In

353

354

355

356

357

In

358

359

360

361

362

363

B-0664 > II / N 30 389 390 B-0665 V 100 568 569 B-0666 BAT Fr. 93 500 501 B-0667 Ηι ~ νΙζ —___ 2_______ 1 54 473 474 B-0668 ° ^ / m_ / ~ Oh Hi 1 66 514 515

364

365

366

367

368

369

370

371

372

373

374

375

376

B-0779 0 79 441 442 B-0780 fc H hr ^ 40 443 444 B-0781 CL..X) 93 505 506 B-0782 kX) 57 477 478 B-0783 Ό 'Uh 99 505 506 B-0784 IZ Jx ° 100 505 506 B-0785 and ^F OH ' ^Ύ 'ν> e 92 495 496 B-0786 91 507 508 B-0787 1'0-? ' 15 457 458 B-0788 Bh 0 48 429 430

377

B-0789 ^{0 about 7} \ 91 537 538 B-0790 ^if ^ ZH ^! T1) 93 482 483 B-0791 -OH SrV Fr. 76 442 443 B-0792 96 444 445 B-0793 -He 0 54 430 431 B-0794 100 455 456 0 I / AW B-0795 -O-S ' ¹ 0 100 455 456 B-0796 94 444 445 ^F - ^ ZH ' i ! 0

378

379

380

381

B-0824 OU-1. 0 82 492 493 B-0825 ί ,, ΧΝ 5 = i 100 506 507 B-0826 97 45S 459 B-0827 100 659 660 B-0828 • ^fh Ch • You Όι 97 514 515

382

B-0829 • T. 63 458 459 -He B-830 70 588 589 B-0831 100 428 429 We are B-0832 81 480 48.1 ^fh CH B-0833 about ---- 0 73 442 443 B-0834 p V 79 486 487 0 B-0835 to 5 400 401

383

384

385

B-0856 Όο 0 75 492 493 B-0857 86 506 507 B-0858 84 458 459 -Sch ί _ / _! b-k B-0859 - Vol 80 659 650 B-0860 94 5 1 · '. I

386

NHCH ₃

B-0861 -He Ηθ 0 84 583 584 B-0862 He is 0 96 475 476 B-0863 -He 69 423 424 B-0864 ? 0 86 437 438 B-0865 - He l · / o; 62 395 - B-0866 HE hr- Fr. 81 421 42'2 B-0867 -He ο I 100 535 536

387

388

389

NHCH ₃

B-0885 _v o ο 51 583 - B-0886 97 475 - '-Ch B-0887 0 29 423 424 B-0888 82 437 438 B-0889 Γ-Ύ • ________ 0 ' 93 395 396 -H2h B-0890 || 91 421 422 ^{! fh} O ~ 0 B-0891 XX 0 43 535 536 ιΗΖΜ

390

391

B-0902 Bn ο 1 93 431 432 B-0903 cheat 100 511 512 B-0904 0 95 410 411 B-0905 ^if 4ZH 89 490 491 B-0906 'YU cu 69 500 501 B-0907 < . NH 1— < 28 424 425 B-0908 | Η ^ ^Ζ loo I \ 64 532 533

392

393

394

395

N— NH

396

397

398

399

B-0970 That I 38 461 462 B-0971 -He ^c,? \ c / i 95 469 470 B-0972 -He V-Mr 98 479 480 B-0973 n2n eV '' 96 485 486 B-0974 —He ^K 4j- / 74 443 444 B-0975 -He VyS 100 495 496 B-0976 ΗΛΟ c 70 453 454 B-0977 ^iFH O4 Ί> ii ^ A. SW ^: 100 467 468 B-0978 <3 91 431 432 B-0979 : _ς \. i. 54 491 492

400

401

402

403

404

405

406

407

408

409

410

411

412

413 ·

414

415

416

417

418

419

420

421

422

B-1185 / o 90 430 431 B-1186 Fr. 86 444 445 B-1187 V-X. 74 396 397 ΎΗ B-1188 HS: 76 597 598 • Ό-1 B-1189 60 452 453 '- (Ή

423

424

425

426

427

428

B-1235 -He 1 h 1 II 0 50 514 515 B-1236 0 ο 100 493 494 B-1237 Όη Ο \ Χγ \ ^ζ ° 91 514 515 B-1238 V '° 100 470 471 B-1239 ⁰ V4 ^! :> And! / \: 0 / ' 71 510 511 B-1240 -He 04 27 510 511 B-1241 'Oh? ¹ HO with ^CI 1 73 520

429

430

431

B-1262 97 496 497 B-1263 Mb! D - 100 504 505 B-1264 Me ο I 100 504 505 B-1265 0, _____, I l Hmmm 0 100 464 i I 465 I B-1266 C ___ / 1-Yu 79 466 451 B-1267 -M 100 470 471 B-1268 -Sch op □ 87 470 i 471 B-1269 CH-R Ci * 100 504 505 B-1270 Q 100 504 505 B-1271 Όη eM 56 488 489

432

433

B-1282 • -CH h-oh 100 478 479 B-1283 n-h Cl 58 500 501 B-1284 ¹ v £ T 0 58 461 462 B-1285 65 575 576 HH-fZ B-1286 87 512 513 0 B-1287 79 562 563 '-CH «Uh B-1288 ~ SN 100 519 520

B-1289 ^p -CH ^! ~ HcX. _z 'O i 77 582 583 B-1290 ^PH CH 100 509 510 B-1291 ^p H = H J o L 91 440 4 * 11

434

B-1292 35 403 404 \ II / I II V Fr. B-1293 IL / 1 O '! ° / ^h °! 73 582 583 B-1294 ./ I 49 514 515 B-1295 ρ \ ΧΧι W | ⁰ Art 48 487 - B-1296 HTO.J 76 528 529

435

436

437

B-1314 A ' 69 444 445 -He B-1315 And ι = Oh 57 450 451 hon B-1316 75 393 394 • He r \ ^: n B-1317 -W .: 100 461 462 B-1318 «RO μυο; 31 450 451 B-1319 P- \ 23 464 465 HE B-1320 In · 59 512 513 '--04

438

439

440

441

442

443

444

445

B-1383 46 416 417 Vo 0 B-1384 56 432 433 Vo 0 B-1385 59 426 427 -Sch V 0 B-1386 50 427 428 VO o B-1387 12 427 428 ^F Oi VC! 0 B-1388 66 504 505 'So- ⁸ ' · 0 B-1389 48 460 461 and ^f 4Dh o I

446

ΑΑΊ

448

B-1410 42 512 513 X ' B-1411 X I about; 19 462 463 B-1412 74 462 463 'X X Fr. B-1413 X And oh 75 494 495 B-1414 X 0 68 462 463 -X B-1415 ^ x. 0 48 462 463 B-1416 48 494 495 X ι ο I GC B-1417 57 494 495 'X ; Χ ! 0 i B-1418 Cl X 0 49 494 495 x ^ B-1419 X » o 39 494 495

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

The following Table shows the proton NMR spectra of selected compounds according to Examples B-0001 to B-1573.

Plate ID 1H NMR (solvent). d ppm B-0120 (DMF-d7) d 8.53 (bd, J = 4.99Hz, 2H). 7.44-7.24 (m, 11H), 4.41 (s, 2H), 4.31 (br, 2H) B-0224 (DMF-d7) d 8.56 (bd, J = 4.98Hz. 2H), 7.78-7.69 (m, 4H), 7.39-7.19 (m, 6H), 4.23 (br, 2H) B-0235 (DMF-d7) d 8.47 (br, 2H), 7.91-7.75 (m, 3H), 7.57-7.53 (m, 1H), 7.38-7.34 (m, 2H), 7.21-7.13 (m, 4H), 4.20 (br, 2H) B-0244 (CDCI3 / CD3OD) d 8.38 (d. J = 5.38 Hz, 1H), 7.62-7.32 (m, 9H), 7.04-6.95 (m, 4H), 6.86-6.80 (m, 2H), 4.52 (q. J = 6.96 Hz. 1H), 1.40 (d, J = 6.88 Hz. 3H). B-0256 (DMF-d7) d 8.45 (bd, J = 2.85, 2H), 7.87 (br s, 4H), 7.76-7.75 (m, 2H), 7.53- 7.33 (01.5H), 7.18-7.13 (No, 4H) B-0426 (DMF-d7), 1.32 (br, 3H), 1.67 (br, 3H), 4.17 (br, 2H), 5.12 (br, 1H), 7.50 (m. 6H), 8.77 (01, 2H), 13.54 ( No. 1H). B-0438 (DMSO), 1.14 (t, J = 6.9 Hz, 3H), 4.54 (m, 1H). 6.99 (br, 2H), 7.21 (br, 4H), 7.45 (s. 1H), 7.61 (q. J = 8.7 Hz, 2H), 8.52 (d. J = 5.2 Hz, 2H). B-0466 (DMF-d7), 1.61 (brd, J = 30.6 Hz, 3H), 4.61 (br, 1H), 7.25 (m, 6H), 7.65 (m, 3H), 8.59 (br, 2H) (13.34 (br. J = 34.8 Hz, 1H). B-0473 (CD3OD), 1.53 (d, J = 7.2 Hz, 3H), 4.59 (q, J = 7.2 Hz, 1H), 6.88 (d, J = 4 Hz. 1H), 7.09 (m, 3H), 7.15 (dd, J = 4.4, 1.6 Hz, 2H), 7.26 (m, 2H), 8.46 (d. J = 6.0 Hz, 2H). B-0477 (DMF), 1.80 (br, 3H), 2.35 (s, 1H), 4.98 (br, 1H), 7.38 (m, 6H), 7.85 (m, 2H). 8.45 (br, 1H). 8.75 (d, J = 6.0 Hz, 2H). B-0479 (Methanol-d4), 1.57 (d, J = 5.6 Hz, 3H), 4.74 (br, 1H), 7.23 (m, 4H), 7.60 (m, 2H). 7.81 (m. 4H), 8.67 (br, 2H). B-0487 (DMF), 1.78 (S. 3H), 2.76 (br, 6H), 4.85 (br, 1H), 7.42 (br, 2H), 7.54 (br, 2H), 7.66 (br. 3H), 8.82 (s. 2H). B-0566 (CD3OD), 1.38 (d, J = 7.2 Hz, 3H), 4.15 (br, 2H), 4.50 (br, 1H), 7.04 (br, 2H). 7.18 (no. 2H), 7.30 (m. 7H). 8.45 (m, 2H). B-0569 (CD3OD), 1.56 (br, 3H), 4.66 (q, J = 6.7 Hz, 1H), 7.l7 (m, 8H), 7.56 (πι. 2H). 8.47 (s, 2H). B-0574 (Methanol-d4), 1.49 (br, 3H), 3.86 (br, 3H), 4.60 (br, 1H), 6.92 (br, 2H), 7.19'br. 2H), 7.31 (No. 2H). 7.76 (01.4H). 8.60 (br, 2H). B-0639 (DMF-d7), 1.58 (brd, J = 30.0 Hz, 3H). 4.62 (br, 1H), 7.25 (m, 6H). 7.60 (m, 4H), 8.59 (br, 2H), 13.30 (br, J = 12.3 Hz). B-0643 7.18 (01, 2H), 7.32 (dd, J = 6.0, 4.4 Hz, 1H), 7.70 (bd, J = 9.0, 5.8Hz. 1H). 8.43 (dd, J = 4.8, 3.2 Hz, 2H). B-0650 (CD3OD), 1.58 (br, 3H), 4.62 (q, J = 6.6 Hz, 1H), 6.93 (br, 1H), 7.17 (m, 5H). 7.31 (br, 2H), 8.51 (br. 2H). B-0656 (CDCI3 / CD3OD) d 8.48 (d, J = 5.30 Hz, 2H), 7.72-7.59 (m, 4H), 7.14-7.l0 (m, 2H), 7.03-6.97 (m, 4H). 4.60 (q. J = 7.57Hz. 1H), 1.43 (d, J = 7.26Hz, 3H) B-0663 (CD3OD), 1.52 (d, J = 6.8 Hz, 3H), 3.75 (s, 3H), 7.21 (m, 2H), 7.42 (m, 2H). 7.57 (s, 1H), 7.76 (s, 1H), 7.98 (br, 2H). 8.76 (br, 2H). B-1165 Hz, 2H), 3.06 (m, 1H), 3.43 (q, J = 6.1 Hz, 2H). 7.02 (m, 2H). 7.14 (m, 2H), 7.41 (m, 2H), 8.59 (d. J = 5.6 Hz, 2H). B-1169 = 1.6 Hz, 1H), 7.04 (1, J = 8.6 Hz, 2H), 7.14 (m, 2H), 7.36 (m, 2H), 8.39 (d. J = 1.8 Hz, 1H). 8.60 (m, 2H). B-1171 6.83 (br, 1H), 7.02 (1, J = 8.7 Hz, 2H), 7.15 (d, J = 5.6 Hz, 2H), 7.40 (m, 2H), 8.59 (d, J = 5.0 Hz, 2H).

466

Plate ID 1H NMR (solvent), d ppm B-1179 (CDCl3), 1.94 (br, 2H), 2.53 (s, 3H). 2.85 (1 J = 6.2 Hz. 2H), 3.65 (br, 2H), 6.15 (br, 1H), 7.04 (m, 3H). 7.22 (m, 3H), 7.41 (br, 4H). 8.60 (No. 2H). B-1183 (CDCI3), 2.00 (br, 2H), 2.85 (br, 2H), 3.64 (br. 2H), 7.03 (br, 3H), 7.17 (br, 2H), 7.36 (br, 2H), 7.66 (br. 2H). 8.60 (br, 2H), 8.77 (br, 2H). B-1194 (DMSO), 1.76 (br, 2H), 2.66 (br, 2H), 2.91 (br, 2H), 4.30 (s, 2H), 7.18 (br, 5H), 7.35 (m, 6H), 8.54 (d. J = 5.8 Hz, 2H). B-1200 (DMSO), 1.17 (br, 3H), 1.76 (br, 2H), 2.71 (br. 2H), 2.97 (br, 4H), 7.18 (br, 4H), 7.36 (br. 2H), 8.54 ( br, 2H). B-1206 (DMSO), 1.03 (s, 6H), 1.68 (br, 2H), 2.63 (br, 2H), 3.00 (br, 2H), 3.65 (br, 1H), 5.69 (m, 2H). 7.16 (No, 4H), 7.35 (No, 2H). 8.54 (br, 2H). B-1216 (DMSO), 1.75 (m, 2H), 2.14 (s, 6H), 2.66 (br, 2H). 3.10 (br, 2H), 7.04 (br, 3H), 7.18 (br, 4H), 7.35 (m, 2H), 7.47 (br, 1H). 8.54 (d, J = 4.8 Hz, 2H). B-1226 (DMF), 1.25 (br, 3H), 2.01 (br, 2H), 3.35 (br, 4H), 6.20 (s, 1H), 6.30 (s, 1H). 7.42 (br, 4H); 7.65 (br. 2H). 8.77 (s, 2H). B-1360 (DMSO-d6), 1.80 (br, 4H), 2.82 (br, 1H), 2.94 (br, 1H), 3.10 (br, 1H), 3.60 (br, 1H), 4.54 (br, 1H), 7.18 ( m. 4H). 7.30 (m, 4H), 7.46 (m, 2H), 8.54 (No. 2H). B-1361 (DMSO-d6), 0.99 (br, 6H), 1.73 (br, 4H), 2.89 (br, 2H), 3.03 (m, 1H), 4.04 (br, 2H), 4.44 (m, 1H), 7.18 ( m. 4H), 7.30 (m. 2H), 8.57 (d, J = 4.64 Hz, 2H). B-1363 (DMSO-d6), 1.78 (br, 4H), 2.01 (s, 3H), 2.89 (br, 1H). 3.05 (br, 1H), 3.34 (br, 1H), 3.85 (br, 1H), 4.48 (br, 1H), 7.12 (br. 2H), 7.21 (br. 2H), 7.30 (br. 2H). 8.69 (br, 2H). B-1364. (CDCl3), 0.78 (dd, J = 3.0, 2.9 Hz, 2H), 1.00 (s, 2H), 1.78 (m, 1H), 1.86 (b, 4H), 2.64 (m, 1H) ), 2.99 (m, 1H), 3.16 (m. 1H), 4.33 (br, 1H), 4.70 (br, 1H), 6.99 (m, 2H), 7.14 (s, 2H), 7.29 (m, 2H) , 8.64 (s, 2H). B-1368 (CDCl3), 1.89 (s, 4H), 2.65 (m, 1H), 2.96 (m, 1H), 3.06 (m, 1H), 3.43 (s, 3H). 3.93 (d, J = 13.2 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1H), 4.18 (d, J = 13.5 Hz, 1H), 4.68 (d. J = 12.4 Hz. 1 H). 7.60 (m, 2H). 7.12 (s, 2H). 7.26 (m, 2H). 8.63 (s. 2H).

Similarly to the method of preparation of the compounds shown above in Examples B-0001 to B-0048, the compounds according to Examples B-1574 to B-2269 are prepared.

467

Examples B-1574 to B-1597 are obtained from skeleton C-27

468

469

B-1592 Ή But. V '°. B-1593 Ή B / i _χ ΝΗ: B-1594 In / co ιΎΌ ' B-1595 θ \ OH And B-1596 Nr B-1597 Ο and 0 I

470

Examples B-1598 to B-1621 produced the στ skeleton C-28

B-1598 n ₃ with bn B-1599 H ₃ C He ^! Ϋχ ^: B-1600 H ₃ C 1 H ₂ I ⁰ B-1601 n ₃ with bn 0 c B-1602 n ₃ with bn And oh MY B-1603 H ₃ C | w ! 0 γ B-1604 And ₃ C | He is Οχ I BR '

471

R ² r ^l

472

R ² R ^l

B-1615 H ₃ CI tn and ¹ B-1616 H ₃ C CH 'Ool A: B-1617 H ₃ c ^ | A '. NH ^; 1 << B-1618 H ₃ c! Bn Ό B-1619 H ₃ C and OH B-1620 H ₃ C bH ob 0 B-1621 H ₃ CI Oi ^! X 'A 1 ^HN_ C 1

473

Examples B-1622 to B-1645 are obtained from skeleton C-38

R ² R ^l

474

R ² R ^l

B-1629 J ⁵ . B-1630 ! 0 ' B-1631 % B-1632 CT Ό ____ / B-1633 B-1634 B-1635 B-1636 rO4 B-1637 bC B-1638 • V p ___O J

475

R ² R ^l

B-1639 lY ^ -0 'IS ^ ^U ! n' B-1640 B-1641  NH B-1642 -YH ' _v ^ B-1643 B-1644 'A _A ^ΗΝ Λ B-1645 '-CH “4

476

R ^l

R ²

B-1646 '0 | Co B-1647 B-1648 I 0 o B-1649 O / x B-1650 0 B-1651 4: B-1652 NO

477

R ² R ^l

478

R ² R ^l

B-1663 -Ch : ⁷ O \ B-1664 ^f T2H. . ^ <ol: s == ^u ΒΊ665 ^F ~ CH ^ NH. B-1666 ; ---------- ¹ —f — i B-1667 B-1668 ·. ^ΗΝ Λ B-1669 ; ο 1

479

Examples B-1670 to B-1693 are obtained from skeleton 065

R ² R ^l

480

R ² R ^l

481

R ² R ^l

B-1687 W ₀ | IS ¹ / w ^{1 z} 0 B-1688 ^f ~ Ch o. ₀ o B-1689 -W NH B-1690 ^f ~ CH I'M B-1691 -OH I 1 B-1692 0 B-1693 -Oh 0

482

Examples B-1694 to B-1717 are obtained from skeleton 066

R ²

R ^l

B-1694 B-1695 1 0 Px B-1696 B-1697 -Mr B-1698 X B-1699 ! ^f_ OH 1 0 B-1700 .'- 1 ° 1 BR 1

483

R ² R ^l

484

R ² R ^L

B-1711 ^ _ ₀ ^! s = ^u / ⁴ oi B-1712 o Ι, -ωρ 'X> LL B-1713 A ”/ - ^NH I B-1714 Υ'ό, B-1715 ^f XZH B-1716 pOd o B-1717 • E- ^ΗΝ Λ i

485

Examples B-1718 to B-1741 are obtained from skeleton C-69

R ² R ^l

B-1718 X B-1719 gos Ή B-1720 X? B-1721 x: I Ο μ Gx B-1722 I ο B-1723 I ο ί % B-1724 : X _________

486

R ² R ^l

487

R ² R ^l

488

Examples B-1742 to B-1765 were obtained from skeleton C-70

R ² R ^l

489

R ² R ^l

B-1749 -zY B-1750 ^- i 0 - o \ == N B-1751 ^! ^ ° \! B-1752 ! 'YH S-r Q ^ ° Ό / B-1753 ιΎ id B-1754 I ι- (Υι B-1755 B-1756 -04 and I , ΓΛν-Ο- IXsJ 1 B-1757 -m 0D B-1758 kz o ^ W ^s o

490

R ² R ^l

491

Examples B-1766 to B-1789 were obtained from skeleton C-71

r ^l

492

493

R ² R ^l

494

Examples B-I790 to B-1813 are obtained from skeleton C-72

R ² R ^l

495

496

R ² R ^l

B-1807 ί / ^χ4 ο I B-1808 S ^ ^U ! B-1809 --CH .'V _Z NH B-1810 Υόί B-1811 ----- K ^o b5z B-1812 ^F ^ H ~ A Λ Υ '0 B-1813 ^f K2H / y! . ^ην Λ!

497

Examples B-1814 to B-1837 are obtained from skeleton C-73

R ² R ^l

498

499 r ^l

B-1831 CHU B-1832 K. B-1833 NH i B-1834 ^ '0 B-1835 lvl B-1836 > L: HN-H I ^; 0 B-1837 4- 0 I

500

Examples B-1838 to B-1861 are obtained from skeleton C-33

R ² R ^l

501

R ^: R ^l

502

R ² R ^l

B-1855 , ω o ^ W ^S O B-1856 ο I s ^ ° 'TO u_ B-1857 4 ° I / ^NH i B-1858 TOT B-1859 the Russian Federation B-1860 ~ l X ^ng THAT ^! 0 B-1861 0

503

R ² R ^l

504

4 B-1869  X 'X B-1870 o-zl o = / M x _ B-1871 -from w ' 'i * B-1872 I 0 X B-1873 ! About Z 'χΧ ⁰ ! B-1874 Xs ^! -Cx ° B-1875 B-1876 and χ X B-1877 ^f ”CH o N V ° 5 B-1878 H2H • d- ⁰ o

505

R ² R ^l

B-1879 You η I B-1880 I • V B-1881 'in ^NH B-1882 ίν: 3 B-1883 -9 I___ _______ B-1884 ^F -O4 f —---------------- ', ^hn_ 4, ί I o B-1885 You And? 'Ey and ^HN A

506

Examples B-1886 to B-1909 were obtained from skeleton C-42

R ² R ^l

507

508

R ² R ^l

B-1903 iA _{0 s; S} U O ₀ B-1904 OH ι s ^ ⁰ ! Hl B-1905 'bl ^x o B-1906 | Yt a B-1907 s ) B-1908 ^: ~ About I% B-1909 Oi rb And o

509

Examples B-1910 to B-1933 were obtained from skeleton C-44

R ²

R ^l

510

R ² R ^l

511

R ² R ^l

512

Examples B-1934 to B-1957 were obtained from skeleton C-41

513

514

R ² R ^l

515

Examples B-1958 to B-1981 were obtained from skeleton C-43

R ² R ^l

516

517

R ² R ^l

B-1975 I-Yioi 7y? B-1976 I - <o! B-1977 .Έ / NH B-1978 ^fh CH | V> B-1979 J-E B-1980 Λ ΗΝ-ς Ο B-1981 ^F 4 ^ l El: hn4 ₀ i

518

Examples B-1982 to B-2005 were obtained from the C-30 skeleton

R ²

R ^l

519

R ² R ^l

520

R ² R ^l

521

Examples B-2006 to B-2029 were obtained from skeleton C-60

522

523

524

Examples B-2030 to B-2053 are obtained from skeleton C-36

R ^J

525

526

R ² R ^J

B-2047 n; B-2048 _S ^ U. Ό B-2049 m ^ NH ' B-2050 B-2051 B-2052 H A ΗΝ-ς and 0 B-2053 Jrh 0 -Os

527

Examples B-2054 to B-2077 were obtained from skeleton C-34

R ²

R ^J

528

R ² R ^J

529

R ² R ^J

530

Examples B-2078 to B-2101 are obtained from skeleton C-57

R ² R ⁴

531

R ² R ^J

532

R ² R ^J

533

Examples B-2102 to B-2125 were obtained from skeleton C-52

R ²

R ^J

534

R ² R ^J

535

536

Examples B-2126 to B-2149 were obtained from skeleton C-56

R ² R ^J

537

R ² R ^J

538

R ² R ^J

539

540

541

542

Ο

Examples B-2174 to B-2197 are obtained from skeleton C-64

543

544

545

Η

546

547

548

Examples B-2222 to B-2245 are obtained from skeleton C-29

R ^J

549

R ² R ^J

550

R ² R ^J

551

Examples B-2246 to B-2269 are obtained from skeleton 035

552

553

554

Examples B-2270 to B-2317

In a parallel system reaction unit containing a frit container, each vessel was charged with a 250 mg polymer-bound carbodiimide B48 (1.0 mmol / g resin) and a solution containing the C-49 oxygen skeleton in dimethylformamide (0.1 M, 500 uL). A solution of pyridine in dichloromethane (0.2 M, 1000 µL) was added to each suspension, followed by a solution of amine B47 (0.2 M, 375 µL) in dimethylformamide. The reaction mixtures were stirred in a Labline benchtop orbital mixer at 250 RPM for 16- 20 hours at room temperature The reaction mixture was filtered into conical flasks and the polymer was washed with 1.5 ml of dimethylformamide and 2.0 ml of dichloromethane The filtrates were evaporated to dryness in a Savant apparatus and dimethylformamide (350 µL) was added to each conical flask for dissolution. Then in a conical glass beaker a solution of tetrafluoroftal anhydride (1.0 Μ, 150 µL) in dimethylformamide was added and the mixtures were incubated for 2 hours at room temperature. The polyamine polymer B3Z (4.0 meq N / g resin, 250 mg) and then to the reaction mixture in each conical flask 1.0 ml of dichloromethane was added After stirring the reaction mixtures for 20 hours at 250 RPM per orbital mixer at room temperature, the mixtures were filtered through a polypropylene tube equipped with a foam frit. The polymers were washed twice with dimethylformamide (1.0 ml each) and the filtrates and washings were collected in conical flasks. The filtrates were evaporated to dryness and weighed to give the desired amide products, B-2270 to B-2317, as oils or solids. The analytical data and product yields obtained in this way are given below.

555

556

Yield Calc. Observation. MS

M + H

557

558

559

Yield Calc. Observation. MS MS

M + H

560

The compounds of Examples B-2318 to B-2461 were prepared analogously to the method shown above for the preparation of Examples B2270 to B-2317.

561

R ² R ^B N - R ^c 0 Yield Calc. MS Observation. MS M + H B-2318 w ^: ° 'HN 23 ' 426 427 - TON B-2319 23 394 - n ° NH _ B-2320 Oh 'χ ^' Ν H 50 490 491 -Οι - ~ ..... B-2321 0 _Ch An <^ A> 49 426 427 B-2322 0 ........ V ^ NH . 40 366 367 B-2323 χΛ _Η A 68 410 411 B-2324 Hi ^! Χ.Ά _Η - ° γΑ ₅ -; ο 57 456 457

562

563

R ² R ^B N - R ^c H ' Yield Calc. Observation. MS MS M + H B-2334 o 44 428 429 B-2335 0 JI V 27 406 '407 B-2336 0 cA NH ω 41 428 429 B-2337 0 ΓΊ, 27 423 424 B-2338 0 χ + 'ΝΗ | 'A / 33 469 470 B-2339 Vh 0 V ^ NH XXl ¹ O ₄ 52 518 519 B-2340 Ο I : V'- i 64 442 443 B-2341 Ό 0 ': Ln ^! 'Λ: 41 350 351 B-2342 W 0 'A;'IN NH I O' ¹ '' 34 414 415

564

565

566

R ² R ^B N — R ^C 0 Yield Calc. MS Observation. MS M + H B-2361 0 ⁰ Ύ ° ~~ • Ά _ζ Ν. 13 476 477 B-2362 46 493 494 '° ^Ο Α /> 0 I Ο B-2363 ¹ JL 'Άνη - A 0 57 396 397 B-2364 ο / 61 438 439 B-2365 ο A ^! ° yV '0 ¹ 72 424 425

567

R ⁸ ν— _R c Yield Calc. Observation.

MS MS

M + H

B-2366 o: x ^L p 'k / 0 34 380 381 '-'Ch EJ-2367 0 CI 52 480 481 • - - · B-2368 35 407 407 B-2369 31 435 436 -CH B-2370 33 414 415 B-2371 years 28 366 367 '<I B-2372 -e 37 422 423

568

Yield Calc. Observed

MS

M + H

569

R ⁸

N - _R C Yield Calc. Observation. MS M + H

570

571

572

Yield Calc. Observation. MS MS

M + H

B-2409 47 448 449 B-2410 : ° тоА ί : - ¾ 73 542 543 B-2411 0! with + 81 489 490 B-2412 O i jTO-N ', I ^: > ^ν ί 54 409 410 B-2413 Aq 4¾ 37 493 494

573

CH of

R ² R ^B N — R ^c H _o Yield Calc. Observation. MS MS M + H B-2414 70 14 473 474 B-2415 0 f CI 19 421 422 -He B-2416 0 ~ ' Pffffn ό 13 386 387 -X2h B-2417 Min PU 29 414 415 -He B-2418 , 0 ^ f ~ NH : F Cl 6 420 421 B-2419 Ο 10 454 - hon B-2420 ι 0 I V ^ NH oj 5 442 443

574

R ² R ^B N — R ^c 0 Yield Calc. MS Observation. MS M + H B-2421 X 'Cl: 28 454 455 -He B-2422 47 420 421 okn ı ex -Obi B-2423 -He • i ⁰ I and 53 400 401 B-2424 about and ΙΟΧ-ΝΗ: 'XI 15 400 401 A B-2425 0 F ₃ C _; 18 522 523 -A B-2426 and ο II Ά ^ ΝΗ X 38 464 465 He is B-2427  0; 26 468 469 -He B-2428 kH ι , δχ 22 432 433 Oi B-2429 F ι _F X 41 404 405 -He

575

576

R ² R ^B Ν - R ^c 0 Yield Calc. MS Observation. MS M + H B-2439 - φ CF, 12 454 455 B-2440  '0 kN o '° 8 521 522 B-2441 6 443 444 'He 0 1 ZX x / X 6/0 Vx, ^H ° F B-2442 • ”c> 37 514 515 B-2443 - - - 15 518 - He is B-2444 0 φφ 52 520 - • ^p -FN B-2445 θ. 'X and 33 517 518 ⁼ Ф < B-2446 0 ^; HH In 0 = s - <0 F 70 500 501 -He B-2447 ⁰ ·> - !! .____: - V.; V 5S 488 489

sn

578

R ² R ^s N - R ^Cl n 0 Yield Calc. MS Observation. MS M + H B-2457 ο ·  And 55 540 - B-2458 '- I AM 0 and Ήνη I o-0 | ___________S__________________: 22 488 489 B-2459 0 \ An ! A; cf,: 8 486 487 B-2460 13 534 535 B-2461 ITS '! • OH / I 13 542 -

Example C-l

5-Aminomethyl-4- (4-pyridyl) -3- (4-fluorophenyl) pyrazole

1- (4-fluorophenyl> -2- <4-11-iridyl> -1-ethanol

579

4-Picoline (40.0 g, 0.43 mol) was added to a solution of LiHMDS (0.45 mol, 450 ml of 1.0 M solution in tetrahydrofuran) for 30 minutes at room temperature (slight exotherm was observed). The resulting solution was stirred for 1 hour. This solution was added to 4-fluorobenzoate (75.8 g, 0.45 mol, pure) for 1 hour. The mixture was stirred overnight (16 hours). Water (200 ml) was added and the mixture was extracted with ethyl acetate (2 x 200 ml). The organic layer was washed with brine (1 x 200 ml) and dried over sodium sulfate. The organic layer was filtered and the solvent separated to give an oily solid. Hexane was added to the oil and the resulting solid was filtered and washed with cold hexane. Yellow solid (50 g, 54%) was isolated: * H NMR (CDCl ₃ ): δ 8.58 (d, J = 5.7 Hz, 2H), 8.02 (dd, J = 5.5,8.0 Hz, 2H), 7.12- 7.21 (m, 4H), 4.23 (s, 2H); ¹⁹ FNMR (CDCl3): δ -104.38 (m); LC / MS, 4 = 2.14 minutes (5-95% acetonitrile / water for 15 minutes at 1 ml / ml at 254 pt and 50 ° C), M + H = 216; MS: Calculated for C23H20N4O2F (M + H): 216.0825. Found: 216.0830 (Δt = 0.5).

N-benzyloxycarbonyl-5-ammiomethyl-11L-4- (4-pyridyl) * 3- (4-fluorophenyl) nirazole

557 ml (0.56 mol) of 1 M tBuOK in tetrahydrofuran and 53 ml (0.56 mol) of t-BuOH were placed in a three-liter round-bottom flask equipped with a mechanical stirrer, a nitrogen inlet and an addition funnel. Ketone 1 (60 g, 0.28 mol) was dissolved in 600 ml of THF and added to the mixture at room temperature with stirring. A yellow precipitate was obtained and the mixture was stirred for 1 hour. N-benzyloxycarbonylglycinyl Nhydroxysuccinimide (128.6 g, 0.42 mol) was dissolved in 600 ml of THF and added dropwise at room temperature for 1 hour.

580 hours. The mixture was stirred for 5 minutes and 150 ml of water were added. The pH was adjusted to 6.7 by 70 ml of AcOH. Hydrazine monohydrate (41 ml in 100 ml of water) was added through the funnel. The mixture was stirred for 1 hour and diluted with 500 ml water and 500 ml ethyl acetate. The two-phase mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 300 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to give 157 g of a reddish oil.

The oil was suspended in methylene chloride and filtered to remove insoluble material (DCU, monoketone hydrazone). The solution was split into two portions and each part chromatographed (Biotage 75L, 3% ethyl alcohol / methylene chloride and then 6% ethyl alcohol / methylene chloride). The appropriate fractions of each portion were concentrated to give a yellow solid. The solid was suspended in ethyl acetate and heated to reflux for 10 minutes. The solution was allowed to cool to room temperature overnight. The precipitate was filtered to give 30 g of a white solid (27% yield 2):%): 1 H NMR (DMF-d,): δ 13.36 (s, 1H), 8.57 (d, J = 5.8 Hz, 2H) , 7.16-7.52 (m, 1H), 5.11 (s ^ H), 4.48 (d, J = 5.4 Hz ^ H); ¹⁹ F NMR (DMF-d,): δ -114.9 (m), -116.8 (m) (fluorine signal splitting is due to pyrazole tautomers); LC / MS, N = 3.52 minutes (5-95% acetonitrile / water for 15 minutes at 1 ml / min at 254 nm and 50 ° C), M + H = 403; MS: Calculated for C 22 H 14 N 4 F (M + H): 403.1570. Found: 403.1581 (Δ mmu = ll).

5-Aminomethyl-4- (4 * -pyridinyl) -3- (4-fluorophenyl) pyrazole

To a 1 liter Parr flask was added 7 g (17.4 mmol) of 2 and 180 ml of methanol and 90 ml of tetrahydrofuran to give a clear solution.

581 thieves The flask was purged with nitrogen and 1.5 g of 10% palladium on carbon (Degussa type E101) were added. The Parr flask was pressurized to 40 psi (hydrogen) and stirred. Hydrogen was withdrawn at 5 psi after 5 hours. The flask was again pressurized to 42 psi and stirred overnight. The flask was purged with nitrogen and the contents filtered through Celite. Wash with methanol (x 50 ml) and concentrate the filtrate to give 4.5 g of an off-white solid (94%). Ή NMR (DMSO-d ₆ ): δ 8.52 (d, J = 4.63 Ηζ, 2Η), 7.36 (dd, J = 5.64,8.1 Ηζ, 2Η), 7.16-7.30 (m, 4H), 3.79 (s, 2H) ); ¹⁹ F NMR (DMSO-d ₆ ): δ -114.56 (m); LC / MS, N = 1.21 minutes (5-95% acetonitrile / water for 15 minutes at 1 ml / min at 254 nm and 50 ° C), M + H = 269 m / z; MS: Calculated for C15H14N4F (M + H): 269.1202. Found: 269.1229 (Δ mmu = 2.7).

The following pyridylpyrazoles (C-2 to C-21, Table C-1) were prepared according to the experimental method described above for Example C-1.

Table C-1

Example Structure MW, m + n Calc. Intent. k nmr (solvent) ppr C-2 N-NH 323. 1672 323 .1670 (DMF-d-): 8.77 (t, J = 4.4 Hz, 2H), 7.60 (m, 2Η), 7.44 (t, J = 4.4 Hz, 2H), 7.35 (m, 2H), 3.22 (bd, 2H), 3.01 (septet, J = 5.3) Hz, 1H), 2.74 (m, 2H), 1.95 (m, 4H)

582

with F- Fr. Ν-ΝΗ e ϊ C) N , NH ₂ CH ₃ 282.127 (M) 282.1245 (Μ, El) (DMF-d _? ): 8.77 (br s, 2H), 7.64-7.62 (m, 2H), 7.50 (br s, 2H), 7.38-7.34 (m, 2H), 4.40-4.37 (m, 1H). 1.56 (br s, 3H) C-4 -x. N-NH L \ ^ NH ₂ 282.127 (DMF-d-): 8.77 (or s, F ' ch ₃ (M) 2H), 7.64-7. 62 (X, 2Ή), to J 282.1147 7.50 (br s, 2H), 7.38-7.36 N (Μ, El) (m, 2H), 4.40-4.37 (n, 1H), 1.57 (br s, 3H) C-5 / X, Ν-ΝΗ X'NH 323.1672 (DMSO-di): 8.5 6 (Dr, ΞΗ), F 323. 1687 7.32 (m, 2H), 7.18 (m, to JI N 4H), 2.91 (m, 2H), 2.71 (m, 2H) 1.8 8 (m, 1.4), 1. 6Ξ · (m, 2H), 1.40 (m, 2H) C-6 X- N-NH J / _x nh ₂ 359 (DMSO-d ₆ ): 2.66 (d, 2 - F 359 4.6 Hz, 2 H), 7.32-7.13 _f , LX 1 1 k J N 7 H), 6.98-6.96 (ί: ;, 4 and -, ' ¹ , 4.06 (t, J = 7.0 H: 1H), 2.98-2.95 (m, 2H) C-7 If χ- N-NH J / ^ nh ₂ 359 (DMSO-d ₆ ): 8.4 6 (d, J = F f 359 5.4 Hz, 2 H), 7.32 -7.28 (m, A 11 k JJ N dd 2H), 7. 20-7. 12 (YY, 5H), 6.98-6.96 (m, 4H), 4.06 (t, J = 7.0 Hz, 1H), 2.98- 2.94 (m, 2H) C-8 f X- N-NH , nh ₂ 313.1465 (DMSO-d ₆ ): 13.83 (bs, F ' ^ och. 313.1492 1H), 8.61 (d, J = 5.7 Hz, k J N 2H), 8.33 (bs, 1H), 7.33 (m, 6H), 4.44 (m, 1H), 3.63 (m, 2H), 3.27 (s, 3H)

583

C-9

C-10

C-ll

C-12

C-13

N-NH

N-NH

N-NH

N-NH

N-NH

313 1465

313.1457

354

354

354

354

283.1359

283.1363

297.1515

297.1515 (DMSO-dJ: 8.55 (dd, J =

1-5, 4.4 Hz , 2H), 7. 7.32 (m, 2H) , 7.26 (d = 1.6, 4.4 H z, 2H) 7 7.16 (m, 2H), 4.06 (t, 6.5 Hz , 1H), 3.49 (d, 6.6 Hz, 2H), 3.20 (s,

(DMSO-d ₀ ): 13.03 (bs, 1H), 8.50 (dd, J = 1. 6, 2.7 Hz, 2H), 7.58. (bq, u = 4. 3 Hz, 1H), 7.3 (m, 2H), '7.12-7.21 (m, 4H), 3. 77 (t, J = 6.3 Hz, 1H) , 2.45 (d, J = 4.5 Hz, , 3H), 1.97 (t, J = 7.4 Hz, 2H) , 1.85 (dt, J = 7.3, 7. . 1 Hz ., 2H) (DMSO-d ₆ ): 13.03 (bs, 1H), 8.50 (dd, J = 1. 6, 2.7 Hz, 2H), 7.58 (bq, J = 4. 3 Hz, 1H), 7.3 (m, 2H), 7.12-7.21 (m, 4H), 3.77 (t, J = 6.3 Hz, 1H) , 2.45 (d, J = 4.5 Hz, 3H), 1.97 (t, J = 7.4 Hz, 2H) , 1.85 (dt, J = 7.3, 7-. .1 Hz, 2H)

(DMSO-dfi): 8.53 (d, J =

5.0 Hz, 2H), 7.37-7.32 (m,

2H), 7.21-7.17 (m, 4H),

2.83 (d, J = 6.0 Hz, 2H),

2.77 (d, J = 6.0 Hz, 2H) (DMSO-d ₆ ); 8.53 (d, J =

5.4 Hz, 2H), 7.34 (dd, J =

5.8, 8.2 Hz, 2H), 7.18

584

(dd, J - 5.8, 9.8 Hz, 4H ;, 2.68 (t, J 2.52 (m, 2H 7.3 Hz, 2H), ), 1.64 (m, 2H) 014 Cl N-NH _x nh ₂ 284.0829 (CD ₃ 0D): 8.74 (br, 2H), 284.0806 7.77 (br, 2H), 7.45-7.58 C} (m, 3H), 7.30-7.40 (m, N 1H), 4. 43 (s, 2H) 015 Ό N-NH L. _x nh ₂ 285 (DMSO-dg): 8.53 (br, 2H), Ci- (A. 285 7.56 (br, 2H), 7.26 (m, N 4H), 3. 75 (br, 2H) C-16 - Oh N-NH ^, ΝΗ ₂ 329, 331 (DMS0-d ₆ ): 8.53 (d, J - Br Al 329, 331 4.4 Hz, 2H) , 7.42 (d, J = N 7.9 Hz, 2H) , 7.34 (d, J = 8.5 Hz, 2H) , 7.24 (d, J = 4.6 Hz, 2H) , 3.76 (bs, 2H) 017 CI, Oh N-NH A 339 (DMS0-d _0): 8.53 (t, J = A ^ x ^NH 339 4.3 Hz, 2H) , 7.33 (m, 3H), N 7.19 (t, J = 4.6 Hz, 2H-) · · 7.14 (d, J = 7.3 Hz, 1H), 3.23 (m, 2H), 2.88, (m, 3H), 1.92, (m, 3H), 1.70 (m, 1H) 018 r \ N-NH A 339 (DMSO-dg): 8.57 (d, J = CI- \ == hours ^ NH 339 4.6 Hz, 2H) , 7.41 (d, J = C) N 8.3 Hz, 2H) , 7.29 (d, J = 8.5 Hz, 2H) , 7.20 (d, J = 4.8 Hz, 2H), 3.18 (bd, 2H), 2.88 (m, 1H). 2.7 6 (m, 2H), 1.82 (br, 4H) 019 N-NH 383, 385 (DMSO-d ₆ ): 8.56 (br, 2H), Br A ^ NH 383, 385 7.52 (br, 2H), 7.14-7.29 to J N (m, 4H), 2 .99 (br, 2H),

585

2.71 (br, 1H), 2.51 (or.

2H), 1.68 (br, 4H)

The following pyridylpyrazoles (C-22 to C-40, Table C-2) were prepared according to the general schemes C-1 and C-2 and the experimental methods described above for Example C-1.

Table C-2

Cmpd. No. Structure C-22 N-NH Ό Ο. Λ F ' O-S C) N C-23 O ' N — NH J ['• ** 4 ^ xz ·' '' -. F (A NH L j № = / C-24 O ' N-NH L ^ NH. F ' i Ay Ύ ^ νη k J N

586

587

C-34 N-NH C-35 N-NH C-36 N-NH C-37 N-NH 'NH; C-38 N-NH ^F ^ ^s = ^ 4v ^NH 'N C-39 N-NH 'Mv / ^NH J4 C-40 N-NH C 0 _? 1 · B in ^F NHj C-41 .N-NH _{H f} jO4V-4nh N C-42. N-NH _H ^ N C-43 N-NH _H HN --- 'ΊΨ C-44 N-NH _H HN --- 'Ί4

588

Example C-49

Step A: The pyrazole (2.60 g, 10.3 mmol) of Example 4 was suspended in 52 ml of dichloroethane and 52 ml of 2.5 M sodium hydroxide base. With stirring, tetrabutylammonium hydroxide (0.5 ml of 1 M aqueous solution) was added to the mixture. To this mixture was added t-butyl bromoacetate (2.10 g, 10.8 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was poured onto 200 ml of methylene chloride and 200 ml of water. The phases were separated and the organic phase was washed with water (1 x 100 ml) and brine (1 x 100 ml). The organic layer was dried over sodium sulfate and filtered. The solvent was removed to give an off-white solid. The solid was triturated with hexane and the resulting solid was isolated by filtration. The solid was washed with hexane to give 3.4 g of a white solid (90%).

589

Step B: The alkylated pyrazole (3.7 g, 10.1 mmol) of Step A was treated with 57 ml of 4N hydrochloric acid in dioxane. The solution was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was dissolved in tetrahydrofuran. The solution was treated with propylene oxide (10.3 mmol) and stirred at room temperature for 1 hour. The solvent was removed to give an oil. The residual solvent was separated with several portions of ethanol. The resulting solid was triturated with ethylene oxide and the title compound of Example C-49 was isolated by filtration to give 3.0 g of an off-white solid (95%). MS: M + H calcd: 312; found: 312. * H NMR (DMSO-d ₆ ): δ 8.81 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 5.8 Hz, 2H), 7.40 (m, 2H), 7.23 (t, J = 8.5 Ηζ, ΙΗ), 5.16 (s, 2H), 2.40 (s, 3H).

Example C-50

According to the method described above in Example C-49, the compound of Example C-50 was prepared starting from 4- [3- (4-fluorophenyl) 1H-pyrazol-4-yl] pyridine. MS: M + H calcd: 298; found: 298. * H NMR (DMSO-d6): δ 8.75 (d, J = 6.4 Ηζ, 2Η), 8.68 (s, 1H), 7.78 (d, J = 6.6 Hz, 2H), 7.52 (d, J = 5.4.8.5 Hz, 2H), 7.31 (t, J = 8.9 Hz, 2H), 5.16 (s, 2H).

Example C-51

590

N-N

CO ₂ H

F

According to the methods described in Scheme C-1, the compound of Example C-51 was also prepared starting from the N-boc-piperidyl nyl analogue of the compound of Example C-2.

Example C-52

N-NH

Step A: Picolin is treated with a base selected from, but not limited to, n-butyllithium, LDA, LiHMDS, t-BuOK or sodium hydride in an organic solvent such as tetrahydrofuran, ether, t-butanol or dioxane from -78 ° C to 50 ° C for 10 minutes to 3 hours. The picoline solution was then added to a solution of N-C6- (b) -phenylalanil-1 Nhydroxysuccinimide. The reaction mixture was stirred for 30 minutes to 48 hours, during which time the temperature could range from -20 ° C to 120 ° C. The mixture was then poured into water and extracted with an organic solvent. After drying and removing the solvent, pyridyl mono-ketone is isolated as a solid, which can be purified by crystallization and / or chromatography.

Fr.

Cbz

591

Step B: A solution of pyridyl monoketone in ether, tetrahydrofuran, tbutanol or dioxane is added to a base selected from, but not limited to, n-butyllithium, LDA, LiHMDS, t-BuOK or sodium hydride in hexane, tetrahydrofuran, ether, t -butanol or dioxane from -78 ° C to 50 ° C for 10 minutes to 3 hours. Formylacetic anhydride, as a solution in tetrahydrofuran, ether or dioxane, is then added to the anion of the mono-ketone while maintaining the temperature between -50 ° C and 50 ° C. The resulting mixture was stirred at the specified temperature for 5 minutes to several hours. The resulting intermediate, pyridyl diketone, was used without purification in Step B.

oh

Cbz

Step B: The solution containing pyridyl diketone is fixed with water and the pH is adjusted to between 4 and 8 using an inorganic or organic acid selected from acetic, sulfuric, hydrochloric or nitric acids. The temperature is maintained between -20 ° C and room temperature during this step. Hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between -20 ° C to 40 ° C for 30 minutes to several hours. The mixture was then poured into water and extracted with an organic solvent. N-Cbz-protected pyridylpyrazole is obtained as a solid which is purified by chromatography or crystallization.

592

Step D: The CBZ protecting group is cleaved under the pressure of hydrogen gas under pressure and palladium on carbon in an alcoholic solvent to form a C-52 skeleton after filtration and concentration.

The following compounds C-53 to C-59 in Table C-3 were prepared according to the method described above for the preparation of C-52.

Example C-60

Step A: Boc protected pyridylpyrazole is treated with benzaddehyde in methylene chloride at room temperature in the presence of a desiccant for 1-24 hours. The solvent was then evaporated and the resulting imine was used in Step B without further purification.

HCOPh

Step A

Step B: Pyridylpyrazolimine is dissolved in tetrahydrofuran and stirred under nitrogen at -78 to -20 ° C. To the mixture in drops

593

Table C-3

Example No. Structure C-53 N-NH h ₂ n .__ 7 / A χγ H χ— * 1 ί Χχ X 1 N - C-54 η ₂ ν N-NH J / L uh XXn 1 Δ X _n Boc to J N C-55 η ₂ ν N-NH . J k N χχ- Btc χχ 1 J C-56 h ₂ n n- ^N \ ^H V \ X H - Δ A N C-57 h ₂ n ULH H W A ks. b N C-58 ., N-NH ⁿ 2 '\ // \ NH-Boc V A Ail lx. Jj N C-59 H ₂ \ N-NH NH-Boc XX ΓΪ1 1χ JJ N

A base such as LDA, n-butyllithium or LiHMDS is added to 594 and stirring is continued for 10 minutes to 3 hours. Two equivalents of methyl iodide were then added to the mixture and stirring continued for several hours. The mixture was then fixed with acid and allowed to warm to room temperature and stirred for several hours until the cleavage of Boc and the amino group was complete. The pH was adjusted to 12 and then extracted with an organic solvent, which was dried and evaporated. The crude pyridylpyrazole is then recrystallized and / or chromatographed to give pure C-60.

Stage B

1) Base

2) Me!

3) Acid, water

Example C-61

The compound of Example C-61 was prepared according to the method described in Example C-60 using 1,4-dibromobutane instead of methyl iodide.

Example C-62

595

The compound of Example C-62 was prepared according to the method described in Example C-60 using 1,3-dibromethane instead of methyl iodide.

Example C-63

The synthesis of compound C-63 begins with the condensation reaction of bromomaleic anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride. The maleimide B78 was then treated with 4-fluoroacetophenone in the presence of a catalytic amount of Pdbdba2 and sodium t-butoxide to give fluoracetophenone maleimide B79 substituted. B79 is then treated with 1E-butoxybis (dimethylamino) methane to give α-ketonamine B80. α-ketonamine B80 is condensed with hydrazine to give N-protected maleimidpyrazole B81. The 2,4-dimethoxybenzyl group is cleaved with cerium-ammonium nitrate to give the title compound C-63.

Q81

MeO

C-63

596

Example C-64

The compound of Example C-64 was prepared by the method described for Schemes C-6 and C-7.

Example C-65

The compound of Example C-65 was prepared by the method described for Schemes C-6 and C-7.

Example C-66

The compound of Example C-66 was synthesized by the method described for Schemes C-6 and C-7 using N-2,4-dimethoxybenzyl-4-bromopyridone instead of B78.

Example C-67

597

The compound of Example C-67 was synthesized by the method described for

Schemes C-6 and C-7 using N-2,4-dimethoxybenzyl-4-bromopyridone instead of B78 and N-Boc-glycyl N-hydroxysuccinimide instead of B82.

Example C-68

The compound of Example C-68 was synthesized by the method described for

Schemes C-6 and C-7 using B1-2,4-dimethoxybenzyl-4-bromopyridone instead of B78.

Example C-69

The compound of Example C-69 was synthesized by the method described for Schemes C-6 and C-7 using N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-69

598

The compound of Example C-70 was synthesized by the method described for

Schemes C-6 and C-7 using N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-71

The compound of Example C-71 was synthesized by the method described for

Schemes C-6 and C-7 using N-methyl-3-bromomaleimide instead of B78.

Example C-72

The compound of Example C-72 was synthesized by the method described for Schemes C-6 and C-7 using N-methyl-3-bromomaleimide instead of B78 and N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-73

The compound of Example C-73 was synthesized by the method described for

Schemes C-6 and C-7 using N-methyl-3-bromomaleimide instead of B78 and N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

The biological data for the compounds of Examples B-0001 to B1573 and Examples B-2270 to B-2462 are shown in the following tables.

Data on the in vitro inhibitory activity of P38-alpha kinase are given in the column indicated as:

“P38 alpha kinase IC ₅₀ , uM or% inhib @ zone. (uM) ”

An in vitro cellular assay to measure the ability of compounds to suppress TNF production in human U937 cells stimulated with LPS is shown in the column labeled:

“U937 Cell IC50, uM or% inhib @ zone. (IM) ”

In vitro evaluation of the ability of compounds to inhibit LPS-stimulated TNF release in mice is shown in the column labeled:

“Mouse LPS Model,% TNF inhib @ dose @ predose time”

600 where the dose is milligrams per kilogram (mpk) orally administered by tube, and the overdose time indicates the number of hours before administration of the LPS when the compound is administered.

In vitro evaluation of the ability of compounds to suppress LPS-stimulated TNF release in rats is shown in the column indicated as:

"Rat LPS Model,% TNF inhib @ dose @ predose time" where the dose is milligrams per kilogram (mpk) orally administered by tube and the overdose time indicates the number of hours before the LPS is administered when the compound is administered.

601

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50.UM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose @predose time War LPS Model% inhib @dose © predate it B-0001 53.0%@1.0uM 40.0% @ 1.0uM B-0002 71.0%@1.0uM 28.0%@10.0uM B-0003 70.0%@1.0uM 76.0% 10.0uM B-0004 80.0%@1.0uM 4.61 uM B-0005 95.0%@1.0uM 2.97uM B-0006 82.0%@1.0uM 80%@10.0uM B-0007 74.0%@1.0uM 85.0%@10.0uM B-0008 42.0% @ 1.Ou M 65.0% @ 10. Ou M B-0009 0.04 uM 0.72uM B-0010 0.52 µM 0.65uM B-0011 0.03 uM 4.47uM B-0012 30.0%@1.0uM 44.0% @ 1.0uM B-0013 70.0%@1.0uM 84.0%@10.0uM B-0014 79.0%@1.0uM 80.0%@10.0uM B-0015 82.0% @ 1. Ou M 80.0%@10.0uM B-0016 94.0%@1.0uM 3.98uM B-0017 56.0%@1.0uM 79.0%@10.0uM B-0018 60.0%@1.0uM 59.0%@10.0uM B-0019 84.0%@1.0uM 100.0%@10.0uM B-0020 73.0%@1.0uM 81.0%@10.0uM B-0021 68.0%@1.0uM 76.0%@10.0uM B-0022 69.0%@1.0uM 44.0@1.0uM B-0023 90.0%@1.0uM 77.0%@10.0uM B-0024 94.0%@1.0uM 52.0%@1.0uM B-0Q25 89.0%@1.0uM 79.0%@10.0uM B-0026 96.0%@1.0uM 3.27uM B-0027 94.0% @ 1.0uM 11.0UM B-0028 69.0%@1.0uM 45.0%@10.0uM B-0029 91.0%@1.0uM 58.0% @ 10.Ou M B-0030 92.0%@1.0uM 75.0%@10.0uM B-0031 94.0%@1.0uM 100.0%@10.0uM B-0032 94.0%@1.0uM 78.0%@10.0uM B-0033 97.0%@1.0uM 10.0uM B-0034 95.0%@1.0uM 10.0uM B-0035 94.0%@1.0uM 10.0uM B-0036 92.0%@1.OuM 8.24uM B-0037 91.0%@1.0uM 86.0%@10.0uM B-0038 71.0%@1.0uM 84.0%@10.0uM B-0039 89.0%@1.0uM 72.0%@10.0uM B-0040 93.0%@1.0uM 2.3uM B-0041 65.0% @ 1.Ou M 66.0%@10.0uM B-0042 94.0%@1.0uM 2.76uM

602

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0043 0.22 μM 0.54uM B-0044 0.14 µM. 0.19uM B-0045 94.0%@1.0uM 1.01uM B-0046 96.0%@1.0uM 54.0%@1.0uM B-0047 94.0%@1.0uM 74.0%@10.0uM B-0048 94.0% @ 1.Ou M 76.0%@10.0uM B-0049 88%@1.0uM 33.0%@1.0uM B-0050 73%@1.0uM 34.0%@1.0uM B-0051 3.3uM 2.15uM 47% @ l00mpk @ -6h 79% @ 3mpk @ -4h B-0052 92%@1.0uM 15.0%@1.0uM B-0053 95%@1.0uM 34.0%@1.0uM B-0054 90%@1.0uM 30.0%@1.0uM B-0055 93%@1.0uM > 1.0uM B-0056 96%@1.0uM 21.0%@1.0uM B-0057 96%@1.0uM 29.0%@1.0uM B-0058 79%@1.0uM 18.0%@1.0uM B-0059 83%@1.0uM 35.0%@1.0uM B-0060 73%@1.0uM 22.0%@1.0uM B-0061 62%@1.0uM 27.0% @ 1.Ou M B-0062 94%@1.0uM 36.0%@1.0uM B-0063 96%@1.0uM 40.0%@1.0uM B-0064 90%@1.0uM 4.0%@1.0uM B-0065 83%@1.0uM 21.0%@1.0uM B-0066 94%@1.0uM 28.0%@1.0uM B-0067 91%@1.0uM 1.0%@1.0uM B-0068 72%@1.0uM 22.0%@1.0uM B-0069 96%@1.0uM 37.0%@1.0uM B-0070 92%@1.0uM 30.0% @ 1.Ou M B-0071 86%@1.0uM 31.0%@1.0uM B-0072 77%@1.0uM 32.0%@1.0uM B-0073 91%@1.0uM 24.0%@1.0uM B-0074 92%@1.0uM .42.0% @ 1.Ou M B-0075 91%@1.0uM 35.0%@1.0uM B-0076 58%@1.0uM 21.0%@1.0uM B-0077 0.8uM 10.0uM B-0078 80%@1.0uM 20.0%@1.0uM B-0079 93%@1.0uM 13.0%@1.0uM B-0080 73%@1.0uM 73.0%@1.0uM B-0081 92%@1.0uM 13.0%@1.0uM B-0082 47%@1.0uM 27.0%@1.0uM B-0083 0.22uM 6.51uM B-0084 56%@1.0uM I 30.0% @ 1.Ou M

603

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell lC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0085 83%@1.0uM 21.0%@1.0uM B-0086 91%@1.0uM 37.0%@1.0uM B-0087 0.55uM 2.26uM 38% @ 30mpk @ -6h B-0088 96%@1.0uM 9.0%@1.0uM B-0089 0.04uM ZZZIM B-0090 98%@1.0uM 52.0% @ 1.Ou M B-0091 96%@1.0uM 40.0%@1.0uM B-0092 97%@1.0uM 34.0%@1.0uM B-0093 3.18 uM 1.25uM 30% @ 30mpk @ -6h B-0094 96%@1.0uM 52.0%@1.0uM B-0095 98%@1.0uM 38.0% @ 1.Ou M B-0096 91%@1.0uM 22.0%@1.0uM - B-0097 72.0% @ 10.Ou M 38.0%@1.0uM B-0098 66.0% @ 10. Ou M 12.0%@1.0uM B-0099 43.0% @ 1.0uM > 1.0uM B-0100 75.0% @ 1.0uM 5.0uM B-0101 71.0% @ 1.0uM 2.11uM B-0102 81.0%@1.0uM 15.0%@1.0uM B-0103 71.0%@1.0uM 6.0%@1.0uM B-0104 56.0% @ 1.0uM 2.78uM B-0105 78.0% @ 1.Ou M 5.0uM B-0106 62.0%@1.0uM 5.0uM B-0107 0.27uM 5.0uM B-0108 61.0%@1.0uM 4.85uM B-0109 45.0%@1.0uM 19.0%@1.0uM B-0110 66.0%@1.0uM 13.0%@1.0uM B-0111 57.0%@1.0uM > 1.0uM B-0112 97.0%@1.0uM 1.12uM B-0113 75.0% @ 1.Ou M 43.0% @ 1.Ou M B-0114 45.0%@1.0uM 3.92UM B-0115 47.0%@1.0uM 2.0%@1.0uM B-0116 73.0% @ 1.Ou M 35.0% @ 1.Ou M B-0117 0.46 uM 1.78 µM 30% @ 30mpk @ -6h B-0118 1.18 uM 1.29 μM B-0119 89.0%@10.0uM 2.78uM B-0120 0.008 uM 0.21 μM 77% @ 100mpk @ -6h 70% @ 3mpk @ -4h B-0121 79.0%@1.0uM 1.22uM B-0122 79.0%@10.0uM 2.0%@1.0uM B-0123 59.0%@1.0uM > 1.0uM B-0124 73.0%@1.0uM 15.0%@1.0uM B-0125 70.0% @ 10.Ou M 17.0%@1.0uM B-0126 66.0%@1.0uM 1.57uM

604

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-0127 82.0% @ 1.Ou M 0.96uM B-0128 78.0%@1.0uM 1.81uM B-0129 51.0% 61.0uM 31.0%@1.0uM B-O130 69.0%@1.0uM 58.0%@1.0uM B-0131 43.0%@1.0uM 46.0%@1.0uM B-0132 76.0%@1.0uM 8.0%@1.0uM B-0133 51.0%@1.0uM 42.0%@1.0uM B-0134 60.0%@1.0uM 2.17uM B-0135 78.0%@1.0uM 58.0%@1.0uM B-0136 77.0%@1.0uM 44.0%@1.0uM B-0137 41.0%@1.0uM 37.0%@1.0uM B-0138 50.0%@1.0uM 32.0%@1.0uM B-0139 54.0%@10.0uM 17.0%@1.0uM B-0140 67%@10.0uM 9.0%@1.0uM B-0141 78.0%@1.0uM 10.0%@1.0uM B-0142 86.0% @ 1.Ou M 12.0%@1.0uM B-0143 42.0% @ 1.0uM 3.63uM B-0144 86.0% @ 1.0uM 43.0%@1.0uM B-014S 54.0% @ 10.0uM 12.0% @ 1.0uM 8-0146 77.0% @ 10.0uM 28.0% @ 1.0uM B-0147 44.0% @ 1.0uM 22.0% @ 1.0uM B-0148 51.0% @ 1.0uM > 1.0uM B-0149 1.15 µM 10.0 µM B-0150 27.0% @ 10.0uM 35.0% @ 1.0uM B-0151 43.0% @ 1.0uM 30.0% @ 1.0uM B-0152 51.0% @ 1.0uM 24.0% © I.OuM B-0153 57.0% @ 1.0uM 21.0% @ 1.0uM B-0154 65.0% @ 10.0uM 14.0% @ 1.0uM B-0155 40.0% @ 10.0uM 26.0% @ 1.0uM B-0156 42.0% @ 10.0uM 13.0% @ 1.0uM B-0157 48.0% © 10.0UM 9.0% @ 1.0uM B-0158 58.0% @ 10.0uM 39.0% @ 1.0uM B-0159 54.0% @ 10.0uM 5.0% @ 1.0uM B-0160 59.0% @ 10.0uM 26.0% @ 1.0uM B-0161 72.0% @ 10.0uM 13.0% @ 1.0uM B-0162 23%@1.0uM 2.05 uM B-0163 20.0% @ 10.0uM 10.0% @ 1.0uM B-0164 37.0% @ 10.0uM 20.0% @ 1.0uM B-0165 70.0% @ 10.0uM 19.0% @ 1.0uM B-0166 45.0% @ 10.0uM 37.0% @ 1.0uM B-0167 40.0% @ 1.0uM 37.0% @ 1.0uM B-0168 44%@1.0uM 2.36 µM

605

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-0169 43.0% @ 1.0uM 21.0% @ 1.0uM B-0170 43.0%, @ 1.0uM 30.0% @ 1.0uM B-0171 61.0% @ 10.0uM 21.0% @ 1.0uM B-0172 16.0% @ 10.0uM 11.0% @ 1.0uM B-0173 33.0% @ 10.0uM 48.0% @ 1.0uM B-0174 54.0% @ 10.0uM 43.0% @ 1.0uM B-0175 41.0% @ 10.0uM 31.0% @ 1.0uM B-0176 50.0% @ 1.0uM 30.0% @ 1.0uM B-0177 70.0% @ 10.0uM 27.0% @ 1.0uM B-0178 12.0% @ 10.0uM 35.0% @ 1.0uM B-0179 27.0% @ 10.0uM 37.0% @ 1.0uM B-0180 34.0% @ 10.0uM 23.0% @ 1.0uM • B-0181 5.0%@1.0uM 2.0% @ 1.0uM B-0182 39.0% @ 10.0uM 40.0% @ 1.0uM B-0183 12.0% @ 10.0uM 34.0% @ 1.0uM B-0184 66.0% @ 10.0uM 17.0% @ 1.0uM B-0185 65.0% @ 10.0uM 25.0% @ 1.0uM B-0186 40.0% @ 1.0uM 25.0% @ 1.0uM B-0187 4.0% @ 10.0uM 14.0% @ 1.0uM B-0188 70.0% @ 10.0uM 35.0% @ 1.0uM B-0189 42.0% @ 10.0uM 9.0% @ 1.0uM B-0190 59.0% @ 10.0uM 31.0% @ 1.0uM B-0191 40.0% @ 1.0uM 29.0% @ 1.0uM B-0192 12.0% @ 10.0uM 47.0% @ 1.0uM B-0193 0.54 µM 6%@1.0uM B0194 1.31 µM 22%@1.0uM B-0195 1.03 μM 55%@1.0uM B-0196 2.24 uM > 1.0uM B-0197 2.0 µM 14%@1.0uM B-0198 1.2 uM 2%@1.0uM B-0199 1.34 µM 3%@1.0uM B-0200 1.31 µM 16%@1.0uM B-0201 0.29 µM 59%@1.0uM B-0202 0.55 µM 2.26 uM B-0203 0.16 µM 65%@1.0uM B-0204 0.21 μM 48%@1.0uM B-0205 0.096 uM 54%@1.0uM B-0206 5.76 uM 14%@1.0uM B-0207 0.12 uM 52%@1.0uM B-0208 0.067 μM > 1.0uM B-0209 0.29 µM 8%@1.0uM B-0210 0.057 μM 67%@1.0uM

606

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0211 0.25 µM 30%@1.0uM B-0212 0.12 UM 28%@1.0uM B-0213 0.31 uM 39%@1.0uM B-0214 0.16 µM 50%@1.0uM B-0215 0.11 uM 51%@1.0uM B-0216 0.56 µM > 1.0uM B-0217 0.55 µM > 1.0uM B-0218 0.53 μM 18%@1.0uM B-0219 0.91 µM 18%@1.0uM B-0220 0.13 [mu] M 40%@1.0uM B-0221 2.4 uM > 1.0uM B-0222 0.4uM. 29.0%@1.0uM B-0223 0.2uM 1.0%@1.0uM B-0224 <0.1 μM 93.0%@1.0uM B-0225 0.047UM 37.0%@1.0uM B-0226 0.074uM 20.0%@1.0uM B-0227 0.045uM 1.0%@1.0uM B-0228 0.15uM 44.0%@1.0uM B-0229 <0.1 μM 61.0%@1.0uM B-0230 0.041 μM 30.0%@1.0uM B-0231 0.055uM 40.0% 1.0uM B-0232 0.048UM 24.0% @ 1.Ou M B-0233 0.095uM 43.0%@1.0uM B-0234 0.11uM 68.0%@1.0uM B-0235 1.31uM 90.0%@1.0uM B-0236 0.077UM 46.0%@1.0uM B-0237 0.13uM 60.0%@1.0uM B-0238 0.47uM 82.0%@1.0uM B-0239 5.73uM 84.0%@1.0uM B-0240 0.2uM 70.0%@1.0uM > B-0241 0.1uM 45.0%@1.0uM B-0242 <0.1 μM 78.0%@1.0uM B-0243 0.039uM 53.0%@1.0uM B-0244 0.02uM 57.0%@1.0uM B-0245 0.13uM 24.0%@1.0uM B-0246 <0.1 μM > 1.0uM B-0247 0.082uM 75.0%@1.0uM B-0248 <0.1 μM 11.0%@1.0uM B-0249 <0.1 μM 75.0%@1.0uM B-0250 0.28uM 36.0%@1.0uM B-0251 0.31 uM 1.0%@1.0uM B-0252 0.041 μM 54.0%@1.0uM

607

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib @dose @predose time B-0253 0.061 µM 74.0%@1.0uM B-0254 0.12uM 59.0%@1.0uM B-0255 0.32uM 68.0% @ 1.Ou M B-0256 <0.1 μM 88.0%@1.0uM B-0257 1.71uM 11.0%@1.0uM B-0258 0.37uM 63.0%@1.0uM B-0259 0.35uM 58.0%@1.0uM B-0260 0.56uM 23.0%@1.0uM B-0261 0.49uM 23.0%@1.0uM B-0262 0.41uM 89.0%@1.0uM B-0263 0.62uM 64.0%@1.0uM B-0264 0.14uM 18.0%@1.0uM B-0265 0.92uM 24.0%@1.0uM B-0266 0.25uM 24.0%@1.0uM B-0267 0.48uM 11.0%@1.0uM B-0268 3.39uM 19.0%@1.0uM B-0269 9.81uM 19.0%@1.0uM B-0270 5.79uM 13.0%@1.0uM B-0271 7.55uM 12.0%@1.0uM B-0272 1.81uM 48.0% @ 1.Ou M B-0273 5.03uM 13.0%@1.0uM B-0274 2.68uM 25.0%@1.0uM B-0275 2.67uM 33.0%@1.0uM B-0276 1.25uM 26.0%@1.0uM B-0277 0.68uM 34.0%@1.0uM B-0278 1.26uM 36.0%@1.0uM B-0279 1.39uM 33.0%@1.0uM B-0280 0.86uM 18.0%@1.0uM B-0281 7.37uM 24.0%@1.0uM B-0282 0.75uM 38.0%@1.0uM B-0283 6.66L1M 29.0% @ 1.Ou M B-0284 0.083uM 65.0%@1.0uM B-0285 4.57UM 29.0%@1.0uM B-0286 O.ZZIM 50.0%@1.0uM B-0287 4.0uM 22.0% @ 1.Ou M B-0288 4.46uM 26.0%@1.0uM B-0289 0.15UM 55.0%@1.0uM B-0290 O.BbiM 44.0%@1.0uM B-0291 1.33uM 20.0%@1.0uM B-0292 0.22uM 28.0%@1.0uM B-0293 O.BbiM 53.0%@1.0uM B-0294 0.68uM 45.0%@1.0uM

608

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0295 0.82uM 45.0%@1.0uM B-0296 8.03uM 36.0%@1.0uM B-0297 0.78uM 30.0%@1.0uM B-0298 0.58uM 48.0% @ 1.Ou M B-0299 0.87uM 54.0%@1.0uM B-0300 0.78uM 32.0%@1.0uM B-0301 0.19uM 50.0%@1.0uM B-0302 4.02uM 24.0%@1.0uM B-0303 0.22uM 10.0%@1.0uM B-0304 0.56uM 28.0% @ 1.Ou M B-0305 B-0306 B-0307 B-0308 B-0309 B-0310 B-0311 B-0312 B-0313 B-0314 B-0315 B-0316 B-0317 B-0318 B-0319 B-0320 B-0321 B-0322 B-0323 B-0324 B-0325 B-0326 B-0327 B-0328 B-0329 B-0330 B-0331 B-0332 B-0333 B-0334 B-0335 B-0336

609

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0337 B-0338 B-0339 B-0340 B-0341 B-0342 B-0343 B-0344 B-0345 B-0346 B-0347 B-0348 B-0349 B-0350 B-0351 B-0352 B-0353 1.37uM 55%@1.0uM B-0354 1.0uM 0.6SuM 51% @ 30mpk @ -6h 54% @ 3mpk @ -4h B-0355 0.75uM 40.0%@1.0uM B-0356 0.66uM 24.0%@1.0uM B-0357 1.46uM O.BbiM B-0358 0.37uM 17.0%@1.0uM B-0359 0.45uM 47.0%@1.0uM B-0360 1.6uM 19.0%@1.0uM B-0361 O.ZZIM 46.0%@1.0uM B-0362 0.52uM 27.0%@1.0uM B-0363 4.67uM 25.0%@1.0uM B-0364 1.44uM 27.0%@1.0uM B-0365 0.96uM 27.0%@1.0uM B-0366 0.7uM 46.0%@1.0uM B-0367 1.0uM 23.0%@1.0uM B-0368 I.OuM 0.64UM 37% @ 30mpk @ -6h B-0369 0.16uM 57.0%@1.0uM B-0370 0.65uM 28.0%@1.0uM B-0371 0.49uM 28.0%@1.0uM B-0372 0.35uM 29.0%@1.0uM B-0373 0.45uM 18.0%@1.0uM B-0374 1.38uM 12.0°/o@1.0uM B-0375 1.0uM 19.0%@1.0uM B-0376 2.99uM 12.0%@1.0uM B-0377 1.29uM 36.0%@1.0uM B-0378 1.1uM 36.07o@1.0uM

610

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0379 0.53uM 24.0%@1.0uM B-0380 1.41uM 32.0%@1.0uM B-0381 0.22uM 47.0%@1.0uM B-0382 0.41 µM 32.0%@1.0uM B-0383 1.43uM 10.0%@1.0uM B-0384 4.02uM 16.0%@1.0uM B-0385 0.057uM 0.9uM 30% @ 30mpk @ -6h 0% @ 3mpk @ -4h B-0386 0.13uM 54.0%@1.0uM B-0387 0.41 µM 52.0% @ 1.Ou M B-0388 <0.1 μM 36.0%@1.0uM B-0389 0.01 UM 0.05uM 62% @ 3mpk @ -4h B-0390 0.089uM. 55.0%@1.0uM B-0391 0.86uM 18.0%@1.0uM B-0392 0.13uM 57.0% @ 1.Ou M B-0393 0.043UM 66.0%@1.0uM B-0394 0.13uM 45.0%@1.0uM B-0395 0.087UM 48.0%@1.0uM B-0396 0.097uM 0.44uM B-0397 0.17uM 41.0%@1.0uM B-0398 0.054uM 66.0%@1.0uM B-0399 0.14uM 39.0%@1.0uM B-0400 0.16uM 25.0%@1.0uM B-0401 0.46uM 52.0%@1.0uM B-0402 0.14uM 1.51uM B-0403 1.77uM 2.42UM B-0404 0.31 uM 48.0% @ 1.Ou M B-0405 0.79uM 30.0% @ 1.0u M B-0406 0.54uM 35.0%@1.0uM B-0407 0.76uM 27.0%@1.0uM B-0408 0.5uM 50.0%@1.0uM B-0409 0.53uM 30.0%@1.0uM B-0410 0.38uM 44.0%@1.0uM B-0411 0.62uM 50.0%@1.0uM B-0412 0.24uM 48.0%@1.0uM B-0413 0.18uM 55.0%@1.0uM B-0414 2.54uM 25.0%@1.0uM B-0415 0.42uM 43.0% @ 1.Ou M B-0416 0.32uM 34.0%@1.0uM B-0417 0.91 µM 28.0%@1.0uM - · B-0418 0.22uM 27.0%@1.0uM B-0419 0.85uM 41.0% 21.0uM B-0420 0.83uM 49.0% @ 1.Ou M

611

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Meuse LPS Model% TNF inhib © dose @predose time Rat LPS Model% inhib © dose @predose time B-0421 0.46uM 57.0% @ 1. Ou M B-0422 <0.1 μM 40.0%@1.0uM B-0423 0.18UM 33.0%@1.0uM B-0424 0.083uM 32.0%@1.0uM B-0425 0.26uM 54.0%@1.0uM B-0426 0.055uM 0.74uM 41% @ 3mpk @ -4h B-0427 0.63uM 39.0%@1.0uM B-0428 0.99uM 27.0%@1.0uM B-0429 0.27uM 45.0%@1.0uM B-0430 0.29uM 75.0%@1.0uM B-0431 0.21 μM 64.0%@1.0uM B-0432 <0.1 μM 89.0%@1.0uM B-0433 <0.1uM 92.0%@1.0uM B-0434 0.12uM 65.0%@1.0uM B-0435 O.ZIM 61.0%@1.0uM B-0436 1.11uM 71.0%@1.0uM B-0437 0.58uM 59.0%@1.0uM B-0438 <0.1uM 91.0%@1.0uM B-0439 2.12uM 65.0%@1.0uM B-0440 O.BbiM 63.0%@1.0uM B-0441 0.8uM 58.0%@1.0uM B-0442 <0.1 μM 91.0%@1.0uM B-0443 2.01uM 71.0%@1.0uM B-0444 1.01uM 51.0%@1.0uM B-0445 <0.1 μM 83.0%@1.0uM B-0446 0.78uM 80.0%@1.0uM B-0447 0.19uM 71.0%@1.0uM B-0448 0.4uM 79.0%@1.0uM B-0449 0.83uM 81.0%@1.0uM B-0450 0.26uM 81.0%@1.0uM B-0451 0.071 uM 83.0%@1.0uM 42% @ 30mpk @ -6h B-0452 0.7uM 75.0%@1.0uM B-0453 0.47uM 75.0%@1.0uM B-0454 0.11uM 80.0%@1.0uM B-0455 <0.1 μM 95.0%@1.0uM 36% @ 3mpk% -4h B-0456 1.81uM 67.0%@1.0uM B-0457 0.089uM 81.0%@1.0uM B-0458 O.ZZIM 70.0%@1.0uM B-0459 0.099uM 76.0%@1.0uM B-0460 0.061 µM 92.0%@1.0uM B-0461 0.025uM 96.0%@1.0uM B-0462 <0.1 μM 97.0%@1.0uM ··

612

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose @predose time Rat LPS Model% inhib © dose © predose it B-0463 0.052uM 95.0%@1.0uM B-0464 <0.1 μM 91.0%@1.0uM B-0465 0.084uM 98.0%@1.0uM B-0466 <0.1uM 98.0% @ 1.Ou M 0% @ 3mpk @ -4h B-0467 <0.1 μM 77.0%@1.0uM B-0468 0.031 UM 93.0%@1.0uM B-0469 0.056uM 92.0% @ 1.Ou M B-0470 0.063uM 92.0% @ 1.Ou M B-0471 0.027uM 97.0%@1.0uM B-0472 0.19uM 54.0%@1.0uM B-0473 0.004uM 95.0%@1.0uM B-0474 0.024UM. 86.0%@1.0uM > B-0475 0.21 μM 74.0%@1.0uM B-0476 0.56uM 69.0%@1.0uM B-0477 1.48uM 96.0%@1.0uM B-0478 0.034uM 87.0%@1.0uM B-0479 0.031 μM 90.0% @ 1.Ou M 15% @ 3mpk @ -4h B-0480 0.12uM 88.0%@1.0uM B-0481 0.014uM 95.0%@1.0uM 56% @ 3mpk @ -4h B-0482 0.97uM 68.0%@1.0uM B-0483 0.57uM 68.0%@1.0uM B-0484 0.28uM 62.0% @ 1.Ou M B-0485 0.04uM 95.0%@1.0uM B-0486 0.24uM 80.0%@1.0uM B-0487 0.11uM 89.0%@1.0uM 54% @ 3inpk @ -4h B-0488 0.62uM 88.0%@1.0uM B-0489 O.ZIM 80.0%@1.0uM B-0490 0.91 µM 74.0%@1.0uM B-0491 0.43uM 66.0%@1.0uM B-0492 0.069uM 42.0% @ 1.Ou M B-0493 O.ZIM 36.0%@1.0uM B-0494 0.13UM 30.0%@1.0uM B-0495 0.12uM 25.0%@1.0uM B-0496 0.83uM 16.0%@1.0uM B-0497 0.44uM 31.0%@1.0uM B-0498 O.ZZIM 11.0%@1.0uM B-0499 0.39uM 37.0%@1.0uM B-0500 0.26uM 41.0%@1.0uM B-0501 0.049UM 52.0%@1.0uM B-0502 0.065uM 48.0%@1.OuM B-0503 0.16UM 73.0%@1.0uM B-0504 0.4uM 43.0% @ 1.Ou M

613

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose @predose time Rat LPS Model% inhib © dose © predose it B-0505 0.28uM 44.0% @ 1.Ou M B-0506 0.94uM 43.0%@1.0uM B-0507 0.18uM 75.0%@1.0uM B-0508 2.0uM 48.0%@1.0uM B-0509 0.1uM 86.0%@1.0uM B-0510 0.69uM 61.0%@1.0uM B-0511 0.007uM 90.0%@1.0uM B-0512 1.0uM 53.0%@1.0uM B-0513 0.72UM 52.0% @ 1.Ou M B-0514 0.14uM 87.0% @ 1. Ou M B-0515 0.42uM 61.0%@1.0uM B-0516 0.37uM 84.0% @ 1. Ou M - B-0517 0.094uM 52.0%@1.0uM B-0518 0.11uM 64.0%@1.0uM B-0519 0.043UM 87.0%@1.0uM B-0520 0.4UM 67.0%@1.0uM B-0521 1.37uM 52.0%@1.0uM B-0522 0.15uM 75.0% @ 1.Ou M B-0523 0.19uM 83.0%@1.0uM B-0524 0.4uM 77.0%@1.0uM B-0525 0.16uM 76.0%@1.0uM B-0S26 0.031uM 87.0%@1.0uM B-0527 1.09uM 63.0%@1.0uM 8-0528 0.14uM 70.0%@1.0uM B-0529 0.11uM 73.0% @ 1.Ou M B-0530 5.53uM 45.0%@1.0uM B-0531 0.5uM 48.0%@1.0uM B-0532 0.45uM 1.01uM 41% @ 30mpk @ -6h B-0533 1.23uM 47.0% @ 1.Ou M B-0534 0.41uM 54.0%@1.0uM B-0535 0.44uM 0.87uM B-0536 0.46uM 0.15UM B-0537 3.44uM 51.0%@1.0uM B-0538 1.13uM 45.0% @ 1. Ou M B-0539 2.84uM 21.0%@1.0uM B-0540 3.62uM 54.0% @ 1.Ou M B-0541 3.24UM 28.0%@1.0uM B-0542 1.55uM 50.0% @ 1.Ou M B-0543 1.56uM 43.0%@1.0uM B-0544 1.12uM 27.0% @ 1. Ou M B-0545 1.06uM 41.0%@1.0uM B-0546 1.04uM 18.0%@1.0uM B-0547 1.24uM 21.0%@1.0uM B-0548 1.77UM 28.0%@1.0uM B-0549 2.22uM 22.0%@1.0uM

614

Example # P38 alpha kinase! C50, µM or% U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose @predose time inhib @ conc. (uM) B-0550 2.41uM 14.0%@1.0uM B-0551 1.08uM 56.0°/o@1.0uM B-0552 0.13uM 46.0%@1.0uM B-0553 1.44uM 47.0%@1.0uM B-0554 2.58uM 20.0%@1.0uM B-0555 1.87uM 34.0%@1.0uM B-0556 0.49uM 39.0%@1.0uM B-0557 1.37uM 32.0%@1.0uM B-0558 0.85uM 33.0% @ 1. Ou M B-0559 0.53uM 49.0%@1.0uM B-0560 2.57uM 31.0%@1.0uM B-0561 2.07uM 40.0%@1.0uM B-0562 0.22uM O.ZIM 5% @ 3mpk @ -4h B-0563 0.18uM 0.13uM v B-0564 0.82uM 58%@1.0uM B-0565 0.23uM 0.59uM B-0566 <0.1 μM 0.17UM 0% @ 3mpk @ -4h B-0567 0.14uM 0.28uM B-0568 1.22uM 46.0%@1.0uM B-0569 0.15UM 0.26UM B-0570 0.27uM 46.0%@1.0uM B-0571 0.38uM 44.0%@1.0uM B-0572 0.27uM 41.0%@1.0uM B-0573 0.36uM 1.7uM B-0574 0.13UM O.BbiM 37% @ 3mpk @ -4h B-0575 0.032uM 0.17uM B-0576 0.068UM 0.39uM 65% @ 3mpk @ -4h B-0577 0.091 uM 66.0%@1.0uM B-0578 1.88uM 47.0% @ 1.Ou M B-0579 0.11uM 79.0%@1.0uM B-0580 2.23UM 0.84uM B-0581 0.26UM 2.17uM B-0582 1.03UM 37.0%@1.0uM B-0583 3.93uM 26.0%@1.0uM B-0584 0.66UM 54.0%@1.0uM B-0585 0.83uM 79.0%@1.0uM 50% @ 30mpk @ -6h B-0586 0.81UM 51.0%@1.0uM B-0587 6.84uM 38%@1.0uM B-0588 12.8UM 42%@1.0uM B-0589 1.71uM 42%@1.0uM B-0590 1.57uM 38.0uM B-0591 3.59uM 29.0%@1.0uM B-0592 1.62uM 45.0%@1.0uM B-0593 1.22uM 36.0%@1.0uM B-0594 - 41.0%@1.0uM B-0595 2.42uM 22.0%@1.0uM B-0596 20.0uM 41.0%@1.0uM B-0597 1.68uM 63.0%@1.0uM B-0598 2.12uM 50.0%@1.0uM

615

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell 1C50, IM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © predose this War LPS Model% inhib @dose © predate it B-0599 4.16UM 21.0%@1.0iM B-0600 0.002UM 28.0%@1.0iM B-0601 0.089uM 1.31UM 43% @ 3mpk% -4h B-0602 0.97uM 61.0%@1.0iM ' B-0603 0.09uM 51.0%@1.0iM B-0604 0.3uM 20.0%@1.0iM B-0605 0.18uM 47.0%@1.0iM B-0606 0.17UM 53.0%@1.0iM B-0607 2.79uM 70.0%@1.0iM B-0608 0.059UM 73.0%@1.0iM B-0609 <0.1 μM 87.0%@1.0iM B-0610 <0.1 μM 88.0%@1.0iM B-0611 0.65uM 60.0%@1.0iM B-0612 0.16uM 60.0%@1.0iM B-0613 0.17uM 76.0%@1.0iM B-0614 0.76uM 70.0%@1.0iM 0% @ 3mpk @ -4h B-0615 0.08uM 83.0%@1.0iM B-0616 0.38uM 87.0%@1.0iM B-0617 0.045UM 92.0%@1.0iM B-0618 0.37uM 80.0%@1.0iM B-0619 <0.1 μM 88.0%@1.0iM B-0620 1.59uM 58.0%@1.0iM B-0621 O.ZbiM 68.0%@1.0iM B-0622 0.076uM 78.0%@1.0iM B-0623 0.12uM 76.0%@1.0iM B-0624 0.085uM 54.0%@1.0iM B-0625 0.023UM 88.0%@1.0iM B-0626 <0.1 μM 85.0%@1.0iM B-0627 0.25uM 69.0%@1.0iM B-0628 0.023UM 72.0%@1.0iM B-0629 0.2uM 79.0%@1.0iM B-0630 O. ObiM 77.0%@1.0iM B-0631 0.065UM 81.0%@1.0iM B-0632 <0.1 μM 79.0%@1.0iM B-0633 B.B. 80.0%@1.0iM B-0634 B.B. 40.0%@1.0iM B-0635 0.15uM 55.0%@1.0iM B-0636 <0.1 μM 86.07о@1.0иМ B-0637 0.11mm 92.0%@1.0iM B-0638 0.25mm 89.0%@1.0iM B-0639 0.051 mM 93.0%@1.0iM 50% '®3mpk @ -4h B-0640 O.ZbiM 94.0%@1.0iM B-0641 0.58mm 65.0%@1.0iM B-0642 0.49iM 90.0%@1.0iM B-0643 0.069iM 85.0%@1.0iM 0% @ 3mpk @ -4h B-0644 0.058UM 89.0%@1.0iM B-0645 0.58mm 80.0%@1.0iM B-0646 0.26mm 94.0%@1.0iM B-0647 1.61iM 76.0%@1.0iM

616

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © predose this Rat LPS Model% inhib © dose @predose time B-0648 <0.1 μM 83.0%@1.0uM B-0649 0.83uM 39.0%@1.0uM B-0650 0.006UM 95.0%@1.0uM 8% @ 3mpk @ -4h B-0651 1.78uM 81.0%@1.0uM B-0652 0.19uM 83.0%@1.0uM B-0653 2.01 uM 74.0%@1.0uM B-0654 5.97uM 78.0%@1.0uM B-0655 1.25uM 76.0% @ 1.Ou M B-0656 0.007uM 95.0% @ 1.Ou M 28% @ 3mpk @ -4h B-0657 0.17UM 83.0%@1.0uM B-0658 1.14uM 91.0%@1.0uM B-0659 2.64uM 87.0%@1.0uM B-0660 0.088uM 92.0%@1.0uM B-0661 <0.1 μM. 90.0%@1.0uM B-0662 <0.1uM 95.0%@1.0uM B-0663 0.88UM 74.0%@1.0uM B-0664 0.39UM 80.0%@1.0uM B-0665 0.47uM 72.0%@1.0uM B-0666 0.17uM 73.0%@1.0uM B-0667 0.83uM 75.0%@1.0uM B-0668 0.27uM 78.0%@1.0uM B-0669 0.89UM 34.0%@1.0uM B-0670 3.15uM 32.0%@1.0uM B-0671 6.38uM 36.0%@1.0uM B-0672 6.59uM 32.0%@1.0uM B-0673 8.54uM 48.0%@1.0uM B-0674 2.81 uM 42.0%@1.0uM B-0675 5.42uM 3.0%@1.0uM B-0676 2.09uM 22.0%@1.0uM B-0677 1.63uM 25.0%@1.0uM B-0678 0.38uM 52.0%@1.0uM B-0679 0.062uM 45.0%@1.0uM B-0680 0.42uM 67.0%@1.0uM B-0681 1.96UM 17.0%@1.0uM B-0682 0.76uM 39.0%@1.0uM B-0683 13.0uM 32.0%@1.0uM B-0684 0.54uM 68.0% @ 1. Ou M Β-06Θ5 15.4uM 33.0%@1.0uM B-0686 0.42uM 59.0%@1.0uM B-0687 10.1uM 15.0%@1.0uM B-0688 O.BbiM 58.0%@1.0uM B-0689 14.6uM 27.0%@1.0uM B-0690 27.1uM 36.0%@1.0uM B-0691 0.16uM 48.0%@1.0uM B-0692 0.38uM 29.0%@1.0uM B-0693 0.39uM 28.0%@1.0uM B-0694 0.62uM 21.0%@1.0uM B-0695 0.23uM 32.0% @ 1.Ou M B-0696 0.085UM 35.0%@1.0uM

617

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0697 0.45uM 44.0%@1.0uM B-0698 2.33uM 43.0%@1.0uM B-0699 0.34uM 31.0%@1.0uM B-0700 0.24uM 56.0%@1.0uM B-0701 0.39uM 45.0%@1.0uM B-0702 O.ZbiM 39.07o@1.0uM B-0703 0.12uM 39.0%@1.0uM B-0704 2.19uM 29.0%@1.0uM B-0705 0.44uM 21.0%@1.0uM B-0706 0.44uM 32.0% @ 1. Ou M B-0707 1.7uM B-0708 2.1uM B-0709 0.84uM B-0710 1.99UM B-0711 1.99uM ' B-0712 2.9uM B-0713 4.3uM B-0714 3.7uM B-0715 3.2uM B-0716 4.6uM B-0717 4.3uM B-0718 1.4uM B-0719 3.4uM B-0720 1.3uM B-0721 3.8uM B-0722 0.07uM > 1.0uM B-0723 0.47uM B-0724 O. ObiM 17.0%@1.0uM B-0725 9.7uM B-0726 1.4uM B-0727 0.51UM B-0728 20.0uM B-0729 0.87uM B-0730 0.25uM 11.0%@1.0uM B-0731 0.87uM > 1.0uM B-0732 14.0uM B-0733 32.0UM B-0734 0.92uM B-0735 1.0uM B-0736 26.0uM B-0737 2.6uM B-0738 2.7uM B-0739 4.1uM B-0740 4.4uM B-0741 26.0uM B-0742 2.2uM B-0743 1.2uM B-0744 23.0uM B-0745 6.0uM

618

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell ICSO.uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © predose this Rat LPS Model% inhib © dose © predose it B-0746 0.01 µM 22.0% @ 1.Ou M B-0747 1.1uM B-0748 1.2uM B-0749 4.4uM B-0750 0.92uM B-0751 1.6uM B-0752 O.ZZIM B-0753 0.37uM B-0754 0.55uM B-0755 2.3uM B-0756 0.94uM B-0757 0.54uM 16.0%@1.0uM B-0758 1.5uM B-0759 O.ZIM * B-0760 0.01 µM 13.0%@1.0uM B-0761 <0.1 μM B-0762 0.13uM 5.0%@1.0uM B-0763 0.015uM 17.0%@1.0uM B-0764 0.67uM 26.0%@1.0uM B-0765 O.ZIM 29.0%@1.0uM B-0766 0.95uM B-0767 0.08uM B-0768 1.4uM B-0769 12.7uM B-0770 2.3uM B-0771 0.5uM B-0772 0.8uM B-0773 14.0uM B-0774 1.5uM B-0775 B.B. > 1.OuM B-0776 0.9uM > 1.0uM B-0777 21.0uM B-0778 51.0uM B-0779 0.5uM B-0780 1.1uM B-0781 48.0uM B-0782 22.0uM B-0783 8.0uM B-0784 7.0uM B-0785 23.0uM B-0786 24.0uM B-0787 1.5uM B-0788 1.2uM B-07B9 Z.OiM B-0790 1.0uM 4.0%@1.0uM B-0791 O.ZIM > 1.0uM B-0792 1.1uM B-0793 O.ZIM B-0794 2.9uM 2.0%@1.0uM

619

Example # IC38 p38 alpha kinase, uMor% inhib @ conc. (uM) U937 Cell IC50, uM or% inhibOconc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-0795 1.9uM 11.0%@1.0uM B-0796 1.4uM B-0797 1.04uM - B-0798 1.73uM - B-0799 - > 1.0uM B-0800 1.01uM > 1.0uM B-0801 0.67uM > 1.0uM B-0802 - > 1.0uM B-0803 0.057uM 53.0%@1.0uM B-0804 0.3uM 32.0%@1.0uM B-0805 0.71 μM > 1.0uM B-0806 3.28uM > 1.0uM B-0807 10.8uM - B-0808 3.09uM. > 1.0uM * B-0809 1.22uM 7.0%@1.0uM B-0810 1.11uM > 1.0uM B-0811 2.79uM 2.0%@1.0uM B-0812 2.12uM > 1.0uM B-0813 3.02uM > 1.0uM B-0814 - > 1.0uM B-0815 2.11uM > 1.0uM B-0816 3.46uM > 1.0uM B-0817 3.07uM 33.0%@1.0uM B-0818 4.97uM > 1.0uM B-0819 1.08uM > 1.0uM B-0820 1.64uM 3.0%@1.0uM B-0821 1.44uM - B-0822 1.33uM - B-0823 2.39uM > 1.0uM B-0824 3.41uM - B-0825 - - B-0826 1.74uM - B-0827 15.6uM - B-0828 7.9uM - B-0829 0.61 µM 65.0%@1.0uM B-0830 0.54uM 34.0%@1.0uM B-0831 0.9uM > 1.0uM B-0832 1.49uM - B-0833 0.95uM 23.0%@1.0uM B-0834 1.25uM - B-0835 - - B-0836 1.24uM - B-0837 1.96uM > 1.0uM B-0838 3.1uM - B-0839 4.3uM - B-0840 0.63uM 47.0%@1.0uM B-0841 0.32uM 36.0%@1.0uM B-0842 0.74uM 63.0%@1.0uM B-0843 0.61 µM > 1.0uM

620

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell lC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-0844 0.4uM 25.0% @ 1 .OuM B-0845 1.78uM - B-0846 1.8uM - B-0847 0.73uM 21.0%@1.0uM B-0848 1.56uM - B-0849 1.25uM - B-0850 1.81uM - B-0851 0.91uM 39.0%@1.0uM B-0852 1.02uM - B-0853 - 38.0% @ 1.OuM B-0854 - 25.0%@1.0uM B-0855 - 8.0% @ 1.OuM B-0856 - 38.0%@1.0uM B-0857 6.25uM - > B-0858 2.1uM 48.0% @ 1. OuM B-0859 39.5uM - B-0860 38.1 µM - B-0861 1.32uM 12.0%@1.0uM B-0862 2.15uM 4.0%@1.0uM B-0863 0.81 uM 25.0%@1.0uM B-0864 0.39uM 40.%@1.0uM B-0865 O.BbiM 46.0%@1.0uM B-0866 1.38UM 28.0% @ 1.OuM B-0867 0.62uM > 1.0uM B-0868 3.28uM 8.0%@1.0uM B-0869 4.19uM > 1.0uM B-0870 3.13UM > 1.0uM B-0871 1.9uM > 1.0uM B-0872 3.13uM 3.0% @ 1.OuM B-0873 6.92UM > 1.0uM B-0874 1.92uM > 1.0uM B-0875 2.13UM 8%@1.0uM B-0876 0.89uM > 1.0uM B-0877 1.17uM 13.0%@1.0uM B-0878 O.BbiM 19.0% @ 1.OuM B-0879 0.87uM 1.0%@1.0uM B-0880 0.15uM 40.0% @ 1.OuM B-0881 1.36uM > 1 .OuM B-0882 1.48UM 9%@1.0uM B-0883 1.06uM > 1.0uM B-0884 1.89UM - B-0885 B-0886 B-0887 B-0888 B-0889 B-0890 B-0891 B-0892

621

Example # P38 alpha kinase IC50.UM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © predose this Rat LPS Model% inhib © dose © predose it B-0893 B-0894 B-0895 B-0896 B-0897 B-0898 B-0899 B-0900 B-0901 B-0902 B-0903 B-0904 B-0905 B-0906 , B-0907 B-0908 B-0909 B-0910 B-0911 B-0912 B-0913 B-0914 B-0915 B-0916 B-0917 B-0918 B-0919 B-0920 B-0921 B-0922 B-0923 B-0924 B-0925 B-0926 B-0927 B-0928 B-0929 B-0930 B-0931 B-0932 B-0933 47.0%@1.0uM 37.0%@1.0uM B-0934 67.0% @ 1.Ou Μ 36.0%@1.0uM B-0935 69.0%@1.0uM 54.0%@1.0uM B-0936 69.0%@1.0uM > 1.0uM B-0937 64.0%@1.0uM 1.74UM B-0938 51.O% 01.OuM 29.0%@1.0uM B-0939 78.0%@1.0uM 14.0%@1.0uM B-0940 56.0%@1.0uM 22.0%@1.0uM B-0941 81.0%@1.0uM 25.0%@1.0uM

622

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-0942 82.0%@1.0uM 2.0%@1.0uM B-0943 63.0% @ 10.0uM 24.0%@1.0uM B-0944 45.0%@1.0uM 27.0%@1.0uM B-0945 96.0%@1.0uM 0.93uM B-0946 76.0%@1.0uM 31.0%@1.0uM B-0947 69.0%@1.0uM 34.0% @ 1.Ou M B-0948 68.0%@1.0uM 1.81uM B-0949 90.0%@1.0uM 17.0%@1.0uM B-0950 81.0%@1.0uM 0.58uM B-0951 82.0%@1.0uM 20.0% @ 1.Ou M B-0952 44.0%@1.0uM 21.0%@1.0uM B-0953 63.0% @ 1.Ou M 25.0%@1.0uM B-0954 62.0%@1.0uM 0.52uM B-0955 49.0%@1.0uM 0.54uM B-0956 56.0%@1.0uM 1.33UM B-0957 79.0%@1.0uM 22.0% @ 1.Ou M B-0958 74.0%@1.0uM 0.38uM B-0959 83.0%@1.0uM 39.0%@1.0uM B-0960 48.0% @ 1.Ou M 4.0%@1.0uM B-0961 79.0%@1.0uM 23.0%@1.0uM B-0962 85.0%@1.0uM 2.71 uM B-0963 76.0%@1.0uM 39.0%@1.0uM B-0964 94.0%@1.0uM 5.0uM B-0965 74.0%@1.0uM 1.1uM B-0966 50.0% @ 1.Ou M 5.0%@1.0uM B-0967 80.0%@1.0uM 29.0%@1.0uM B-0968 35.0%@1.0uM 26.0%@1.0uM B-0969 63.0%@1.0uM 35.0%@1.0uM B-0970 76.0%@10.0uM 0.88uM B-0971 61.0%@1.0uM 39.0% @ 1.Ou M B-0972 85.0% @ 1.Ou M 2.0%@1.0uM B-0973 66.0%@10.0uM 48.0%@1.0uM B-0974 57.0%@1.0uM 47.0%@1.0uM B-0975 82.0%@1.0uM 32.0%@1.0uM B-0976 79.0%@1.0uM 36.0%@1.0uM B-0977 60.0% @ 1.Ou M 26.0%@1.0uM B-0978 59.0%@1.0uM 36.0%@1.0uM B-0979 56.0%@10.0uM 23.0%@1.0uM B-0980 68.0%@1.0uM 31.0%@1.0uM B-0981 62.0% @ 1.Ou M 57.0%@1.0uM B-0982 65.0%@1.0uM 23.0%@1.0uM B-0983 75.0%@1.0uM 0.8UM B-0984 60.0% @ 1.Ou M 51.0%@1.0uM B-0985 86.0%@1.0uM 0.75uM B-0986 70.0% @ 1.Ou M 71.0%@1.0uM B-0987 78.0%@1.0uM 79.0%@1.0uM B-0988 72.0% @ 1.Ou M 65.0%@1.0uM B-0989 85.0%@1.0uM 0.85uM B-0990 - 26.0%@1.0uM

623

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose @predose time Rat LPS Model% inhib © dose © predose it B-0991 58.0% @ I.OuM 33.0%@1.0uM B-0992 77.0%@1.0uM 45.0% @ I.OuM B-0993 57.0% © I.OuM 73.0% @ 1.OuM B-0994 55.0% @ I.OuM 43.0% @ I.OuM B-0995 53.0%@1.0uM 14.0% @ I.OuM B-0996 54.0% @ I.OuM 27.0% @ 1.OuM B-0997 69.0% @ 1.0uM 22.0% @ I.OuM B-0998 67.0% @ I.OuM 25.0% @ I.OuM B-0999 61.0%@1.0uM 24.0% @ I.OuM B-1000 55.0% @ I.OuM 42.0% @ I.OuM B-1001 63.0%@1.0uM 31.0%@1.0uM B-1002 70.0% © I.OuM 41.0% @ I.OuM B-1003 74.0% @ I.OuM 29.0% @ I.OuM B-1004 79.0%@1.0uM 45.0% @ I.OuM B-1005 58.0% @ I.OuM 23.0% @ I.OuM B-1006 69.0% @ I.OuM 38.0% @ I.OuM B-1007 52.0% @ I.OuM 34.0% @ I.OuM B-1008 54.0% @ I.OuM 23.0% @ I.OuM B-1009 80.0% © I.OuM 55.0% @ I.OuM B-1010 75.0% @ I.OuM 1.0uM B-1011 72.0% 21 .OuM 17.0% @ I.OuM B-1012 - 20.0% @ I.OuM B-1013 85.0% @ I.OuM 7.0% @ I.OuM B-1014 88.0%@1.0uM 20.0% @ I.OuM B-1015 77.0% @ I.OuM 34.0% @ I.OuM B-1016 58.0%@1.0uM 10.0% @ I.OuM B-1017 96.0% @ I.OuM 58.0% @ I.OuM B-1018 88.0%@1.0uM 34.0% © I.OuM B-1019 82.0%@1.0uM 66.0% @ I.OuM B-1020 87.0% @ I.OuM 36.0% @ I.OuM B-1021 82.0% @ I.OuM 35.0% @ I.OuM B-1022 84.0% @ I.OuM 53.0% @ I.OuM B-1023 93.0%@1.0uM 70.0% @ I.OuM B-1024 89.0% @ I.OuM 57.0% @ 1.OuM B-1025 61.0% @ I.OuM 23.0% @ 1.OuM B-1026 87.0%@1.0uM 53.0% @ 1.OuM B-1027 58.0% @ I.OuM 18.0%@1.0uM B-1028 70.0% @ I.OuM 17.0%@1.0uM B-1029 69.0%@1.0uM 54.0% @ I.OuM B-1030 76.0%@1.0uM 60.0%@1.0uM B-1031 69.0%@1.0uM 42.0% @ I.OuM B-1032 76.0% @ 1.OuM 37.0% @ I.OuM B-1033 86.0%@1.0uM 34.0% @ I.OuM B-1034 66.0% @ I.OuM 39.0%@1.0uM B-1035 75.0% @ I.OuM 52.0% @ I.OuM B-1036 68.0% @ I.OuM 68.0% @ I.OuM B-1037 - 41.0% @ I.OuM B-1038 57.0% @ I.OuM 0.57UM B-1039 - 1.33uM

624

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (im) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-1040 72.0%@1.0uM O.ZvM B-1041 70.0%@1.0uM 73.0%@1.0iM B-1042 79.0%@1.0uM 12.0%@1.0iM B-1043 64.0%@1.0uM 53.0%@1.0iM B-1044 94.0%@1.0uM 0.93UM B-1045 78.0%@1.0uM 25.0%@1.0iM B-1046 72.0% @ 1.Ou M 66.0%@1.0iM B-1047 72.0%@1.0uM 58.0%@1.0iM B-1048 67.0%@1.0uM 19.0%@1.0iM B-1049 67.0%@1.0uM 65.0%@1.0iM B-1050 - 0.54mm B-1051 68.0%@1.0uM 41%@1.0iM B-1052 69.0%@1.0uM 66%@1.0iM B-1053 78.0% @ 1.Ou M 0.4mM B-1054 79.0%@1.0uM 55.0%@1.0iM B-1055 89.0%@1.0uM 63.0%@1.0iM B-1056 89.0%@1.0uM 0.76iM B-1057 85.0%@1.0uM 0.72iM B-1058 0.66UM 43.0%@1.0iM B-1059 0.18UM 24.0%@1.0iM B-1060 0.11uM 32.0%@1.0iM B-1061 0.03UM 19.0%@1.0iM B-1062 <0.1 μM 26.0%@1.0iM B-1063 0.16uM 44.0%@1.0iM B-1064 0.39uM 50.0%@1.0iM B-1065 0.56uM 40.0%@1.0iM B-1066 <0.1 μM 39.0%@1.0iM B-1067 1.6uM 32.0%@1.0iM B-1068 0.48uM 24.0%@1.0iM B-1069 0.22UM 27.0%@1.0iM B-1070 <0.1 μM 44.0%@1.0iM B-1071 <0.1 μM 48.0%@1.0iM B-1072 0.38uM 28.0%@1.0iM B-1073 <0.1 μM 21.0%@1.0iM B-1074 0.23UM 33.0%@1.0iM B-1075 O.OZIM 29.0%@1.0iM B-1076 O. OviM 31.0%@1.0iM B-1077 <0.1 μM 38.0%@1.0iM B-1078 0.26uM 48.0%@1.0iM B-1079 <0.1 μM 40.0%@1.0iM B-1080 0.19UM 28.0%@1.0iM B-1081 <0.1 mM 37.0%@1.0iM B-1082 <0.1 mM 54.0%@1.0iM B-1083 <0.1mM 23.0%@1.0iM B-1084 0.43mm 29.0%@1.0iM B-1085 <0.1 mM 29.0%@1.0iM B-1086 <0.1 mM 42.0%@1.0iM B-1087 0.05mm 32.0%@1.0iM B-1088 0.73iM 49.0%@1.0iM

625

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50.UM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-1089 <0.1 μM 39.0%@1.puM B-1090 <0.1 μM 90.0% @ 1.Ou M B-1091 <0.1uM 73.0%@1.0uM B-1092 0.27uM 85.0%@1.0uM B-1093 O.ZZIM 36.0%@1.0uM B-1094 0.013UM 69.0%@1.0uM B-1095 <0.1 μM 70.0%@1.0uM B-1096 <0.1 μM 32.0%@1.0uM B-1097 <0.1uM 44.0%@1.07uM B-1098 <0.1 μM 82.0%@1.0uM B-1099 0.26uM 74.0%@1.0uM B-1100 0.22UM 56.0%@1.0uM B-1101 0.026uM 82.0% @ 1.Ou M B-1102 0.035uM · 83.0%@1.0uM B-1103 0.094uM 90.0%@1.0uM B-1104 0.12uM 69.0% @ 1.Ou M B-1105 <0.1 μM 84.0%@1.0uM B-1106 <0.1 μM 86.0% @ 1.Ou M B-1107 0.057uM 84.0%@1.0uM B-1108 0.22uM 81.0%@1.0uM B-1109 0.054uM 80.0% @ 1.Ou M B-1110 0.47uM 64.0%@1.0uM B-1111 0.19uM 64.0%@1.0uM B-1112 0.58uM 43.0%@1.0uM B-1113 <0.1 μM 72.0%@1.0uM B-1114 0.069UM 51.0%@1.0uM B-1115 0.024uM 89.0%@1.0uM B-1116 0.41 µM 81.0%@1.0uM B-1117 0.13uM 73.0%@1.0uM B-1118 O.ZZIM 91.0%@1.0uM B-1119 0.35UM 80.0%@1.0uM B-1120 0.47uM 9.0%@1.0uM B-1121 3.58uM 29.0% @ 1.Ou M B-1122 1.84uM 32.0%@1.0uM B-1123 2.93uM 27.0%@1.0uM B-1124 1.49uM 52.0%@1.0uM B-1125 0.56uM 41.0%@1.0uM B-1126 1.5uM > 1.0uM B-1127 0.71 μM 7.0%@1.0uM B-1128 2.55uM 26.0% @ 1.Ou M B-1129 1,07uM 46.0%@1.0uM B-1130 0.5uM 29.0% @ 1.Ou M B-1131 0.076UM 34.0%@1.0uM B-1132 0.72uM 11.0%@1.0uM B-1133 0.38uM 33.0%@1.0uM B-1134 1.71uM 33.0% @ 1.Ou M B-1135 0.23uM 38.0%@1.0uM B-1136 1.17uM 40.0%@1.0uM B-1137 0.038uM 35.0%@1.0uM

626

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose @predose time War LPS Model% inhib @dose © predate it B-1138 1.82uM > 1.0uM B-1139 0.041 μM 29.0%@1.0uM B-1140 1.68UM 39.0%@1.0uM B-1141 2.47uM 32.0%@1.0uM B-1142 0.11uM 37.0%@1.0uM B-1143 0.17uM 40.0%@1.0uM B-1144 0.44uM 72.0% @ 1.Ou M B-1145 1.07uM 71.0%@1.0uM B-1146 0.47uM 61.0%@1.0uM B-1147 0.095UM 53.0%@1.0uM B-1148 0.43uM 61.0%@1.0uM B-1149 1.55uM · 48.0%@1.0uM B-1150 0.47uM 75.0%@1.0uM B-1151 0.32uM 72.0%@1.0uM - B-1152 0.73uM 53.0%@1.0uM B-1153 2.22uM 52.0% @ 1.Ou M B-1154 0.085uM 46.0% @ 1.Ou M B-1155 3.22uM 30.0%@1.0uM B-1156 0.27uM 78.0%@1.0uM B-1157 0.26uM 66.0%@1.0uM B-1158 74%@1.0uM 0.68uM 53% @ 30mpk @ -6h B-1159 66.0%@1.0uM 1.03UM 60% @ 30mpk @ -6h B-1160 79.0%@1.0uM 0.38uM B-1161 64.0% 21.0uM 0.93uM 40% @ 30mpk @ -6h 45% @ 3mpk @ -4h B-1162 79.0%@1.0uM 0.59uM 40% @ 30mpk @ -6h B-1163 74.0%@1.0uM 0.37uM B-1164 - 0.35uM B-1165 66.0%@1.0uM 0.99uM B-1166 77.0%@1.0uM 0.39UM 50% @ 30mpk @ -6h 50% @ 3mpk @ -4h B-1167 70.0%@1.0uM 1.06uM B-1168 66.0%@1.0uM 0.63uM B-1169 80.0% @ 1.Ou M 0.11uM B-1170 82.0%@1.0uM 0.57uM B-1171 78.0%@1.0uM 0.23UM B-1172 68.0%@1.0uM 1.95uM B-1173 65.0%@1.0uM 62%@1.0uM B-1174 80.0%@1.0uM 0.86uM B-1175 72.0%@1.0uM 1.83uM B-1176 67.0%@1.0uM 67.0%@1.0uM B-1177 70.0%@1.0uM 1.16uM B-1178 92.0%@1.0uM 1.61uM B-1179 86.0%@1.0uM 0.41 µM B-1180 78.0%@1.0uM 0.53uM B-1181 79.0%@1.0uM 66%@1.0uM B-1182 72.0%@1.0uM 0.65uM B-1183 77.0%@1.0uM 0.2uM B-1184 69.0% @ 1.Ou M O.BZIM B-1185 71.0%@1.0uM 0.79UM B-1186 83.0%@1.0uM 60%@1.0uM

627

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it War LPS Model% inhib @dose © predate it B-1187 76.0%@1.0uM 1.89uM B-1188 - 36.0% @ 1.OuM B-1189 68.0%@1.0uM 0.83uM B-1190 78.0%@1 .OuM 62.0% @ 1.OuM B-1191 74.0%@1.0uM 57.0% @ 1.OuM B-1192 84.0%@1.0uM 0.47uM B-1193 69.0%@1.0uM 65.0%@1.0uM • B-1194 87.0% @ 1.OuM 0.58uM B-1195 52.0%@1.0uM 60.0% @ 1.OuM B-1196 74.0%@1.0uM 68.0% @ 1.OuM B-1197 77.0% @ 1.OuM 45.0%@1.0uM B-1198 92.0% @ 1.OuM 0.46UM B-1199 87.0% @ 1.OuM 49.0%@1.0uM B-1200 95.0% @ 1.OuM 0.64uM - B-1201 84.0% @ 1.OuM 0.51uM B-1202 71.0%@1.0uM 58.0%@1.0uM B-1203 84.0%@1.0uM 58.0% @ 1.OuM B-1204 68.0% @ 1.OuM 59.0%@1.OuM B-1205 74.0% @ 1.OuM 46.0% @ 1.OuM B-1206 81.0%@1.0uM 0.34uM B-1207 90.0%@1.0uM 58.0% @ 1.OuM B-1208 82.0% @ 1.OuM 51.0%@1.0uM B-1209 86.0% @ 1.OuM 55.0% @ 1.OuM B-1210 82.0% @ 1.OuM 57.0%@1.0uM B-1211 88.0% @ 1.OuM 59.0%@1.0uM B-1212 90.0%@1.0uM 57.0%@1.0uM B-1213 84.0% @ 1.OuM 0.62uM B-1214 76.0% @ 1.OuM 58.0% @ 1.OuM B-1215 86.0% @ 1.OuM 0.23uM B-1216 88.0% @ 1.OuM 0.18uM B-1217 87.0%@1.0uM 0.46UM B-1218 88.0%@1.0uM 76.0%@1.0uM B-1219 85.0% @ 1.OuM 37.0% @ 1.OuM B-1220 81.0%@1.0uM 53.0% @ 1.OuM B-1221 82.0% @ 1.OuM 44.0%@1.0uM B-1222 65.0% @ 1.OuM 9.0% @ 1.OuM B-1223 80.0% @ 1.OuM 61.0%@1.0uM B-1224 82.0% @ 1.OuM 74.0% @ 1.OuM B-1225 89.0%@1.0uM 73.0% @ 1.OuM B-1226 89.0% @ 1.OuM 0.18uM B-1227 83.0% @ 1.OuM 0.22uM B-1228 90.0%@1.0uM 0.72uM B-1229 87.0% @ 1.OuM 0.65UM B-1230 90.0% @ 1.OuM 0.25uM B-1231 94.0% @ 1.OuM 0.56uM B-1232 81.0%@1.0uM 54.0%@1.0uM B-1233 85.0%@1.0uM 0.36uM B-1234 89.0% @ 1.OuM 0.49uM B-1235 0.04uM 76.0% @ 1.OuM

628

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-1236 0.1uM 53.0%@1.0uM B-1237 0.22uM 39.0%@1.0uM B-1238 0.14uM 16.0%@1.0uM B-1239 <0.1 μM 38.0%@1.0uM B-1240 <0.1 μM 59.0%@1.0uM B-1241 0.04uM 81.0%@1.0uM B-1242 0.08uM ' 83.0%@1.0uM B-1243 0.04uM 47.0%@1.0uM B-1244 0.26uM 44.0%@1.0uM B-1245 0.49uM 42.0%@1.0uM B-1246 0.27uM 40.0%@1.0uM B-1247 <0.1 μM 58.0%@1.0uM B-1248 <0.1 μM 68.0%@1.0uM B-1249 0.24uM. 60.0%@1.0uM B-1250 0.14uM 18.0%@1.0uM B-1251 0.41 µM 38.0%@1.0uM B-1252 0.17uM 46.0% @ 1.Ou M B-1253 0.15uM 57.0%@1.0uM B-1254 0.16UM 68.0%@1.0uM B-1255 12.9uM 75.0%@1.0uM B-1256 0.12uM 41.0%@1.0uM B-1257 1.48uM 40.0%@1.0uM B-1258 0.07uM 56.0%@1.0uM B-1259 <0.1 μM 0.48uM B-1260 0.11uM 48.0%@1.0uM B-1261 0.74uM 44.0%@1.0uM B-1262 <0.1 μM 63.0%@1.0uM B-1263 1.05uM 57.0%@1.0uM B-1264 0.32uM 47.0%@1.0uM B-1265 0.43uM 51.0%@1.0uM B-1266 <0.1 μM 58.0%@1.0uM B-1267 <0.1 μM 73.0%@1.0uM B-1268 <0.1 μM 79.0%@1.0uM B-1269 0.46uM 84.0%@1.0uM B-1270 0.47uM 83.0%@1.0uM B-1271 0.13UM 74.0%@1.0uM B-1272 0.014uM 38.0%@1.0uM B-1273 <0.1 μM 36.0%@1.0uM B-1274 <0.1 μM 41.0%@1.0uM B-1275 <0.1 μM 50.0%@1.0uM B-1276 0.062UM 11.0%@1.0uM B-1277 <0.1 μM 47.0%@1.0uM B-1278 0.12uM 85.0%@1.0uM B-1279 <0.1 μM 79.0% @ 1.Ou M B-1280 0.039uM 83.0%@1.0uM B-1281 <0.1 μM 85.0%@1.0uM B-1282 <0.1 μM 75.0%@1.0uM B-1283 <0.1 μM 64.0%@1.0uM B-1284 <0.1 μM 75.0%@1.0uM

629

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-1285 0.057UM 80.0% @ 1. Ou M B-1286 0.15uM 78.0% 21.0uM B-1287 0.25 µM 55.0% @ 1.Ou M B-1288 0.15uM 74.0%@1.0uM B-1289 0.73uM 35.0%@1.0uM B-1290 0.26uM 75.0%@1.0uM B-1291 0.097uM 55.0%@1.0uM B-1292 0.01uM 74.0%@1.0uM B-1293 0.31 uM 48.0%@1.0uM B-1294 0.013uM 54.0%@1.0uM B-1295 0.079UM 74.0%@1.0uM B-1296 0.038uM 48.0% @ 1.0u M B-1297 0.02UM > 1.0uM B-1298 0.055uM 20.0%@1.0uM B-1299 0.091UM ' > 1.0uM B-1300 0.071 uM 18.0%@1.0uM B-1301 0.12uM 15.0%@1.0uM B-1302 0.023UM 11.0%@1.0uM B-1303 0.08uM > 1.0uM B-1304 0.11uM 10.0%@1.0uM B-1305 0.64uM 9.0%@1.0uM B-1306 0.11uM > 1.0uM B-1307 0.009uM 16.0%@1.0uM B-1308 <0.1 UM > 1.0uM B-1309 0.045uM > 1.0uM B-1310 0.12uM 11.0%@1.0uM B-1311 0.05uM 57.0%@1.0uM B-1312 0.35uM > 1.0uM B-1313 0.035UM 37.0% @ 1.Ou M B-1314 0.045uM 24.0%@1.0uM B-1315 0.055UM 12.0%@1.0uM B-1316 0.026UM 36.0% @ 1.Ou M B-1317 0.019uM 9.0%@1.0uM B-1318 <0.1 μM 1.0%@1.0uM B-1319 0.24uM > 1.0uM B-1320 0.047uM 43.0%@1.0uM B-1321 0.47UM 66.0%@1.0uM B-1322 0.12uM 87.0%@1.0uM B-1323 0.013uM 85.0%@1.0uM B-1324 0.16uM 83.0%@1.0uM B-1325 0.27uM 95.0%@1.0uM B-1326 0.092UM 84.0%@1.0uM B-1327 0.13uM 65.0%@1.0uM B-1328 0.032uM 86.0%@1.0uM B-1329 O.BbiM 54.0% @ 1.Ou M B-1330 0.053uM 85.0%@1.0uM B-1331 0.004uM 85.0%@1.0uM B-1332 0.007UM 81.0%@1.0uM B-1333 0.45uM 76.0%@1.0uM

630

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-1334 0.13uM 73.0%@1.0uM B-1335 0.097uM 63.0%@1.0uM B-1336 0.072uM 83.0%@1.0uM B-1337 0.4uM 90.0% @ 1.Ou M B-1338 0.18uM 73.0%@1.0uM B-1339 0.12uM 67.0%@1.0uM B-1340 0.043uM 63.0%@1.0uM B-1341 0.42UM 52.0%@1.0uM B-1342 0.25uM 59.0%@1.0uM B-1343 0.065UM 83.0%@1.0uM B-1344 0.014uM 86.0%@1.0uM B-1345 0.27uM 73.0%@1.0uM B-1346 0.043UM 86.0% @ 1.Ou M B-1347 0.021 μM 84.0%@1.0uM B-1348 0.009uM 69.0%@1.0uM B-1349 0.037UM 86.0%@1.0uM B-1350 0.019 µM 78.0% @ 1.Ou M B-1351 0.068UM 78.0%@1.0uM B-1352 0.013UM 76.0% @ 1.Ou M B-1353 0.062uM 80.0%@1.0uM B-1354 0.013uM 83.0%@1.0uM B-1355 0.07uM 75.0%@1.0uM B-1356 0.059uM 91.0%@1.0uM B-1357 0.18uM 84.0%@1.0uM B-1358 0.16uM 76.0% @ 1.Ou M B-1359 0.005 84.0%@1.0uM B-1360 0.11 0.15UM 54% @ 3mpk @ -4h B-1361 0.03 0.29uM B-1362 0.003 0.29UM B-1363 0.009 0.28uM 51.0%@30pmk @ 6H 53% @ 3mpk @ -4h B-1364 0.009 0.27uM 53.0% @ 30mpk @ - 6.0H 17% @ 3mpk @ -4h B-1365 0.17 88.0%@1.0uM B-1366 0.04 0.27uM B-1367 <0.1 0.22UM B-1368 0.031 O.ZZIM 44.0%@30mpk B-1369 <0.1 0.29uM B-1370 <0.1 0.77UM B-1371 0.06 83.0%@1.0uM B-1372 <0.1 0.41UM 48.0%@30mpk B-1373 0.016 0.17uM B-1374 <0.1 0.28uM B-1375 0.01 0.25uM B-1376 0.009 0.26uM 3.0%@30mpk @ -6H B-1377 0.12 5.0uM B-1378 0.02 1.04uM B-1379 <0.1 0.092UM B-1380 <0.1 0.26UM

631

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Meuse LPS Model% TNF inhib @ dose © overtake it Rat LPS Model% inhib © dose © predose it B-1381 0.055 0.73uM B-1382 <0.1 0.44uM B-1383 0.0012 0.15uM B-1384 0.57 0.37uM B-1385 <0.1 0.11uM B-1386 <0.1 0.25uM B-1387 <0.1 0.1uM B-1388 0.57 1.38uM B-1389 0.06 0.57uM B-1390 <0.1 71.0%@1.0uM B-1391 0.016uM 82.0%@1.0uM B-1392 0.059uM 82.0%@1.0uM B-1393 3.17uM 80.0%@1.0uM B-1394 0.32uM. 78.0%@1.0uM > B-1395 1.48 61.0%@1.0uM B-1396 1.55 73.0%@1.0uM B-1397 0.92 85.0%@1.0uM B-1398 0.67 83.0%@1.0uM B-1399 0.14 74.0%@1.0uM B-1400 0.024 83.0%@1.0uM B-1401 0.033 75.0%@1.0uM B-1402 0.12 76.0%@1.0uM B-1403 4.54 71%@1.0uM B-1404 0.6 70%@1.0uM B-1405 0.28 70%@1.0uM B-1406 1.39 56.0%@1.0uM B-1407 0.4 71.0%@1.0uM B-1408 0.27 69.0%@1.0uM B-1409 <0.1 72.0%@1.0uM B-1410 <0.1 69%@1.0uM B-1411 <0.1 81.0%@1.0uM B-1412 0.097 80.0%@1.0uM B-1413 0.016 78.0%@1.0uM B-1414 0.025 83.0%@1.0uM B-1415 1.41 79.0%@1.0uM B-1416 0.14 81.0%@1.0uM B-1417 0.069 69.0%@1.0uM B-1418 1.01 82.0%@1.0uM B-1419 0.3 84.0%@1.0uM B-1420 <0.1 82.0%@1.0uM B-1421 0.014 75.0%@1.0uM B-1422 0.58 68.0%@1.0uM B-1423 1.58 84.0%@1.0uM B-1424 0.86 76.0%@1.0uM B-1425 0.09 83.0%@1.0uM B-1426 0.19 80.0%@1.0uM B-1427 <0.1 84.0%@1.0uM B-1428 <0.1 86.0%@1.0uM B-1429 <0.1 87.0%@1.0uM

632

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell lC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © dose © overtake it Rat LPS Model% inhib © dose © predose it B-1430 0.75uM 35.0% @ 1.0uM B-1431 O.ZbiM 58.0% @ 1.0uM B-1432 0.11uM 51.0% @ 1.0uM B-1433 0.26uM 21.0% @ 1.0uM B-1434 0.19uM 28.0% @ 1.0uM B-1435 1.8uM 45.0% @ 1.0uM B-1436 1.0uM 20.0% @ 1.0uM B-1437 O.ZIM 23.0% @ 1.0uM B-1438 2.01uM 27.0% @ 1.Ou M B-1439 1.7uM 17.0% @ 1.0uM B-1440 0.87uM 3.0% @ 1.0uM B-1441 1.95uM 66.0% @ 1.0uM B-1442 1.54uM 18.0% @ 1.0uM B-1443 0.014uM 83.0% @ 1.0uM B-1444 O.ZIM 24.0% @ 1.0uM B-1445 0.43uM 27.0% @ 1.0uM B-1446 0.77uM 36.0% @ 1.0uM B-1447 0.5uM 34.0% @ 1.0uM B-1448 1.43uM 22.0% @ 1.0uM B-1449 1.61uM 50.0%@1.0uM B-1450 2.1 uM 49.0%@1.0uM B-1451 2.88uM 50% @ 1.0uM B-1452 2.41uM 47.0%@1.0uM B-1453 2.53uM 49.0% @ 1.0uM B-1454 1.6uM 12.0% @ 1.0uM B-1455 1.21uM 8.0% @ 1.0uM B-1456 1.29uM > 1.0uM B-1457 0.43uM 43.0% @ 1.0uM B-1458 0.95UM 65.0% @ 1.0uM B-1459 0.67uM 46.0% @ 1.0uM B-1460 0.96uM 29.0% @ 1.0uM B-1461 0.4uM 39.0% @ 1.0uM B-1462 0.22uM 50.0% @ 1.0uM B-1463 2.34uM 26.0% @ 1.0uM B-1464 1.18uM 27.0% @ 1.0uM B-1465 3.23uM 31.0% @ 1.0uM B-1466 1.69uM > 1.0uM B-1467 1.22uM 1.0% @ 1.0uM B-1468 1.61uM 10.0% @ 1.0uM B-1469 0.37uM 14.0% @ 1.0uM B-1470 B.B. 28.0% @ 1.0uM B-1471 0.85uM 25.0% @ 1.0uM B-1472 0.93uM 12.0%@1.0uM B-1473 1.24uM 14.0% @ 1.0uM B-1474 1.23uM 31.0% @ 1.0uM B-1475 2.1uM 24.0% @ 1.0uM B-1476 0.047uM 42.0% @ 1.0uM B-1477 2.5uM 34.0% @ 1.0uM B-1478

633

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ reach out to them Rat LPS Model% inhib © dose @predose time B-2270 0.72uM 31%@10.0uM B-2271 0.93uM 387o@10.0uM B-2272 0.26uM 53.07o@10.0uM B-2273 1.92uM 39.07o@10.0uM B-2274 0.26uM 59.07o@10.0uM B-2275 2.16uM 53.07o@10.0uM B-2276 11.5uM 37.07o@10.0uM B-2277 14.9uM 44.07o@10.0uM B-2278 0.8uM 51.07o@10.0uM B-2279 0.32uM 36.07o@10.0uM B-2280 0.4uM 57.07o@10.0uM B-2281 0.81 uM 60.07o@10.0uM B-2282 0.91uM 41.07o@10.0uM B-2283 0.04uM 53.07o@10.0uM B-2284 4.61uM 62.07o@10.0uM B-2285 2.29uM 49.07o@10.0uM B-2286 0.017uM 0.78uM 257o @ 30mpk @ -1h B-2287 2.56uM 61.07o@10.0uM B-2288 6.51uM 46.07o@10.0uM B-2289 3.0uM 30.07o@10.0uM B-2290 2.37uM 59.07o@10.0uM B-2291 0.019uM 417o@10.0uM B-2292 8.82uM 57.07o@10.0uM B-2293 2.11uM 56.07o@10.0uM B-2294 1.68uM 50.07o@10.0uM B-2295 1.79uM 56.07o@10.0uM B-2296 17.3uM 63.07o@10.0uM B-2297 3.59uM 57.07o@10.0uM B-2298 0.29uM 4.22uM B-2299 1.97uM 62.07o@10.0uM B-2300 0.07uM 43.07o@10.0uM B-2301 0.18uM 44.07o@10.0uM B-2302 1.0uM 58.07o@1.0uM B-2303 0.011uM 54.07o@10.0uM B-2304 1.41uM 50.07o@10.0uM B-2305 0.54uM 60.07o@10.0uM B-2306 5.88uM 39.07o@10.0uM B-2307 2.29uM 69.07o@10.0uM B-2308 O.BbiM 56.07o@10.0uM B-2309 0.29uM 47.07o@10.0uM

634

Example # P38 alpha kinase IC50, µM or% inhibOconc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model% TNF inhib © reach out to them Rat LPS Model% inhib © dose © predose it B-2310 0.12uM 1.2uM 50% @ 30mpk @ -6h B-2311 7.18uM 607o@10.0uM B-2312 2.93uM 43.07o@10.0uM B-2313 42.3uM 58.07o@10.0uM B-2314 11.0uM 66.07o@10.0uM B-2315 0.49uM 36.07o@10.0uM B-2316 0.46uM 58.07o@10.0uM B-2317 1.0uM 60.07o@10.0uM B-2318 73.0%@10.0uM 25.07o@10.0uM B-2319 75.07o@10.0uM 40.07o@10.0uM B-2320 44.07o@10.0uM 35.07o@10.0uM B-2321 69.07o@10.0uM 27.07o@10.0uM B-2322 76.07o@10.0uM 38.07o@10.0uM B-2323 69.07o@10.0uM 46.07o@10.0uM B-2324 58.07o@10.0uM 36.07o@10.0uM B-2325 60.07o@10.0uM 51.07o@10.0uM B-2326 76.07o@10.0uM 33.07o@10.0uM B-2327 76.07o@10.0uM 23.07o@10.0uM B-2328 65.07o@10.0uM 28.07o@10.0uM B-2329 72.07o@10.0uM 53.07o@10.0uM B-2330 81.07o@10.0uM 37.07o@10.0uM B-2331 74.07o@10.0uM 44.07o@10.0uM B-2332 70.07o@10.0uM 47.07o@10.0uM B-2333 58.07o@10.0uM 36.07o@10.0uM B-2334 81.07o@10.0uM 45.07o@10.0uM B-2335 82.07o@10.0uM 50.07o@10.0uM B-2336 48.07o@10.0uM 35.07o@10.0uM B-2337 46.07o@10.0uM 59.07o@10.0uM B-2338 73.07o@10.0uM 50.0% @ 10.Ou M B-2339 84.07o@10.0uM > 10.0uM B-2340 35.07o@10.0uM 12.0%@10.0uM B-2341 75.07o@10.0uM 50.0%@10.0uM B-2342 83.07o@10.0uM 46.0%@10.0uM B-2343 43.07o@10.0uM 27.0%@10.0uM B-2344 71.07o@10.0uM 50.0%@10.0uM B-2345 64.07o@10.0uM 38.0%@10.0uM B-2346 45.07o@10.0uM 48.0%@10.0uM B-2347 49.07o@10.0uM 50.0%@10.0uM B-2348 76.07o@10.0uM 48.0%@10.0uM B-2349 75.07o@10.0uM 27.0%@10.0uM

635

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model 7o TNF inhib © reach out to them Rat LPS Model% inhib © dose © predose it B-2350 38.0%@10.0uM 56.07o@10.0uM B-2351 77.0%@10.0uM 1.0%@10.0uM B-2352 37.07o@10.0uM 19.07o@10.0uM B-2353 38.0%@10.0uM 33.0%@10.0uM B-2354 65.07o@10.0uM 25.0%@10.0uM B-2355 84.07o@10.0uM 50.0%@10.0uM B-2356 77.07 »@ 10.OuM 45.0%@10.0uM B-2357 47.07o@10.0uM 41.0%@10.0uM B-2358 17.07o@10.0uM 52.0%@10.0uM B-2359 76.07o@10.0uM 35.0%@10.0uM B-2360 45.07o@10.0uM > 10.0uM B-2361 19.07o@10.0uM 46.0%@10.0uM B-2362 607o@100.0uM 39.0%@10.0uM B-2363 44.07 = @ 10.0uM 1.0%@10.0uM B-2364 47.07o@10.0uM 4.0%@10.0uM B-2365 82.07o@10.0uM 43.0%@10.0uM B-2366 70.0% @ 10.OuM 59.0%@10.0uM B-2367 46.0%@10.0uM 40.07o @ I.OuM B-2368 65.0%@10.0uM 55.0%@10.0uM B-2369 32.0%@10.0uM > 10.0uM B-2370 73%@100.0uM 20.0%@10.0uM B-2371 54.07o@10.0uM 36.0%@10.0uM B-2372 55.0%@100.0uM > 10.OuM B-2373 50.07o@100.0uM 6%@10.0uM B-2374 35.0%@10.0uM 20.0%@10.0uM B-2375 62.0%@100.0uM > 10.OuM B-2376 32.0%@10.0uM 17.0%@10.0uM B-2377 34.0%@10.0uM 17.0%@10.0uM B-2378 48.0%@10.0uM 61.0%@10.0uM B-2379 73.0%@100.0uM 45.0% @ I.OuM B-2380 81%@100.0uM 53.0%@10.0uM B-2381 68%@100.0uM 2.0%@10.0uM B-2382 51.0%@10.0uM 24.0%@10.0uM B-2383 63.0%@10.0uM 35.0%@10.0uM B-2384 497o@100.0uM 10.0%@10.0uM B-2385 79.0%@10.0uM 19.07o@10.0uM B-2386 38.0%@10.0uM 19.0%@10.0uM B-2387 50.07o@100.0uM > 10.0uM B-2388 42.0%@10.0uM 24.0%@10.0uM B-2389 39.0%@10.0uM 29.0%@10.0uM

636

Example # P38 alpha kinase IC50, µM or% inhib @ conc. (uM) U937 Cell IC50, uM or% inhib @ conc. (uM) Mouse LPS Model 7 ₀ TNF inhib © dose © predose time Rat LPS Model 7o inhib © dose © predose it B-2390 34.07o@10.0uM 27.07o@1.0uM B-2391 40.07o@10.0uM 59.07o@10.0uM B-2392 63.0%@10.0uM 46.07o@10.0uM B-2393 43.07o@10.0uM > 10.0uM B-2394 37.07o@10.0uM 22.07o@10.0uM B-2395 32.07o@10.0uM 28.07o@10.0uM B-2396 75.07o@10.0uM > 10.0uM B-2397 83.07o@10.0uM 22.07o@10.0uM B-2398 557o@100.0uM. 10.07o@10.0uM B-2399 69.07o@10.0uM 18.07o@10.0uM B-2400 60.07o@10.0uM 40.07o@10.0uM B-2401 78.07o@10.0uM 44.07o@10.0uM B-2402 43.07o@10.0uM 52.07o@10.0uM B-2403 727o@100.0uM 52.07o@10.0uM B-2404 587o@100.0uM 52.07o@10.0uM B-2405 477o@100.0uM > 10.0uM B-2406 45.07o@10.0uM 24.07o@10.0uM B-2407 477o@100.0uM 27.07o@10.0uM B-2408 39.07o@10.0uM 10.07o@10.0uM B-2409 78.07o@10.0uM 26.07o@10.0uM B-2410 33.07o@10.0uM 32.07o@10.0uM B-2411 267o@100.0uM 13.07o@10.0uM B-2412 40.07o@10.0uM 31.07o@10.0uM B-2413 75.07o@10.0uM 37.07o@10.0uM B-2414 86.07o@10.0uM 38.07o@10.0uM B-2415 94.07o@10.0uM 50.07o@10.0uM B-2416 85.07o@10.0uM 43.07o@1.0uM B-2417 83.07o@10.0uM 18.07o@10.0uM B-2418 88.07o@10.0uM 34.07o@10.0uM B-2419 86.07o@10.0uM 66.07o@10.0uM B-2420 70.07o@10.0uM 34.07o@10.0uM B-2421 89.07o210.0uM 38.07o@10.0uM B-2422 90.07o@10.0uM 17.07o@10.0uM B-2423 85.07o@10.0uM > 10.0uM B-2424 86.07o@10.0uM 43.07o@10.0uM B-2425 79.07o@10.0uM 42.07o@10.0uM B-2426 88.07o@10.0uM 53.07o@10.0uM B-2427 87.07o@10.0uM 59.07o@10.0uM B-2428 82.07o@10.0uM 50.07o@10.0uM B-2429 92.07o@10.0uM 32.07o@10.0uM

637

Example # P38 alpha kinase IC50.UM or% inhib @ conc. (uM) U937 Cell lC50, uM or 7o inhib @ conc. (uM) Mouse LPS Model% TNF inhib @ dose © predose Rat LPS Model% inhib © dose © predose it B-2430 90.0%@10.0uM 61.0% @ 1 O.OuM B-2431 85.0% 21O.OuM 68.0%@10.0uM B-2432 86.0% 210.0uM 40.0%@1 O.OuM B-2433 94.0%@1 O.OuM 84.0%@10.0uM B-2434 92.0% @ 10. Ou M 63.0%@10.0uM B-2435 84.0%@10.0uM 4.07o@10.0uM B-2436 80.0%@10.0uM 54.0%@10.0uM B-2437 82.0% @ 1 O.OuM 41.0%@1 O.OuM B-2438 75.0%@1 O.OuM 40.07o@10.0uM B-2439 81.0%@10.0uM 44.0%@10.0uM B-2440 77.0%@10.0uM 78.0%@10.0uM B-2441 86.0%@1 O.OuM 46.07o@10.0uM B-2442 86.0%@1 O.OuM > 1 O.OuM B-2443 84.07o@1 O.OuM 44.0%@10.0uM B-2444 89.07o@10.0uM 7.0%@10.0uM B-2445 94.0%@10.0uM 15.0%@1 O.OuM B-2446 90.0%@10.0uM 28.0%@10.0uM B-2447 94.0%@10.0uM > 1 O.OuM B-2448 75.0%@10.0uM 30.0% @ 1 O.OuM B-2449 86.0%@10.0uM 42.07o@10.0uM B-2450 87.0%@10.0uM 46.0%@1.0uM B-2451 87.0%@10.0uM 45.0%@10.0uM B-2452 89.0%@10.0uM 33.0%@10.0uM B-2453 91.0%@1 O.OuM > 1 O.OuM B-2454 88.0%@10.0uM 40.0%@1 O.OuM B-2455 87.0%@10.0uM 54.0%@10.0uM B-2456 86.0%@10.0uM 53.0%@10.0uM B-2457 90.07o@1 O.OuM 18.0% @ 1 O.OuM B-2458 83.0%@10.0uM 36.0%@10.0uM B-2459 82.0%@10.0uM 81.0%@1 O.OuM B-2460 80.0% @ 10.Ou M 79.0%@10.0uM B-2461 67.0%@10.0uM 59.0%@10.0uM

638

Claims (25)

A compound, a tautomer of the compound or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound corresponds to a structure of Formula I: t> 1 ^x ί as for R: R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenyl-alkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkyl, hydroxyalkyl. hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkoxyalkyl, alkyloxyalkyl, aryloxyalkyl. heterocyclyloxyalkyl, alkoxyalkyloxy, mercaptoalkyl. alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene. amino. aminoalkyl, alkylamino, alkenylamino, alkynylamino. arylamino. heterocyclylamino, alkylsulfinyl, alkenylsulfinyl. alkynylsulfinyl. arylsulfinyl, heterocyclylsulfinyl. alkylsulfonyl, alkenylsulfonyl. alkynylsulfonyl. arylsulfonyl. heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene. heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene. alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene and heterocyclylcarbonyloxyalkylene; or 639 R ¹ corresponds to a structure of formula (II): R ²⁵ O ⁿ (R); in which i is a number from 0 to 9; R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamino; as for R ²⁶ and R ²⁷ : R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R ²⁷ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene. alkylarylalkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene. alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene. alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene. aryloxyarylene, aralkoxyarylene. alkoxyheterocyclylalkylene. aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene. alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonyl 640 arylene, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where: 641 said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : R ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylboxycarboxycarboxylcarboxy cycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbylamino; said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl; or R corresponds to a structure of formula (III): 642 _R 30 C ----- (CH 2) j R ³¹ H " C R ³⁴ (ΙΠ) or R ² e-CR ⁴¹ R ⁴² ; R is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl. arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ¹ ', R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 643 wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, allyloxy, aryloxy, aryloxy, aryloxy, aryloxy, , arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkylcarboxycarbonylcarbonylcarbonylcarbonylcarbonyl oxycarbonyl, alkoxycarbonylamino, alkoksiaralkilamino, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilheterotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil and -NR ⁴⁴ R ^45; R '' is not 2-pyridinyl. when R ⁴ is a phenyl ring containing a 2hydroxy substituent and when R ¹ is hydrogen; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino: R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: 644 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, alkylthio, alkylthio, alkylthioalkyl arylalkyl, arylalkyl, arylalkyl, aryl, alkyl noalkilen, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. A compound, tautomer or salt according to claim 1, characterized in that for R ¹ : R ¹ is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, alkyalkylalkyl, alkyloalkyl, alkyloalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, lower arylamino, lower alkylaminoalkylene and lower heterocyclylalkylene; or R ¹ corresponds to a structure of formula (II): 645 i is selected from the group consisting of 0, 1 or 2; le Is selected from the group consisting of: hydrogen, as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene and lower alkylaminoalkyl; and R ²⁷ is selected from the group consisting of lower alkyl, lower cycloalkyl, lower alkynyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower tsikloalkenilalkilen, lower tsikloalkilarilen, lower tsikloalkiltsikloalkil, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl. lower phenylalkylphenylene, lower alkylheterocyclyl. lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene. lower alkoxyphenylalkyl, lower alkoxyheterocyclyl. lower alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene. lower alkoxycarbonylheterocyclyl. lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxy 646 fenilaminokarbonilalkilen, lower aminokarbonilalkilen, lower arilaminokarbonilalkilen, lower alkilaminokarbonilalkilen, lower fenilkarbonilalkilen, lower alkoksikarbonilfenilen, lower fenoksikarbonilfenilen, lower alkilfenoksikarbonilfenilen, lower fenilkarbonilfenilen, lower alkilfenilkarbonilfenilen, lower alkoksikarbonilheterotsiklilfenilen, lower alkoksikarbonilalkoksifenilen, lower heterotsiklilkarbonilalkilfenilen, lower alkiltioalkilen, tsikloalkiltioalkilen, lower alkiltiofenilen, lower fenilalkiltiofinilen, lower heterocycles ophenylene, lower phenylthioalkylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene, where: said lower alkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower fenalkil, lower cycloalkylalkylene, lower alkilheterotsiklilfenilen, lower alkoxyphenyl, lower fenoksifenilen, lower fenilaminokarbonilalkilen, lower fenoksikarbonilfenilen, lower fenilkarbonilfenilen, lower alkiltiofenilen, lower heterotsikliltiofenilen, lower feniltioalkilfenilen and lower alkylsulfonylphenylene are optionally substituted by one or more radicals independently selected from the group consisting of lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ⁴⁶ R ⁴⁷ or R and R together with the nitrogen atom to which they are attached form from a 4 to 8 membered heterocyclic ring, said heterocycle being optionally substituted by one or more radicals independently selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl , heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenyloxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower 647 alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino; wherein said phenyl, biphenyl, naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene are optionally substituted by one or more radicals independently selected from the group consisting of halogen, lower alkyl and lower alkoxy; R ⁴⁶ is lower alkoxycarbonyl; R ⁴⁷ is selected from the group consisting of lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene and lower phenylalkylthioalkyl, where: said phenylalkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : Lower, lower alkyl, lower alkyl, phenyl; , lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenylcarbonylalkyl, lower cycloalkenyl, lower carboxyalkylcarbonylcarbonyl terotsiklil, lower alkoksikarbonilheterotsiklilkarbonil, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoksikarbonilaminoalkilamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; where 648 said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, lower alkyl, lower alkynyl, phenyl, 5- to 6-membered heterocyclylcysteylcyclylcyclylalkyl lower heterocyclopaedic phenylalkylsulfonyl and phenylsulfonyl; or R ² is -CR ⁴¹ R ⁴² or R ² corresponds to a structure of the formula selected from the group consisting of: D Η Ί (VII) in which: j is selected from the group consisting of 0, 1 or 2; m is 0; R 0 and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, 649 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocycloalkyl; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ³⁵ , C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; as for R ³⁵ : R is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, tsikloalkenilalkilen, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylaryl, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkyl, alkoksiaralkil, alkoxyarylene, aryloxyalkylene, aralkoksialkilen , cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonyl eterocyclyl, arylcarbonyloxyalkylaryl and alkylthioalkylene; where said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, alkoxycarbonyl, and alkylcarbonyl, may be substituted by one or more amino, nitro and cyano; or R ³⁵ is CHR ⁴⁸ R ⁴⁹ or R ³⁵ is -NR ⁵⁰ R ⁵¹ ; wherein R ³⁶ is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, 650 arylaryl, aralkyl, aralkenyl, heterotsiklilheterotsiklil, karboksiarilen, alkoxyarylene, alkoksikarbonilarilen, alkilkarbonilaminoarilen, alkilkarbonilaminoheterotsiklil, arilkarbonilaminoalkilheterotsiklil, alkylaminoaryl, alkylamino, alkylaminoaryl, alkilsulfonilarilen, alkilsulfonilaralkil and arilsulfonilheterotsiklil; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl and alkylsulfonylarylene are optionally substituted by one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkyl, alkoxy, alkoxy, alkoxy, alkoxy R is selected from the group consisting of arylsulfonylamino and alkylarylsulfonylamino; R ⁵⁰ is alkyl; R ⁵¹ is aryl; as for R ³⁷ and R ³⁸ : R is selected from the group consisting of hydrogen and alkyl; and R is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylaryl, cycloalkylalkylene, heterocyclylalkylene, alkilheterotsiklilalkilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, ariloksiarilen, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoksikarbonilarilen, alkilkarbonilkarbonilalkilen , alkylaminoalkylene, alkylamino aralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonyl aralkyl and aminosulfonyl aralkyl; wherein said aryl, heterocyclyl, aralkyl and heterocyclylalkylene are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; or 651 R ³⁸ e -CR ⁵² R ⁵³ or R and R together with the nitrogen atom to which they are attached form a heterocycle; R ⁵² is alkoxycarbonyl; R ⁵³ is alkylthioalkylene; as for R ³⁹ and R ⁴⁰ : R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl, and: R ⁴⁰ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alk ksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen alkylene oarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen where: 652 said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ³⁹ is -CHR ²⁸ R ²⁹ or R ³⁹ and R ⁴⁰ together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, wherein said aralkyl and heterocyclyl are optionally substituted by one, or more, subgroups, or subgroups; R ⁴¹ is phenyl; R ⁴² is hydroxy; k is a number from 0 to 3; 653 as for R ⁵⁶ and R ⁵⁷ ; R ⁵⁶ is selected from the group consisting of hydrogen or lower alkyl; and R is selected from the group consisting of hydrogen or lower alkyl; or R ⁵⁶ and R ⁵⁷ form a lower alkylene bridge; R is selected from the group consisting of hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C (O) R ⁵⁹ , -SO ₂ R ⁶⁰ and -C (R) and ( ⁶¹ ) C (O) R ⁶⁰ and ( ⁶¹ ) C ( ⁶⁰ ) 61C ( ⁶¹⁾ ; R ⁵⁹ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenyloxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaryl; wherein said aryl, heterocyclyl and aralkyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶⁰ is selected from the group consisting of alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylethylsilylalkyl; wherein said aryl, heterocyclyl and aralkyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; R ⁶¹ is selected from the group consisting of alkyl, aryl, alkylarylene and alkoxyarylene; where 654 said aryl group being optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; R is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl and ⁴³ (IV), wherein R ³ radicals of pyridinyl, pyrimidinyl, quinolinyl and purinyl are optionally substituted by one or more radicals independently selected from the group consisting of lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower fenilheterotsiklil, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkyl carbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino. lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino. lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino. lower alkylaminocarbonyl, lower alkoxyphenylalkylamino. hydrazinyl. lower alkylhydrazinyl and -NR ⁴⁴ R ⁴⁵ ; wherein R ⁴³ is selected from the group consisting of hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkoxyalkyl and lower aryloxyalkyl; 655 wherein R ⁴⁴ is selected from the group consisting of lower alkylcarbonyl and amino, R ⁴⁵ is selected from the group consisting of lower alkyl or lower phenylalkyl; R ⁴ is selected from the group consisting of hydrogen, lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, naphthyl, and 5- to 10-membered heterocyclyl, where lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, naphthyl, and 5- 10-membered heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of lower alkylthio, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, haloalkyl, haloalkyloxy, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl, haloalkyl amino, cyano, nitro, lower alkylamino and hydroxy; unless otherwise noted, lower alkyl is a linear or branched radical having from one to ten carbon atoms; unless otherwise noted, lower alkenyl is a linear or branched radical having from two to six carbon atoms; unless otherwise noted, lower alkynyl is a linear or branched radical having from two to six carbon atoms; unless otherwise noted, lower cycloalkyl is a saturated radical having from three to eight carbon atoms; unless otherwise noted, lower cycloalkenyl is a partially unsaturated radical having from three to eight carbon atoms; unless otherwise noted, the lower aryl is a monocyclic aryl radical; and 656 unless otherwise noted, the lower heterocyclyl represents a 4-8 membered heterocyclyl. A compound, tautomer or salt according to claim 1 R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl, trifluoromethyl, propylthiophenyl, pyrrolidinyl, pyrrolidinyl; dichloropropyl, ethenyl, propenyl, ethynyl, propyrgyl, 1-propynyl, 2-propyl, benzyl, phenylmethyl, morpholinyl, pyrrolidinylmethyl, ethylenediamine dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercapto-methyl and methylthiomethyl; as for R ² : 'Y R is selected from the group consisting of hydrogen, chlorine, fluorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloropropylmethyl , difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, morpholino ynyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, Ν, Νdimetilamino, N-ethylamino, Ν, Ν-diethylamino, N-n-propylamino, Ν, Ν 657 dimethylamino, 1H-methyl-L1-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobenyl, cyclopentenyl, cyclopentyl , Ν, Ν-dimethylaminoethylamino, Ν, Ν-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylaminoethylaminocarbonyl amino, 1,1-dimetiletoksikarbonilaminopropilamino, piperazinylcarbonyl, and 1,1-dimetiletoksikarbonilpiperazinilkarbonil; wherein aryl, heteroaryl, cycloalkyl and cycloalkenyl are optionally substituted by one or more radicals independently selected from the group consisting of chlorine, fluorine, bromine, keto, methyl, ethyl, isopropyl, tertbutyl, isobutyl, benzyl, carboxy, methoxy, ethoxy , phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl and 1,1-dimethylethylcarbonyl; or R ² is -CR ⁴¹ R ⁴² ; R ⁴¹ is phenyl; R ⁴² is hydroxy; R is selected from the group consisting of pyridinyl, pyrimidinyl and purinyl; wherein the pyridinyl, pyrimidinyl, and purinyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, chlorine, fluorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, amoxycarbonyl, amino , methylcarbonylamino, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethyl, 658 chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, p-butoxy, methylamino, ethylamino, dimethylamino, diethyl amino, 2-methylbutylamino, propargylamino, aminoethylamino, aminoethylamino, aminomethyl diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, Ν, мети-dimethylaminoethylamino, hydroxypropylamino, hydroxypropylamino, ethyloxyethylaminoethylaminoethylamine hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, fenilmetilpiperidinilamino, phenylmethylamino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, metoksifenilmetilamino, hydrazinyl, 1-metilhidrazinil and -NR ⁴⁴ R ^45; R ⁴⁴ is selected from the group consisting of methylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of methyl, ethyl and phenylmethyl; and R ⁴ is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl, piperidinyl. thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydro-pyranyl, tetrahydrofuryl, benzhydrobenzylbenzorobenzyl wherein cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, chlorine, fluorine, 659 bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy. A compound, tautomer or salt according to claim 3, characterized in that R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl and morpholinylethyl; R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N, N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, Nmethylpiperazinyl and piperazinylamino; wherein phenyl, piperidinyl and pyridinyl are optionally substituted by one or more radicals independently selected from the group consisting of chlorine, fluorine, bromine, methyl, ethyl and trifluoromethyl; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl and quinolinyl; wherein the pyridinyl, pyrimidinyl and quinolinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamylamines , aminomethyl, amino, hydroxy and methylcarbonyl; and R ⁴ is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl are optionally substituted by one or more radicals independently selected from the group, 660 consisting of methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy. Compound, tautomer or salt according to claim 4, characterized in that R ¹ is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, methyl and ethyl; R 1 is selected from the group consisting of pyridinyl, pyrimidinyl and quinolinyl; wherein pyridinyl, pyrimidinyl and quinolinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamylamines , aminomethyl, amino, hydroxy and methylcarbonyl; and R ⁴ is phenyl optionally substituted by one or more radicals independently selected from the group consisting of methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy. A compound, tautomer or salt according to claim 2, characterized in that R ⁵ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, trifluoromethyl, chloromethyl, dichloromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl, trifluoromethyl dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperazinylmethyl, piperazinylmethyl, piperazinylmethyl, methyl, ethoxymethyl, amino, methylamino, dimethylamino, 661 phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl and methylthiomethyl; R corresponds to a structure of the formula selected from the group consisting of: r ³⁰ ------ C ----- (CH3), R ³¹ _r 53 (VI), in which: j is selected from the group consisting of 0, 1 or 2; m is 0; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen and lower alkyl; R ³² is selected from hydrogen, lower alkyl. lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene. aryloxyalkylene. aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl. lower alkylcarbonylalkylene, lower phenylcarbonylalkylene and lower heterocyclylcarbonylaminoalkylene; R ³³ is selected from the group consisting of hydrogen, lower alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ as for R ³⁵ : R ³⁵ is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower 662 phenylalkyl, lower phenylcycloalkyl, lower tsikloalkenilalkilen, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, fenilfenilen, lower fenilheterotsiklil, lower alkoxy, lower alkenoxy, lower alkoxyalkyl, lower alkoksifenalkil, lower alkoxyphenyl, lower fenoksialkilen, lower fenilalkoksialkilen, lower cyclo-alkiloksialkilen, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonyl heterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene and lower alkylthioalkylene; wherever, where phenyl, naphthyl, lower heterocyclic, lower heterocyclic, lower alkyloxy, lower heterocyclic, heterocyclyl; from halo, alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; R ³⁵ is CHR ⁴⁸ R ⁴⁹ or R ³⁵ is -NR ⁵⁰ R ⁵¹ ; R is selected from the group consisting of phenylsulfonylamino and lower alkylphenylsulfonylamino; R ⁴⁹ is selected from the group consisting of lower phenylalkyl, amino, lower alkylamino and lower phenylalkylamino; R ⁵⁰ is lower alkyl; R ⁵¹ is aryl selected from the group consisting of phenyl, biphenyl and naphthyl; R 'is selected from the group consisting of lower alkyl, lower haloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower 663 cycloalkylalkylene, lower alkylphenylene, lower alkenilfenilen, fenilfenilen, lower fenalkil, lower phenylalkenyl, lower heterotsiklilheterotsiklil, karboksifenilen, lower alkoxyphenyl, lower alkoksikarbonilfenilen, lower alkilkarbonilaminofenilen, lower alkilkarbonilaminoheterotsiklil, lower fenilkarbonilaminoalkilheterotsiklil, lower alkilaminofenilen, lower alkylamino, lower alkilaminofenilen, lower alkilsulfonilfenilen, lower alkylsulfonylphenylalkyl and lower phenylsulfonylheterocyclyl; wherein said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl and lower alkylsulfonylphenylene are optionally substituted by one or more radicals independently selected from halo, hydroxyl, halo, hydroxy alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; as for R ³⁷ and R ³⁸ : R is selected from the group consisting of hydrogen and lower alkyl; and Lower alkyl, lower alkenyl, lower phenyl, lower phenyl, lower phenyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminosulfonylaminoalkylalkylaminoalkylalkylaminoalkyl yl, lower alkilkarbonilaminoalkilen, lower alkiltiofenilen, lower alkilsulfonilfenilalkil and lower aminosulfonilfenilalkil; wherein said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl and lower heterocyclylalkylene are optionally substituted by one 664 or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or R ³⁸ is -CR ⁵² R ⁵³ or 37 38 R hR together with the nitrogen atom to which they are attached form 4 to An 8-membered heterocycle; R ⁵² is lower alkoxycarbonyl; R ⁵³ is lower alkylthioalkylene; as for R ³⁹ and R ⁴⁰ : R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl, and: R ⁴⁰ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alk ksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, alkylene arilaminokarbonilalkilen, alkylene aminokarbonilalkilen, aminoalkyl, alkilaminoalkoksiarilaminokarbonilarilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoxycarbonyl heterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkyl 665 thioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene and alkylaminosulfonylarylene, where: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ³⁹ is -CHR ²⁸ R ²⁹ or R ³⁹ and R ⁴⁰ together with the nitrogen atom to which they are attached form a heterocycle where: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; k is a number from 0 to 2; R ⁵⁶ is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, aryl selected from the group consisting of phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower 666 alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C (O) R ⁵⁹ , -SO ₂ R ⁶⁰ , -C (O) NHR ⁶¹ ; R ⁵⁹ is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkyl, lower alkoxyphenyl, lower alkoksifenalkil; wherein said phenyl, biphenyl, naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower haloalkoxy, nitro and cyano; R ⁶⁰ is selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower heterotsiklilheterotsiklil, lower alkoxyphenyl, lower alkylamino, lower alkilaminofenilen, lower alkilsulfonilfenilen and lower fenilsulfonilheterotsiklil; wherein said phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower haloalkoxy, lower haloalkoxy, nitro and cyano; R ⁶¹ is selected from the group consisting of lower alkyl, phenyl, biphenyl and naphthyl, lower alkylphenylene and lower alkoxyphenylene; wherein said phenyl, biphenyl and naphthyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; 667 R 'is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl and purinyl; wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl aminocarbonyl, methylcarbonyl, methylcarbamide; and, ethoxy, propyloxy, p-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-L1phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cytosylamino, cytosylamino, cytosylamino, cytosylamino, cytosylamino, cytosylamino, cytosilyl methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2hydroxy) ethylamino, piperidinylmethyl, pyridinylaminomethyl, pyridinylaminomethyl nilamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylA7 A! hydrazinyl or -NR R, R is selected from the group consisting of methylcarbonyl and amino; R ⁶³ is selected from the group consisting of methyl, ethyl and phenylmethyl; and R ⁴ is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, 668 biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl , dihydrobenzofuryl and benzodioxolyl; wherein cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, chlorine, fluorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy , phenoxy, benzyloxy, fluoromethyl, difluoromethyl, trifluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy. A compound, tautomer or salt according to claim 6, characterized in that R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl and morpholinyl ethyl; R ² corresponds to a structure of the formula selected from the group consisting of: ------------------------- (VII), (VIII); 669 j is selected from the group consisting of 0, 1 and 2; m is 0; R ³⁰ is hydrogen; R 'is selected from the group consisting of hydrogen and lower alkyl; R ³² is selected from the group consisting of hydrogen and lower alkyl; R ³³ is selected from the group consisting of lower alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkoxy, lower alkoxyalkylene, lower phenoxyalkylene and lower phenylalkoxy; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted is one or more radicals independently selected from the group consisting of halo, lower alkyl and lower haloalkyl; R is selected from the group consisting of lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenyl; wherein said phenyl and lower heterocyclyl groups are optionally substituted is one or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; R ³⁷ is hydrogen; R is selected from the group consisting of lower alkyl, phenyl and lower alkylphenylene; as for R ³⁹ and R ⁴⁰ : R ³⁹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl, and: 670 R ⁴⁰ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alk ksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen alkylene oarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen where: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ³⁹ is -CHR ²⁸ R ²⁹ or 671 R ³⁹ and R ⁴⁰ together with the nitrogen atom to which they are attached form a heterocycle where: said heterocyclic heterocyclic moiety; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; k is selected from the group consisting of 0 and 1; R ⁵⁶ is hydrogen; R ⁵⁷ is hydrogen; R ⁵⁸ is selected from the group consisting of -C (O) R ⁵⁹ and -SO ₂ R ⁶⁰ ; R ⁵⁹ is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, phenyl, lower alkylphenylene and lower alkoxyalkylene, where: said phenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; R ⁶⁰ is lower alkyl; R 1 is selected from the group consisting of pyridinyl, pyrimidinyl and quinolinyl; wherein the pyridinyl, pyrimidinyl and quinolinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxide, methoxy, dimethylamino, benzylamylamines , aminomethyl, amino, hydroxy and methylcarbonyl; and 672 R ⁴ is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, chloro, fluoro, ethyl, bromo, methyl, methyl , ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy. A compound, tautomer or salt according to claim 7, characterized in that R ¹ is selected from the group consisting of hydrogen and methyl; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl and quinolinyl; wherein the pyridinyl, pyrimidinyl and quinolinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamylamines , aminomethyl, amino, hydroxy and methylcarbonyl; and R ⁴ is phenyl optionally substituted by one or more radicals independently selected from the group consisting of methylthio, chlorine, fluorine, bromine, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy . A compound, tautomer or salt according to claim 1, wherein R ¹ is hydrogen. A compound, tautomer or salt according to claim 2, wherein R ¹ is hydrogen. A compound, tautomer or salt according to claim 3, wherein R ¹ is hydrogen. 673 A compound, tautomer or salt according to wherein R ¹ is hydrogen. A compound, tautomer or salt according to claim 1, wherein R ¹ is selected from the group Claim Claim 6, 3, from methyl and ethyl. A compound, tautomer or salt according to claim 1, wherein R ¹ is selected from the group consisting of claim 6, from methyl and ethyl. A compound, tautomer or salt, wherein R ² is hydrogen. A compound, tautomer or salt, wherein R ² is hydrogen. A compound, tautomer or salt according to claim 1, wherein R ⁴ is optionally substituted phenyl. A compound, tautomer or salt according to claim wherein R ⁴ is optionally substituted phenyl. A compound, tautomer or salt according to claim 1, wherein R ⁴ is optionally substituted phenyl. A compound, a tautomer, wherein R ^{1 is a} claim 2, 3, 2, 3, 6, or and the R ² salt according to claim are independently selected from 2, hydrogen, methyl or ethyl. 21. A compound, tautomer or characterized in that R ¹ and R ² salt according to claim 3 are independently selected from hydrogen, methyl or ethyl. A compound, tautomer or salt according to claim 2, characterized in that 1 2 R and R- are independently selected from hydrogen, methyl and ethyl; and R ⁴ is optionally substituted phenyl. 674 A compound, tautomer or salt according to claim 3, characterized in that 1 2 R and R are independently selected from hydrogen, methyl or ethyl; and R ⁴ is optionally substituted phenyl. A compound, tautomer or salt according to claim 1, characterized in that: the compound corresponds to a structure of Formula IX: Z is selected from the group consisting of = N- and = C (H) -; and R ¹ is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and as for R ² : R ² is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl. lower hydroxyalkyl. lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkilaminoalkilamino, lower aminoalkyl, lower aminoalkylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower karboksitsikloalkil, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoksikarbonilaminoalkilamino, lower heterocyclylcarbonyl, lower 675 alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; where: phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkyl lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² is -CR ^4, R ⁴² ; R ⁴¹ is phenyl; R ⁴² is hydroxy; R ⁴ is selected from the group consisting of hydrogen, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- to 10-membered heterocyclyl, phenyl, biphenyl and naphthyl; wherein lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5 to 10 membered heterocyclyl, phenyl, biphenyl and naphthyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, lower alkoxy , lower haloalkyl, lower alkylthio, lower alkylamino, nitro and hydroxy; R ⁵ is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, alkyloxycarbonyl, alkyloxycarbonyl aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylaminoalkylalkylalkylalkylaminoalkylamino 676 aminocarbonyl, lower alkoxy aralkylamino, hydrazinyl and lower alkylhydrazinyl, and -nr ⁴⁴ r ⁴⁵ , R ⁴⁴ is selected from the group consisting of lower alkylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer or salt according to claim 24, characterized in that: R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl and propargyl; R ² is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N- propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinylamino, , 1 - dimethyl) ethylcarbonyl l am inopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1 dimethylethylpiperazinylcarbonyl; wherein phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl , and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is selected from the group consisting of cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, 677 thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl are optionally substituted by one or more radicals, independently selected from, selected from, chloro, , methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; R ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylaminylamino, 2-methylaminoamino, 2 dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpyridinylmethylamino, aminomethyl, cyclopropylamino, amino, aminocarbonylamino, amino methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ , R ⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of methyl and benzyl. A compound, tautomer or salt according to claim 24, wherein R ¹ is hydrogen. A compound, tautomer or salt according to claim 25, wherein R ¹ is hydrogen. A compound, tautomer or salt according to claim 24, wherein R ¹ is lower alkyl. A compound, tautomer or salt according to claim 25, wherein R ¹ is lower alkyl. 678 30. Compound, tautomer or salt, according to claim 24, wherein R ² is hydrogen. 31. Compound, tautomer or salt, according to claim 25, wherein R ² is hydrogen. 32. Compound, tautomer or salt, according to claim 24, characterized in that R ¹ and R ² are independent selected from hydrogen, methyl and ethyl. 33. Compound, tautomer or salt, according to claim 25, characterized in that R ¹ and R ² are independent selected from hydrogen, methyl and ethyl. 34. Compound, tautomer or salt, according to claim 25, characterized in that Z is = C (H) -. 35. Compound, tautomer or salt, consent • claim 1, characterized in that the compound corresponds to a structure of Formula X: Z is selected from the group consisting of = N- = C (H) -; R ¹ is selected from the group consisting of lower alkyl. lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; as for R ': 'Y R is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, 679 pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkilaminoalkilamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxy xicarbonylheterocyclylcarbonyl; wherein phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkyl lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² e-CR ⁴¹ R ⁴² , R ⁴¹ is phenyl; R ⁴² is hydroxy; R ⁴ is selected from the group consisting of 5- to 10-membered heteroaryl, phenyl, biphenyl and naphthyl; wherein heteroaryl, phenyl, biphenyl and naphthyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino hydroxy ; R ⁵ is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, alkyloxycarbonyl, alkyloxycarbonyl 680 aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoksiaralkilamino, lower alkilaminoalkilamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkilheterotsiklilamino, lower alkylaminocarbonyl, lower alkoksiaralkilamino, hydrazinyl, lower alkilhidrazinil, and -NR ⁴⁴ R ^45, R ⁴⁴ is selected from the group consisting of lower alkylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer or salt according to claim 35, characterized in that: R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; R ² is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-propylamino, N-propylamino, N-propylamino, N-propylamino Aminopropylamine, amino acid , 1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinyl carbonyl and 1,1-dimethylethylpiperazinylcarbonyl; wherein phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, chlorine, bromine, keto, 681 methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, ethyl, methoxy, methyl, methyl ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; R ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylaminomethylamino, dimethylmethylamino, dimethylmethylamino, dimethylamino, , hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpyridinylmethylamino, aminomethyl, cyclopropylamino, amino, amino, amino, amino, amino carbonylamino, metoksifenilmetilamino, phenylmethylamino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, hydrazinyl, 1-metilhidrazinil h-NR ⁴⁴ R ^45; R ⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of methyl and benzyl. A compound, tautomer or salt according to claim 35, wherein R ¹ is lower alkyl. A compound, tautomer or salt according to claim 36, wherein R ¹ is lower alkyl. 682 A compound, tautomer or salt according to claim 35, wherein R ² is hydrogen. A compound, tautomer or salt according to claim 36, wherein R ² is hydrogen. A compound, tautomer or salt according to claim 35, characterized in that R ¹ is selected from the group consisting of methyl and ethyl, and R is selected from the group consisting of hydrogen, methyl and ethyl. A compound, tautomer or salt according to claim 36, characterized in that R ¹ is selected from the group consisting of methyl and ethyl, and 'Y' R is selected from the group consisting of hydrogen, methyl and ethyl. A compound, tautomer or salt according to claim 35 wherein Z is = C (H) -. A compound, tautomer or salt according to claim 1, characterized in that: the compound corresponds to a structure of Formula XI: R '(XI); Z is selected from the group consisting of = N- and = C (H) -; R ¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; as for R ² ; 683 Lower alkyl, phenyl, biphenyl, lower alkyl, lower alkaloid; , lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkyl, alkyloxycarboxy onilaminoalkilamino, lower heterocyclylcarbonyl, lower alkoksikarbonilheterotsiklil and lower alkoksikarbonilheterotsiklilkarbonil; wherein phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkyl lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² is -CR ⁴¹ R ⁴² ; R ⁴¹ is phenyl; R ⁴² is hydroxy; R ⁴ is selected from the group consisting of 5- to 10-membered heteroaryl, phenyl, biphenyl and naphthyl; wherein heteroaryl, phenyl, biphenyl and naphthyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, hydroxyamino ; R is selected from the group consisting of Baloxyl / amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower 684 alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoksiaralkilamino, lower alkilaminoalkilamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkilheterotsiklilamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoksiaralkilamino, hydrazinyl, and lower alkylhydrazinyl or -NR ⁴⁴ R ⁴⁵ ; R ⁴⁴ is selected from the group consisting of lower alkylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer or salt according to claim 44, characterized in that: R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; R is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-propylamino, N-propylamino, N-propylamino phenylamino, aminomethyl, aminobutyrate ) ethylcarbonylaminopropyl but, (1,1-dimethyl) etilkarbonilaminoetilamino, piperazinylcarbonyl, and 1,1-dimetiletilpiperazinilkarbonil; wherein phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, chlorine, bromine, keto, 685 methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl are optionally substituted by one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, ethyl, methyloxy, methyloxy, methyl , ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; R ⁵ is selected from the group consisting of fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, dimethylaminoethylamine hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyloxycarbonyloxycarbonyl nilmetilamino, phenylmethylamino, fluorfenilmetilamino, fluorfeniletilamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1 -metilhidrazinil and -NR ⁴⁴ R ⁴⁵ ; R ⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of methyl and benzyl. A compound, tautomer or salt according to claim 44, wherein R ¹ is lower alkyl. A compound, tautomer or salt according to claim 45, wherein R ¹ is lower alkyl. 686 A compound, tautomer or salt according to claim 44, wherein R ² is hydrogen. A compound, tautomer or salt according to claim 45, wherein R ² is hydrogen. A compound, tautomer or salt according to claim 44, characterized in that: R ¹ is selected from the group consisting of methyl and ethyl; and R is selected from the group consisting of hydrogen, methyl and ethyl. A compound, tautomer or salt according to claim 45, characterized in that: R ¹ is selected from the group consisting of methyl and ethyl, and R ² is selected from the group consisting of hydrogen, methyl and ethyl. A compound, tautomer or salt according to claim 44, wherein Z is = C (H) -. A compound, tautomer or salt according to claim 1, characterized in that: the compound corresponds to a structure of Formula IX, N (IX); Z is selected from the group consisting of = N- and = C (H) -; 687 R ¹ is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; as for R ² : R ² is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, phenylalkyl, alkylamino, alkylamino, alkylamino, alkylamino, alkylamino lower aralkin, lower aliphatic, ect. ino, lower alkoksikarbonilaminoalkilamino, lower heterocyclylcarbonyl, lower alkoksikarbonilheterotsiklil and lower alkoksikarbonilheterotsiklilkarbonil; wherein phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylaminoalkylaminoalkylaminoalkylaminoalkyl lower heterocyclylalkylamino, lower alkylcarbonyl, lower hydroxyalkylcarbonyl, and lower alkoxycarbonyl; or R ² is -CR ⁴¹ R ⁴² ; R ⁴¹ is phenyl, R ⁴² is hydroxy; R ⁴ is phenyl optionally substituted by one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; 688 R ⁵ is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, alkyloxycarbonyl, alkyloxycarbonyl lower carboxylic acid ylamino, hydrazinyl and lower alkylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ ; R ⁴⁴ is selected from the group consisting of lower alkylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer or salt according to claim 53, characterized in that: R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl and propargyl; R is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-propylamino, N-propylamino, N-propylamino phenylamino, aminomethyl, aminobutyrate ) ethylcarbonylaminopropyl but, (1,1-dimethyl) etilkarbonilaminoetilamino, piperazinylcarbonyl, and 1,1-dimetiletilpiperazinilkarbonil; where 689 phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, chlorine, bromine, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is phenyl optionally substituted by one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; R ⁵ is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylaminylamino, 2-methylaminoamino, 2 dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) -ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, aminobutyric, amino toxiphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl and 1-methylhydrazinyl, h-NR ⁴⁴ R ⁴⁵ ; R ⁴⁴ is selected from the group consisting of methylcarbonyl and amino; and R ⁴⁵ is selected from the group consisting of methyl and benzyl. A compound, tautomer or salt according to claim 53, wherein R ¹ is selected from the group consisting of hydrogen and lower alkyl. A compound, tautomer or salt according to claim 53, wherein R ¹ is selected from the group consisting of hydrogen and lower alkyl. 690 57. Compound, tautomer or salt, according to claim 53, wherein R ¹ is hydrogen. 58. Compound, tautomer or salt, according to claim 54, wherein R ¹ is hydrogen. 59. Compound, tautomer or salt, according to claim 53, wherein R ² is hydrogen. 60. Compound, tautomer or salt, according to claim 54, wherein R ² is hydrogen. 61. Compound, tautomer or salt, according to claim 53, wherein R ⁴ is phenyl substituted by one or more radicals independently selected from the group consisting of fluorine, chlorine and bromine. A compound, tautomer or salt according to claim 54, wherein R ⁴ is phenyl substituted with one or more radicals independently selected from the group consisting of fluorine, chlorine and bromine. 63. A compound, tautomer or salt according to claim 53, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen, methyl and ethyl. A compound, tautomer or salt according to claim 54, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen, methyl or ethyl. 65. A compound, tautomer or salt according to claim 53, wherein Z is -C (H) ~. 66. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, characterized in that: the compound corresponds to a structure of Formula IX: 691 ε r ¹ (ix); ί Z is selected from the group consisting of = N- and = C (H) -. R ¹ is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl and lower alkynyl; R ² is selected from the group consisting of hydrogen and lower alkyl; R ⁴ is selected from the group consisting of phenyl and benzodioxolyl; wherein the phenyl is optionally substituted by one or more halo radicals; R ⁵ is selected from the group consisting of hydrogen, halo and alkylhydrazinyl; unless otherwise noted, lower alkyl is a linear or branched radical having from one to ten carbon atoms; unless otherwise noted, lower alkynyl is a linear or branched radical having from two to six carbon atoms; unless otherwise noted, lower hydroxyalkyl is a linear or branched radical having from one to six carbon atoms and one or more hydroxyl groups. 67. A compound, tautomer or salt according to claim 66, wherein: Z is = C (H) -; R ¹ is selected from the group consisting of hydrogen, methyl, hydroxyethyl and propargyl; R ² is hydrogen; 692 R ⁴ is selected from the group consisting of phenyl and benzodioxolyl; wherein the phenyl is optionally substituted by one or more radicals independently selected from the group consisting of chlorine, fluorine and bromine; R ⁵ is selected from the group consisting of hydrogen, fluorine and 1methylhydrazinyl. 68. A compound, tautomer or salt according to claim 67, characterized in that: Z is = C (H) -; R ¹ is selected from the group consisting of hydrogen and methyl; R ² is hydrogen; R ⁴ is phenyl optionally substituted by one or more radicals independently selected from the group consisting of chlorine, fluorine and bromine; and R ⁵ is selected from the group consisting of hydrogen and fluorine. A compound, tautomer or salt according to claim 1, characterized in that the compound is selected from the group consisting of: 4- [5- (3-fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazole -4-yl] pyridine; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; 4- [5-methyl-3- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5-methyl-3- [4- (methylthio) phenyl] -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (2,5-dimethylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (1,3-benzodioxol-5-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (1,1'-biphenyl) -4-yl] -3-methyl-1H-pyrazol-4-yl] pyridine; 693 4- [3-methyl-5- [3- (phenoxyphenyl)] -1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- [3- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- [2- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine; 2- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol; 3- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol; 1-hydroxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridinium; 5- (4-fluorophenyl) -1H, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-fluorophenyl) -1'-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 4- [5- (4-Fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] pyridine; 4- (5-cyclohexyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Fluoro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-methylphenyl) -3-propyl-1H-pyrazol-4-yl] pyridine; 4 - [(3-methyl-5-phenyl-1H-pyrazol-4-yl) methyl] pyridine; 4- [3,5-bis (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [4-methyl-2- (2-trifluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (2-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (2,4-dimethylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (4-Chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-fluoro-2-methylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3,5-dimethylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3,5-dimethoxyphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (3-nitrophenyl) -1H-pyrazol-4-yl] pyridine; B1, N-dimethyl-4- [5-methyl-4- (4-pyridinyl) -1H-pyrazol-3-yl] benzenamine; 4- [3- (2,3-dihydrobenzofuran-5-yl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-bromophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (2-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 694 4- [3-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine; 4- (3-ethyl-4-phenyl-1H-pyrazol-4-yl) pyridine; 4- [5- (3-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-ethyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (3,4-difluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Ethoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine; 4- [3-methyl-5- (3-thienyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (2,4-Dichlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Chloro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; ethyl 3- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazole-5-propanoate; 4- [3- (4-fluorophenyl) -1-methyl-pyrazol-4-yl] pyridine; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [3-methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2-amine; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine; 2-methoxy-5- [3-methyl-5- (3-methylphenyl) -1H-pyrazo-4-yl] pyridine; 2-methoxy-5- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 695 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine; 2-methoxy-4- [3-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 2-methoxy-4- [3-methyl-5- (2-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine; 4- [5- (4-fluorophenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxypyridine; 2-methoxy-4- [3-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl] pyridine; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-ol; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-methanamine; 5- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (3-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Chlorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (4-Methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-carboxamide; 4- [5- (3-Fluoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (4-Fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 696 4- [5- (4-Chloro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (2,3-Dihydrobenzofuran-6-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (Benzofuran-6-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Fluoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Chloro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (1-cyclohexylene-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- (5- (1,3-cyclohexadien-1-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (5,6-Dihydro-2H-pyran-4-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl) pyridine; 4- [5- (4-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Methoxy-5-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-furyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; 2-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2-carboxylate; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-2-carboxylate; 1- [4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-2-yl] ethanone; N, 1-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-2-amine; 3-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; 3-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3-carboxylate; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine-3-carboxamide; 1- [4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridin-3-yl] ethanone; 3-bromo-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine; N, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-3-amine; 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine; 2-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidine; 697 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine; T4, L-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine; 4- (5,6-dihydro-2H-pyran-4-yl) -3-methyl-5-phenyl-1H-pyrazole; 3-methyl-5-phenyl-4- (3-thienyl) -1H-pyrazole; 4- (3-furyl) -3-methyl-5-phenyl-1H-pyrazole; 3-methyl-5-phenyl-4- (2-thienyl) -1H-pyrazole; 4- (2-furyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (3-Isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 3-methyl-5-phenyl-4- (5-thiazolyl) -1H-pyrazole; 3-methyl-4- (5-oxazolyl) -5-phenyl-1H-pyrazole; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 2-methyl-4- [3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- (1-methyl-3-phenyl-1H-pyrazol-4-yl) pyridine; 4- (3-phenyl-1H-pyrazol-4-yl) pyridine; 2-methyl-4- (3-phenyl-1H-pyrazol-4-yl) pyridine; 4- [3- (3-chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1-methyl-pyrazol-4-yl] pyridine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] 2-methylpyridine; 4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3-chlorophenyl) -1-methyl-pyrazol-4-yl] -2-methylpyridine; 5- (4-chlorophenyl) -1H-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -L-methyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine 698 dihydrate; 5- (3-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; N, N-dimethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N-ethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N, L-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -1H-1H-diethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] morpholine; 5- (4-chlorophenyl) -E1-propyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -1H- (phenylmethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine hydrate (2: 1); 5- (4-chlorophenyl) -N4- (2-methoxyethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine monohydrate; 1,1 - dimethylethyl 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1 piperazinecarboxylate; 1- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine trihydrochloride; 1- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methylpiperazine; 1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] - 1-piperazinecarboxylate; 1- [5- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine trihydrochloride; B1- [5- (4-chlorophenyl) -4- [2- (phenylmethyl) amino] -4-pyridinyl] -1H-pyrazole- 3-yl] -1,3-propandiamine trihydrochloride; 1- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4- (phenylmethyl) piperazine; 4- [3- (4-fluorophenyl) -5- (1-piperazinyl) -1H-pyrazol-4-yl] pyrimidine dihydrochloride; 1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 699 amino] propyl] carbamate; N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1,3-propandiamine trihydrochloride monohydrate; 1,1-dimethylethyl [2 - [[5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] amino] ethyl] carbamate; 1,1-dimethylethyl 4- [5- (4-chlorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) - 1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-3yl] -1-piperazinecarboxylate; 1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (2-fluoro-4-pyridinyl) -1Hpyrazol-3-yl] amino] propyl] carbamate; 1- [5- (4-Chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-ethylpiperazine; N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1,2-ethanediamine; 4- [3- (2,6-difluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-ethylphenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-chlorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3-ethyl-5- (3-ethylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -5- (1-methylethyl) -1H-pyrazol-4-yl] pyridine; 4- [3-cyclopropyl-5- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine); 5- Cyclopropyl-3- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol; 3- (4- (fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol; 4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone; 1-acetyl-4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone; ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H700 pyrazol-5-yl] cyclopropanecarboxylate; 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylic acid; 3- (4- (fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol; 4- [3- (4-chloro-3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 5- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-carboxylic acid; 5- (4- (fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-methanol; 1- [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] piperazine; 1,1-dimethylethyl 4 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3yl] carbonyl] -1-piperazinecarboxylate; 4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine; 4- (1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl) pyridine; 4- [3- (4-chlorophenyl) -1,5-dimethyl-1H-pyrazol-4-yl] pyridine; 4- [5- (4-chlorophenyl) -1,3-dimethyl-1H-pyrazol-4-yl] pyridine; 4- [5-ethyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3-ethyl-1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -2-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (2-chlorophenyl) -1H-pyrazol-4-yl] pyridine; 3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol; 3- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-1-ethanol; 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 2- [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] -1-butanol; 4- [5-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile; 701 4- [2- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-yl] ethyl] morpholine; 3- (4-fluorophenyl) -1-methyl-α-phenyl-4- (4-pyrimidinyl) -1H-pyrazole-5-methanol; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinethane amine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -1H- (phenylmethyl) -2-pyridinamine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylethyl) -2-pyridinamine; 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -1H-ethyl-2-pyridinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide; methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N-methyl-2-pyridinecarboxamide; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylic acid; 4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- (3- (1,3-benzodioxol-5-yl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyridine; 4- (3- (1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine; 4- [5- (3-Chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylpyridine; 4- (3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 2-methyl-4- [1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 2-methyl-4- [1-methyl-5- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine; 4- (3-phenyl-1H-pyrazol-4-yl) pyridine; 4- [3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine; 4- [1-methyl-3- [3- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine; 702 4- [3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine; 4- [3- (4-bromophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; (E) -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-phenylethenyl) pyridine; (S) -4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N- (2-methylbutyl) -2-pyridinamine; 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N - [(4-methoxyphenyl) methyl] -2-pyridinamine; N-4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridinmethane amine; N-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridinomethane amine; 2-fluoro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-iodophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (4-iodo phenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [1-methyl-3- [4- (trifluoromethyl) phenyl] -1H-pyrazol-4-yl] pyridine; N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine; N - [(3-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinamine; 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2- (1-methyl-drazino) pyridine; 2-fluoro-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine; 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -3-methylpyridine; 4- (3- (3,4-difluorophenyl) -1H-methyl-1H-pyrazol-4-yl] -2-fluopyridine; 703 3- (4-fluorophenyl) -N, X-dimethyl-4- (4-pyridinyl) -1H-pyrazole-1-ethanamine; 2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H- [1- (phenylmethyl) -4-piperidinyl] -2-pyridinamine; N '- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -N, N-dimethyl- 1,2-ethanediamine; 2,4-bis [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; N4- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -4-morpholinethanamine; 3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1-ethanol; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -L- [2- (1H-imidazol-1-yl) ethyl] -2-pyridinamine; 4- [2- [3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-1-yl] ethyl] morpholine; (E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] -4-pyridinyl] -1H-pyrazole-1-ethanol; 3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) ethenyl] -4-pyridinyl] -N, N-dimethyl-1H-pyrazol-1-ethanamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -1H-pyrazole- 1-ethanol; 4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N, N-dimethyl-2-pyridinamine; 4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1X [(4-fluorophenyl) methyl] -2-pyridine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -N, N-dmethyl-1H-pyrazole-1-ethanamine; N - [(4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1 - [[2- (4704 morpholinyl) ethyl] -1H-pyrazol-4-yl] -2 -pyridinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N-4-piperadinyl-2-pyridinamine; N, N-diethyl-3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazo-1-ethanamine; 4- [1- [2- (diethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H- [(4-fluorophenyl) methyl] -2-pyridinamine; 2 - [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol; 2- [[4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol; 3- [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] 1-propanol; 3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] 4-pyridinyl] -1H-pyrazole-1-ethanol; 5- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazol-1-ethanol; N, N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanamine; B1 - [(4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4-morpholinyl) ethyl] 1H-pyrazol-4-yl] -2-pyridinamine; B1- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholine propanamine; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -N, N-dimethyl- 1,3-propandiamine; 5- (4-fluorophenyl) -1H-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazo-1-ethanol; 5- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazole-1-ethanol; 4- [3 - [(4-fluorophenyl) -1H-pyrazol-4-yl] quinoline; 705 N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-glycine methyl ester; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-glycine; 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine; 4- [5- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine; 4,4 '- (1H-pyrazole-3,4-diyl) bis [pyridine]; 4- [3- (3,4-dichlorophenyl) -1H-pyrazol-4-yl] pyridine; N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-piperidinamine; 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -4-pyrimidine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyrimidinone hydrazone; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H, N-dimethyl-2-pyrimidinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H-methyl-2-pyrimidinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidine amine; N-cyclopropyl-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidine amine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -1H - [(4-methoxyphenyl) methyl] -2-pyrimidine amine; B1- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -N- (phenylmethyl) acetamide; ethyl [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] carbamate; 4- [3- (3-methoxyphenyl) -1H-pyrazol-4-yl] pyrimidine; 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] pyrimidine; 4- [3- (3-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine; and 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine. A compound, tautomer or salt according to claim 1, characterized in that the compound is selected from the group consisting of: 706 707 708 709 710 N - NH 711 71. A compound, tautomer or salt according to claim 1. wherein the compound is 4- [5- (4fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine. A compound, tautomer or salt according to claim 1, characterized in that it is 3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-ethanol. 712 74. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2- (1-metho). you lhidrazino) pyrid yn. 75. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3-cyclopropyl-5- (4fluorophenyl) -1H-pyrazol-4-yl] pyridine. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methylpiperazine. 79. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine. A compound, tautomer or salt according to claim 1, characterized in that it is 2-fluoro-4- [3- (4-fluorophenyl) 1H-pyrazol-4-yl] pyridine. 81. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (3,4-difluorophenyl) -1methyl-1H-pyrazol-4-yl] pyridine. 82. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-bromophenyl) -1H-pyrazol-4-yl] pyridine. 713 83. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine. 84. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (1,3-benzodioxol-5-yl) 1-methyl-1H-pyrazol-4-yl] pyridine. 85. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine. 86. A compound, tautomer or salt according to claim 1, characterized in that it is 4- [3- (3-fluorophenyl) -1-methylpyrazol-4-yl] pyridine. 87. A compound, tautomer or salt according to claim 1, characterized in that it is 5- (4-fluorophenyl) -1H-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine. 88. Substituted pyrazole, characterized in that: the substituted pyrazole is a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, in which the compound corresponds to a structure of formula (XII): R ¹ (XII); R ¹ is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl, where: 714 hydrocarbyl, hetero-substituted hydrocarbyl or heterocyclyl have a molecular weight of less than about 360 atomic mass per unit; R is selected from the group consisting of hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl, where: hydrocarbyl, hetero-substituted hydrocarbyl or heterocyclyl bind to p38 kinase at said ATP binding site of p38 kinase; R is selected from the group consisting of hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl, where: hydrocarbyl, hetero substituted hydrocarbyl or heterocyclyl have a hydrogen bond acceptor functional group; R ⁴ is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl, where: hydrocarbyl, hetero-substituted hydrocarbyl or heterocyclyl have a molecular weight of less than about 360 atomic mass per unit; R ³ is not 2-pyridinyl when R ⁴ is 2-hydroxyphenyl and when R ¹ is hydrogen; R is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R ⁴ is hydrogen; R ⁴ is not methylsulfonylphenyl; the substituted pyrazole specifically binds to the ATP binding site of the p38 kinase; unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, the rings being bonded to one another or may be condensed; and 715 unless otherwise noted, heterocyclyl is a saturated, partially saturated or unsaturated ring-shaped radical containing a heteroatom, the heteroatoms being independently selected from the group consisting of nitrogen, sulfur and oxygen. 89. Substituted pyrazole according to claim 88, characterized in that R is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl, wherein the hydrocarbyl, hetero substituted hydrocarbyl and heterocyclyl bind to Lys ₅₂ , Glu ₇₃ , Glu ₆₉ , ₇₃ He _82, Leu _{84, Leu] O} i and Thri ₀₃ side chains of said ATP binding site of p38 kinase, said radical is mainly positioned in a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site. 90. Substituted pyrazole according to claim 88, characterized in that R is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl, wherein the hydrocarbyl, the hetero substituted hydrocarbyl and the heterocyclyl have a functional hydrogen with an acceptor N-linker H skeleton of Met ₁₀₆ of p38 kinase. 91. Substituted pyrazole according to claim 88, characterized in that R ¹ is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl, wherein the hydrocarbyl, the hetero substituted hydrocarbyl and the heterocyclyl have a molecular weight of about 250 molecular weight, unit mass. 92. Substituted pyrazole according to claim 88, characterized in that R ⁴ is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl, wherein the hydrocarbyl, the hetero substituted hydrocarbyl and the heterocyclyl have a molecular weight of about 250 to about a molecular weight unit. 716 93. Substituted pyrazole according to claim 88 ', characterized in that: R ¹ is selected from the group consisting of hydrocarbyl, hetero-substituted hydrocarbyl and heterocyclyl, wherein the hydrocarbyl, hetero-substituted hydrocarbyl and heterocyclyl have a molecular weight of less than about 360 atomic mass per unit; R is selected from the group consisting of hydrocarbyl, hetero substituted hydrocarbyl and heterocyclyl radical in which: said hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical bind to Lys ₅ 2, Glu ₆₉ , Leu ₇₇ , lie ₈₂ , Leu ₈₄ , Leu _iO i, and Tbuz side chains of said ATP binding site of the p38 kinase, said radical being located in the hydrophobic cavity formed during said binding by the p38 kinase at the ATP binding site; • 5 R is selected from the group consisting of hydrocarbyl, hetero substituted hydrocarbyl and heterocyclyl, where: hydrocarbyl, hetero substituted hydrocarbyl and heterocyclyl have a functional group as a hydrogen bond acceptor with the basic N-H skeleton of Meti ₀ 6 of p38 kinase; and R ⁴ is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl, where: hydrocarbyl, hetero-substituted hydrocarbyl and heterocyclyl have a molecular weight of less than about 360 atomic mass per unit. 94. Substituted pyrazole according to claim 93, characterized in that R ¹ and R ⁴ are independently selected from the group consisting of hydrocarbyl, hetero substituted hydrocarbyl and heterocyclyl; and ΊΥΊ R ¹ and R ⁴ have a total molecular weight of less than about 360 atomic mass per unit. 95. A pharmaceutical composition, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 1. 96. A pharmaceutical composition according to claim 95, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 3. 97. A pharmaceutical composition according to claim 95, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 4. 98. A pharmaceutical composition according to claim 95, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 5. 99. The pharmaceutical composition of claim 95 ', wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 6. 100. A pharmaceutical composition, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 24. 101. A pharmaceutical composition according to claim 100, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 25. 102. A pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 25. 718 103. A pharmaceutical composition according to claim 103, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 36. 104. A pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 44. 105. A pharmaceutical composition according to claim 104, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 45. 106. A pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 53. 107. A pharmaceutical composition according to claim 106, wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 54. 108. A pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 66. 109. A pharmaceutical composition wherein the composition comprises a therapeutically effective amount of a compound, salt or tautomer described according to claim 69. 110. The pharmaceutical composition of claim 109, wherein said compound is 4- [3 (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine. 111. Administration of a therapeutically effective amount of a compound, tautomer of the compound, or pharmaceutically acceptable 719 salt of the compound or tautomer for the preparation of a pharmaceutical composition for the treatment of a TNF-related disorder in a patient suffering from or predisposed to such a disorder, characterized in that: the compound corresponds to a structure of Formula I: as for R ¹ : R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cyclo alkenilalkilen, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl , alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylaminoalkylaminoalkylamino o. heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl. heterocyclylsulfonyl. alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl. alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene. heterocyclylcarbonyalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene and heterocyclylcarbonyloxyalkylene; or R ¹ corresponds to a structure of formula (II): 720 R ²⁵ Ο ----- C ---- (CH ₂ ), ----- C ---- N IV H (II); In which i is a number from 0 to 9; R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamino; as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R ²⁷ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene. alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylalkenylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylalkylaminoalkylalkyloxyalkylene alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkyl 721 thioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclythioarylene, arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene and alkylaminosulfonarylene, where: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic moiety; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R is alkoxycarbonyl; R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where: said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; 722 as for R ² : R ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylboxycarboxycarboxylcarboxy cycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbylamino; said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl. alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl. epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino. heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl. alkoxycarbonyl, arylsulfonyl and aralkylsulfonyl; or R corresponds to a structure of formula (III): R ³⁰ I C ----- (CH 2) j or (III), R ² e-CR ⁴¹ R ⁴² ; 723 R 'is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R ³² is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamines; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ¹⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl. pyrimidinyl. quinolinyl, purinyl, (IV), (V), 724 wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, allyloxy, aryloxyalkyl , arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkylcarboxycarbonylcarbonylcarbonylcarbonylcarbonyl oxycarbonyl, alkoxycarbonylamino, alkoksiaralkilamino, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilheterotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil and -NR ⁴⁴ R ^45; R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2hydroxy substituent and when R ¹ is hydrogen; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl, alkylthioalkyl , alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxy 725 carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 112. Use of a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the preparation of a pharmaceutical composition for treating a p38 kinase related disorder in a patient suffering from or predisposed to such a disorder, characterized in that the compound corresponds to a structure of Formula I: as for R ¹ : R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl. cycloalkylalkylene, cycloalkenyl-alkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoksialkil, alkinoksialkil, aryloxyalkyl, heterotsiklil726 oxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkiltioalkilen, alkeniltioalkilen, alkiltioalkenilen , amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocycles klilsulfinil, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkilkarbonilalkilen, arilkarbonilalkilen, heterotsiklilkarbonilalkilen, alkilkarboniloksialkilen, arilkarboniloksialkilen and heterotsiklilkarboniloksialkilen; or R ¹ corresponds to a structure of formula (II): R ²⁵ is in which i is a number from 0 to 9; R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene. aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl. alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, hetero 727 tsiklilalkilen, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoksiaralkil, alkoksiheterotsiklil, alkoksialkoksiarilen, ariloksiarilen, aralkoksiarilen, alkoksiheterotsiklilalkilen, ariloksialkoksiarilen, alkoxycarbonylalkyl, alkoksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminocarbonyl alkylene arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R and R together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocycle being optionally substituted by one or more radicals independently selected from the group consisting of alkyl, aryl, 728 heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino, where: said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonyl alkylene, alkylthioalkylene and aralkylthioalkylene, where: said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : Is selected from the group consisting of: , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl chloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbonylamino; 729 said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkyl, heterocyclyl, alkyl, heterocyclyl, heterocyclyl, alkyl amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl; or R ² corresponds to a structure of formula (III): R ³⁰ 1 ---- (CH ₂ ) j H with _____ R ³⁴ J m (III), R ² is -CR ⁴¹ R ⁴² ; R is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene. aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R ³² is selected from the group consisting of hydrogen, alkyl, aralkyl. heterocyclylalkyl, alkoxyalkylene. aryloxyalkylene, aminoalkyl. alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; R - is selected from the group consisting of hydrogen, alkyl, -C (O) R, 730 -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, (IV), wherein the radicals pyridinyl, pyrimidinyl, quinolinyl and purinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy. alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino. alkenylamino, alkynylamino. cycloalkylamino. cycloalkenylamino, arylamino, heterocyclylamino. aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl. aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino. alkoxyalkylamino, alkylaminoalkylamino, hydroxyalkylamino. aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino. nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl. 731 aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl and -NR ⁴⁴ R ⁴⁵ ; R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2hydroxy substituent and when R ¹ is hydrogen; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl , alkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkyl, aryl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl alkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 732 113. Use of a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the preparation of a pharmaceutical composition for the treatment of inflammation, in a patient suffering from or predisposed to such a disease, characterized in that: the compound corresponds to a structure of Formula I: as for R ¹ : R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, tsikloalkenilalkilen, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy. mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino. arylamino. heterocyclylamino. alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl. alkylsulfonyl, alkenylsulfonyl, aryl sulfonyl, alkylcarbamide arylcarbonyalkylene, heterocyclylcarbonyalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene and heterocyclylcarbonyloxyalkylene; or 733 R ¹ corresponds to a structure of formula (II): R ²⁵ with (CH ₂ ) i and X ^with X ²⁷ 1 BC (N); in which i is a number from 0 to 9; R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamino; as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R 'is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene. alkylarylalkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclylene, alkoxyalkyloxyarylenearylarylarylarylarylarylarylarylarylarylarylarylloxyarylene, alkoxyalkyloxyarylene, alkoxyalkyloxyarylene, alkoxyalkyloxyarylene; alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene. arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene. aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, 734 ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; 735 R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where: said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : R ² is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylboxycarboxycarboxylcarboxy cycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbylamino; said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl; or R corresponds to a structure of formula (III): 736 R ³⁰ C ----- (CH2)) R ³¹ H _ c R ³⁴ or (ΙΠ), R ² e -CR ⁴¹ R ⁴² ; R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocycloalkyl; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ³ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴ 'is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 737 wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, allyloxy, aryloxyalkyl , arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkylcarboxycarbonylcarbonylcarbonylcarbonylcarbonyl oxycarbonyl, alkoxycarbonylamino, alkoksiaralkilamino, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilheterotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil and -NR ⁴⁴ R ^45; R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2hydroxy substituent and when R ¹ is hydrogen; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino: R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals, 738 independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkiltioalkilen, ariltioalkilen, alkilsulfinilalkilen, arilsulfinilalkilen, alkilsulfonilalkilen, arilsulfonilalkilen, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 114. Use of a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, for the preparation of a pharmaceutical composition for treating arthritis, in a patient suffering from or predisposed to such a disease, characterized in that: the compound corresponds to a structure of Formula I: R ¹ W; as for R ¹ : 739 R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, tsikloalkenilalkilen, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkylamino, alkylamino, alkylamino o, heterocyclylamino, alkylsulfinyl, alkenilsulfinil, alkylsulfinyl, arylsulfinyl, heterotsiklilsulfinil, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkilkarbonilalkilen, arilkarbonilalkilen, heterotsiklilkarbonilalkilen, alkilkarboniloksialkilen, arilkarboniloksialkilen and heterotsiklilkarboniloksialkilen; or R ¹ corresponds to a structure of formula (II): R ²⁵ 0 • C ---- _(CH:) i- Mr p26 n (I): in which i is a number from 0 to 9; R is selected from the group consisting of hydrogen, alkyl, aralkyl. heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; as for R ²⁶ and R ²⁷ : 740 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R ²⁷ is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alk ksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl, arilaminokarbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen alkylene oarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen where: alkyl, aryl, heterocyclylate, carboxylic acid, carboxylic acid; 741 or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R and R together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; R is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where: said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : Is selected from the group consisting of: , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, 742 alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboksitsikloalkil, karboksitsikloalkenil, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonil, alkoxyalkylamino, alkoksikarbonilaminoalkilamino and heterocyclylsulfonyl, wherein: said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl (hydroxyalkyl) carboxy, alkoxy, aryloxy, aryloxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonylsulfonylsulfonyl; or R ² corresponds to a structure of formula (III): R ³⁰ with ---- (CH 2) j or R ³¹ R ³⁴ (III), R ² e -CR ⁴¹ R ⁴² ; R is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl or cycloalkenyl when R ⁴ is hydrogen; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1: R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl. heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; 743 R ³² is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamines; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl. quinolinyl, purinyl, where the radicals are pyridinyl, pyrimidinyl. quinolinyl and purinyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl. aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl. alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino. heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino. 744 alkoksiaralkilamino, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkilheterotsiklilamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkilhidrazinil, arilhidrazinil and -NR ⁴⁴ R ^45; R ³ is not 2-pyridinyl when R ⁴ is a phenyl ring containing a 2hydroxy substituent and when R ¹ is hydrogen; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl , alkylsulfinyl, arylsulfinyl, alkylsulfonyl, alkyl, aryl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl alkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings, in which the rings can be linked together as hanging or condensed; and unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, heteroatom-containing radical in the form of 745 ring in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 115. Use of a therapeutically effective amount of a compound, tautomer of the compound, or pharmaceutically acceptable salt of the compound or tautomer, for the preparation of a pharmaceutical composition for treating a p38 kinase related disorder in a patient suffering from or predisposed to such a disorder, characterized in that: the compound corresponds to a structure of Formula IX. Z is selected from the group consisting of = N- and = C (H) -. R ¹ is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl and lower alkynyl; R 'is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl and lower alkynyl; R ⁴ is selected from the group consisting of phenyl and benzodioxolyl: wherein the phenyl is optionally substituted by one or more halo radicals; R ⁵ is selected from the group consisting of hydrogen, halo and alkylhydrazinyl; 746 unless otherwise noted, lower alkyl represents a linear or branched radical having from one to ten carbon atoms; unless otherwise noted, lower alkynyl is a linear or branched radical having from two to six carbon atoms; unless otherwise noted, lower hydroxyalkyl is a linear or branched radical having from one to six carbon atoms and one or more hydroxyl groups. 116. An application according to claim 111, wherein the TNF-related disorders are selected from the group of disorders including bone resorption, graft response, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, local inflammatory disease, respiratory distress syndrome in the elderly, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombosis, glomerulonephritis, Crohn's disease, ulcerative colitis, zpalenie bowel and cachexia. 117. The use according to claim 111, wherein the TNF-related disorder is inflammation. 118. The use according to claim 111, wherein the TNF-related disorder is arthritis. 119. The use according to claim 111, wherein the TNF-related disorder is asthma. 120. The use according to claim 111, wherein the compound is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine. 121. The use according to claim 111, wherein the compound is 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazole- 3-yl] -4-methylpiperazine. 747 122. The use of claim 112, wherein the disorder is a p38a kinase-related disorder. 123. The use according to claim 112, wherein the disorders associated with p38 kinase are selected from the group of disorders including bone resorption, graft response, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis , local inflammatory disease, respiratory distress syndrome in the elderly, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombosis, glomerulonephritis, Crohn's disease, peptic ulcer ols, inflammatory bowel disease and cachexia. 124. The use according to claim 112, wherein the p38 kinase-related disorder is inflammation. An application according to claim 112, wherein the p38 kinase-related disorder is arthritis. 126. The use according to claim 112, wherein the p38 kinase-related disorder is asthma. 127. The use according to claim 115, wherein the disorder is a p38 kinase related disorder. Use according to claim 115, characterized in that the disorders associated with p38 kinase are selected from the group of disorders including bone resorption, graft response, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis , local inflammatory disease, respiratory distress syndrome in the elderly, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombosis, 748 glomerulonephritis, Crohn's disease, ulcerative colitis, bowel inflammation and cachexia. 129. The use according to claim 115, wherein the p38 kinase-related disorder is inflammation. An application according to claim 115, wherein the p38 kinase-related disorder is arthritis. 131. The use of claim 115, wherein the p38 kinase-related disorder is asthma. 132. A process for the preparation of a substituted pyrazole compound, a tautomer of the substituted pyrazole compound, or a pharmaceutically acceptable salt of the substituted pyrazole compound or of a tautomer, characterized in that: the method involves the preparation of acylhydrazone and condensation to give a substituted pyrazole compound; the substituted pyrazole compound corresponds to a structure of formula I: r> 1 D 'νλ as for R: R ¹ is selected from the group consisting of hydrogen, alkyl. cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl. cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene. haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl. hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy. carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkyloxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, 749 aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenilsulfinil, alkylsulfinyl, arylsulfinyl, heterotsiklilsulfinil, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkilkarbonilalkilen, arilkarbonilalkilen , heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclyl carbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or corresponds to a structure of formula (II): _r 25 Fr. I II R ²⁶ 1 II / ----- c ----- (CH ₂ ), ---- -C ---- N \ _R 27 n (P) in which i is a number from 0 to 9; R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene. aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl. alkoxycarbonylalkylene and alkylaminoalkyl; and R is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cyclo 750 alkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene, alkoksiaralkil, alkoksiheterotsiklil, alkoksialkoksiarilen, ariloksiarilen, aralkoksiarilen, alkoksiheterotsiklilalkilen, ariloksialkoksiarilen, alkoxycarbonylalkyl, alkoksikarbonilheterotsiklil, alkoksikarbonilheterotsiklilkarbonilalkilen, aminoalkyl, alkylaminoalkyl , arylamine rbonilalkilen, alkoksiarilaminokarbonilalkilen, aminokarbonilalkilen, arilaminokarbonilalkilen, alkilaminokarbonilalkilen, arilkarbonilalkilen, alkoksikarbonilarilen, ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen, arilsulfonilaminoalkilen, alkilsulfonilari flax and alkylaminosulfonylarylene, where: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted is one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R and R together are the nitrogen atom to which they are attached to form a heterocycle, such as: said heterocycle being optionally substituted is one or more radicals independently selected from the group consisting of alkyl, aryl, 751 heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonyl amino, where: said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; R ²⁸ is alkoxycarbonyl; R ²⁹ is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene, where: said aralkyl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of alkyl and nitro; as for R ² : Is selected from the group consisting of: , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl chloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminoalkyloxycarbonylaminoalkyloxycarbonylamino; 752 said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkyl, heterocyclyl, alkyl, heterocyclyl, alkyl amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl; or R ² corresponds to a structure of formula (III): _R 3 ° • C ----- (CH 2)] _R 31 n 1 m or (III), R ² e-CR ⁴¹ R ⁴² ; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R ² is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl. alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; R '' is selected from the group consisting of hydrogen, alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; , K, K, K, R and R are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and 753 heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R ³ is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, arylsulfonyl, arylsulfonyl, alkylamino, alkylamino arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl. heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxy aralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitrocarbonylamino. alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl and -NR ⁴⁴ R ⁴⁵ ; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; 754 R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl alkylsulfinyl, alkylsulfinyl, alkylsulfonyl; ylamino, arylamino, alkylaminoalkyl, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings in which the rings can be linked together as hanging or condensed, and unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom radical in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 133. The method of claim 132, wherein the acylhydrazone is prepared by reaction of the ketone with acylhydrazide. 134. The method of claim 132, wherein the condensation is carried out at a temperature of from about 25 ° C to about 200 ° C. 135. Process for the preparation of a substituted pyrazole compound, a tautomer of the substituted pyrazole compound, or a pharmaceutical 755 acceptable salt of the substituted pyrazole compound or tautomer, characterized in that: the method involves treating the substituted ketone with acylhydrazide to give the substituted pyrazole compound; the substituted pyrazole compound corresponds to a structure of formula I: as for R ¹ : R ¹ (I); R ¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, tsikloalkenilalkilen, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkyloxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl, aminoalkyl inylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl. alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkyl, alkilsulfonilalkilen, acyl, atsiloksikarbonil, alkoxycarbonylalkyl, ariloksikarbonilalkilen, heterotsikliloksikarbonilalkilen, alkilkarbonilalkilen, arilkarbonilalkilen, heterotsiklilkarbonilalkilen, alkilkarbonilarilen. arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, 756 alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or R ¹ corresponds to a structure of formula (II): ----- C ---- (CH ₂ )> ---- C ---- N IA n (I); in which i is a number from 0 to 9; R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamino; as for R ²⁶ and R ²⁷ : R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene and alkylaminoalkyl; and R is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, tsikloalkenilalkilen, tsikloalkilarilen, tsikloalkiltsikloalkil, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkilarilen, alkylheterocyclyl alkilheterotsiklilalkilen, alkilheterotsiklilarilen, aralkilheterotsiklil, alkoxyalkyl, alkoxyarylene. alkoxy aralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene. arylacrylate, aryl, acrylic, orthiazole; alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, 757 ariloksikarbonilarilen, alkilariloksikarbonilarilen, arilkarbonilarilen, alkilarilkarbonilarilen, alkoksikarbonilheterotsiklilarilen, alkoksikarbonilalkoksiarilen, heterotsiklilkarbonilalkilarilen, alkiltioalkilen, tsikloalkiltioalkilen, alkiltioarilen, aralkiltioarilen, heterotsikliltioarilen, ariltioalkilarilsn, arilsulfonilaminoalkilen, alkilsulfonilarilen and alkilaminosulfonilarilen, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkilheterotsiklilarilen, alkoxyarylene, ariloksiarilen, arilaminokarbonilalkilen, ariloksikarbonilarilen, arilkarbonilarilen, alkiltioarilen, heterotsikliltioarilen, ariltioalkilarilen and alkilsulfonilarilen are optionally substituted with one or more radicals independently selected from the group consisting of alkyl , halo, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle, such as: said heterocyclic heterocyclic acid; said aryl, heterocyclylalkylene and aryloxyalkylene being optionally substituted by one or more radicals independently selected from the group consisting of halogen, alkyl and alkoxy; as for R ² : R is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, 758 aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkyl, arilaminoarilen, alkylaminoaryl, alkilaminoalkilamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio , carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxy sicarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino and heterocyclylsulfonyl, where: said aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl being optionally substituted by one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl, aralkyl (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino. alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl and aralkylsulfonyl; or R corresponds to a structure of formula (III): R30 C ----- (CH ₂ ) j R ³¹ H " With ______ R ³⁴ - ΠΊ or (W), R ² is -CR ⁴¹ R ⁴² ; j is a digit from 0 to 8; m is selected from the group consisting of 0 and 1; 759 R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl and alkylcarbonyloxyalkyl; R ³² is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylalkylaminoalkylaminoalkylamines; R ³³ is selected from the group consisting of hydrogen, alkyl, -C (O) R ³⁵ , -C (O) OR ³⁵ , -SO 2 R ³⁶ , -C (O) NR ³⁷ R ³⁸ and -SO 2 NR ³⁹ R ⁴⁰ ; R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, hetero substituted hydrocarbon and heterocyclyl; R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; R ⁴¹ is aryl; R ⁴² is hydroxy; R is selected from the group consisting of pyridinyl, pyrimidinyl. quinolinyl, purinyl, wherein the pyridinyl, pyrimidinyl, quinolinyl and purinyl radicals are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl. aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl. alkoxy, aryloxy, alkylthio. arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, 760 arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoksiaralkilamino, aminosulfinyl, aminosulfonyl, alkilaminoalkilamino, hydroxyalkylamino, aralkylamino , heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, and alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl and -NR ⁴⁴ R ⁴⁵ ; R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; R ⁴⁴ is selected from the group consisting of alkylcarbonyl and amino; R ⁴⁵ is selected from the group consisting of alkyl and aralkyl; R ⁴ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl, where: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl are optionally substituted by one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthioalkyl alkylsulfinyl, alkylsulfinyl, alkylsulfonyl; ylamino, arylamino, alkylaminoalkyl, arylaminoalkylene, aminoalkylamino, and hydroxy; and unless otherwise noted, aryl is a carbocyclic aromatic system containing one, two or three rings in which the rings can 761 be connected to each other as hanging or condensable; and, unless otherwise noted, the heterocycle is a saturated, partially unsaturated or unsaturated, ring-shaped heteroatom in which the heteroatoms are independently selected from the group consisting of nitrogen, sulfur and oxygen. 136. The method of claim 135, wherein the treatment of the substituted ketone with acylhydrazide is carried out in an acidic solvent. 137. The method of claim 136, wherein the acidic solvent comprises acetic acid. 138. The method of claim 136, wherein the acidic solvent comprises an organic solvent comprising an acid. Please add the following new claims. Compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: 762 A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: 763 A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: 764 148. A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 1, characterized in that the compound corresponds to a structure of the following formula: A compound, tautomer or salt according to claim 9, wherein R ⁴ is optionally substituted phenyl. A compound, tautomer or salt according to claim 151, wherein R ⁴ is phenyl substituted with one or more 765 radicals independently selected from the group consisting of fluorine, chlorine and bromine. A compound, tautomer or salt according to claim 152, wherein R ³ is selected from the group consisting of pyridinyl, pyrimidinyl and quinolinyl, characterized in that: pyridinyl, pyrimidinyl and quinolinyl are optionally substituted by one or more radicals independently selected from the group consisting of fluorine, bromine, methyl, cyano, methoxy carbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, benzylamino, benzylamino phenethylamino, aminomethyl, amino, hydroxy and methylcarbonyl. . A compound, tautomer or salt according to claim 153, wherein R is selected from the group consisting of unsubstituted pyridinyl, unsubstituted pyrimidinyl and unsubstituted quinolinyl. A compound, tautomer or salt according to claim 154, wherein R ² is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkilaminoalkilamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower hetertsiklilalkil, lower heterocyclylalkylamino, lower alkylhalo terrocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylcarbonyl, where: 766 phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkilaminoalkilamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, lower hydroxyalkylcarbonyl and lower alkoxycarbonyl. 155. A compound, tautomer or salt according to claim 155, wherein R ² is substituted piperidinyl. 156. A compound, tautomer or salt according to claim 156, 'Y' wherein the hydroxyalkylcarbonyl of R is selected from the group consisting of hydroxymethylcarbonyl and hydroxyethylcarbonyl. 157. A compound, tautomer or salt according to claim 57, characterized in that R ⁴ e is optionally substituted phenyl. 158. A compound, tautomer or salt according to claim 158, wherein R ⁴ is phenyl substituted with one or more radicals independently selected from the group consisting of fluorine, chlorine and bromine. A compound, tautomer or salt according to claim 159, wherein Z is = N-. A compound, tautomer or salt according to claim 160, wherein R ⁵ is hydrogen. 161.. A compound, tautomer or salt according to claim 161, wherein R ² is substituted piperidinyl. 162. A compound, tautomer or salt according to claim 162, characterized in that the hydroxyalkylcarbonyl of R ² is selected from the group consisting of hydroxymethylcarbonyl and hydroxyethylcarbonyl.