CZ411899A3 - Substituted pyrazoles functioning as inhibitors of p38 kinase, process of their preparation and pharmaceutical composition - Google Patents

Abstract

Substituted pyrazoles of formula I wherein R 1, R 2, R 3 and R 4 are specific, may be used as such p38 kinase inhibitors for treating p38 kinase mediated diseases. Process for preparing said substituted pyrazoles and pharmaceutical compositions thereof.

Description

Technical field

The present invention relates to a novel class of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.

BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAP) are a group of proline-oriented serine / threonine kinases that activate their substrates by dual phosphorylation. Kinases are activated by a variety of signals, including nutritional and osmotic stress, UV radiation, growth factors, endotoxin, and inflammatory cytokines. The p38 MAP kinase family is a MAP set of various isoforms, including ρ38α, ρ38β, and ρ38γ, which cause phosphorylation and activation of transcription factors (eg ATF2, CHOP and MEF2C) as well as other kinases (eg ΜΑΡΚΆΡ-2 and ΜΆΡΚΆΡ-3). P38 isoforms are activated by bacterial lipopolysaccharides, physical and chemical stress, and pro-inflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-1 (IL-1).

P38 phosphorylation products mediate the production of inflammatory cytokines, including TNF and IL-1 and cyclooxygenase-2.

\ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ···· · ·

TNF-α is a cytokine produced by primarily activated monocytes and macrophages. Excessive or unregulated TNF production is thought to mediate a variety of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid arthritis. Other studies have shown that TNF inhibition has broad applications in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF is also involved in viral infections such as HIV, influenza virus and herpes viruses, including, but not limited to, herpes simplex type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV) , varicelazoster virus (VZV), Epstein-Barr virus, human herpes virus-β (HHV-6), human herpes virus-7 (HHV-7), human herpes virus-8 (HHV8), pseudorabinosis and rhinotracheitis.

IL-8 is another pro-inflammatory cytokine that is produced by mononuclear cells, fibroblasts, endothelial cells and keratinocytes and is associated with conditions involving inflammation.

IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses, including rheumatoid arthritis, fever, and reduction of bone resorption.

TNF, IL-1 and IL-8 affect a large number of cells and tissues and are important inflammatory mediators of a large number of diseases and conditions. Inhibition of these cytokines by inhibiting p38 kinase is useful in controlling, reducing and relieving these disease states.

Various pyrazole derivatives have been previously described. US. No. 4,000,281 to Beiler and Binon discloses 4,5-aryl / heteroaryl substituted pyrazoles with antiviral effects against RNA and DNA viruses such as myxoviruses, adenoviruses, rinoviruses and various herpes family viruses.

WO 92/19615, published November 12, 1992, discloses pyrazoles as novel fungicides. U.S. Patent No. 3,984,431 to Cueremy and Renault discloses pyrazole-5-acetic acid derivatives as having anti-inflammatory activity. Specifically, [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl] acetic acid is disclosed. U.S. Patent No. 3,245,093 to Hinsgen et al. Describes a process for producing pyrazoles. WO 83/00330, published February 3, 1983, discloses 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 preparing pyrazole derivatives. U.S. Patent 5,589,439 to T. Goto et al. Describes tetrazole derivatives and their use as herbicides. EP 515,041 discloses pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides. Japanese Patent 4,145,081 discloses pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 discloses novel pyrazole derivatives as acetylcholinesterase inhibitors.

Pyrazoles have been described for use in the treatment of inflammatory conditions. Japanese Patent 5,017,470 describes the synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec. 30, 1983, discloses 4-imidazolyl-pyrazole derivatives as inhibitors of synthesis. 4 < RTI ID = 0.0 > 4 < / RTI > · Thromboxane. Specifically, 3- (4-isopropyl-1-methylcyclohex-1-yl) -4- (imidazol-1-yl) -1H-pyrazole is disclosed. WO 97/01551, published Jan. 16, 1997, discloses pyrazole compounds as adenosine antagonists. It is specifically described

4- (3-Oxo-2,3-dihydropyridazin-6-yl) -3-phenylpyrazole. U.S. Pat. Patent No. No. 5,134,142 to Matsuo et al. describing

1,5-diaryl pyrazoles as substances having anti-inflammatory activity.

U.S. Pat. Patent No. No. 5,559,137 to Adams et al. Discloses novel (1,3,4, -substituted) pyrazoles as cytokine inhibitors used in the treatment of cytokine diseases. Specifically, 3- (4-fluorophenyl) 1- (4-methylsulfinylphenyl) -4- (4-pyridyl) -5H-pyrazole is disclosed. WO 96/03385, published Feb. 8, 1996, discloses 3,4-substituted pyrazoles as having anti-inflammatory activity.

Specifically, 4- [1-ethyl-4- (4-pyridyl) 5-trifluoromethyl-1H-pyrazol-3-yl] benzenesulfonamide is disclosed.

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

• Φ ·· · · · · · · ·

• · • ·

SUMMARY OF THE INVENTION

The invention relates to a class of substituted pyrazolyl compounds useful for the treatment of p38 mediated disorders as defined by Formula I:

in which

R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheteroc carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene,

• · »aryloxykarbonylaikylen, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyklyloxykarbonylarylen, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyklylkarbonylalkylen, alkylkarbonylarylen, arylkarbonylarylen, heterocyklylkarbonylarylen, alkylkarbonyloxyalkylen, arylcarbonyloxyalkylene, heterocyklylkarbonyloxyalkylen, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or

R ¹ has the general formula

H (II) in which:

i is an integer 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 heterocyclylcarbonylaminoalkylene; and

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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene,

44 »4 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyalkylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylyl alkylene, alkoxyheterocyclylyl alkylene, axyheterocyclylalkylene, alkoxyheterocyclylalkylene, alkoxyheterocyclyl alkylene, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylaikylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylaikylarylen, alkylthioalkylene, cykloalkylthioalkylen, alkylthioarylen, aralkylthioarylen, heterocyklylthioarylen, arylthioalklylarylene, arylsulfonylam inoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene;

wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylakylene, alkoxycarbonylakylene, 4 4 4 4

4- 4 4 4 · «• 4 44 · 4 • w ····

44

4 4 4 4 4

4 4 4 4

4 4 4 4 4

4 4 4 4

4444 44 44 alkylthioalkylene and aralkylthioalkylene;

wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino;

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

R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocycle · alkylamino, aralkylamino , aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, aíkoxykarbonylheterocyklyl, a1koxykarbonylheterocyklylkarbony1 , alkoxyalkylamino, alkoxycarbonylaminoalkylamino and heterocyclylsulfonyl;

Wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl , amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkyinylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or

R ² has the formula:

-c-ccnp ..

, 31

H

C

R ³² /

-N \ _R 33 m

(III) in which:

j is an integer from 0 to 8; and m is 0 or 1; and

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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; and

R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents hydroxy; and

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

(IV) (V) wherein R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; and wherein the R ³ pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino,

- Tk1 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aminoalkylamino, aralkylamino, heterocyclylamino, aralkylamino, heterocyclylamino, aralkylamino, aralkylamino, , haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and

R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , 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 hydrido;

further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and

further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof.

The compounds of formula I are useful, but not limited to, the treatment of any disorder or condition in a human or other mammal that is exacerbated or caused by excessive or unregulated TNF or p38 kinase production by such a mammal. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective dose of a cytokine affecting a compound of Formula I or a pharmaceutically acceptable salt thereof.

The compounds of Formula I are useful, but not limited to, treatment of inflammatory conditions in a subject and as antipyretics for treating fever. The compounds of the present invention are useful for the treatment of arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathy, posterior arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, posterior arthritis and other arthritis. Such compounds may be useful in the treatment of pulmonary disorders or pulmonary inflammation, including adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory diseases. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia caused by infection or cancer, cachexia caused by syndrome acquired. 9 9 4

- Immune deficiency (AIDS), AIDS, ARC (AIDS-related complex), pneumonia and herpesvirus.

The compounds are also useful for treating diseases related to bone resorption such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft versus host disease and allograft rejection, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure and cardiac reperfusion injury, renal reperfusion injury, liver and nephritis disease, and infection-related myalgia. The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematodes (SLE), skin conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders. The compounds of the present invention may also be used to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis. The compounds of the present invention are also useful for treating ocular diseases such as retinitis, retinopathy, uveitis, ocular photophobia, and acute ocular tissue injuries. The compounds of the present invention are also useful for treating angiogenesis, including neoplasia; metastasis; ophthalmic conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization due to injury or infection, diabetic retinopathy, retrolental fibroplasia, and neovascular glaucoma; ulcer diseases such as stomach ulcer; pathological but non-malignant conditions such as hemaginoma, including

- 14-Invantile hemaginoma, nasopharynx angiofibroma, and avascular bone necrosis; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the present invention are also useful for preventing the production of cyclooxygenase-2.

In addition to being useful for the treatment of humans, the compounds of the present invention are also useful for the veterinary treatment of domestic animals, exotic animals and livestock, including mammals, rodents and the like. More preferred animals include horses, dogs and cats.

The compounds of the present invention may also be used for concomitant use, partially or completely, with other anti-inflammatory drugs such as, for example, steroids, cyclooxygenase-2 inhibitors, DMARDs, immunosuppressive agents, NSAIDs, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.

As used herein, the term TNF-mediated disorder refers to any disorder or disease state in which TNF plays a role that is caused directly by TNF or through the release of another monokine, such as but not limited to, for example, IL-1, IL -6 or IL-8, which is caused by TNF. Thus, a disease state in which, for example, it is a major component of IL-1 and its production or action is exacerbated or caused in response to TNF will be considered a disorder mediated by TNF.

As used herein, the expression p38-mediated disorder is • · ·· * · • »·

φφ vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje vztahuje disease states in which p38 plays a role which is caused directly by p38 or through the release of another factor, such as, but not limited to, for example, IL-1, IL-6 or IL-8 due to p38 action. Thus, a disease state in which, for example, it is a major component of IL-1 and its production or action is exacerbated or caused in response to p38 will be considered a disorder mediated by p38.

Since TNF-β has tight structural homology to TNF-α (also known as cachectin) and since both induce similar biological responses and bind to the same cellular receptors, synthesis of both TNF-α and TNF-β compounds is inhibited by the compounds of the present invention. of the invention and therefore both types of TNF are referred to herein as TNF, unless expressly stated otherwise.

A preferred class of compounds consists of compounds of formula I wherein:

R ¹ is selected from the group consisting of hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino , lower arylamino, lower alkylaminoalkylene and lower heterocyclylalkylene; or

R ¹ has the general formula φ φ · »» »

- 1-Q;

R ²⁵ 26 II II ^R - C - (CH?) .- _C Η _ _N V ⁷ (II) in which: i is 0, 1, or 2; and R ²⁵ is selected from the group consisting of hydrogen atom, lower

alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene and lower heterocyclylcarbonylaminoalkylene; and

R ²⁶ is selected from 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 lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene lower alkylfenylen, lower alkylphenylalkyl, lower fenylalkylfenylen, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyklylfenylen, lower fenylalkylheterocyklyl, lower alkoxyalkylene, lower alkoxyfenylen, lower alkoxyfenylalkyl, lower alkoxyheterocyklyl, lower alkoxyalkoxyfenylen, lower fenoxyfenylen, lower fenylalkoxyfenylen, lower alkoxyheterocyklylalkylen, lower fenoxyalkoxyfenylen, lower • 3 »····

Alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl · alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl , lower alkylaminoalkylene, lower fenylaminokarbonylalkylen, lower alkoxyfenylaminokarbonylalkylen, lower aminocarbonylalkylene, arylaminokarbonylalkylen lower alkylaminokarbonylalkylen, lower fenylkarbonylalkylen, lower alkoxykarbonylfenylen, lower fenoxykarbonylfenylen, lower alkylfenoxykarbonylfenylen, lower fenylkarbonylfenylen, lower alkylfenylkarbonylfenylen, lower alkoxykarbonylheterocyklylfenylen, lower alkoxykarbonylalkoxyfenylen, lower heterocyklylkarbonylalkylfenylen, lower alkylthioalkylene, cykloalkylthioalkylen, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalkylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene lower alkylaminosulfonylphenylene; wherein said lower alkyl, lower cycloalkyl, aryl group selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenyl, alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalkylphenylene and lower alkylsulfonylphenylene are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, lower haloalkyl, lower alkoxy, keto, amino, nitro and cyano; or

R ²⁷ is -CHR ⁴⁶ R ⁴⁷ wherein R ⁴⁶ is lower alkoxycarbonyl and R ⁴⁷ is selected from the group consisting of lower O;

18-phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene and lower phenylalkylthioalkylene;

wherein said phenylalkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle, wherein said heterocycle is optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, aryl selected from the group consisting of phenyl , biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino;

wherein said aryl radicals selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and

R ² is selected from hydrido, halo, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- or 6-membered heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino , lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower • ·

phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonyl alkoxycarbonyl, lower alkoxycarbonyl alkoxy, and lower heterocyclylthio; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, lower alkyl, lower alkynyl, phenyl, 5- or β-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino (hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl and phenylsulfonyl; or ^R2 has the formula:

_r 30

AND

-C-CCH3

R ³¹

H

I c I _ R, 33 (III) in which:

j is 0, 1 or 2; and • · · · · · · · · ·

- 20 9 9 9 9 m 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 the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; and

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 ; wherein R ³⁵ is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyalkylene, alkoxyarkylene, alkoxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylene;

wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene cycloalkoxyalkylene, alkoxycarbonylalkylene and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl, halo, haloalkyl, alkoxy, alkoxy, , nitro and cyano; or

219 9 9 9 9 9 · · 9 9 ·· ··

9 9 9 9 99 99 9999

9999 99999 9

9999 999 9999

99 99 99 99 99

R ³⁵ is CHR ⁴⁸ R ⁴⁹ wherein R ⁴⁸ is arylsulfonylamino or alkylarylsulfonylamino and R ⁴⁹ is selected from the group consisting of aralkyl, amino, alkylamino and aralkylamino; or

R ³⁵ represents -NR ⁵⁰ R ⁵¹ wherein R ⁵⁰ represents alkyl and R ⁵¹ represents aryl; and wherein R ³⁶ is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoalkylene, alkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino alkylsulfonylarylene, alkylsulfonylaralkyl and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl and alkylsulfonylarylene groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ is selected from the group consisting of hydrogen and alkyl; and wherein R ³⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylakylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyonylene, alkoxyarylene, aryloxyarylene, aryloxyarylene, aryloxyarylene, alkoxycarbonylarylene, alkylcarbonylcarbonylakylene, alkylaminoalkylene,

- 22alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl and aminosulfonylaralkyl;

wherein said aryl, heterocyclyl, aralkyl and heterocyclylalkylene groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; or

R ³⁸ represents -CR ⁵² R ⁵³ wherein R ⁵² represents alkoxycarbonyl and R ⁵³ represents 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 are as defined for R ²⁶ and R ²⁷ in claim 1; or

R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; or

R ² is selected from the group consisting of

CCH ₃ ) _k (VI) (VII) (VIII) wherein k is an integer from 0 to 3; and

R ⁵⁶ is hydrogen or lower alkyl; and ·· ·· <· • ·

- 23 · 9 · 9 · 9 · 9

R ⁵⁷ is hydrogen or lower alkyl; or

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

R ⁵⁸ 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 (O) NHR ⁶¹ ; wherein R ⁵⁹ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl;

wherein said aryl, heterocyclyl and aralkyl groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, 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 arylsulfonylheterocyclyl;

wherein said aryl, heterocyclyl and aralkyl groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶¹ is selected from the group consisting of alkyl, aryl, alkylarylene, and alkoxyarylene;

wherein said aryl group is optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and • · · »9 ·

- 24 ········ 4 · 4> 9 9 4 · 9 · · · 99 · 99 99 99 99 99 99

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

wherein R ⁴³ is selected from the group consisting of hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl; and wherein the R ³ pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halogen, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halenesulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; and

2544 44 44 44

4,444 444 ·

444 44 4 4445

4444 444 444 5

44 44 4444

R ⁴ is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl and naphthyl and 5- or 6-membered heterocyclyl;

wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from the group consisting of lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halogen, lower alkyl, lower alkynyl lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

A particularly important class of compounds consists of the compounds of formula (I) wherein:

R ¹ is selected from the group consisting of hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorfluoromethyl, difluoroethyl, difluoropropyl , dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, , dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,

- 26ΦΦ ·· ·· ·· · · · · · · φ · ♦ · ♦ · · · · φ · · · · · · · · · · methyl · methyl · methyl · methyl · methyl · methyl · hydroxyethyl, mercaptomethyl and methylthiomethyl; and

R ² is selected from the group consisting of hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazoline, morpholinyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino,

N, N-dimethylamino, N-ethylamino, N, N-diethylamino,

N, N-propylamino, N, N-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino,

N, N-dimethylaminoethylamino, N, N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl,

1,1-dimethylethoxycarbonylamino-ethylamino,

1,1-dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl and

1,1-dimethylethoxycarbonylpiperazinylcarbonyl;

wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more

- 274 4,444 · ♦ 4 4 4 · · · 4 4 4 · · 4 4 · 4 4 4 4 4 4

4 4 4 4 4 5

44 44 4444

44

4 4 4

4 4 ·

4 4 4

4 4 4

4,444 radicals selected independently from the group consisting of fluorine atom, chlorine atom, bromine atom, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl and 1,1-dimethylethylcarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and

R ³ is selected from pyridinyl, pyrimidinyl and purinyl; where

R ³ is optionally substituted with one or more radicals selected independently from methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl , aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, ethoxy, methoxy, methoxy, methoxy, methoxy, methoxy, methoxy, methoxy, , dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino

N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino,

- 28 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

99 99 9999 phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl, ethyl or phenylmethyl ; and R ⁴ is selected from the group consisting of hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, isoxazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl and benzodioxolyl;

wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert. butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of compounds of formula I wherein R ¹ is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;

φφ ♦ * ·· φ φ φ φ

Φ · φφ • φφφ φ φ φ ♦ * φ * φ φφφ φ

ΦΦΦΦ

R ² is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N, N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl and piperazinylamino;

wherein the phenyl, piperidinyl and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl and trifluoromethyl;

R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl;

wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl;

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

A class of compounds of particular interest consists of compounds of formula I wherein R ¹ is hydrido or methyl;

R ² is selected from the group consisting of hydrido, methyl, or φφφφ

- 30ΦΦ ·· Μ ·· • »φ ΦΦΦΦ · Φ · Φ

ΦΦΦ ΦΦ ΦΦΦΦΦ

ΦΦ ΦΦΦΦ ΦΦΦΦΦΦ • ΦΦΦ φφφ ΦΦΦΦ

ΦΦ ΦΦ ΦΦ ΦΦΦΦ ΦΦ ΦΦ ethyl;

R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl;

wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl;

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

Yet another class of compounds of particular interest consists of compounds of formula I wherein R ¹ is selected from the group consisting of hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl , pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylmethyl, morpholinylmethyl, morpholinylmethyl , piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino,

0000

- 3100 00 ·· ·· 00 0 0000 0000 000 00 0 0000 00 0000 0 * 0 00 0 0000 000 000 0 00 00 00 0000 00 00 methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl and methylthiomethyl; and

R ² has the formula:

30, 32, 33

AND

-C-CCH ₂ D j (III) in which:

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

R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen and lower alkyl;

R ³² is selected from the group consisting of 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 ; wherein R ³⁵ is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower

- 32 • 4444 44 44 44 44

4 4444 4444

44 44 44 4444

4444 44444 3

44 * 4

44 44 4444 ·· 44 alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyloxyalkylene, lower alkoxycarbonyloxyalkylene, lower alkoxy alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene and lower alkylthioalkylene; wherein said aryl selected from the group consisting of phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene and lower alkylcarbonylheterocyclyl groups are optionally alkyl groups; selected independently from the group consisting of lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or

R ³⁵ is CHR ⁴⁸ R ⁴⁹ wherein R ⁴⁸ is phenylsulfonylamino or lower alkylphenylsulfonylamino and R ⁴⁹ is selected from the group consisting of lower phenylalkyl, amino, lower alkylamino and lower phenylalkylamino; or

R ³⁵ is -NR ⁵⁰ R ⁵¹ wherein R ⁵⁰ is lower alkyl and R ⁵¹ is aryl selected from phenyl, biphenyl and naphthyl; and wherein R ³⁶ is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower;

- 3344 4 · 4

4,444 4 4 4 4

4,444 4,444

4444 444444

4444 444 4444

44 44 4444 44 44 cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenyl, lower alkylcarbonylamine, lower alkylcarbonylamine lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl and lower phenylsulfonylheterocyclyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl and lower alkylsulfonylphenylene are optionally substituted with one or more radicals independently selected from lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ is selected from the group consisting of 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, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylcarbonylcarbonylalkylene,

- 34 ·· · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9

99 99 9999 9 · ·· alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl and lower aminosulfonylphenylalkyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl and lower heterocyclylalkylene are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or R ³⁸ represents -CR ⁵² R ⁵³ wherein R ⁵² represents lower alkoxycarbonyl and R ⁵³ represents lower alkylthioalkylene; or R ³⁷ and R ³⁸ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle;

R ³⁹ and R ⁴⁰ are as defined in claim 2; or R ² is selected from the group as well as the groups R and R 2 inclusive

C ^CH 2 - k - (VI) (VII) (VIII) wherein k is an integer from 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 the group consisting of hydrogen, lower alkyl, lower phenylalkyl, aryl selected from the group consisting of:

- 35 • Φ ΦΦΦΦ

Φ φ φ ΦΦΦΦ φ φ φ φ φ φ φ φ φ

Including phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C (O) R ⁵⁹ , -SO ₂ R ^60, and -C -C ΦΦΦΦ 2 φ φ φ φ φ (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 alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl;

wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro 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 heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene and lower phenylsulfonylheterocyclyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and ··· ··

- 36 · 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 36 ® 36 ® ® ® ® ® ® ® ® 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 with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and

R ³ is selected from pyridinyl, pyrimidinyl and purinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl , ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, chlorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, chlorophenylpyrazolyl, chlorophenylpyrazolyl, chlorophenylpyrazolyl, chlorophenylpyrazolyl, chlorophenylpyrazolyl, , dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, N, methoxyphenylmethyl -dimethylaminoethylamino, hydroxypropylamino , hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, ···

- 37 9 9

9 9

9 9 9

9 9

9999

99

«« 9 »

9

9 9 9

99 phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl, ethyl or phenylmethyl; and R ⁴ is selected from the group consisting of hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, isoxazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl and benzodioxolyl;

wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert. butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof.

Yet another class of compounds of particular interest consists of compounds of formula I wherein R ¹ is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;

··

38 ·· ····

R ² has the formula

C — CCH-3 I

L ii (III) in which:

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

R ( ³⁰⁾ is hydrogen; and

R ³¹ is selected from the group consisting of hydrogen and lower alkyl; and

R ³² is selected from the group consisting of hydrogen and lower alkyl; and

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 ;

wherein R ³⁵ is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene and lower phenylalkoxyalkylene;

wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen and lower haloalkyl; and wherein R ³⁶ is selected from the group consisting of lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower.

-39- alkylamino;

wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ represents a hydrogen atom; and wherein R ³⁸ is selected from the group consisting of lower alkyl, phenyl and lower alkylphenylene; wherein R ³⁹ and R ⁴⁰ are R ²⁷ in claim 2; or R ² is selected from the group defined as R 2 and including

N

AND

CCHp _k

° CCHp _{K -} (VII) (VIII) (VI) wherein k is an integer from 0 to

R ⁵⁶ represents a hydrogen atom; and R ⁵⁷ represents a hydrogen atom; and

R ⁵⁸ is selected from the group consisting of -C (O) R ⁵⁹ and -SO ₂ R ⁶⁰ ; wherein R ⁵⁹ is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene and lower alkoxyalkylene;

wherein said phenyl group is optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶⁰ is selected from the group consisting of lower alkyl; and

R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl;

wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl; and

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

Yet another class of compounds of specific importance consists of compounds of formula I wherein R ¹ is hydrido or methyl; and

R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl;

- wherein R ³ is optionally substituted with one or more radicals selected independently from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy and methylcarbonyl; and

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

In one embodiment of the present invention, compounds of Formula I meet one or more of the following conditions:

R ¹ represents hydrido or lower alkyl; more preferably, R ¹ represents hydrido or methyl; and even more preferably, R ¹ represents hydrido;

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

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

R ⁴ represents substituted or unsubstituted phenyl; and preferably, R ⁴ represents phenyl substituted with a halogen atom.

In addition, when R ³ represents a substituted pyrimidinyl, preferably at least one R ³ substituent is bonded to a carbon atom located between two nitrogen atoms

42 of the pyrimidinyl ring.

A class of specific compounds of particular interest of formula (I) consists of the following compounds, tautomers and pharmaceutically acceptable salts thereof:

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-methyl-phenyl) -1H-pyrazol-4-yl] -pyridine;

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

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

4- [5- (2,5-Dimethyl-phenyl) -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-phenoxy-phenyl) -1H-pyrazol-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;

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

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

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

• ·

• 9 9 9

9999 98 99

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-Chloro-phenyl) -5-methyl-1H-pyrazol-4-yl] -pyridine;

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

4- [5- (4-Chloro-phenyl) -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-dimethyl-phenyl) -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-Bromo-phenyl) -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;

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

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

• 99 9

444- [5- (3,4-difluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

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

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

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

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

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

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

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

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

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

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

- 45 «« ····································

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

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

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

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

2-methoxy-5- [5- (4-methoxy-phenyl) -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-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; 4- [5- (3-Chloro-phenyl) -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-Methyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; 4- [5- (4-Chloro-phenyl) -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-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol

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

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

·· 44 * · 4 4

4 4 4 4

4 4 ·

2-methanamine;

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

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

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

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

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

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

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

- 4,999,999

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

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

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

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

4- [5- (3-Methoxy-5-methyl-phenyl) -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-carboxamide;

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

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

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

· «ΦΦΦΦ • Φ

- 48 φ · · methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 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;

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

N, N-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-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -pyridine;

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

- 49 · · · · 4 4 4 4 4 4 4 4 4 4 4 4 4

444 44 4 4445

4444 44444 3

4444 444 4444

44 44 4444

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

4- [3- (4-Chloro-phenyl) -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-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -2-methyl-pyridine;

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

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

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

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

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

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

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

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

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

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

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

5- (4-chlorophenyl) -N- (phenylmethyl) -4- (4-pyridinyl) -1H-pyrazole

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;

- 50 ·· · · · · · · ·

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

9999 98 99

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

1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methyl-piperazine;

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;

1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -piperazine;

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

1- [5- (4-Chloro-phenyl) -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) -1H-pyrazol-3-yl] -1-piperazinecarboxylate;

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

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

1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-ethyl-piperazine;

N- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -51-

99 99 * · • 9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99

1,2-ethanediamine;

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

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

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

4- [3-ethyl-5- (3-ethyl-phenyl) -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) -4-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) -1H-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-methyl-phenyl) -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-pyrazole]

- 5299 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 99

3-yl] carbonyl] piperazine;

1,1-dimethylethyl 4 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 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-Chloro-phenyl) -1,5-dimethyl-1H-pyrazol-4-yl] -pyridine;

4- [5- (4-Chloro-phenyl) -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-Chloro-phenyl) -1-ethyl-5-methyl-1H-pyrazol-4-yl] -pyridine;

4- [3- (4-Chloro-phenyl) -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) -4-pyrazole-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-methanol;

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-pyridinyl) -1H-pyrazole-5-methanol;

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

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

- 53 · φ φ φ 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

4444 444 4444

44 4 4444 44 44 hydrazone;

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

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

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

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

4- [5- (3-Chloro-phenyl) -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;

9

9 • 9 · 9 9

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-Bromo-phenyl) -1H-pyrazol-4-yl] -pyridine;

4- [3- (3,4-Difluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-Bromo-phenyl) -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-Chloro-phenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine-methanamine;

N- [4- [3- (4-Fluoro-phenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine-methanamine;

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;

• · · · ·

- 5599 9 99 9 999

4- [3- (3,4-Difluoro-phenyl) -1H-pyrazol-4-yl] -2-fluoro-pyridine; 4- [3- (4-Fluoro-phenyl) -1H-pyrazol-4-yl] -3-methyl-pyridine;

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-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] -N- [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-pyrazole-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) -N, N-dimethyl-1H-pyrazole-1-ethanamine;

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl]

ΙΗ-pyrazole-1-ethanol;

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

• · · ·

564- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -4-pyrazol-4-yl] -N - [(4-fluorophenyl) methyl] -2-pyridinamine;

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] N, N-dimethyl-1H-pyrazole-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] -N-4-piperadinyl-2-pyridinamine;

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

4- [1- [2- (diethylaminolethyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N - [(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] -4-pyrazole-1-ethanol;

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

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

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

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

5- (4-fluorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1H-pyrazole-57-amine;

3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -4-pyrazole-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] glycine methyl ester;

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] glycine 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazole -4-yl] pyrido; 4- [5- (4-Fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyrido; 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] 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] -N-methyl-2-pyrimidinamine;

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

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

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

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

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

• ·· ·

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

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

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

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

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] pyrimidine.

There is another class of compounds of formula I of particular importance that are represented by formula IX:

in which

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocyclyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl , lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, •

- 59 • phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or

R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and

R ⁴ is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5 or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl;

wherein R ⁴ is optionally substituted at a substitutable position by one or more radicals selected independently from halogen, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R ⁵ is selected from the group consisting of halogen, 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, ♦ · 9 9 9 9 9 9 9 9 9 »99 9 9 · 9 9 9 9 • · 9 9 9 9 999999 - • 999 999 9999 ·· ·· 999999 99 99 carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of compounds of formula IX wherein:

R ¹ is selected from the group consisting of hydrido, methyl, ethyl, hydroxyethyl and propargyl; and

R ² is selected from the group consisting of hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino,

N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morphol pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally

Substituted by one or more radicals selected independently from the group consisting of fluorine atom, chlorine atom, bromine atom, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-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 with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and

R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, methylmethylamino, fluoromethylbenzylamino, fluororphenylbutyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or • · 999 9

9

- 62 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

99 99 9999 99 99 or a pharmaceutically acceptable salt or tautomer thereof.

There is another class of compounds of formula I of high importance, consisting of compounds represented by formula X:

in which

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower • 4 4 4 4 4 • 4

4

4 4 4 4

4 heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or

R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and

R ⁴ is selected from the group consisting of 5- or 6-membered heteroaryl and aryl selected from the group consisting of phenyl, biphenyl and naphthyl;

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

R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower

0 «0000

- 640 »00 • 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ·

0 0 0 0 0 0

0 · 00 00 000

0 0 0

0 0 0

0 0 0

Alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of compounds of formula X wherein:

R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; and

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-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, methoxy, carboxymethylamino) (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl and 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl; and • 0 0 0 ·

- 6500

00 0

0 0 * 0 «00

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

R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylethylamino, phenylmethylamino, fluoromethylamino, phenylmethylamino, phenylmethylamino, , hydrazinyl and

1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

There is another class of compounds of formula I of high importance, consisting of compounds represented by formula XI:

• t · ♦ · »

(XI) # 9 9 in which

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxyycycloalkyl, lower carboxyycyckyalkyl, lower carboxyycyckyalkyl lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl;

- 67 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9 9 • 9 9 ·

Wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkylcarbonyl; lower alkoxycarbonyl; or

R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and

R ⁴ is selected from the group consisting of 5- or 6-membered heteroaryl and aryl selected from the group consisting of phenyl, biphenyl and naphthyl;

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

R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof.

«Β φφφφ • · φ • φ φ

φ Φ Φ Φ · • • • • • φ φ φ φ φ φ φ φ φ φ

A preferred class of compounds consists of compounds of formula XI wherein:

R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; and

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-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonyl, ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl;

R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl,

69 · · · · · · · · · · · · · · · · · · · · ·

methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; and

R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethyipiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, methylmethylamino, fluoromethylbenzylamino, fluororphenylmethylamino, fluorophenyl hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds consists of compounds of formula IX wherein:

Z represents a carbon atom or a nitrogen atom; and

R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6- membered heterocyclyl selected from the group consisting of piperidinyl, piperazinyl, imidazolyl, pyridinyl • · 9

- 70a morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or

R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and

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

R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower

71heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof.

A class of compounds of particular importance consists of compounds of formula IX in which:

R ¹ is selected from the group consisting of hydrido, methyl, ethyl, hydroxyethyl and propargyl;

R ² is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, Ν, Ν-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1-dimethyl) ethylcarbonyl, (1-dimethyl) ethylcarbonyl, ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) • · • ·

- 72ethoxycarbonyl;

R ⁴ is phenyl optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy ; and R ⁵ is selected from fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylethylamino, phenylmethylethylamino, phenylmethylamino-phenyl, , hydrazinyl and

1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof.

Another class of compounds of particular interest consists of compounds of formula IX wherein Z is carbon or nitrogen; and R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and

R ² is selected from the group consisting of hydrido and lower alkyl;

• • •

- 73a

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

R ⁵ is selected from the group consisting of hydrido, halogen and alkylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof.

Yet another class of compounds of specific importance consists of compounds of formula IX wherein Z is carbon; and

R ¹ is selected from hydrido, methyl, hydroxyethyl, propargyl; and R ² represents hydrido; and

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

R ⁵ is selected from hydrido, fluoro, and 1-methylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof.

A preferred class of compounds of particular interest consists of compounds of formula IX wherein Z is carbon; and

R ¹ is selected from the group consisting of hydrido and methyl; and R ² represents hydrido; and

R ⁴ is selected from phenyl optionally substituted with one or more radicals selected independently from chloro, fluoro and bromo; and • · · · «·

R ⁵ is selected from hydrido and fluoro; or a pharmaceutically acceptable salt or tautomer thereof.

The term hydrido refers to a single hydrogen atom (H). This hydride moiety may be attached, for example, to an oxygen atom to form a hydroxyl moiety, or two hydride moieties may be attached to a carbon atom to form a methylene (-CH ₂ -) moiety. When used, either alone or together with other terms such as haloalkyl, alkylsulfonyl, alkoxyalkyl and hydroxyalkyl, cyanoalkyl and mercaptoalkyl, the term alkyl includes linear or branched radicals having from one to about twenty carbon atoms or, preferably, from one to about twelve atoms carbon. More preferred alkyl radicals are lower alkyl radicals having from one to about ten carbon atoms. Most preferred are lower alkyl radicals having from one to about six carbon atoms. Examples of such residues 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 and containing from two to about twenty carbon atoms or, preferably, from two to about twelve carbon atoms. More preferred alkenyl radicals are lower alkenyl radicals having from two to about six carbon atoms. Examples of alkenyl residues include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms alkenyl and lower alkenyl include radicals having cis and trans orientations or alternatively E and Z orientations. The term alkynyl includes linear or branched radicals having at least one carbon-carbon triple bond and containing from two to about 3 carbon atoms.

75 twenty carbon atoms or preferably from two to about twelve carbon atoms. More preferred alkynyl radicals are lower alkynyl radicals having from two to about six carbon atoms. Examples of alkynyl residues include propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 1-pentynyl. The term cycloalkyl includes saturated carbocyclic radicals having from three to about twenty carbon atoms. The term cycloalkyl includes saturated carbocyclic radicals having from three to about twelve carbon atoms. More preferred cycloalkyl radicals are lower cycloalkyl radicals having from three to about eight carbon atoms. Examples of such residues include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term cycloalkylalkylene includes alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are lower cycloalkylalkylenes which include lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such residues include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The term cycloalkenyl includes partially unsaturated carbocyclic radicals having from three to twenty carbon atoms. Cycloalkenyl residues that are partially unsaturated carbocyclic residues that contain two double bonds (which may or may not be conjugated) may be called cycloalkyldienyls. More preferred cycloalkenyl radicals are lower cycloalkenyl radicals having from four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term halogen atom means a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The term haloalkyl includes radicals in which any one or more alkyl carbon atoms is

• φ φ

- 76 • φ φφ φφ ΦΦΦΦ substituted by a halogen atom as defined above. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, as an example, may be substituted with an iodine atom, a bromine atom, a chlorine atom, or a fluorine atom. The dihalogen and polyhaloalkyl radicals may contain two or more of the same halogen atoms or a combination of different halogen atoms. Lower haloalkyl includes radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term hydroxyalkyl includes linear or branched alkyl radicals having from one to about ten carbon atoms, any of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are lower hydroxyalkyl radicals having from one to six carbon atoms and one or more hydroxyl radicals. Examples of such residues include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms alkoxy and alkyloxy include linear or branched oxy-containing radicals having an alkyl moiety containing from one to about ten carbon atoms. More preferred alkoxy radicals are lower alkoxy radicals having from one to six 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 basic alkyl radical, e.g., monoalkoxyalkyl and

- 77 ·························

9 · · * 9 9 9 9 9

9 9 9

9 · 99 dialkoxyalkyl radicals. The alkoxy radicals may be further substituted with one or more halogen atoms, such as a fluorine atom, a chlorine atom or a bromine atom, to form haloalkoxy radicals. The term aryl, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings in which such rings may be bonded together or may be condensed. The term aryl includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The aryl moieties may also be substituted at a substitutable position by one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyllalkylene, alkylsulfinyllalkylene alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, alkoxyalkyloxy, carboxyalkylaminoalkylene, aminoalkylaminoalkylene, aminoalkylaminoalkylene, aminoalkylaminoalkylene carboxy and aralkoxycarbonyl.

The term heterocyclyl includes saturated, partially unsaturated and unsaturated heteroatoms containing and ring-formed moieties, which may also be called heterocyclyl, heterocycloalkenyl, and heteroaryl, wherein the heteroatoms may be selected from the group consisting of nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl and φφφ * * * * *φφφφφφφφφφφφφφφφφφφ φ · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ podobně podobně); saturated 3-6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (for example, morpholinyl and the like); saturated 3-6 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example, thiazolidinyl and the like). Examples of partially unsaturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl residues may include pentavalent nitrogen such as tetrazolium and pyridinium residues. The term heteroaryl includes unsaturated heterocyclic radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H1.2.4-triazolyl, 1H-1,2,3,3 triazolyl, 2H-1,2,3-triazolyl and the like), tetrazolyl (e.g., ΙΗ-tetrazolyl, 2H-tetrazolyl and the like) and the like; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g. tetrazolo [1,5-b] pyridazinyl and the like) and the like; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom such as pyranyl, furyl and the like; unsaturated 3-6 membered sulfur-containing heteromonocyclic groups such as thienyl and the like;

unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl (e.g.

1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like) and the like; unsaturated condensed heterocyclic • · 9 ···

7900 99 9 »

9 9 9 · 9 9

9 ♦ 9 · 99

9 9 9 9 9

Groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl and the like); unsaturated 3 to β-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (for example

1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like) and the like; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (for example, benzothiazolyl, benzothiadiazolyl and the like) and the like. The term heterocycle also includes radicals in which the heterocyclic radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene and the like. Said heterocyclic group may have 1 to 3 substituents such as alkyl, hydroxyl, halogen, alkoxy, oxo, amino, alkylthio and alkylamino. The term heterocyclylalkylene includes heterocyclyl substituted alkyl radicals. More preferred heterocyclylalkylene radicals are lower heterocyclylalkylene radicals having from one to six carbon atoms and heterocyclic radicals. The term alkylthio includes radicals containing a linear or branched alkyl radical containing from one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are lower alkylthio radicals containing alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylthio residues are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term alkylthioalkylene includes radicals containing an alkylthio radical bonded via a divalent sulfur atom to an alkyl radical containing from one to about ten atoms.

- 80 ·· • 9 99 • 9 9 9 9

9 9 9

9

9 9 9 • 9 9 9 9 9 »9 9«

9 9 9 · 9 · 9 9 More preferred alkylthioalkylene radicals are lower alkylthioalkylene radicals having alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl. The term alkylsulfinyl includes radicals containing a linear or branched alkyl radical containing from one to about ten carbon atoms bound by the divalent radical -S (= O) -. More preferred alkylsulfinyl radicals are lower alkylsulfinyl radicals having alkyl radicals containing from one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term sulfonyl, used alone or linked to other terms such as alkylsulfonyl, halosulfonyl refers to the divalent radical -SO ₂ -. Alkylsulfonyl includes alkyl radicals bonded to a sulfonyl radical, wherein alkyl is as defined above. More preferred alkylsulfonyl radicals are lower alkylsulfonyl radicals having from one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The alkylsulfonyl radicals may be further substituted with one or more halogen atoms, such as a fluorine atom, a chlorine atom or a bromine atom, to form haloalkylsulfonyl radicals. The term halosulfonyl includes halogen residues bonded to sulfonyl residues. Examples of such halosulfonyl radicals include chlorosulfonyl and bromosulfonyl. The terms sulfamyl, aminosulfonyl and sulfonamidyl denote NH ₂ O ₂ S-. The term acyl refers to a residue formed by a residue upon removal of hydroxyl from an organic acid. Examples of such acyl residues include

II 4 4

813 4 4 • 4

alkanoyl and aroyl residues. Examples of such alkanoyl residues include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and residues formed from succinic, glycolic, gluconic, lactic, malonic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, fumaric, fumaric , almond, pantothenic, p-hydroxybutyric, galactar and galacturonic. The term carbonyl, used alone or together with other terms, such as alkoxycarbonyl, denotes - (C = O) -. The terms carboxy or carboxyl, used alone or together with other terms such as carboxyalkyl, denotes -CO ₂ H.

The term carboxyalkyl includes alkyl radicals substituted with a carboxy radical. More preferred are lower carboxyalkyls which contain lower alkyl radicals as defined above and can be additionally substituted on the alkyl radical with a halogen atom. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to the carbonyl radical. More preferred are lower alkoxycarbonyl radicals having alkyl moieties having one to six 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 alkoxycarbonyl radicals as defined above. More preferred are lower alkoxycarbonylalkyl radicals having alkyl moieties having one to six carbon atoms. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted alkoxycarbonylalkyl radicals

unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl. The term alkylcarbonyl includes radicals having alkyl or hydroxylalkyl radicals as defined above, attached to a carbonyl radical. Examples of such residues include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl. The term aralkyl includes aryl substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino and nitro. The terms benzyl and phenylmethyl are interchangeable. The term heterocyclylalkylene includes saturated and partially unsaturated heterocyclyl substituted alkyl radicals (which may also be called heterocycloalkylakylene and heterocycloalkenylalkylene, respectively) such as pyrrolidinylmethyl and heteroaryl substituted alkyl radicals (which may also be called heteroarylalkylene) such as pyridylmethyl, quinolyl, quinolyl, quinol . The heteroaryl in said heteroaralkyl may additionally be substituted by a halogen atom, an alkyl, alkoxy, haloalkyl and haloalkoxy group. The term aryloxy includes aryl radicals bonded through an oxygen atom to other radicals. The term aralkoxy includes aralkyl radicals bonded via 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 residues include aminomethyl, aminoethyl and the like. The term alkylamino refers to amino groups which are substituted with one or two alkyl radicals. Lower alkylamino radicals having alkyl moieties containing from one to six carbon atoms are preferred. Suitable lower alkylamino radicals may be monosubstituted N-alkylamino or disubstituted N, N-alkylamino groups such as N-methylamino, N-ethylamino, N, N-dimethylamino,

N, N-diethylamino and the like. The term arylamino refers to amino groups which are substituted with one or two aryl radicals, such as N-phenylamino. Arylamino residues may be further substituted on the aryl ring of the residue. The term aminocarbonyl refers to an amide group of formula C (= O) NH ₂ . The term alkylaminocarbonyl refers to an aminocarbonyl group which has been substituted with one or two alkyl radicals on the nitrogen atom of the amino group. Preferred are N-alkylaminocarbonyl and

N, N-dialkylaminocarbonyl residues. More preferred are lower N-alkylaminocarbonyl and lower

N, N-dialkylaminocarbonyl radicals containing lower alkyl moieties as defined above. The term alkylcarbonylamino includes amino groups which are substituted with one alkylcarbonyl radical. More preferred alkylcarbonylamino radicals are lower alkylcarbonylamino radicals having lower alkylcarbonyl radicals, as defined above, attached to amino radicals. The term alkylaminoalkylene includes radicals having one or more alkyl radicals attached to an aminoalkyl radical.

Hydrocarbons are organic compounds or residues • · · ·

containing exclusively carbon and hydrogen. These include alkyl, alkenyl, alkynyl and aryl groups. These also include alkyl, alkenyl, alkynyl and aryl groups substituted with other aliphatic or cyclic hydrocarbon groups such as alkaryl, alkenaryl and alkynaryl. Preferably, these groups contain 1 to 20 carbon atoms.

Heterosubstituted hydrocarbon groups described herein are hydrocarbons that are substituted with at least one atom other than a carbon atom, including groups in which the carbon atom of the chain is substituted with a heteroatom such as a nitrogen atom, an oxygen atom, a sulfur atom, or a halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; a halogen atom such as a chlorine atom or a fluorine atom; ethers; acetals; ketals; esters; heterocyclyls such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.

Other terms used to describe these pyrazole ring substituents not specifically defined herein have definitions that are analogous to the above definitions. As mentioned above, more preferred substituents are those containing lower residues. Unless otherwise indicated, the term lower as used in the present application means that each alkyl moiety in a pyrazole ring substituent containing one or more alkyl moieties contains one to about six carbon atoms; each alkenyl radical in the pyrazole ring substituent containing one or more alkenyl radicals contains one to about six carbon atoms; each alkynyl residue in the pyrazole ring substituent containing one or more alkynyl residues contains one to about six carbon atoms; each cycloalkyl or cycloalkenyl radical in the pyrazole ring substituent containing one or more cycloalkyl and / or cycloalkenyl radicals is a 3- to 8-membered cycloalkyl or cycloalkenyl radical; each aryl moiety in the pyrazole ring substituent containing one or more aryl moieties is a monocyclic aryl moiety; and each heterocyclic radical in a pyrazole ring substituent containing one or more heterocyclic radicals is a 4-8 membered heterocyclyl.

The present invention also relates to tautomeric forms of the compounds of formulas I and IX. As illustrated below, the pyrazoles of formulas I and 1 'are magnetically and structurally equivalent due to the prototropic tautomeric nature of the hydrogen atom:

The present invention also relates to compounds of formulas I, IX, X and XI which contain one or more asymmetric carbon atoms. It is known to those skilled in the art that those pyrazoles of the present invention that contain asymmetric carbon atoms may exist in diastereomeric, racemic

- * or optically active forms. All such forms are included within the scope of the present invention. More particularly, the present invention includes enantiomers, diastereomers, racemic mixtures thereof, and other mixtures of compounds of formulas I, IX, X and XI.

The present invention includes pharmaceutical compositions for the treatment of TNF-mediated disorders, p38 kinase mediated disorders, inflammation, and / or arthritis, comprising a therapeutically effective amount of a compound of Formula I, or a therapeutically acceptable salt or tautomer thereof, together with at least one pharmaceutically acceptable carrier, adjuvant or diluent.

The present invention further relates to substituted pyrazoles that specifically bind to the ATP binding site of p38 kinase. Without being bound by detailed theory, Applicants assume that substituted pyrazoles interact with p38 kinase as described below. When the substituent at position 3 on the pyrazole ring approaches the ATP binding site of p38 kinase, a hydrophobic cavity of the p38 kinase is formed at the binding site around the substituent at position 3.

This hydrophobic cavity is believed to form when the substitutent at position 3 binds to a specific peptide sequence of the enzyme. Specifically, it is assumed that binds to the side chains of Lys ₅ 2, Glu ₆ g, Leu _73, Ile _82, Leu ₈ 4 Leuioi and the methyl group of side chain Thri ₀ 3 p38 kinase at the ATP binding site (wherein the numbering corresponds to the conventional numbering used for ERK-2). If the substituent at the 3-position is aryl or heteroaryl, then such aryl or heteroaryl may be further substituted. It is believed that such substituents ·· ·· ► * · <

9

····· $ 7 may be useful to prevent hydroxylation or further ring metabolism.

The substituent at position 4 of the pyrazole ring is one that partially mimics the adenine ring of ATP, but can be further developed. Preferably it is a planar substituent terminated with a suitable functional group forming the hydrogen bond acceptor. This acceptor is believed to form a hydrogen bond with the N-H backbone in the Meticm residue, while one edge of this substituent is in contact with the bulk solvent.

Substitution at the 5-position of the pyrazole ring is well tolerated and may result in increased binding ability and selectivity. It is believed that such substituents extend outwardly into the bulk solvent and that a suitable polar functional group located at the end thereof may interact with the side chains in Aspi ₀ 9, resulting in increased binding ability and selectivity.

Similarly, substitution at the nitrogen atom at the 1 or 2 position of the pyrazole ring is well tolerated and may result in increased binding ability. The hydrogen substituent bonded to one of the ring nitrogen atoms is believed to be a hydrogen atom that binds to Aspi ₆ s. Preferably, the nitrogen atom at the 2-position binds by a double bond to the carbon atom at the 3-position of the pyrazole while the nitrogen atom at the 1-position. pyrazole is available for substitution with a hydrogen atom or other substituents.

The substituent at the 5-position and the substituent at the 1 or 2 position of the pyrazole can be selected to improve the physical

• φ φ φ φ φ · · · · · ·

The properties of the substituted pyrazole, especially water solubility and substance availability. However, it is preferred that these substituents each have a molecular weight of less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight of less than about 250 atomic mass units. Even more preferably, these substituents together have a molecular weight of less than about 360 atomic mass units.

A class of substituted pyrazoles of particular importance consists of compounds having the general formula:

in which

R ¹ represents a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a molecular weight of less than about 360 atomic mass units; and

R ² represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue that binds to a p38 kinase at said ATP binding site of the p38 kinase; and

R ³ represents a hydrocarbon radical, heterosubstituted

89 a hydrocarbon radical or a heterocyclic radical having a functional group forming a hydrogen bond acceptor; and R ⁴ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 360 atomic mass units;

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; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further 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 compounds of formula XI wherein R ¹ is a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a molecular weight of less than about 360 atomic mass units; and

R ² is hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclic radical wherein said radical binds with Lys ₅₂ side chains, Glu69,

Leu ₇₃ Ile ₈₂ , Leu ₈₄ , Leu _{X 10} and Thr ₁₀ 3 at said ATP binding site of p38 kinase, wherein said residue is substantially within a hydrophobic cavity formed during said p38 kinase binding at the ATP binding site; and

R ³ represents a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a functional group forming a hydrogen bond acceptor which

9 · · · · · · · ·

I> »1 1 1 1 1 1 1 1 1 1 1

9 * 0 * forms a hydrogen bond with the NH backbone in Meti ₀ 6 p38 kinase; and R ⁴ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 360 atomic mass units.

The present invention also relates to a therapeutic method for treating TNF-mediated disorders, p38 kinase mediated disorder, inflammation and / or arthritis in a subject, comprising treating a subject suffering from or susceptible to said disorder or condition with a therapeutically effective amount of a compound of Formula

(I) in which

R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl ··· • 9 9 * 9 9 9 _Λ 9.9

- 91 • 9 9

9 • 9

9 • 99

9 9 9

9 9 9

9 9 9

Arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkynyl, alkynyl, alkynyl, alkynyl, alkynyl, alkynyl, alkynyl; -alkynylsulfinyl, arylsulfinyl, heterocyklylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyklyloxykarbonylaikylen, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyklyloxykarbonylarylen, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyklylkarbonylalkylen, alkylkarbonylarylen, arylkarbonylarylen, heterocyklylkarbonylarylen, alkylkarbonyloxyalkylen, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene ; or R ¹ has the general formula

R ²⁵ I-C - CH 1

H, 26 (II) in which:

i is an integer from 0 to 9;

R ²⁵ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene

99

9 9 9

9 9 9

9 9 9

9 9 9

99

·· ··

9 9 9

9 9

9 9

9 9

9999 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; and

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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, · alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylaikylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylalkylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxykarbony1arylen, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyclylcarbonylalkylarylene, alkylthi oalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene;

wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene,

Alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylakylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalkylarylene and alkylsulfonylarylene are optionally substituted with one or more alkyl, halo, selected from independently selected from halo, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylakylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene;

wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino;

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

R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, »• · • •» »» »»

95 '' arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or

R ² has the formula:

R ³⁰ I - C-CCHP 3 R ³¹ , 34

-N, 32, 33 (III) wherein:

j is an integer from 0 to 8; and «· ·· ·· * ·

9

9 •

M is 0 or 1; and

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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and

R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents hydroxy; and

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

(IV)

0 0 0

0

-96- · ·· ·

0 0 0

Wherein R ⁴³ is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R ³ pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halenesulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and

R ⁴ is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from halo, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkisulfonylalkylene,

arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, 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 hydrido;

further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof.

The invention also relates to a class of pharmaceutically acceptable salts of the compounds of formula I. The term pharmaceutically acceptable salts includes salts generally used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salts is not critical, provided they are pharmaceutically acceptable salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula (I) may be prepared from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are:

9

9

9

formic acid, acetic, propionic, succinic, glycolic, gluconic, lactic, malonic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesyl, stearic, hydroxy-salicyl, , almond, embon (pamo), methanesulfone, ethanesulfone, benzenesulfone, pantothene, toluenesulfone,

2-hydroxyethanesulfonic, sulfanyl, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic. Suitable pharmaceutically acceptable base addition salts of the compounds of formula I include metal salts and organic salts. More preferred metal salts include, but are not limited to, suitable alkali metal salts (group Ia), alkaline earth metal salts (group IIa), and other physiologically acceptable metals. Such salts may be aluminum, calcium, lithium, potassium, sodium and zinc salts. Preferred organic salts may be formed from tertiary amines and quaternary ammonium salts, including, but not limited to, tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be prepared by conventional methods from the corresponding compounds of formulas I-III by reacting, for example, the corresponding acid or base with a compound of formulas I-III.

General methods of synthesis

The compounds of the present invention can be prepared according to the following procedures described in Schemes I-XVIII wherein R ^1, R ² , R ³ , R ⁴ , R ⁵ and Ar ¹ are as defined above for compounds of Formula I, ··· 44 ·· ·· ··

4 · ········· · · · · 44 4 444 *

IX, X and XI, unless expressly stated otherwise.

• · ··· ·

Scheme I

Scheme I shows the synthesis of pyrazole 5 in two ways.

Condensation of pyridylmethylketone 1 with an aldehyde 2 in the presence of a base such as piperidine in a solvent such as toluene or benzene, either in the absence or in the presence of acetic acid at reflux, yields α, β-unsaturated ketone 3. it is converted to epoxide 4, such as by treatment with a hydrogen peroxide solution at ambient temperature in the presence of a base such as sodium hydroxide. Treatment of epoxide 4 with hydrazine in ethanol or another suitable solvent at a temperature in the range up to the reflux temperature gives pyrazole 5. In path 2, ketone 3 is condensed directly.

Alternatively, the tosyl hydrazone 6 intermediate can be isolated and converted to pyrazole 5 by treatment with a base such as potassium hydroxide in a suitable solvent such as ethylene glycol at a temperature of at room temperature. range from 25 ° C to 150 ° C.

Scheme II

Scheme II illustrates the synthesis of pyrazoles 12 of the present invention. Treatment of the pyridine derivative 7 with ester 8 in the presence of a base such as sodium bis (trimethylsilyl) amide in a suitable solvent such as tetrahydrofuran affords ketone 9. Treatment of ketone 9 or ketone hydrogen halide salt 9

·· 9999

A 10299 halogenating agent such as bromine, N-bromosuccinimide or N-chlorosuccinimide, in a suitable solvent such as acetic acid, methylene chloride, methanol, or a combination thereof, forms the α-halogenated ketone 10 (wherein X represents a halogen atom). Examples of suitable hydrohalogenic salts include hydrochloride and hydrobromide salts. Reaction of haloketone 10 with thiosemicarbazide 11 (where R ⁶ and R ⁷ may represent hydrido, lower alkyl, phenyl, heterocyclyl and the like or where R ⁶ and R ⁷ form a heterocyclic ring optionally containing an additional heteroatom) gives pyrazole 12. Examples of suitable solvents for this reaction are ethanol and dimethylformamide. The reactions may be carried out in the presence or absence of a base or acid at temperatures ranging from ambient temperature to 100 ° C.

Thiosemicarbazides that are not commercially available can be conveniently prepared by one skilled in the art by first reacting the corresponding amine with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide. Treatment of the resulting alkyldithiocarbamate with hydrazine results in the desired thiosemicarbazide. These reactions are further described in E. Lieber and R.C. Orlowski, J.

Org. Chem., Vol. 22, p. 88 (1957). An alternative approach 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 are incorporated herein by reference.

Scheme III

9999 * «

Scheme III shows the synthesis of pyrazole 19 in a more general way in three ways. In Route 1, the ketone 13 is condensed with hydrazine 14 to give a substituted hydrazide 16, which is then reacted with an acyl halide or anhydride 17 at low temperature to obtain acylhydrazone 18. Upon heating to 200 ° C, the acylhydrazone 18 is converted to pyrazole 19.

In Route 2, acylhydrazone 18 is formed directly by reacting ketone 13 with acylhydrazide 15, formed by reacting hydrazine with a carboxylic acid ester at ambient temperature. Heating of acylhydrazone 18 as above gives pyrazole 19. In path 3, ketone 13 is treated with acylhydrazide 15 at a suitable temperature ranging from ambient temperature to about 200 ° C to give pyrazole 19 directly. Alternatively, this condensation may be performed in an acidic solvent such as acetic acid or in a solvent containing acetic acid.

104 ·

Scheme IV φφ φφφφ

Φ ···· φφ ·· Φ Φ 4 Φ ·

»Φ Φ 4

I Φ φ 4

ΦΦ ΦΦ

ο

NKR ¹ ΝΗJ perfect

Synthetic Scheme IV describes the preparation of pyrazoles 19.

·· 9999

- 10599 · «99 99 99

9999 9999

9 9 9 9 9

999 99 9 99 99 9

9 ·· 9999

9999 98 99

Scheme V

4-imidazolyl

Scheme V depicts a two-step synthesis of the 3-substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclizing hydrazondianions with carboxylates. In step 1, the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as shown in Scheme IX below) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32. Examples of suitable hydrazines include, but are not limited to, phenylhydrazine and p-methoxyphenylhydrazine. In step 2, the hydrazones 32 are treated with two equivalents of a base such as sodium bis (trimethylsilyl) amide in a suitable solvent such as tetrahydrofuran to form dianions. This reaction can be carried out at temperatures around 0 ° C or lower.

In the same step, the dianions are then condensed with esters such as methyl isonicotinate, methyl cyclopropanecarboxylate and thereby

9 9999

The desired pyrazoles 33 are obtained. In some cases, it may be necessary to treat the product of this step with a dehydrating agent as an inorganic acid to obtain the target pyrazole.

4

- 107-:

• 4 4 4 4 • 4 4 4 4 4 •

44 4444 44

Scheme VI = heteroaryl

- 108 c · c c c c c 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108 108

9 9 • 9 9

9

9 9 ·

99

Scheme VI illustrates an alternative method of synthesizing pyrazoles that are not substituted at the 5-position of the ring. According to this method, heteroaryl methyl ketone 34 is synthesized by first treating the heteroarylmethane with a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide. Examples of suitable heteroarylmethanes are 4-methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine. The resulting heteroarylmethyl lithium is then reacted with a substituted benzoate ester to provide ketone 34. Examples of suitable benzoate esters are methyl ethyl p-fluorobenzoate and ethyl and methyl p-chlorobenzoate. Ketone 34 is converted to the aminomethylene derivative 35 by reaction with an aminomethylene reagent such as dimethylformamide dimethylacetal or tert-butoxybis (dimethylamino) methane. Ketone 35 is converted to pyrazole 36 by hydrazine treatment.

Modifications of this synthetic pathway serve for the regioselective synthesis of pyrazole 38, which contains a substituted nitrogen at the 1-position of the ring. The ketone 34 is first converted to the hydrazone 37 by reaction with a suitable substituted hydrazine. Examples of suitable hydrazines are N-methylhydrazine and

N- (2-hydroxyethyl) hydrazine. Reaction of hydrazone 37 with an aminomethylene reagent gives pyrazole 38. Examples of suitable aminomethylene reagents include dimethylformamide dimethylacetal and tert-butoxybis (dimethylamino) methane.

In cases where the R ³ substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen, subsequent treatment with an amine gives amino substituted • ·

- 1095-.

heteroaromatic derivative. Examples of such amines include benzylamine, cyclopropylamine and ammonium.

The leaving group can also be replaced by other nucleophiles such as mercaptides and alkoxides. Examples of suitable R ³ groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl groups.

• ·

- no:

Scheme VII

KMnO

• ·

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

Scheme VIII

Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole.

43. Alkylation of the nitrogen atoms of the pyrazole ring 43 can be achieved using conventional methods. Treatment of pyrazoles 43 with a suitable base (e.g. sodium hydride) followed by treatment with an alkyl halide (e.g. CH ₃ I) affords a mixture of isomers 44 and 45.

• · • ·

Scheme IX

hehamethyldisilazide lithium tetrahydrofuran ambient temperature

desoxybenzoin

Scheme IX illustrates the synthesis of 3-aryl-4-pyridyl-pyrazoles according to • 0 0 · 0 ·

0 0

114 of the present invention. The 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 afford desoxybenzoin 48. The desoxybenzoin 48 is then converted to ketone 49 by excess dimethylformamide. . Ketone 49 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to give pyrazole 50. In Scheme IX, R ¹² represents one or more radicals selected independently of one another from the possible substituents listed above for R ⁴ . Preferably R ¹² is hydrogen, alkyl, halogen, trifluoromethyl, methoxy or cyano or represents methylenedioxy.

The 3-aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized by the method of Scheme IX by replacing pyridine 47 with the corresponding pyrimidine. In a similar manner, Schemes X to XVII can be used for synthesis

3-aryl-4-pyrimidinyl-pyrimidines corresponding to the 3-aryl-4-pyrimidinyl-pyrazoles shown in these schemes.

99 a · · · · · · ·

- 115

9 ~ · · ·

99

9 999

Scheme X

Scheme X illustrates one variation of Scheme IX which can be used to synthesize 3-aryl-4-pyridyl-pyrazoles which are further substituted at the nitrogen atom at the 1-position of the pyrazole ring. When the desoxybenzoin 48 (prepared according to Scheme IX) is first converted to the hydrazone 51 by treatment with hydrazine and the hydrazone 51 is then treated with dimethylformamide dimethylacetal, then the resulting product is pyrazole 52.

• · ··· · ·· · »··

Schemes XI to XVIII illustrate further modifications that may be made in Scheme IX for the synthesis of additional 3-aryl-4-pyridyl-pyrazoles having alternative substituents.

«9 9999

· 9 ♦

9 9 * 9 9 9

9 9 9

99 »999

118 *. 9 9 9 9

9 9 9

9 · 9 *

9 9 9

99 9999

Scheme XII

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

• 9,999 · • · ·· ··

9 9 9

9 9 · · ··· „ _Λ 9 · ··· ♦ · · · ·

119 * ··· · · ·· · ·· ·

9 «99 ·· ···· · * ··

Scheme XIII

·· ·

·· ΦΦΦΦ • Φ

- 121 *

Scheme XV

In Scheme XV, n is 1, 2, 3, 4, or 5; and R ¹⁴ and R ¹⁵ are independently selected from hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring which may contain one or more additional heteroatoms selected from the group consisting of: including an oxygen atom, a nitrogen atom or a sulfur atom.

0 0 0 0 0

In Scheme XVI, R ^{17 is} selected from the group consisting of, for example, hydrogen, alkyl, and phenyl.

* · ·· «· ·· ··

- 123+ ·

I · 4 · 4 · · 4 ·· ··

Scheme XVII

R

In Scheme XVII, for example, alkyl, R ^{17 is} selected from phenylalkyl and heterocyclylalkyl.

· ♦ φ

Ί 2 4 - · φ # # # # # # # # # # #

Scheme XVIII

[Ο]

TMSCN

DM? methylation / MeOH

..., 0 ...

R ¹⁸ Β ^1θ ΝΗ,

1

Compounds in which the 2-position of the pyridine ring is substituted with a carboxyl group or a carboxyl derivative may be synthesized as outlined in Scheme XVIII. The starting pyridylpyrazole 67 is converted to

The 2-cyano derivative 68 was first converted to its pyridine N-oxide

4

4 4 • 4 ·

• · ·

4444

4 4

4 4

4 »

By reacting with an oxidizing agent such as m-chloroperoxybenzoic acid. Treatment of pyridine N-oxide with trimethylsilyl cyanide followed by dimethylcarbamoyl chloride gives 2-cyano 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. The carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethylacetal in methanol. The ester 70 is converted to the corresponding 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 and the like. The ester 70 can also be converted to the substituted amide 72 by treatment with the desired amine, such as methylamine, at a suitable temperature. Temperatures can range from ambient to 180 ° C. In Scheme XVIII, R ¹⁸ and R ^{19 are} independently selected, for example, from the group consisting of hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring which may contain one or more additional heteroatoms selected from the group , including an oxygen atom, a nitrogen atom or a sulfur atom.

DETAILED DESCRIPTION OF THE INVENTION

The following examples provide a detailed description of methods for preparing compounds of formulas I, XI, X and XI. These detailed descriptions are within the scope of the invention and serve to exemplify the above general synthetic procedures forming part of the present invention. These detailed descriptions are intended only as

I · t · · · Α ··

- 126 Φ · · 126 126 126 126 126 126 126 126 126 126 126 126 126 126 126 126

And are not intended to limit the scope of the present invention. All ratios are by weight and temperatures are in degrees Celsius unless otherwise indicated. All compounds show NMR spectra consistent with their structure. In some cases, the structure of the compounds was confirmed by nuclear overhauser effect (NOE) experiments.

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 sulfite

NaOH sodium hydroxide

KOH potassium hydroxide

P2O5 phosphorus pentoxide

Me methyl

Et ethyl

MeOH methanol

EtOH ethanol

HOAc (or AcOH) acetic acid

EtOAc ethyl acetate

H2O water

H2O2 hydrogen peroxide

CH2Cl2 methylene chloride

K2CO3 potassium carbonate

KMnO ₄ potassium permanganate

NaHMDS sodium hexamethyldisilazide

DMF dimethylformamide

EDC 1- (3-dimethylaminopropyl) - hydrochloride 3-ethylcarbodiimide HOBT 1-hydroxybenzotriazole mCPBA 3-chloroperoxybenzoic acid Ts tosyl TMSCN trimethylsilyl cyanide Me ₂ NCOCl N, N-dimethylcarbamoyl chloride SEM-C1 2- (trimethylsilyl) ethoxymethyl chloride THF tetrahydrofuran TLC thin layer chromatography DSC differential scanning calorimetry eg equivalent

Example A-1

4- [5- (3-fluoro-4-methoxyphenyl) -3-methyl-4-pyrazol-4-yl] pyridine

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

A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-panisaldehyde (1.25 g, 8.1 mmol) and piperidine (0.13 g, 1.5 mmol) in toluene (50 mL) ) was heated to reflux. After 18 hours, the reaction mixture was cooled to ambient 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-methoxy) phenyl) -3-pyridyl-3-butene-2- He as a pale yellow solid (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 3-pyridyl-4- (3-fluoro-4-methoxy) phenyl) -3-buten-2-one (step 1) (0.99 g, 3.65 mmol) in acetic acid (25 mL) was added p. -toluenesulfonylhydrazide (0.68 g, 3.65 mol). The reaction solution was heated to reflux for 6 hours. The acetic acid was removed by distillation from the reaction solution. The resulting residue was diluted with CH ₂ Cl ₂ (150 mL), washed with H ₂ O ( ₂ x 100 mL), dried (Na ₂ SO ₄ ), 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%):

Elementary analysis:

Calcd for C16H14N3OF. 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

Step 1: Preparation of 4-Pyridylacetone

4-Pyridylacetone was prepared according to the method of Ippolito et al., U.S. Pat. No. 4,681,944.

Step 2: Preparation of 4-phenyl-3- (4-pyridyl) -3-buten-2-one Using the method of Example A1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3- (4-pyridyl) -3-buten-2-one (1.3 g, 78%) was obtained as a crystalline solid;

Mp 101-103 ° C.

Elementary analysis:

Calcd. For C 15 H 13 NO (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 Using the method of Example A1, step 2 was a solution of 4-phenyl-3- (4-pyridyl) -3-butene-2. -one (step 2) (1.25 g, 5.6 mmol) in methanol (20 mL) was treated 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

Using the method of Example A1, Step 3, a solution of 4-phenyl-3- (4-pyridyl) -3,4-epoxy-2-butanone (Step 3) (250 mg, 1 mmol) in ethanol (15 mL) was treated with anhydrous hydrazine ( 50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1: 1 acetone / hexane). The product was recrystallized from ethyl acetate and hexane to give 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine (81 mg, 35%) as a crystalline solid: mp 212-214 ° C.

Elementary analysis:

Calcd for C ₁₅ H ₁₃ N ₃ (235.29): C, 76, 57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.

Example A-3

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

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

A solution of 4-pyrridyl acetone (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. The water formed during the reaction was removed with a Dean-Stark trap. After refluxing for 5 hours, the reaction mixture was stirred at ambient temperature for 15 hours. The mixture was concentrated to an oily orange residue. The crude ketone was purified by chromatography to give 4- (2-methylphenyl) -3- (4-pyridyl) -3-buten-2-one. Elementary analysis:

Calcd. For C ₁₆ H ₁₅ NO (237.30): C, 80.98; H, 6.37; N, 5.90. Found: C, 80.78; H, 6.61; N, 5.85.

Step 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 solution H ₂ O ₂ (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 ambient temperature for 70 hours. After the methanol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the biphasic mixture was stirred for 30 minutes. The layers were separated and the aqueous layer was washed with ethyl acetate (100 mL). The combined organic layers were dried over Na ₂ SO ₄ , 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.

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

A solution of 4- (2-methylphenyl) -3- (4-pyridyl) -3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g,

0.866 mmol) in ethanol (50 mL) was 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) -1H-pyrazol-4-yl] pyridine.

Elementary analysis:

Calcd. For C 3 H 15 N 3 (249.32): C, 77.08; H, 6.06; N, 16.65. Found: C, 76.66; H, 5.91; N, 16.84.

Example A-4

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

Following the procedure described in Example A-3 using p-fluorobenzaldehyde instead of o-tolualdehyde, the title compound was prepared:

Elementary analysis:

Calc'd for C16H12N3F + 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.

Example A-5

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

Following the procedure described in Example A-3 (with one small modification: in step 2, the preparation of the epoxy intermediate was achieved at 0-10 ° C for 1 hour and the reaction was terminated by partitioning between water containing 2 equivalents of sodium sulfite and ethyl acetate) using ptolualdehyde instead of o-tolualdehyde the title product was isolated:

Elementary analysis:

Calcd for C ₁₆ H ₅ N ₃ (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.97; H, 6.09; N, 16.90.

Example A-6

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

999 · 9 9 · 999 999

Following the procedure described in Example A-5 using 4- (methylthio) benzaldehyde instead of p-tolualdehyde, the title product was prepared:

Elementary analysis:

Calcd. For C 16 H 15 N 3 S (281, 38): C, 68.30; H, 5.37; N, 14.93 Found: C, 68.34; H, 5.09; N, 14.78.

Example A-7

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

Following the procedure described in Example A-5 using p-chlorobenzaldehyde instead of p-tolualdehyde, the title product was obtained.

Elementary analysis:

Calcd. For C 15 H 12 N 3 Cl (269.77): C, 66, 79; H, 4.48; N, 15.58.

Found: C, 66.43; H, 4.44; N, 15.78.

Example A-8 · ΐ5δ · · · · · · · ········

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

Following the procedure described in Example A-5 using m-tolualdehyde instead of p-tolualdehyde, the title product was obtained:

Elementary analysis:

Calcd. For C ₁₆ H ₅ N ₃ + 0.2H 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-Dimethyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine

Following the procedure described in Example A-5 using 2,5-dimethylbenzaldehyde instead of p-tolualdehyde, the title product was obtained:

• 9

9999

9 9

9999

99

9 9 9

9 9 ·

9 9 9

9 9 9

Elementary analysis:

Calcd. For C 17 H 17 N 3 + 0.1H ₂ O: C, 77.01; H, 6.54; N, 15.85. Found: C, 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-Pyridylacetone (1.5 g, 12 mmol), piperonal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol) and piperidine (110 mg, 1.3 mmol) were dissolved in toluene (30 mL) and heated at reflux for 2 hours in a flask equipped with a Dean-Stark trap. The solution was cooled to ambient temperature and ethyl acetate was added to precipitate a solid that was collected on the filter plate (1.25 g). A sample (500 mg) of this solid was heated with ptoluenesulfonylhydrazide (348 mg, 1.81 mmol) in acetic acid (5 mL) at 80 ° C for 1 hour. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous potassium carbonate and water. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give a yellow solid. This solid was triturated with methylene chloride to give HF

- ι · 37 ~

ΦΦ φ> φ>>>>>> »» »»

ΦΦ ΦΦ

4- [5- (1,3-benzodioxol-5-yl) -3-methyl-1H-pyrazol-4-yl] pyridine collected on the filter plate (220 mg, 42% yield).

Elementary analysis:

Calcd for C ₁₆ H ₁₃ N ₃ O ₂ : C, 68.81; H, 4.69; N, 15.04. Found: C, 68.02; H, 4.54; N, 14.76.

MS (M + H): 280 (base peak).

Example A-11

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

4-Pyridylacetone (1.5 g, 12 mmol), 4-phenoxybenzoldehyde (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 to reflux in a flask equipped with a Dean-Stark trap for 2 hours. The solution was cooled to ambient temperature and ethyl acetate was added to precipitate a solid that was collected on the filter plate. A sample (223 mg) of this solid was heated with p-toluenesulfonylhydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium hydroxide (77 mg) at 110 ° C for 0.5 h. The final treatment was as described in Example A-10. Obtained 4- [3-Methyl-5- (4-phenoxyphenyl) -1H-pyrazol-4-yl] pyridine (100 mg, 66%).

0 · 0000

0-0 0 '• 9 00 ·· 00 00 0 0 0 0 0

0 · 00 00 · 0 0 0 0 0 0 0

0000 00 0 · yield):

Elementary analysis:

Calcd. 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

The same procedure was used as for the preparation of the Example

A-10 using 4-formylbiphenyl instead of piperonal to give 4- [5 - [(1,1'-biphenyl) -4-yl] -3-methyl-1H-pyrazol-4-yl] pyridine as a white solid :

Mass spectrum (M + H): 312 (base peak).

Example A-13

9999

9 9 • 9

9

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

The same procedure was used as for the preparation of Example A-10 using 3-phenoxybenzaldehyde instead of piperonal to give 4- [3-methyl-5- [3- (phenoxyphenyl) -1H-pyrazol-4-yl] pyridine as a white solid substances.

Example A-14

CH

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

The same procedure was used as for the preparation of Example A-10, using 3-benzyloxybenzaldehyde instead of piperonal to give 4- [3-methyl-5- [3- (phenylmethoxy) phenyl] -1H-pyrazol-4-yl] pyridine as white solids:

Mass spectrum (M + H): 342 (base peak).

Example A-15 • · ····

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

The same procedure was used as for the preparation of Example A-10 using 2-benzyloxybenzaldehyde instead of piperonal to give 4- [3-methyl-5- [2- (phenylmethyloxy) phenyl] -1H-pyrazol-4-yl] pyridine.

Mass spectrum (M + H): 342 (base peak).

Example A-16

2- [3-Methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] pyridine

The same procedure was used as for the preparation of Example A-10 using 2-hydroxybenzaldehyde instead of piperonal to give 2- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol:

·· ····

- tól · I · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

Mass spectrum (M + H): 252 (base peak).

Example A-17

3- [3-Methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] pyridine

The same procedure was used as for the preparation of Example A-10 using 3-hydroxybenzaldehyde instead of piperonal to give 3- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yl] phenol:

Mass spectrum (M + H): 252 (base peak).

Example A-18

1-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 · »» ···

1Í42Í99 · 4 · 4 · 4 · 9 · 4 · 4 · Example 4 (Example A-2) ) (2.06 g, 8.76 mmol) in CH ₂ C1 ₂ (10 ml) and

MeOH (20 mL) was added 3-chloroperoxybenzoic acid (57-86%) (2.65 g, 8.76 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, quenched with K ₂ CO ₃ solution (25%, 15 mL) and concentrated.

The resulting residue was partitioned between EtOAc (2.0 L) and H ₂ O (500 mL). The organic layer was separated, washed with H ₂ O (500 mL), dried over MgSO ₄ , filtered and concentrated to give 1-hydroxy-4- [3-methyl-5-phenyl-1H-pyrazol-4-yl] pyridinium (1). , 12 g, 54.5%):

Mass Example spectrum A-19 (M + H); 252 (base peak) 1 N- rPT F'' 1 H

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

Step 1: Preparation of 1-fluoro-4- (4'-pyridylacetyl) benzene To a solution of sodium bis (trimethylsilyl) amide (200 mL, 1.0 M in THF) at 0 ° C was added a solution of 4-picoline (18, 6 g, 0.20 mol) in anhydrous THF (200 mL) over 30 minutes.

The reaction mixture was stirred at 0-10 ° C for an additional 30 minutes, then added to a solution of ethyl 4-fluorobenzoate (16.8 g, 0.10 mol) in anhydrous THF (200 mL) at a rate such that the temperature did not exceed 15 ° C. Deň: 32 ° C. After completion of ·· ·· ·· ···· • · · · • · · • · ·

Addition, the resulting yellow suspension was stirred at ambient temperature for 3 hours. Water (600 mL) was added and the aqueous phase was extracted with ethyl acetate (3 X 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 at rest:

Mp 90-91 ° C;

Elementary analysis:

Calcd. For C 13 H 10 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'-pyridylbromoacetyl) benzene To a solution of 1-fluoro-4- (4'-pyridylacetyl) benzene (step 1) (10.0 g, 0.046 mol) in acetic acid (200 mL). mL) was added dropwise a solution of bromine (8.2 g, 0.052 mol) in acetic acid (20 mL). The reaction mixture was stirred at ambient temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air dried to give 1-fluoro-4- (4'-pyridylbromoacetyl) benzene (14.5 g). The compound was used in 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, 0.01 mol) and 4,4-dimethylamino-3-thiosemicarbazide (1.2 g, 0.01 mol) ) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark green solution was cooled and poured into water (100 mL). The aqueous phase was extracted with methylene chloride (100 mL). Merged Organic • · • ·

The 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) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine (0.3 g). , 11%) as a pale yellow solid:

Mp 245-247 ° C.

Elementary analysis:

Calcd. For C 16 H 15 FN 4: C, 68.07; H, 5.36; N, 19.84. Found: C, 68.00; H, 5.37; N, 19.61.

Example A-20

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

5- (4-fluorophenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine was prepared in the same manner as described in Example A 19:

Melting point 218-219 ° C.

Elementary analysis:

Calcd. For C 20 H 15 FN 4 + 0.1 H 2 O: C, 72.33; H, 4.61; N, 16.87.

Found: C, 72.16; H, 4.56; N, 16.77.

Example A-21

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

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

To a solution of benzoic hydrazide (1.36 g, 0.01 mol) in THF (20 mL) was added 1-fluoro-4- (4'-pyridylacetyl) benzene (2.15 g, 0.011 mol) in one portion followed by a drop concentrated HCl. The reaction mixture was stirred at ambient temperature overnight. A white precipitate formed, which was filtered, washed with ether and air dried to give 1-fluoro-4- (4'-pyridyl-acetyl) -benzene N-benzoylhydrazone (2.90 g, 79%) as a mixture of cis and trans isomers (1: 9 ratio).

Step 2: Preparation of 4- [5- (4-fluorophenyl) -3-phenyl-1H-pyrazol-4-yl] pyridine 1-fluoro-4- (4'-pyridylacetyl) benzene N-benzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180 ° C under N ₂ for 15 minutes, then cooled. 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%) in the form of • · • 0

146 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00·· 00 ···· · Pale yellow solid:

Melting point 265-267 ° C.

Elementary analysis:

Calcd. For C 20 H ₁₄ FN 3 + 0.25 H ₂ O: C, 75.10; H, 4.57; N, 13.14.

Found: C, 74.98; H, 4.49; N, 12.87.

Example A-22

4- [5- (3-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine

Step 1: Preparation of 3- (4'-Pyridylacetyl) toluene

3- (4'-Pyridylacetyl) toluene was prepared in the same manner as described in Example A-19, step 1, in 70% yield.

Step 2: Preparation of trifluoroacetyl hydrazide

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 heated at reflux for 6 hours. The solvent was removed and the resulting residue was dried in vacuo to give trifluoroacetyl hydrazide (12.3 g, 96%) as a clear oil that solidified at rest.

• · • ·

- 147- * · · · · · · · · · · · ·

Step 3: Preparation of 4- [5- (3-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-4-yl] pyridine

A mixture of 3- (4'-pyridylacetyl) toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 0.01 mol) was heated to 200 ° C under an N ₂ atmosphere 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) in in the form of a white solid:

Mp 237-239 ° C.

Elementary analysis:

Calcd. For C 16 H 12 F 3 N 3: C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70.

Example A-23

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

A mixture of 1-fluoro-4- (4'-pyridylacetyl) benzene (1.0 g, 4.6 mmol) and isonicotin hydrazide (0.63 g, 4.6 mmol) in THF (25 mL) was heated to dissolution and then evaporated to dryness. The resulting solid was heated first to 140 ° C, which was

1490 99 99

9 · · ♦

9 · 9 ·

9 9 9 9 caused a phase change and was then melted by heating up to 180 ° C, after which the solid crystallized.

The reaction mixture was immediately cooled, diluted with 10% HCl (50 mL) and washed with chloroform. The aqueous layer was neutralized with bicarbonate and a light brown solid precipitated. The solid was purified by treatment with activated carbon (Darco®) in boiling MeOH (100 mL) followed by filtration and concentration to give 4- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole- 5-yl] pyridine (1.05 g, 69%) as a bright brown solid:

304 ° C (DSC).

Mass Spectrum: (MH +) 137 (100%).

Elementary analysis:

Calcd. For C 19 H 13 N 4 F. 1 / 4H ₂ O: C, 71.13; H, 4.24; N, 17.46. Found: C, 70.88; H, 3.87; N, 17.38.

Example A-24

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

Step 1: Preparation of 4-cyclohexyl-3-pyridyl-3-buten-2-one 4-Cyclohexyl-3-pyridyl-3-buten-2-one was prepared according to the method of Example A1, step 1 by replacing 3-fluoro-p- of anisaldehyde by cyclohexanecarboxaldehyde.

• · ♦ ·

- 149- · .. ··

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

4- (5-Cyclohexyl) -3-methyl-1H-pyrazol-4-yl] pyridine was prepared according to the method of Example A1, step 2, substituting 4- (3-fluoro-4-methoxy) phenyl) -3-pyridyl- 3-Buten-2-one 4-Cyclohexyl-3-pyridyl-3-buten-2-one (Step 1):

Elementary analysis:

Calcd. For C ₁₅ H ₁₉ N ₃ : C, 73.56; H, 7.98; N, 17.16. Found: C, 73.72; H, 7.51; N, 19.98.

Example A-25

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

4- (5- (3-fluoro-5-methoxyphenyl) -3-methyl-3-methyl-1H-pyrazol-4-yl) pyridine was prepared by the method of Example A1, steps 1 and 2 by replacing 3-fluoro-p-anisaldehyde 3-fluoro-manisaldehyde:

Elementary analysis:

Calcd. For C 16 H 14 N 3 OF: C, 67.83; H, 4.98; N, 14.83. Found: C, 67.68, H, 4.92; N, 14.92.

0 »···

- 150-

0 · ··

0 0 0 ·

0 0 0 0 0 0 0 0 0 0 0 0 0

0000 «1 ·

0 0

0 0

0

The following examples (No. 26-55) listed in Table 1 were prepared by the methods described above:

C. AND- R ^l R ^J R ³ R ⁴ or DSC what Anal.calc. for formula Analysis (calculated / found) C H N 26 H Hi H- 185-186 CijH ₁₉ N ₃ 77.95 / 77.51 6.90 / 6.93 15.15 / 14.73 27 Mar: H | CH, 142-144 ^C 1 «Hi5 ^N 3 75.71 / 75.69 6.16 / 6.11 16.55 / 16.49 28 H Yt ^ h k, N • iQ 240-242 C ^ H.pN, .0.25H, O 80.09 / 79.74 5.96 / 5.90 12.74 / 13.01 29 H F, C Vh • 1 ch ₃ 228.8 C _le H ₁₂ N ₃ F ₃ 63.36 / 63.28 3.99 / 3.73 13.85 / 13.69 | ch ₃ 'Ό ,! 189.6 C _I5 H ₁₂ N ₃ .0.15H c-.O 66.13 / 65.98 4.55 / 4.31 15.42 / 15 74 3) H | ch ₃ Vfi * <Í, N • ip- 171.6 c ₁₇ H | ₇ n ₃ 0.2 H, O 76.49 / 76.69 6.57 / 6.53 15.74 / 15.61 í ^3: VCHJ • | CHJ 'AT 88.6 C ₁₆ H ₁₄ N ₃ C! 67.72 / 67.35 4.97 / 5.29 14.81 / 15.02 33 H 1 CHj »5> N •'AND 188.8 C ₁₄ H ₁₄ N ₃ F 71.89 / 71.72 5.28 / 5.45 15.72 / 15.77 34 H ’| CHj tench 215.7 c ₁₇ h ₁₇ n ₃ 77.54 / 77.24 6.51 / 6.80 15.96 / 15.71 l · ⁵ - • ₃ <· 201.4 C ₇ H] N ₃ O _7; , 0.25H ₂ O 68.10 / 67.92 5.88 / 5.65 14.01 / 13.65 ³⁶ H h. NO 210.7 c ₁₅ h ₁₂ n ₄ o. .0.25H ₂ O 63.26 / 63.59 4.42 / 4.39 19.67 / 19.31 1 ” « • ₃ Yr ^ ft 252.5 Ci ₇ H _lt N ₄ 73.35 / 72.61 6.52 / 6.79 20.13 / 19.59 38 H • | CHj 196.3 C 11 H 11 N 3 O 2 73.63 / 73.43 5.45 / 5.46 15.15 / 15.19 39 H Y | ^ 1 ,Σ, Ν {CHj 252.8 C ₁₂ H ₁₂ N ₃ Bi 57.34 / 57.09 3.85 / 3 79 13.37 / 13.06 40 H Yi ^ h ’<, N •} CH, 198.5 c ₁₅ h ₁₂ n ₂ f 71.13 / 71.23 4.78 / 5.01 16.59 / 16.76 41 H • ₃ Yr ^ i * Í, N F 225.6 c _is h ₁₂ n ₃ f _; 71.13 / 70.74 4.78 / 4.66 16.59 / 16.44 42 H • ₃ YrOí tench CF, 219.5 ^ 16 ^ 12 ^ 3 ^ 3 63.36 / 63.19 3.99 / 4.07 13.85 / 13.38 43 H •} -CH3CH ₃ Yl ^ 1 «%, N • * <2> 227.7 C ₆ H ₁₅ Nj .Ο.ΙΗ, Ο 76.53 / 76.53 6.10 / 6.20 16.73 / 16.49

9 9999

9 ·· 99

9 9 ·

9 9 9

9 9 9

9 9 9

C. AND- R ^l R ^J R ^J R ⁴ or DSC CO Anal.calc. for formula Analysis (calculated / found) C H N 44 H • VCHj ,Σ, Ν ^Z © ⁰ ' 175.6 C _u H ₁₅ N ₃ O .0.15H, O 71.70 / 71.92 5.75 / 5.76 15.68 / 15.29 45 H TCHjCH; ’Ξ, Ν - Ο ₁₇ Η 'Ν3 77.54 / 77.13 6.51 / 6.28 15.96 / 15.69 46 H • (• ch ₃ 1%, N 412.1 ΗυΗ _π Ν ₃ Ρ ₂ 66.42 / 66.12 4.09 / 3.86 15.49 / 15.25 47 H VcHj Ιξ, Ν 168.5 C ₁₇ H N _I7 O ₃ .0.15H, O 72.40 / 72.39 6.18 / 5.87 14.90 / 14.50 48 H • VcHj Vil ίς, Ν 211.2 c, _s h, n ₃ f ₃ .0.2H, O 62.62 / 62.64 4.07 / 4.06 13.69 / 13.35 49 H Vchj »%, N - C ₁₃ H _n N ₃ S 64.71 / 64.44 4.59 / 4.58 17.41 / 17.27 50 H • Vch ₃ <4, N ^CI T3 £ 189.2 C _h H _for N ₃ C1 ₂ 59.23 / 59.22 3.65 / 3.24 13.81 / 13.81 51 H • Vch ₃ Vt, N '12r ^cl 211.7 C ₃ H ₁₁ N ₃ Cl. 0.15 H, O 66.13 / 66.33 4.55 / 4.62 15.42 / 15.05 52 H 4-CH 3 kt, N ^c i 219.8 Whether _T H _l4 N ₃ Cl 64.11 / 63.85 4.71 / 4.69 14.02 / 13.93 53 H Μλ 1 <, N N, Cl 163.4 C18H17NjQjCl 64.32 / 63.98 4.83 / 5.08 11.84 / 11.80 54 ₃ -ch ₃ 'Whose. 1%, N H - c ₁₅ h ₁₃ n ₃ f .0.2 H, O 70.15 / 70.18 4.86 / 4.60 16.35 / 16.47 55 H Vh «Σ, Ν H - c 'h ₁₀ n ₃ f 70.28 / 69.97 4.21 / 3.84 17.56 / 17.53

9 • 9 «9

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

Example A-56

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

Example A-57

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

Example A-58

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

Example A-59

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

Example A-60

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

Example A-61

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

Example A-62

5- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine Example A-63

4- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine Example A-64

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

Example A-65 ·

0 0

0 0 0 0 0

0 0

- 0 • 0

00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

00 0000

00

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

Example A-66

4- [5- (4-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine Example A-67

4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridin-2-amine Example A-68

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

Example Ά-69

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

Example A-70

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

Example A-71

2-methoxy-5- [5- (4-methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -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 ·· * ···

154 * · «•» »• * * * * * * * * * * * * * * * * * * * * * * · · ·· · »

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-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; Example A-79

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

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

Example A-81

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

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

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

Example A-84

4- [5- (4-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol Example A-85

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

Example A-86

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

Example A-87

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

Example A-88

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

9 * 9999

1558 «99 99 99

9,990 «999

998 9 9 «9999

9 99 ·· 999999

9999 999 9999

99 99 99 99 99

Example Α-89

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

Example A-90

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

Example A-91

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

Example A-92

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

Example A-93

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

Example A-94

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

Example A-95

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

Example A-96

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

Example A-97

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

Example A-98

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

Example A-99

- 156 · · 156 156 φ 156 156 156 · · · · · · · · · ·

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

Example A-102

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

Example A-103

4- [5- (Benzofuran-6-yl) -3-methyl-1H-pyrazol-4-yl] pyridine; Example A-104

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

Example A-105

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

Example A-106

4- [5- (1-Cyclohexadien-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 • ·

1574- [5- (4-methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine;

Example A-III

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

Example A-112

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

Example A-113

4- [5- (3-Furanyl) -3-methyl-4-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-4-pyrazol-4-yl) pyridine;

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

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-3-carboxylate;

·· »·

Example A-123

4- (3-methyl-5-phenyl-4-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

N, 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) pyrimidine; Example A-130

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

Example A-135

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

Example A-136

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

Example A-137

φφ ΦΦΦ · ·· φ

φ · · * φφ · φ φφ · <

φ φ ·>

• φ φ>

• φ · · # φ · φ> · φ

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

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

Example A-13

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

Example A-145

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

Example A-146

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

Example A-147

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

4- [3- (4-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -pyridine; Example A-149

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

Example A-150

4- [3- (4-Chloro-phenyl) -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;

99

9 9

9 9

9 9

9 9

- 160 · · * * * 160 160 160

99

Example A-153

4- [3- (3-Fluorophenyl) -TH-pyrazol-4-yl] pyridine; and

Example A-154

4- [3- (3-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -2-methyl-pyridine

The compounds of Examples A-155 to A-172 were synthesized according to the methods described above (especially Scheme II) and illustrated by many of the above Examples by selecting the appropriate starting reagents:

Example A-155

5- (4-Chloro-phenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine: DSC 261 ° C.

Elementary analysis:

Calcd for C ₂₀ H ₁₅ ClN ₄ + 0.25 H ₂ O (MW 351.32): C, 68.38, H, 4.30, N, 15.95.

Found: C, 68.25, H, 4.41, N, 15.74.

Example A-156

161- · .. ·

5- (4-Chloro-phenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazol-3-amine: DSC 260 ° C.

Elementary analysis:

Calcd for C 15 H 13 ClN 4 + 0.125 H ₂ O (MW 287.00): C, 62.77, H, 4.57, N, 19.52.

Found: C, 62.78, H, 4.33, N, 19.22.

Example A-157

5- (4-chlorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine, dihydrate: DSC 230 ° C.

Elementary analysis:

Calcd for C ₁₆ H ₁₅ ClN ₄ + 2 H ₂ O (MW 334.81): C, 57.40, H, 4.52, N, 16.73.

Found: C, 57.72, H, 4.85, N, 16.54.

Example A-158

5- (3-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine: DSC 227 ° C.

Elementary analysis:

Calcd for C ₁₆ H ₅ FN ₄ + 0.125 H ₂ O (MW 284.57): C, 67.53, H, S.31, N, 19.69.

Found: C, 67.60, H, 5.20, N, 19.84.

Example A-159

N, N-dimethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine: DSC 222 ° C.

Elementary analysis:

• · · · · · · · · · · ·

- 163 “* ·· · ^χ ·· ··

Calcd for C ₁₇ H ₁₈ N ₄ + 0.25 H ₂ O (MW 282.86): C, 72.19, H 6.41, N, 19.81.

Found: C, 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.

Elementary analysis:

Calcd for C ₁₆ H ₆ N ₄ + 0.125 H ₂ O (MW 266, 58): C, 72.09, H 6.05, N, 21.02.

Found: C, 72.12, H, 6.12, N, 20.83.

Example A-161

NH

OF

Et • ·

- 164

N-ethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine DSC 227 ° C.

Elementary analysis:

Calcd for C ₁₇ H ₁₈ N ₄ + 0.125 H ₂ O (MW 280, 61): C, 72.77, H, 6.47, N, 19.97.

Found: C, 72.63, H, 6.40, N, 19.73.

Example A-162

N, N-Diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine:

DSC 234 [deg.] C.

Elementary analysis:

Calculated for C ₁₉ H ₂₂ N ₄ (MW 306, 41); C, 74.48; H, 7.24; N, 18.29.

Found: C, 74.12, H, 7.18, N, 18.13.

Example A-163

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

Melting point 260-261 ° C.

Elementary analysis:

Calcd for C ₁₈ H ₁₉ ClN ₄ (MW 326, 83): C, 66.15, H, 5.86, N 17.14.

Found: C, 66.03, H, 5.72, N, 17.23.

Example A-164

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

DSC 279 ° C.

Elementary analysis:

• ·

- 166 00 00

Calcd for C ₁₈ H ₁₇ ClN ₄ O + 0.25 H ₂ O (MW 345, 32): C, 62.61, H, 4.96, N, 16.23.

Found: C, 62.52, H, 4.77, N, 16.52.

Example A-165

5- (4-Chloro-phenyl) -N-propyl-4- (4-pyridinyl) -1H-pyrazol-3-amine: DSC 244 ° C.

Elementary analysis:

Calculated for C ₁₇ Hi ₇ C1N ₄ + 0.125 H ₂ O (MW 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) -N- (phenylmethyl) 99 9 ···

- 168 »..«

9 «99 99 99

100 9 9 9 «·

9 9 · · 9 9

9 9 9 9 9 • 9 9999 99 99

4- (4-pyridinyl) -1H-pyrazol-3-amine hydrate (2: 1):

DSC 237 ° C.

Elementary analysis:

Calcd for C ₂₁ H ₁₇ ClN ₄ + 0.5 H ₂ O (MW 369, 86): C, 68.20, H, 4.63, N, 15.15.

Found C, 68.0 _9; H, 4.55; N, 15.15.

Example A-167

\

Isolated as 5- (4-chlorophenyl) -N- (2-methoxyethyl) 4- (4-pyridinyl) -1H-pyrazol-3-amine, monohydrate:

DSC 223 ° C.

Elementary analysis:

Calcd for C ₁₇ H ₁₇ ClN ₄ O + H ₂ O (MW 346, 82): C, 58.87, H, 4.94, N, 16.15.

Found: C, 58.59; H, 4.79; N, 16.0 _2nd

Example A-168 ·· ♦ ·

- 168 - ··.

44 44 ··

4 4 4

4 · 4 · 4 ·

4 <···· 4

4 4 · 4 · · 4 4 4 4

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

DSC 251 [deg.] C.

Elementary analysis:

Calcd for C ₂₃ H ₂₆ ClN ₅ O (MW 439, 95): C, 62.79, H, 5.96, N 15.92.

Found: C, 62.40, H, 5.82, N, 15.82.

Example A-169

Isolated as 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H • · ··· ·

- 169 pyrazol-3-yl] piperazine trihydrochloride:

DSC 99 ° C.

Elementary analysis:

Calcd for C ₁₈ H ₁₈ ClN ₄ + 3 HCl (MW 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:

Melting point 247-241 ° C.

Elementary analysis:

Calcd for C ₁₉ H ₂₀ ClN ₅ + 0.75 H ₂ O (MW 367.33): C, 62.12, H, 5.49, N, 19.06.

Found: C, 62.45, H, 5.86, N, 11.32.

Example A-171 ·· ·· «··

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

Melting point 243-244 ° C

Elementary analysis:

Calcd for C 23 H ₂₆ FN ₅ O ₂ + 0.5 CH ₃ CH ₂ CO ₂ CH ₂ CH ₃ (MW 4 67.55): C, 64.22, H, 6.47, N, 14.98.

Found: C, 63.90, H, 6.61, N, 14.88.

Example A-172 v

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

Mp 204-206 ° C.

• «φ φ«

171 * -., ·· .. · ·., ··. »·

Elementary analysis:

Calcd for C ₁₈ H ₁₈ ClN ₅ + 3 HCl + 0.5 H ₂ O (MW 441.77): C, 48.94, H, 4.79, N, 15.85.

Found: C, 48.66, H, 4.88, N, 15.50.

1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -piperazine:

Melting point 264-265 ° C.

Elementary analysis:

Calcd for C ₁₈ H ₁₈ ClN ₅ + 0.125 H ₂ O (MW 342.08): C, 63.20, H 5.30, N, 20.47.

Found: C, 63.04, H, 5.36, N, 20.33.

Other compounds that were synthesized according to the methods described in Scheme II by selecting the appropriate starting reagents further include those described in Table 2.

φ φ φ φ φ · φφφ

·· φ · · φ · · · · φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Table 2

Ο W ρ CM 00 © "Whose CM 00 r * O CM CM whose O CM Q © © CM Q CM CM CM CM CM OF CM CM Ň 00 I.E· i.e- C* Tt r » r- Sat O O m · CM Γ * Ί SO r *> Tt m OO i.e·* sd © S © v> sd i.e· © sn Γ ** Η CM · - • m ”* · * · »Ό ο Sat O CM C* 00 Γ * Os SO Ω_ r ** CM O m m 00 TT m Γ * Whose sd d sd "whose sd oš "Whose from ζ CM * “* * “· w » · * si í * í Sat SO Tť r *. "Whose «Cl ΤΓ Tf WITH (0 O «Η 00 O oo 00 CM CM "Whose © Γ- & (D X "whose Tf * «D τΤ "whose sd sd she knows "Whose * «T C § > ϋ and SO O Sat CM "Whose "Whose "Whose Whose 2 5- © SO Ki s © oo CM 00 SO 00 "Whose X ττ "Whose ττ sd TT "whose sd "whose *whose "Whose TT si 00 "Whose C* sO SO Sat 00 r * r * as "Whose cn Tf "Whose Os "C C* 00 © Os C*% C d © 00 © w * © from CM «D O »C> Sat Tf Sat Sat SO Sat "Whose « ττ »D and cn C- Tr "Whose "Whose 3 Tt Sat sO 00 Sat s © r * 00 O Os CM © Mg. © © oo «Μ ΤΓ O CM © © CM "Whose O "Whose SO tt Sat TT Sat SO Sat "Whose SO tt O O CM x O CM O O CM CM • WM O CM O formula 3HCM.5 M u- < m CM © Φ "whose CM mm «C | CM • O C1N5O2 • 2 »M • IN, "Whose CM O • CM O C1N5O3 X "Whose © • CM δ CM O "whose of Um 0 CM "Whose r * © • "Whose O MM cn • "Whose OF ΤΓ O φ -Q Ο Sat OF C of O •in OF at- C* 2H26 of Q 00 ICIN5 O Whose «Cl of here un "Whose CM X C CM AT © «Η CM Tt CM O CM «Η cm at X r ~~ O C2 MM r- υ C21H24 CM at CM X CM CM AT CM 3 X © CM at 3 O as '(0 at. Η Σ3 I.E »M · - »- » M ►M M »- » · - * M ^ MM MM ?! 8 43 43 4 = 4Ϊ 43 43 43 45 43 43 43 ο O O O O O O Q AT O O O O Q. w IN) M 00 00 00 IN) Cfí oq ω n ό m "Whose Sat Γ- 00 Os O CM Whose (0 C* Γ- r * C* r- r * 00 00 00 00 32 * · « we «Μ > ι_ 1 « 1 »» 1 1 t 1 < α. < < < < < < < < < <

173-./ · »99 · · · · · · · · · · · ·

9999

* • «

9

9

9

Example A-173

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

Example A-114

1- [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-pyrazol-4-yl] pyrimidine dihydrochloride

Example A-176

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

Example A-177

040-0

4 ·

4 0

- i7S »-:. :

·· ·· ··> «4 44 5

4 4 0 0 0 0 • 44 44444 »• 44 β 44 4

4444 44 44

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

Example A-178

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

Example A-179

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

Example A-182

1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-ethyl-piperazine

Example A-183

- 178- ·

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

The compounds of Examples A-184 to A-189 were synthesized according to the methods described above (especially in Schemes I and IV) and illustrated in the Examples by selecting the appropriate starting reagents:

Example A-184

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

Calcd. For C 15 H 11 F 2 N 3: C, 66.42; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16;

Mp 236.67 ° C.

- 179Example A-185

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

Calcd. For C 17 H 17 N 3: C, 77.54; H, 6.51; N, 15.96. Found: C, 77.16; H, 6.27; N, 15.69.

Melting point (DSC): 189.25 ° C

Example A-186

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

Calcd. For C ₁₆ H ₁₄ ClN ₃ . 0.1 mol of H ₂ O: C, 67.15; H, 4.91; N • ·

180- · .. · · .. ’

14.33.

Found: C, 66.95; H, 5.00; N, 14.36. DSC: 176.18 ° C.

Example A-187

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

Calcd. For C ₁₈ H ₉ N ₃ . 0.1 mole of H ₂ O: C, 77.44; H, 6.93; N, 15.05.

Found: C, 77.39; H, 6.94; N, 14.93.

Melting point (DSC): 192.66 ° C.

Example A-188

• φ

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

Elementary analysis:

Calcd. For C ₁₇ H ₁₆ ClN ₂ . 0.4M EtOAc: C, 67.08; H, 5.81; N, 12.62.

Found: C, 67.40; H, 6.15; N, 12.34.

Example A-189

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

Calcd for C ₁₇ H ₁₄ FN ₃ : C, 73.1; H, 5.05; N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63;

Mp 239-240 ° C.

The compound of Example A-190 was synthesized as described above (especially in Scheme III) and illustrated by the above Examples by selecting the appropriate starting reagents:

Example A-190

0000

182- · .. ·

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

This compound was prepared in the same manner as described for example in A-22 by replacing 3- (4'-pyridylacetyl) toluene with 1-fluoro-4- (4'-pyridylacetyl) benzene (prepared according to Example A-19).

Elementary analysis:

Calcd 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.

Melting point (DSC): 281.94 ° C.

The compounds of Examples A-191 to A-198 were synthesized according to the methods described above (especially in Scheme V) by selecting the appropriate starting reagents:

Example A-191

183— · ·· · ^U 99 9 9

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

Step 1: Preparation of methylhydrazone 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone

NNHMe

1- (4 Fluorophenyl) -2- (4 pyridinyl) ethanone methylhydrazone

To a solution of 4-fluorobenzoyl-4 &apos; -pyridinylmethane (8.60 g, 0.04 mol) and methylhydrazine (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 ambient 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 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.

9 • * 99

98 · 9 9 • 9 9 9

9 9 9

9 9 9

9 · 99 substances (77% yield), 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone methylhydrazone.

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

To a solution of sodium hexamethyldisilazide (5.5 mL, 1.0 M in THF) at 0 ° C was added dropwise a solution of the compound prepared in Step 1 (0.67 g, 0.0028 mol) in 10 mL of anhydrous THF. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methyl cyclopropanecarboxylate (0.34 g, 0.0034 mol) in 5 mL of anhydrous THF was then added. The reaction mixture was allowed to warm to ambient 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 silica gel chromatography (ethyl acetate / hexane / acetone, 10: 9: 1) to give 0.45 g of the product 4- [5- (cyclopropyl-3- (4- (fluorophenyl) -1-methyl- 1H-pyrazol-4-yl] pyridine as a light yellow solid (55% yield).

Mp 129-130 ° C;

¹ H 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, 1 H), 0.95 (m, 2 H), 0.36 (m, 2 H);

Elementary analysis:

Calcd. For C ₁₈ H ₁₆ FN ₃ : C, 73.70; H, 5.50; N, 14.32.

Found: C, 13.63; H, 5.57; N, 14.08.

Example A-192 ·· ·· ♦ ·

5-Cyclopropyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol

Step 1: Preparation of 1- (4-fluorophenyl) -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, 0.04 mol). The yellow oil was stirred at this temperature overnight. The cooled reaction mixture was dissolved in hot ethyl acetate and then triturated with hexane to give 8.9 g of the product 1- (4-fluorophenyl) 2- (4-pyridinyl) ethanone (2-hydroxyethyl) hydrazone as yellow crystals ( 81%).

Melting point 122-123 ° C.

• 9,999

18699 99

9 · · · 9

9 9

9 9

9999

Step 2: Preparation of 1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone [2 - [[(1,1-dimethylethyl) dimethylsilyl) oxy] ethyl] hydrazone

NNHCH3CH3OSI t-BuMe ₂

1- (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 prepared in Step 1 (2.73 g, 0.01 mol) and (1,1-dimethylethyl) dimethylsilyl chloride (1). 0.5 g of 0.01 mol) in 25 ml of DMF was added portionwise imidazole. The reaction mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate, the organic layer was washed with water, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 3.8 g of crude product,

1- (4-fluorophenyl) -2- (4-pyridinyl) ethanone [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] hydrazone, as a yellow oil, which was used in the next step without further purification .

Step 3: 5-Cyclopropyl-1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3,4-diphenyl-1H-pyrazole

4

4 ·

5-Cyclopropyl-1- [2 [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3,4-diphenyl-1H-pyrazole

To a solution of sodium hexamethyldisilazide (4.2 mL, 1.0 M in THF) at 0 ° C was added a solution of the compound prepared in Step 2 (0.78 g, 0.002 mol) in 10 mL of anhydrous THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methyl cyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 mL of anhydrous THF was then added. The reaction mixture was allowed to warm to ambient 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 silica gel chromatography (ethyl acetate / hexane, 3: 7) to give 0.30 g of the product, 5-cyclopropyl-1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxylethyl] 3,4 diphenyl-lH-pyrazole as a pale yellow oil (35% yield), ^X 1 HNMR (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);

Elementary analysis:

Calcd. For C25H32FN3OSi: C, 68.61; H, 7.37; N, 9.60.

·

9 · 9999 • 9 99

• 9 99

9

9 ·

9 9 · ·· · ♦

Found: C, 68.39; H, 7.81; N, 9.23.

Step 4: Preparation of 5-cyclopropyl-3- (4-fluorophenyl) 4- (4-pyridinyl) -1H-pyrazole-1-ethanol

To a solution of the compound prepared in Step 3 (0.27 g, 0.00062 mol) in 5 mL of THF was added tetrabutylammonium fluoride (1.9 mL of a 1.0 M THF solution) at ambient temperature. After 1 hour, water was added and the mixture 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 silica gel chromatography (ethyl acetate / hexane, 9: 1) to give 0.16 g of the product, 5-cyclopropyl-3- (4-fluorophenyl) 4- (4-pyridinyl) -1H-pyrazole- 1-ethanol, as a pale yellow solid.

Mp 155-157 ° C;

¹ H NMR (CDCl ₃ ): δ 8.53 (br s, 2H), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97 (m, 2H), 4.42 (t, J = 4.8Hz, 2H), 4.14 (t, J = 4.8Hz, 2H), 1.83 (m, 1H), 0.93 (m, 2H), 0.35 (m,

2H);

Elementary analysis:

Calcd. For C19H18FN3O: 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 THF) at 0 ° C was added dropwise a solution of the compound prepared in Step 2 of Example A-192 (1.25 g, 0.0034 mol) in 15 mL of anhydrous THF. The dark brown solution was stirred at this temperature for 30 minutes. A solution of methyl 4- (2-methoxy) pyridinecarboxylate (0.05.5 g, 0.0035 mol) in 5 mL of anhydrous THF was then added. The reaction mixture was allowed to warm to ambient 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 silica gel chromatography (ethyl acetate / hexane, 1: 1) to give 0.28 g of product,

3- (4-Fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol as a yellow solid.

Mp 168-169 ° C;

¹ H NMR (CDCl ₃ ): δ 8.42 (m, 2H), 8.20 (dd, J = 0.7, 5.2 Hz, 1H), 7.37 (m, 2H), 7.02 (m, 2H), 6.95 (m, 2H), 6.71 (dd, J 1.4, 5.2 Hz, 1H), 6.66 (t, J = 0.7 Hz, 1H), 4.20 (m, 2H), 4.14 (m, 2H), 3.95 (s, 3H);

190 · ♦ ·· • ΦΦΦ ΦΦΦΦ · · · φφφ · φφ φφφφφ ·

Elementary analysis:

Calcd. For C ₂ H ₁₉ FN ₄ O ₂ : C, 67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03.

4- [1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] 3- (4-fluorophenyl-4- (4-pyridinyl) -1H-pyrazol-5-yl) 2-methoxypyridine

Second compound, 4- [1- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3- (4-fluorophenyl-4- (4-pyridinyl) -1H-pyrazol-5-yl) -2 -methoxypyridin was also isolated from the above reaction as a yellow oil by chromatography. ^X 1 HNMR (CDCl _3): δ 8.45 (m, 2H), 8.20 (m, IH), 7.40 (m, 2H ), 7.04 (m, 2H), 6.93 (m, 2H), 6.81 (m, 2H), 4.24 (m, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 0.83 (s, 9H), 0.02 (s, 6H).

Example A-194 »· ····

- 191 ** · 9 · · 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99

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

To. of a solution of 3- (4-fluorophenyl) -5- (2-methoxy-4-pyridinyl) 4- (4-pyridinyl) -1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acid acetic acid was added with 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hours. The cooled mixture was then 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 silica gel chromatography (MeOH / CH ₂ Cl ₂ / NH ₄ OH, 5: 94: 1) to give 0.07 g of the product 4- [3- (4-fluorophenyl) -1- ( 2-hydroxyethyl) 4- (4-pyridinyl) -1H-pyrazol-5-yl] -2 (1H) -pyridinone as a yellow solid (32% yield).

Mp 250-251 ° C;

¹ H NMR (DMSO-d ₆ ). δ 11.74 (s, 1H), 8.45 (d, J = 5.0Hz, 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 Hz, 1H), 5.0 (m, 1H), 4.13 (m,

2H), 3.81 (m, 2H);

Elementary analysis:

····

9 · · · 9 9 9 9 9 9

9 9 9 9 9

9,999 9,999,999 9

Calcd. For C ₂₁ H ₁₇ FN ₄ O ₂ . 0.2 H ₂ O: C, 66.06; H, 4.65; N, 14.67.

Found: C, 66.31; H, 4.49; N, 14.27.

Example A-195

1-Acetyl-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 was obtained as a by-product of the reaction of Example A -194 as a yellow solid (38% yield).

Mp 220-221 ° C;

¹ H NMR (CDCl 3) δ 8.50 (m, 2H), 7.39 (m, 3H), 7.02 (m, 4H), 6.59 (m, 1H), 6.08 (dd, J) = 1.4, 5.2 Hz, 1H), 4.52 (t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 2.04 (s 3H); Elementary analysis:

Calcd. For C ₂₃ H ₉ FN ₄ O 3. 0.3 H ₂ O: C, 65.46; H, 4.63; N, 13.28.

Found: C, 65.09; H, 4.64; N, 12.99.

0000

0

- 1930 0 3

4 0

0 4

0 0 4

44

0 0 0 0 0 0

0 0404

40

0 0

0 0

0 0

3 0 «0 00

Example Α-196

Ethyl 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 THF) at 0 ° C was added dropwise a solution of the compound prepared in Step 1 of Example A-192 (1.37 g, 0.005 mol) in 20 mL of anhydrous THF . The dark brown solution was stirred at this temperature for 30 minutes. A solution of diethyl 1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 mL of anhydrous THF was then added. The reaction mixture was allowed to warm to ambient 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 purified by silica gel chromatography (ethyl acetate / hexane, 8: 2) to give 0.18 g of the product, ethyl 2- [3- (4-fluorophenyl) 1- (2-hydroxyethyl) -4- ( 4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylate as a pale yellow oil (35% yield).

- 194 ^X 1 HNMR (CDCl _3): δ 8.55 (m, 2H), 7.32 6.97 (m, 2H), 4.38 (m, 2H), 4.16 (m, (m, 2H), 1.26 (t, J = 7.0Hz, 3H), (m, 2H), 0.90 (m, 2H);

Elementary analysis:

Calcd. For C 22 H 22 FN 3 O 3. 0.25 H ₂ 0: C, 66 07; H, 5.67; N, 10.51

Found: C, 65.89; H, 5.80; N, 9.95.

Example A-197 (m, 2H), 7.11 (m, 2H), 4H), 2.47 (m, 1H), 1.53

2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-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) A solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water was added. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HCl and stirred for 30 minutes. The pH was then adjusted to 5-6 by the addition of 1N sodium hydroxide solution and the mixture was then extracted with ethyl acetate. The organic layer was washed

- brine, dried over magnesium sulphate and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, m.p.

2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylic acid as a white solid (60% yield).

Mp 253-255 ° C;

NMR (CD 3 OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J = 5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H);

Elementary analysis:

Calcd. For C 20 H 18 FN 3 O 3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20.

Example A-198

3- (4-Fluorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol

Step 1: Preparation of methyl 1 - [[2- (trimethylsilyl) ethoxy] methyl] -1H-pyrrole-3-carboxylate

196 · ♦ ·

TM5

Ν

CO ₂ Me

Methyl 1 - [[2- (trimethylsilyl) ethoxy] methyl] -1H-pyrrole-3-carboxylate

To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 mL of DMF was added portionwise methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) at ambient temperature. The mixture was stirred at ambient temperature for 0.5 hours. SEM-C1 (4.17 g, 0.025 mol) was then added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours and quenched with 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 was purified by silica gel chromatography (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-trimethysilyl) ethoxy] methyl-1H -imidizol-4-yl] -1H-pyrazol-4-yl] pyridine

TMS

4- [1- [2 [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] 3- (4-fluorophenyl) -5- [1 - [[2-trimethylsilyl] ethoxy] methyl] -1Himidazol-4 -yl] -1H-pyrazol-4-yl] pyridine

To a solution of sodium hexamethyldisilazide (4.5 mL, 1.0 M in THF) at 0 ° C under Ar was added a solution of the compound prepared in Step 2 of Example A-192 (0.8 g, 0.002 mol) in 10 mL dropwise. ml of anhydrous THF. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of the compound prepared in Step 1 of this Example (0.54 g, 0.0021 mol) in 5 mL of anhydrous THF was added. The reaction mixture was allowed to warm to ambient 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 silica gel chromatography (ethyl acetate / hexane, 8: 2) to give 0.98 g of the product as a pale yellow oil that solidified at rest (91% yield).

Mp 79-80 ° C;

NMR (CDCl ₃ ): δ 8.48 (d, J = 6.0 Hz, 2H), 7.68 (d, J = 1.3 Hz, 1H), 7.38 (d, J = 6.0 Hz, 2H), 7.10 (m, 2H), 7.00 (m,

2H), 6.93 (d, J = 1.3Hz, 1H), 5.25 (s, 2H), 4.53 (t, J = 6.0Hz, 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) r

Elementary analysis:

Calcd. For C31H44FN5O2S12: 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-pyrazole-1-ethanol

To a solution of the compound prepared in Step 2 of this Example (0.54 g, 0.001 mol) in 10 mL of THF was added a solution of tetrabutylartionium fluoride (1.0 M in THF). After the mixture was heated at reflux for 3 hours, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered.

The filtrate was concentrated and the crude product was purified on silica gel (methylene chloride / methanol, 95: 5) to give 0.22 g of the product, 3- (4-fluorophenyl) -5- (4-imidazolyl) 4- (4- pyridinyl) -4-pyrazole-1-ethanol as a white solid (63% yield).

Mp 227-228 ° C;

¹ H NMR (DMSO-d ₆ ): 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);

Elementary analysis:

Calcd. For C19H16FN5O: C, 65.32; H, 4.62; N, 20.05. Found: C, 64.98; H, 4.55; N, 19.79.

The compound of Example A-199 was synthesized by the method.

199 described above (especially in Scheme VI) by selecting the appropriate starting reagents:

Example A-199

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

Elementary analysis:

Calcd. For C 15 H 12 N 3 Cl (269, 74): C, 66, 79; H, 4.48; N,

15.58.

Found: C, 66.57; H, 4.15; N, 15.54.

Melting point (DSC): 198.17 ° C.

The compounds of Examples A-200 to A-202 were synthesized according to the methods described above (especially in Scheme VII) by selecting the appropriate starting reagents:

Example A-200

9 98 9 • 9

- 200-

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

A mixture of 4- [3- (4-fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine prepared according to the method of Example A-4 (5.83 g, 24.0990 mmol) and potassium permanganate (7.6916) g, 48.1818 mmol) in water (7.5 mL) and tert-butanol (10 mL) were heated at reflux for 6 hours (or until all the potassium permanganate was consumed). The mixture was then stirred at ambient temperature overnight and then diluted with water (150 mL). The manganese dioxide was removed from the mixture by filtration. The filtrate was extracted with ethyl acetate to remove the starting material. The aqueous layer was acidified with 1N HCl to raise the pH to about 6. A white precipitate formed, was collected by filtration, washed with water and dried in a vacuum oven to give 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H -pyrazole-3-carboxylic acid (isolated as salt monohydrate) (2.9777 g, 43.7%).

Elementary analysis:

Calcd. For C ₁₅ H ₁₀ N ₃ FO ₂ . H ₂ O (283 + 18): C, 59.80; H, 4.01; N, 13.95;

Found: C, 59.48; H, 3.26; N, 13.65.

Mass spectrum (MH +): 284 (base peak).

• ·

- 201Example A-201

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

To a suspension of 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-carboxylic acid monohydrate prepared in Example A-200 (0.526 g, 2.0 mmol) in anhydrous THF (15 mL) at A solution of 1 N lithium aluminum hydride in THF (4.0 mL, 4.0 mmol) was added dropwise over 15 minutes. A precipitate formed. The mixture was kept boiling for an additional hour. Excess lithium aluminum hydride was then compensated by the careful addition of a solution of 4N potassium hydroxide in water (0.5 mL). After hydrolysis, a white salt precipitated. After the addition was complete, the mixture was heated to reflux for 15 minutes. The hot solution was vacuum filtered through a Buchner funnel and the remaining product was extracted from the precipitate by heating to reflux with THF (15 mL) for 1 hour, followed by re-vacuum filtration. The combined filtrates were concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate, washed with water and brine, dried over MgSO ₄ 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

ΦΦΦΦ

- 202 φ • Φ · · · · · 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 0,2 (

DSC: 260.26 ° C;

Elementary analysis:

Calcd. For C15H12N3FO (269): C, 66.91; H, 4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20.

Mass spectrum (MH +): 270 (base peak).

Example A-202

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

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

To the solution of 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole

9

- 203 • 9999

3-carboxylic acid monohydrate, prepared in Example A-200 (0.9905 g, 3.5 mmol) and 1-hydroxybenzotriazole (0.4824 g, 3.57 mmol) in DMF (20 mL) at 0 ° C hydrochloride was added under nitrogen

1- (3-dimethylaminopropyl) 3-ethylcarbodiimide (0.6984 g, 3.57 mmol, Aldrich Chemical Co.). The solution was stirred at 0 ° C under nitrogen for 1 hour and 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 NaHCO ₃ solution, water and brine, and dried over MgSO ₄ . 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.

Elementary analysis:

Calcd. For C ₂₄ H ₂₆ N ₅ O ₃ F. (451): C, 63.85; H, 5.80; N, 15.51;

Found: C, 63.75; H, 5.71; N, 15.16.

Mass spectrum (MH +): 452 (base peak).

Step 2: Preparation of 1- [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] piperazine, bis (trifluoroacetate), monohydrate

A solution of the compound prepared in Step 1 (0.1804 g, 0.4 mmol) in methylene chloride (1.0 mL) and TFA (0.3 mL) was stirred at ambient temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and TFA was driven out of methylene chloride and methanol. Resulting colorless * 4

- 2044 · 4444 oily residue was dried in a vacuum oven overnight to give 1 - [[5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] carbonyl] piperazine (isolated as bis (trifluoroacetate) monohydrate salt (0.2400 g, 100%) as a white solid.

Elementary analysis:

Calcd. For C ₁₉ H ₈ N ₅ OF. 2CF ₃ COOH. H ₂ O (351 + 228 + 18): C, 46.24; H, 3.71; N, 11.72;

Found: C, 45.87; H, 3.43; N, 11.45.

Mass spectrum (MH +): 352 (base peak).

The compounds of Examples A-203 to A-206 were synthesized according to the methods described above (especially in Scheme VIII) by selecting the appropriate starting reagents:

Example A-203

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

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

A 60% dispersion of sodium hydride (41 mg, 0.00172 moles) (pre-washed with hexane) in mineral oil (69 mg) was added with 5 ml dioxane to a stirred solution of 4- (3-methyl-5-phenyl-1H-pyrazole-4- yl) pyridine (200 mg, 0.00086 mol) (prepared as described in Example A-2) in 50 mL dioxane. After 3 hours, a solution of CH ₃ I (122 mg, 0.00086 mol) in 10 mL of dioxane was added and the mixture was stirred at ambient 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 Na ₂ SO ₄ , filtered and concentrated to a solid. The products were purified and separated by radial chromatography. NMR (NOE experiments) showed that the first component leaving the column (minor component) was 4- (1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl) pyridine and the second component leaving the column was 4 - (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine.

Major isomer (4- (1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl) pyridine):

Mp 94-11 ° C.

Elementary analysis:

• 0,000 ·

- 20600 0 ·

0 0 0

0 · 00 00 0 0

0000

0 · 00 * 0 ·

0 0 · · 0 ·

0 0 ·

0 0 0

Calculated for C ₁₆ H ₅ N ₃ . 0.1 H ₂ O: C, 77.08; H, 6.06; N, 16.8S. Found: C, 76.51; H, 5.70; N, 16.62

Example A-204

4- [3- (4-Chloro-phenyl) -1,5-dimethyl-1H-pyrazol-4-yl] -pyridine

4- [5- (4-Chloro-phenyl) -1,3-dimethyl-1H-pyrazol-4-yl] -pyridine (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-pyrazole-4- yl] pyridine was prepared in the same manner as described in Example A 203 by replacing 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine 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):

Elementary analysis:

Calcd. For C 16 H 14 N 3 Cl (283.76): C, 67.72; H, 4.97; N, 14.81;

Found: C, 67.45; H, 4.71; N, 14.63.

Melting point (DSC): 190.67 ° C.

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

Melting point 82-88 ° C.

Elementary analysis:

Calcd. For C 16 H 14 N 3 Cl: 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

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

4- [5-ethyl-1-methyl-3- (3-methylphenyl) -1H-pyrazol-4-yl] pyridine and 4- [3-ethyl-1-methyl-5- (3-methylphenyl) -1H-pyrazol-4- yl] pyridine were prepared in the same manner as described in Example A-203 by replacing 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine 4- (3- (4-methylphenyl) -5-ethyl-1H-pyrazole) -4-yl] pyridine (prepared according to Example A-45).

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

Elementary analysis:

Calcd. For C 18 H 19 NO 3. 0.45 MH ₂ O: C, 75 73; H, 7.03; N, 14.77.

Found: C, 76.03; H, 6.87 N, 14.28.

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

Elementary analysis:

Calculated for C ₁₈ H ₉ NO ₃ . 0.45 MH ₂ O: C, 76 46; H, 6.99; N,

14.86.

• 00

- 20900 0

4 4

00

0 0 0

0 0

0 4 * 0 · 0 4004

00

0 0 · «0 3

0 0 4 3

0 0 O

00

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:

Elementary analysis:

Calcd. For C 17 H 16 N 3 Cl 14.11. (297.79): C, 68.57; H, 5.42; N, Found: C, Melting point 68.33; H, (DSC) 164 5.27; Deň: 32 ° C N, 14.08; Example A-207

4- [3- (4-Chloro-phenyl) -2-ethyl-5-methyl-1H-pyrazol-4-yl] -pyridine:

210Elementary Analysis:

Calcd for C ₁₇ 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;

Melting point (DSC) 153.46 ° C.

The compounds of Examples A-208 and A-209 were prepared by the methods described above (especially in Scheme IX):

Example A-208

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

Step 1: Preparation of 4-fluorobenzoyl-4'-pyridylmethane

To a mixture of 4-picoline (32.6 g, 0.35 mol) and ethyl 4-fluorobenzoate (50.45 g, 0.3 mol), maintained at 20 ° C, was added lithium bis (trimethylsilylamide) (600 mL ( 1M)) in a uniform but fast current to maintain the ambient temperature. The initially yellow solution turned into a suspension, which was then stirred for an additional 2 hours. Toluene (250 mL) was added and the mixture was cooled to 0 ° C. The reaction was quenched with concentrated HCl at 0 ° C to reduce the pH to about 7. The organic layer was separated and the aqueous layer re-extracted with toluene (100 mL).

• · · · · · · · ·

The organic layer was dried (sodium sulfate) and concentrated to give a yellow solid which, after trituration with hexanes (200 mL) gave pure desoxybenzoin, 4-fluorobenzoyl-4'-pyridylmethane, in 90% yield (58 g).

¹ H NMR was consistent with the proposed structure.

Step 2:

To the suspension of desoxybenzoin prepared in step 1 (30 g,

0.14 mol) in tetrahydrofuran (50 ml) was added dimethylformamide dimethylacetal (50 ml) and the mixture was stirred at ambient temperature for two days. The solution was then concentrated to dryness and the resulting solid paste was triturated with hexanes (150 mL) to give a yellow solid of sufficient purity (determined by NMR) and was used in the next step without further purification. Yield: 33.9 g (90%) NMR was consistent with the proposed structure.

Step 3:

The vinylamine prepared in Step 2 (33.9 g, 0.1255 mol) was dissolved in 125 ml ethanol and cooled to 0 ° C. Hydrazine hydrate (8.0 g anhydrous or 16.0 g hydrate, 0.25 mol) was added. then added in one batch. The mixture was stirred well and allowed to warm to ambient temperature with a total reaction time of 3 hours. The mixture was concentrated and taken up in 200 mL of chloroform. After washing with water (100 mL), the organic layer was extracted with 150 mL of 10% HCl. The aqueous layer was then treated with 0.5 g of activated carbon at 70 ° C for 10 minutes, filtered through celite and neutralized carefully to pH 7-8 with vigorous stirring and cooling (20% sodium hydroxide was used). Gentle whitish • ·

- 212 • 9 9 • 9 9 •

The precipitate was filtered and dried to obtain

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] pyridine. Yield: 27.3g (91%).

Mass spectrum: m / z = 240.

¹ H NMR was consistent with the proposed structure.

Elementary analysis:

Calcd for C ₁₄ H ₁₀ FN ₃ : C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H, 4.33; N, 17.61.

Example A-209

4- [3- (2-Chloro-phenyl) -1H-pyrazol-4-yl] -pyridine

This compound was prepared in the same manner as described, for example, in A-208 using the corresponding starting reagents.

Elementary analysis:

Calcd for C ₁₄ H ₁₀ ClN ₃ : C, 65.76; H, 3.94; N, 16.43. Found: C, 65.22; H, 3.91; N, 16.50.

DSC: 208.46 ° C

The compounds of Examples A-210 and A-211 were prepared by the methods described above (especially in Scheme X);

Example A-210

3- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol

The desoxybenzoin prepared in Step 1 of Example A-208,

4-Fluorobenzoyl-4'-pyridylmethane (12.7 g, 0.059 mol) was mixed with 90% hydroxyethylhydrazine (5.3 g, 0.062 mol) in 30 mL ethanol containing 0.5 mL acetic acid in a 500 mL Erlenmeyer flask. After gentle boiling (1 hour) a small sample was evacuated under high vacuum and examined by ¹ H NMR to confirm completion of hydrazone formation. After cooling to ambient temperature, the reaction mass solidified to a yellow cake. DMF dimethylacetal (36 mL, 0.27 mol) was then added and the mixture was heated to 80 ° C for 10 minutes when all solids dissolved and a clear yellow viscous solution was obtained. The reaction mixture was immediately allowed to cool slowly to 25 ° C and water (20 mL) was added dropwise with stirring to give a cloudy yellow oily suspension. The solution was now warmed to about 50-60 ° C, then the solution turned to a clear yellow. Slow cooling to ambient temperature with stirring (crystal seed, if available, will speed up this process) leads to abundant crystal formation. Vacuum filtration followed

- 214 washes with 10% ethanol-water (50 ml) followed by drying gave 3 - (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol as a pale yellow crystalline solid. Re-heating the filtrate to a clear state, as before, followed by cooling gives another product. The third and fourth portions of the mother liquor after standing overnight gave the remaining 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%) ·

Mass spectrum, m / z = 284.

¹ H NMR was consistent with the proposed structure.

Elementary analysis:

Calcd. For C ₁₆ H ₄ FN ₃ O + H ₂ O: C, 63.78; H, 5.35; N, 13.95. Found: C, 63.55; H, 5.07; N, 13.69.

Example A-211

3- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-1-ethanol

This compound was prepared in the same manner as described in Example A-210 except that the 4-picoline used for the synthesis of desoxybenzoin was replaced by 4-methylpyrimidine.

Compound of Example A-212

It was prepared according to Scheme XI:

Example A-212

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

The vinylamine prepared in Step 2 of Example A-208 (5.0 g, 0.0185 moles) was taken up in ethanol (75 mL) and cooled to 0 ° C. Methylhydrazine (1.7 g, 0.037 mol) in ethanol (75 mL) was added in one portion while maintaining the temperature between 0 and 10 ° C. After 3 hours at ambient temperature, the solvent 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 the crude regioisomeric mixture as a light brown solid (80:20 by NMR in favor of the title compound). The crude isomeric mixture was taken up in 10% HCl (100 mL) and washed with methylene chloride (100 mL) and the aqueous layer was 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 colored precipitate was filtered, washed with water and dried. The solid (5 g) was dissolved in hot 10% heptane / toluene (70 mL) allowed to cool slowly, first to ambient temperature and then to 15 ° C. Scraping the sides of the flask started the crystallization process. After 2 hours standing

- 216 · 9 9 9 9 9 ·

9 * · · · · · · ·

9 9 · 9 9 ** the formed solids were filtered, washed with cold 50% toluene / heptane (25 mL) followed by hexane (25 mL) and dried to give the pure title compound.

¹ H NMR confirmed the structure of the compound (including regiochemistry using NOE experiments).

Yield: 2.1 g, (45%).

Mass spectrum, m / z = 254 (base peak).

Elementary analysis:

Calc'd for C15H12FN3 + 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 method of Scheme XII:

Example A-213

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

Carefully prepared mixture of 2-fluoro-pyridinylpyrazole (0.2 g, '(prepared in the same manner as described in Example A-210)

- 217 except that the 4-picoline used for the synthesis of desoxybenzoin was replaced by 2-fluoro-4-methylpyridine) and (R, S) -2-amino-1-methanol (4-fold molar excess) was heated to 210-220 ° C at 210-220 ° C. sealed container for 1.5 hours. After cooling to 100 ° C, the vessel was carefully opened and 5 ml of toluene and 5 ml of water were added and stirred well for 1 hour. The obtained solid, 2 - [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] -1-methanol, was vacuum filtered and washed with an additional 5 mL of water followed by toluene and dried . Yield: 190 mg, (71%).

Mass spectrum, m / z = 343.

^{Χ Η} NMR was consistent with the proposed structure.

The compound of Example A-214 was prepared by the method of 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 DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at ° C overnight. TLC indicated the reaction was complete. The reaction was quenched by the slow addition of K ₂ CO ₃ (25g). When the pH was approximately 5, a precipitate formed. The precipitate was washed with water (50 mL x 5) to give 4- [5-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine (1.24 g,

%):

Mp 174.38 ° C;

Mass spectrum m / z = 332, 334;

¹ H NMR was consistent with the proposed structure.

Elementary analysis:

Calcd. For C ₁₅ H ₁₁ N ₃ FBr. 0.2 H ₂ O: C, 53.66; H, 3.42; N,

12.51.

Found: C, 53.58; H, 3.12; N, 12.43.

The compound of Example A-215 was prepared according to the method of Scheme XIV:

Example A-215

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarbonitrile

Step 1:

219 »

To a solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine (4.3 g, 17.97 mmol) (prepared as described in Example A-208) in methanol (100 mL) was added 3-chloroperoxybenzoic acid (5.44 g in 57% purity, 17.97 mmol). The solution was stirred at 25 ° C overnight. The mixture was concentrated. To ₂ CO ₃ (10%, 100 mL) was added to the residue. A precipitate formed, was filtered and washed with water (30 mL x 3) to give the corresponding N-oxide (3.764 g, 81.66%).

Step 2:

To a suspension of the N-oxide prepared in Step 1 (0.40 g, 1.567 mmol) in DMF (5 mL) was added trimethysilyl 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 at 25 ° C for 2 hours. TLC showed starting materials were consumed. The mixture was partitioned between ethyl acetate: water (100 mL: 20 mL).

The organic layer was washed with K ₂ CO ₃ (10%, 20 mL), water (50 mL), brine (50 mL), dried over MgSO ₄ , filtered and concentrated to give 4- [3- (4-fluorophenyl)]. -1H-pyrazole- (4-fluorophenyl) -1H-pyridinecarbonitrile (0.23 g, 56% yield):

Mp 209.22 ° C;

Mass spectrum (chemical ionization): m / z = 265;

¹ H NMR was consistent with the proposed structure.

Elementary analysis:

Calcd for C ₁₅ H ₉ N ₄ F. 0.2 H ₂ O: C, 67.26; H, 3.54; N, 20.92. Found: C, 67.44; H, 3.40; N, 20.69.

The compound of Example A-216 was prepared by the method of Scheme XV:

«« «9

9 ♦ 9

AND

• 9

- 220Example Α-216

4- [2- [3- (4-Fluorophenyl) -4- (4-pyridinyl) -4-pyrazol-1-yl] ethyl] morpholine

Step 1:

3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol (prepared as described in Example A-210) (10.0 g, 0.0353 mol) was suspended in pyridine (100 mL) ) and cooled to 0 ° C. Methanesulfonyl chloride (4.4 g, 0.0388 mol) was added slowly while maintaining the temperature at 0 ° C. After stirring 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 re-extracted with 100 mL of methylene chloride and the organic layer was dried and concentrated to a paste. After drying under high vacuum, the obtained light brown cake was triturated with ether (75 mL), filtered and dried to give a cream-colored solid in 79% yield (10.1 g).

^{Χ Η} NMR was consistent with the proposed structure. The compound was used as such in step 2.

Step 2:

«« «

4 4444 * 4444 * 4

4 4 4

4 4 ·

The mesylate prepared in Step 1 (5.0 g, 0.0138 moles) was dissolved in an eight-fold excess of morpholine (9.6 g, 0.11 moles) in methanol (50 ml) and heated at reflux for 3-4 hours. . After the NMR sample confirmed the completion of the reaction, the mixture was concentrated and taken up in methylene chloride (150 mL) and washed with water (100 mL) and then 75 mL of 5% HCl. The aqueous layer was neutralized to pH 8 and extracted with methylene chloride (100 mL). After drying and concentration, a pale yellow pasty solid was obtained, which was triturated with 25 mL of ether to give a solid.

Recrystallization from toluene / hexane gave 4- [2- [3- (4-fluorophenyl) 4- (4-pyridinyl) -4-pyrazol-1-yl] ethyl] morpholine as a solid. Yield: 4.5g (86%).

Mass spectrum, m / z = 353.

¹ H NMR was consistent with the proposed structure.

Elementary analysis:

Calcd for C ₂₀ H ₂₁ FN ₄ O: C, 68.16; H, 6.01; N, 15.50. Found: C, 68.20; H, 6.21; N, 15.80.

Example A-217 was prepared according to Scheme XVI:

Example A-217

- 22244 »445

4 4: í ♦.

4 4 4

44

44

4 4 4

4 4

4 4

4444 <3 «3 4

4 4

4 4

4 4

3- (4-Fluorophenyl) -1-methyl-α-phenyl-4- (4-pyridinyl) -1H-pyrazole-5-methanol

To solid magnesium (60 mg, 5 mmol) under a nitrogen atmosphere was added a solution of 4- [5-bromo-3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine (450 mg, 1.35 mmol) (prepared as described in 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. Quench the reaction with HCl (10 mL, 1N) and wash with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO ₄ , filtered and concentrated to give a residue. The residue was purified on a silica gel column to give the title compound (59 mg, 12% yield).

MS: m / z = 360 (M + 1);

“Ή NMR was consistent with the proposed structure.

Elementary analysis:

Calcd for C22H18N2OF. 0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.

- 223 • Φ φφφ φ

ΦΦ · · φ · · φ φ · φ φ φ · · · · φ

ΦΦΦΦ φφφ ΦΦΦΦ φφ φφ φφ ΦΦΦΦ φφ «φ

The compound of Example Α-218 was prepared by the methods described above (especially Scheme XVII):

Example A-218

N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinethanamine

The starting desoxybenzoin prepared in Step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridylmethane, (1.0 g, 0.0046 mol) was dissolved in 10 mL of DMF and cooled to -10 ° C (dry ice-aqueous). isopropanol). N-chlorosuccinimide (0.62 g, 0.0046 mol) was added in one portion maintaining the temperature at -10 ° C. After 5 minutes, thiosemicarbazide (0.0046 moles) was added in one portion at 0 ° C and the mixture was allowed to warm to ambient temperature slowly over 1 hour. After stirring overnight, the solvent was removed under high vacuum and water and toluene (25 mL each) were added and stirred well. The toluene layer was separated and the aqueous layer (starting pH 5.5) was treated with bicarbonate to pH 8. A fine precipitate formed which was filtered and washed with water, toluene and ether. Final trituration with ether (25 mL) gave an off-white substance, N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] • 9

9 «9999 • 9

224

9

9999

4-morpholinethanamine, which was again filtered and dried. Yield: 0.95 g, (56%).

Mass spectrum m / z: 368 (base peak).

Elementary analysis:

Calcd for C 20 H 22 FN 5 O. C, 55.38; H, 6.04; N, 19.06. Found: C, 64.90; H, 5.92; N, 18.67.

Example A-219

H

4- [3- (3-Chloro-phenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone

Step 1: Preparation of (E) -2- (2-bromo-4-pyridinyl) N, N-dimethylethenamine

4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t-butoxybis (dimethylamino) methane (5 mL) were heated at 150 ° C for 16 hours. 4-Methyl-2-bromopyridine was

- 22500; :

0 • ·

000 00 00 ·· · * «0 0 0 0 0 0 · ♦« 0 0 0 0 * 0 * »· 0 0 0 0 0 00 0 0

0 00 000 0 0 0 »· prepared according to the procedure podle. Adger et al., J. Chem. Soc., Perkin Trans. 1, pp. 2791-2796 (1988), which is incorporated herein by reference. The contents were evaporated and the residue dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 1.0 g of (E) 2- (2-bromo-4-pyridinyl) -N, N-dimethylethenamine as an oil suitable for use in step 2. .

Step 2: Preparation of (Z) -2- (2-bromo-4-pyridinyl) 1- (3-chlorophenyl) -3- (dimethylamino) -2-propen-1-one

The product of Step 1 (1.0 g, 4.4 mmol) was dissolved in methylene chloride (15 mL). Triethylamine (900 mg, 8.8 mmol) was added at 0 ° C, followed by addition

3-chlorobenzoyl chloride (350 mg, 4.5 mmol). The mixture was stirred under a nitrogen atmosphere for 16 hours. The solvent was evaporated in vacuo and the residue was dissolved in ether (25 mL), stirred with magnesium sulfate (500 mg) and silica gel (500 mg) and filtered. The ether was evaporated and the residue was chromatographed on silica gel using acetone / methylene chloride mixtures as eluents to give 670 mg of the product, (Z) -2- (2-bromo-4-pyridinyl) 1- (3-chlorophenyl) -3- (dimethylamino) -2-propen-1-one, in the form ♦ · · «··

2270 9 «* 99 99

9 9 9 9 9 9-9

9 9 9 9 9 9 9 ·

9 9 9 9 9 9 9 9 9 9 • 9 9 9 9 9 9 9 9 9 9

99 99 9999 99 99 glass that was used in step 3 without further purification.

Step 3: Preparation of 2-bromo-4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] pyridine

A solution of the product of Step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 mL) was heated to 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%). ) in the form of oil:

Calcd for CuHgBrClNg: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.

Continued elution with ethyl acetate / methanol gave 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone (190 mg, 36%) as a crystalline solid:

Mp 163-164 ° C .;

Mass spectrum (M + H) - 286.

Elementary analysis:

Calcd. For C 14 H 12 N 5 Cl: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87.

- 2278 «99

9 9 9 9 9

9, 9, 9, 9 »

9999 · 9

9 9 9 9 9

99 99 9900 «9 9900

9

9

9

9

9

9 ·

9

9

Example A-220

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyridinamine

A solution of the bromopyridine compound prepared in Step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 mL) was heated at 175 ° C for six hours. After cooling, excess benzylamine was removed by high vacuum distillation and ethyl acetate added to the residue. After washing the organic phase with water and drying over magnesium sulfate, the solvent was removed in vacuo and the residue chromatographed on silica gel using ethyl acetate-toluene mixtures to give 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- ( phenylmethyl) -2-pyridinamine (110 mg, 61%) as a solid.

Melting point 179-180 ° C.

Elementary analysis:

Calcd. For C 21 H 17 ClN 4: C, 69, 90; H, 4.75; N, 15.53. Found: C, 69.69; H, 4.81; N, 15.11.

• 9 «♦ ♦ 9

2290 «9«

99 9 9 9 9 9 9 9 99 99 99999

9 9 9 9 9 9 • 9 ♦ * ♦ · 99 99

Example A-221

4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylethyl) 2-pyridinamine

A solution of the bromopyridine compound prepared in Step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 mL) was heated at 175 ° C for six hours under a nitrogen atmosphere. The excess amine was distilled off 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 on silica gel with ethyl acetate-toluene to give 4- [3- (3-chlorophenyl) -1H-pyrazol-4-yl] -N- (phenylethyl) 2-pyridinamine ( 230 mg, 81%) as a solid.

M.p. 185-186 ° C.

Elementary analysis:

Calcd for C 22 H 19 ClN 4: C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66.

Example A-222

- 229φφ φφφφ

ΦΦ ΦΦ ·· ΦΦ • · φ φφφφ Φ Φ * Φ

Φ Φ Φ Φ Φ · · · φ φ φ φ φ Φ

ΦΦΦΦ ΦΦΦ ΦΦΦΦ

ΦΦ ΦΦ ΦΦ ΦΦΦΦ ΦΦ Φ

4- [3- (3-Chloro-phenyl) -1H-pyrazol-4-yl] -N-ethyl-2-pyridinamine

A solution of the bromopyridine compound prepared 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 sealed vessel for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with 70 ethyl acetate / 30 toluene to give 4- [3- (3-chlorophenyl) 1H-pyrazol-4-yl] -N-ethyl-2-pyridinamine (125 mg, 46%) as a solid.

Melting point 186-187 ° C.

Elementary analysis:

Calcd. 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.

The compounds of Examples A-223 to A-226 were synthesized according to the methods described above (especially in Scheme

XVIII) by selecting the appropriate starting reagents:

Example A-223 • 9 99 ··

- 230 • 9

99 99 99

99 9 9

9 9 9 9 9 ·

99999 9

9 9 9 9 9

9999 98 99

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide

Step 1:

To a suspension of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine (prepared according to Example A-208) (8.8 g, 0.037 mol) in methylene chloride was added m-chloroperoxybenzoic acid (mCPBA) in one dose at ambient temperature. After stirring for 16 hours, the solvent was removed and the residue was treated with saturated sodium bicarbonate solution. The precipitate was filtered, air dried to give 8.2 g of the product as a white solid (87%).

Melting point: 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 DMF was added trimethylsilyl cyanide (2.5 g, 0.025 mol), followed by a solution of N, N-dimethylcarbamoyl chloride (2.7 g, 0.025 mol) in 5 ml DMF at ambient temperature. After stirring overnight, the reaction mixture was basified with 200 mL of 10% aqueous potassium carbonate solution. The aqueous phase was extracted

AA AAAA

A ♦ ♦

- 231A * AA • AAAA AAA «

A A A A A A A A A A A A

A A A A A A A A A A

AA AA AA AAAA AA AA Ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude 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 substances.

Mp 238-2390C.

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 DMSO 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 and allowed to warm to ambient temperature. Water was added and the precipitate was collected by filtration and air dried to give 0.32 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] 2-pyridinecarboxamide as a white solid (67%). yield).

Melting point 230-231 ° C.

Elementary analysis:

Calcd. For C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found: C, 63.42; H, 3.66; N, 19.58.

Example A-224 · »··

- 232

9

9 *

9 9 9

99

9 9

9999

9 9

9 9 «» »

Methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate

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 N N-dimethylformamide dimethylacetal (3.67 g, 0.03 mol). The reaction mixture was stirred at ambient temperature overnight and refluxed for 4 hours. After cooling, the precipitate was isolated by filtration and air dried to give 2.0 g of methyl 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylate as a white solid (69%). yield).

Mp 239-2410C.

Elementary analysis:

Calcd. For C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.

Example A-225

- 233 ·· φφφφ

ΦΦ φ · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

ΦΦ Φ »ΦΦ φ · φφ φφ φφ

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -N-methyl-2-pyridinecarboxamide

A 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% aq. solution) was heated at 120 ° C in a sealed tube 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

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -N-methyl-2-pyridinecarboxamide as a white solid.

Mp 88-89 ° C.

Elementary analysis:

Calcd for C 16 H ₁₃ FN ₄ O + 0.4 H ₂ O: C, 63.32; H, 4.58; N,

18.46.

Found: C, 63.10; H, 4.62; N, 18.35.

Example A-226

9999

99 99 ··

9,999,999

999 99 9 999 • 9 99 999 99999 9

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 ethanol was added sodium hydroxide solution (0). (24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After removal of the solvent, the residue was dissolved in water and acidified to pH 5 with citric acid solution. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude material was purified by ether treatment to afford 0.62 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylic acid as a white solid (73% yield).

Mp 245 ° C (dec.).

Elementary analysis:

Calcd 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; H, 3.42; N, 14.58.

Other compounds of the present invention that were

- 235φφ ···· φφ · · · · · · ·

9 • 99

9 9 9

9 9

9 9 9

9 9

Φ · * Φ

Φ Φ Φ ·

Φ Φ Φ 9

9 9 9

9 9 9

99 prepared by the method according to one or more of the above reaction schemes (especially Schemes IX to XVIII) are shown in Table 3. Specific synthetic scheme (s) or schemes as well as mass spectra and elemental analysis results for each compound are also shown in Table 3.

- 237 • · · · · · · · · · · · · · ·

4 4 4 4 4 5

4 4 4 4 4

4 44 44 44

ns tH rH 05 / O O O kD rH 04 / tn Ol fH tn 04 / in r * tn O· fH tH <φ tn θ ' rH 25 tn 05 / 05 / O O O O O O O O O O O O r-1 <φ kD 04 / 00 ro <φ tH Ch ch what tn ro kD ro tn O- tn WHAT Ch 00 O ΙΛ « ro ro r- r * 00 tn 00 <h O «0 tn tn rH rH ^Γ . H 05 / rH ro O Ol ro H ⁴ tn • φ O* O tn O tn θ ' Γ0 04 / 04 / H ⁴ O kD (h CD T — t tH rH rH rH 04 / tH tH tH H rH tH rH Ol <H rH «Η rH rH ro tn Γ ro <h tn 04 / Ol ro tn kO 00 kD 00 θ ' 04 / ro «Φ <0 what r * in H ⁴ O tn ch O 00 kD tH xr ¹ ; rH 04 / rH ro H ⁴ «♦ 20 May ro tn m tn r * rH tn O kD what ro 05 / 05 / H ⁴ O O- O Ch rH rH rH iH Ol tH iH rH rH tH rH H 04 / tH <H rH iH 04 / tH kD tH »H fH kD WHAT 00 tn 00 tn ch ro tn 00 H ⁴ rH kD WHAT kD WHAT WHAT tn WHAT O* ro M ⁴ Ol fH Ol 51 » Ol ch «Φ O 04 / ro Ol kD 04 / Ol ro ro rr ro m ro tn ro kO kD kD <jt kD * φ H ⁴ in H ⁴ tn tn kD tn Ch ΙΛ σ » tn 04 / Ch kD what 00 03 / what Ch what 0 » 04 / rH Ol tn tn what ro ro Ch tn r · r) · O O 04 / rH OJ ro 04 / <Φ O· 00 ro 05 / ro ro ro ΙΛ ’Φ ro tn ro kO tn kD kD * Φ kD -φ tn tn Φ tn tn kD kD 07 / 68 M * ro 17J ¹² ’Φ H ⁴ ID 00 tn ”Φ ro kD tH * Φ 04 / tn <h tn kD 0 * O· 0 * 00 ro tn what Ol what ro ro rH 04 / rH 48. 49. ro Φ WHAT \ d kD ko 67 M ⁴ kD kD kD | 60 rH θ ' Ol 10 Ch kD Ol O· 1 70. ro ko kD kD 62. 62. ro kD rH kD O ⁶⁵ 1 70. kO ro kD WHAT kD tH fO ro 04 / rH σ \ WHAT kD tH tH σ \ what 04 / kD σι tn kD 00 tn <h kD 00 ro 04 / ro kD tr r-t 00 Ol 04 / O* WHAT O· rH ro kD 00 kO ch 00 íh ro 00 w r * u> * Φ kO O tH Ol Ch 04 / O ro kD Ol 04 / 04 / kD iH O in kD Ch kD kD ro kD ko kD id kO kO kD O* kD id 0 * kD id 10 kD kD kD 00 04 / ro tn what 04 / kD WHAT O rH kO what kD O WHAT 04 / <h rH XJ ⁴ O\ kO H ⁴ * r «Φ ko O O* k0 kD <h O* r · tn kD Ch tH r> Ol 04 / O kO O h ⁴ O Ol O tn ro m ro ro ro ro 04 / 04 / 04 / 04 / Ol 04 / Ol ro ro ro ro ro ro ro M ⁴ ro H ⁴ ro > X > > > tH IX IX XI XII IIX XIV XII TO X IX IX XI X w X M tH X XII X IH XII IX XII X tH X Ί X w IX XI M X> X X X X n X O rH 04 / ro tn tn 10 O· 00 ch O tH 04 / ro H ⁴ tn 10 0 * 00 <h O rH Ol ro ^ ⁴ tn in tn Ift tn H in in m in tn kD ko M> ID 10 it it it 10 ko t r- θ ' Γ- r * Ol n η 04 / 04 / 04 / « Of Of Of 04 / 04 / 04 / N 04 / 04 / Ol 04 / Ol 04 / 04 / 04 / 04 / Ol 04 / 04 / if if < if ii and ii if ii if ii if < if ii < if if <i if ii ii 4 ii and

• 9 • ·

- 238 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ··· 9999 ·· 99

lp in O O w un kO cn CN cn LP CN d) CN m CN LP Γ- rd Ν ’ Ν ’ 00 ΓΩ O O O O O O O O CN rp O rd Ο H H ^{05 /} ω rd vo 00 r- rd CN 00 Ν ' 00 rp CN CN kO in kO > CN cn O LP Ν ' LP Γ * cn r * cn IP r ~ N * LP 12. PP rd kO rd Ν ' rd pp rd > ' rd rd r * rd rp rd kO rd ΓΡ rd kO rd rd cn H m H (N H N * rd kD Η kO H H AFTER H LP CN Ν ' rd N ⁴ vo rp lp r · m kO kO 00 rp PP r * kO PP r- kO rd CN LP O 00 rp LP 00 IP CN CN N * CN LP cn H m H 00 rd rd PP rd t * · rd t * · rd r · rd ΓΡ rd k £> rd N * rd kD rd Γ- Η cn H rp H H Nř H kO Η kO H LP H rd IP CN Tr rd n rd cn rp k £> CN rd rd PP kO ΓΡ Ν » CN cn CN ko LP rd kD LP <n CN m LP CN O (N AFTER r- cn <0 kO kO kO in lp ip lp kO kO kO t * · <3 * I.e* N * N * Ν * N * N N * N * CN 18 H 00 Ν ' lp r · fp lp lp LP w LP cn t- rd 00 H rp CN LP LP cn CN Γ * Γ- LP 00 N * cn LP rd k0 W ko ko kO in lp lp kO LP kO r- N * LP Ν ' Ν ' Ν ' Tf N * Ν ' m Ν ' r · CN CN O 00 rd N * * 3 * cn rd 00 r · rp lp <n kD kD CN Ν ' LP LP σ) kO Ν ' 00 cn CN Γ · Ν ' r * 1 70. CTR p m kD m kO > kO rd kO N < kO N < kO kO O what kO cn LP kO LP cn ko Γ- kD Ν ' kD Ν ' r * Η kO IP LP m r * > k £> O P- r- IP N * n * Ch rd rd CN N * P * CN fp kO PP kO CN O CN > O > O CN I.E* what Ν ' r- CN CN LP r- k £> Okay PP cn O r- LP k £> rd kO N * kO kO rd kO Ν ' kO N * kO P * kO what kO cn LP kD LP cn kO kD kO Ν ' Η kO LP LP m r * > kO O r- > LP ΓΡ kO WHAT r * CN cn rp rp r * cn kD CN O rp r · P- Ο kO m 00 WHAT rp PP lp kO <n rd rd O P0 r> WHAT Tt * cn O O cn CN rd r * Ν ' N * rp PP I.E* CN AFTER rp Ν ' n I.E* rp rp CN N · N * CN AFTER AFTER CN CN > Hd > Hd Hd > Hd Hd M X Hd X> Hd X Hd X> Hd Hd Hd X X l-d X> Hd Hd Hd Hd Hd H X X X H Hd hd l-d H H X X Hd X X H X X w X X l-l X X X X Hd X l-d X X w X > X > X > X l-d X l-d X Η > X > X X X Hd Hd tn it r WHAT cn O rd CN CP N < IP U0 C 00 cn O Η CN cn N · LP it P * t r * r- r- » 00 00 00 «0 00 00 00 00 00 00 <n cn cn σν cn Okay Okay cn cn CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN <4 <4 <4 <4 <4 <4 > 4 <4 4 <4 <4 <4 <4 <4 <4 <4 «4 <4 > 4 <4 > 4 <4 <4

- 239 ·······················

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

- 240 • 9999

99 99 99

9,999 β 999,99 9

9999 999 9999

99 99 9900 «9 99

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

Example A-230

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

Example A-231 • 4,444

- 241-

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

Example A-232

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

Example A-233

- 242 ·· · · ·· ·

9 99

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

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-Methyl-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 ·· 00

0 0 0 0 0 0 0 0 000 000 0 0 0 0 0 0 0 0 00 0000 00 00

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

Example A-238

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

Example A-239 ··

9 9 9

9 99

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 • Φ φφφφ ·· φφ

φ φ φ φ φ φ φ φ • φ φ φ φ φ

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

Example Α-242

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

Example A-243

φφ φφφφ

- 247 φ · «« «« φ · · · »» »φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

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

Example Α-244

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

Example A-245

S (S) -4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N- (2-methylbutyl) -2-pyridinamine

- 248ΦΦ «φ φφ φφ φφ φ ΦΦΦΦ φφφ φ · φ ΦΦΦΦ φφ φ ΦΦΦΦΦΦ

ΦΦΦΦ φφφ ΦΦΦΦ φφ φφ φφ ΦΦΦΦ Φφ φφ

Example Α-246

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

Example A-247

N- [4- [3- (4-Chloro-phenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine-methanamine

Example A-248

999 ·

- 249 • 9

9-9

9 »

9

9

9

9

9999

99

9 9 9

9 9 9

9 9 9

9 9 9

99

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridinomethanamine

Elementary analysis:

Calcd. For 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

9 9

9 9 9

9 9 »*

9 9

9999 • 9999

·

4 • 9

9

4- [3- (4

Example iodophenyl) -1H-pyrazol-4-yl] pyridine

A-251

4- [3- (4

Example

iodophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine

A-252

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

- 251 φ φ · · Φ Φ Φ '' '' 'φ φ φ · · · Φ φ φ φ φ φ φ φ

Example Α-253

Ν- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -4-pyrazol-4-yl] -2-pyridinamine

Example A-254

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

Example A-255 · 999 • 9 99

• 9 9 9

9 9 • 9 99

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 · «·· * ·

- 253

9 9 • 9 9

9 9 9

9 9 9

99

99

9

9 9 9

9

9 9 9

9999

9 9

9 9

9 9

9 9

9 «

4- [3- (3,4-Difluorophenyl) -1H-pyrazol-4-yl] -2-fluoro-pyridine

Example A-258

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine

Example A-259 ·· · <* <·

- 254φ φφ φφ φ φ φ φ φ φ φ

ΦΦΦ φ φ φ φ ► ► ► ► ►

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

Example Α-260

4- [3- (3,4-Difluorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-fluoropyridine

Example A-261

44

4 4 4

- 25545 44

4 4 4

4 4 4

4 4 4

4 4 4

44

CH, i

N, CH

3- (4-Fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazole-1-ethanamine

Example A-262

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

Example A-263.0

00 «0 0«

0 «0

0 0 0

0 0 0 ·

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

Example A-264

Ν '- [4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] N, N-dimethyl-1,2-ethanediamine

Example A-265 »9 0000

- 25700 0 «• 0 0 0 0 0 0 · 0 0 0 ♦ · · · ·

0000

00

0 0 0 · 0

0 «0 • 0 0 0

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 · «·· <··

3- (4-Fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1-ethanol

Example A-268

N \ z = J

4- [3- (4-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-yl] ethyl] morpholine

Example A-270

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

Example A-271

3- (4-Fluorophenyl) -4- (2-fluoro-4-pyridinyl) -N, N-dimethyl-1H-pyrazole-1-ethanamine

Example A-272

OH

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

Example A-273

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

Example A-274

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

Example A-275

3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] N, N-dimethyl-1H-pyrazole-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] -N-4-piperadinyl-2-pyridinamine

Example A-278

N, N-Diethyl-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 - [(4-fluorophenyl) methyl] -2-pyridinamine

Example A-280

'OH

2 - [[4- [3- (4- (Fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] amino] ethanol] ··· ···· · · · · · ····

26? ·;. · · .. * · · · · ···· «« ··

Example Α-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

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

Example A-284

N, N-Diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole

1-ethanamine

Example A-285 ·· ·

4 «· ·

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-morpholinpropanamine

Example A-287

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

Example A-288

5- (4-Fluorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1H-pyrazole

3-Amin

Example A-289

44

4 4 4

4 4 4

4 4 4

4 4 4

44

• 4,444 • 4,444

4 4 4 4 4

4 4 4 4 4

44 4444

3- (4-Fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -1H-pyrazole-6-ethanol

Example A-290

5- (4-Fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] 4-pyridinyl] -1H-pyrazole-6-ethanol

Example A-291

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

Example A-292

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

Example A-293

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

N

2724- [5- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine

Example A-296

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

Example A-297

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

Example A-298

0 · 00

0 0 *

0 0 · 0 0 0 ·

0 0 0

00 · 0 · «• 0 0

0 0 0 0 0

273 .-. ·· .. · ♦ 0 00

0 0 0

0 0 • 00 ·

0 0 · 0000

N- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-piperidinamine

The pyrimidine-substituted compounds of Examples A-299 to A312 were synthesized according to the methods described in Schemes I-XVIII by selecting the appropriate starting reagents.

Example A-299

Step 1:

• 9 99

9 ♦

9 9 9

9 · ··

NMe ₂

NMe «>

A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g, 0.031 mol), triethylamine (6.23 g, 0.062 mol) and a catalytic amount of 5% Pd / C in 100 mL THF was hydrogenated in a Parr apparatus at 40 psi. dogs at ambient temperature. After 0.5 h, the catalyst was filtered and the filtrate was concentrated. The crude product was purified by silica gel chromatography (ethyl acetate / hexane, 3: 7) to give 2.36 g of the product as pale yellow crystals (50% yield);

Melting point 47-45 ° C.

Step 2: Preparation of 2- (2-chloro-4-pyrimidinyl) 1- (4-fluorophenyl) ethanone

O

2- (2-chloro-4-pyrimidinyl) -1- (4-fluorophenyl) ethanone

To a solution of lithium diisopropylamide (obtained from BuLi (0.045 mol) and diisopropylamine (0.048 mol) in THF) at -78 ° C

99

9 9 9

9 9 »99«

99 • 9 9 9 ·

9 9

273, 9 9 9 99 9999

9 9 9

99 was slowly added a solution of the compound prepared in Step 1 (5.5 g, 0.037 mol) in THF over 30 minutes. After 1 hour, a solution of ethyl 4-fluorobenzoate (7.62 g,

0.045 mol) in THF and the reaction mixture was stirred overnight and allowed to warm to ambient 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 silica gel chromatography (ethyl acetate / hexane, 3: 7) to give 4.78 g of a yellow solid (51% yield).

Melting point 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-propen-1-one

A mixture of the compound prepared in Step 2 (4.7 g, 0.017 mol) in 100 mL of dimethylformamide dimethyl acetal was stirred at ambient temperature overnight. Excess dimethylformamide dimethyl acetal was removed in vacuo to give 4.5 g of crude product as a thick brown oil which was used without further purification.

· »»

271- i

In · · · · · · · · · · · · · · · · · · · · · · · ·

Step 4: Preparation of 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine

A solution of the compound prepared in Step 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirred at ambient temperature for 6 hours. The resulting yellow precipitate was collected by filtration and air dried to give 1.85 g of 2-chloro 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine as a yellow solid.

Mp 204-205 ° C;

Elementary analysis:

Calcd for C ₁₃ H ₈ ClFN ₄ : C, 56.84; H, 2.94; N, 20.40; Cl, 12.91.

Found: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97.

Example A-300

nhnh ₂

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

A solution of the compound prepared in Step 3 of Example A-299 (1.5 g) and hydrazine hydrate (5 mL) in ethanol was heated at reflux overnight. After the mixture, 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 was purified by recrystallization from ethyl acetate and hexane to give 0.5 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) pyrimidinone hydrazone, as a pale yellow solid (38% yield).

Mp 149-150 ° C;

Elementary analysis:

Calcd for C ₁₃ H ₁₁ FN 6: C, 57.77; H, 4.10; N, 31.10.

Found: C, 57.70; H, 4.31; N, 30.73.

Example A-301

N

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

Step 1: Preparation

NMe ₂

NMe ₂

A solution of the compound prepared in Step 2 of Example A-299 (3.0 g, 0.02 mol) and tert-butylbis (dimethylamino) methane (10.45 g, 0.06 mol) in 40 mL of DMF was stirred at 110 ° C. ° C Overnight. After the solvent was removed in vacuo, water was added and the mixture 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 recrystallization from ethyl acetate and hexane to give 1.23 g of a yellow solid (32% yield).

Mp 76-77 ° C;

Elementary analysis:

Calcd. For C 10 H 16 N 4: C, 62.47; H, 8.39; N, 29.14.

Found: C, 62.19; H, 8.58; N, 29.02.

Step 2: Preparation of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] N, N-dimethyl-2-pyrimidinamine

To a solution of the compound prepared 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 layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product (1.6 g) was then dissolved in 50 mL of ethanol. The solution was treated with hydrazine hydrate (0.36 g, 0.006 mol) and the mixture was stirred

- 279heated at reflux for 2 hours. After removal of the ethanol, the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (ethyl acetate / hexane, 1: 1) to give 0.6 g of the product 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] - N, N-dimethyl 2-pyrimidinamine, as a yellow solid (33% yield). Mp 155-156 ° C;

Elementary analysis:

Calcd. For C ₁₅ H ₁₄ 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] -N-methyl-2-pyrimidinamine

A suspension of 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to the method of 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 ambient temperature and the precipitate was filtered, air dried to give 0.2 g of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N-methyl-2-pyrimidinamine product. , as a white solid (68% yield). Melting point 217-218 ° C.

Elementary analysis:

Calcd. For C 14 H 12 FN 5: C, 62.45; H, 4.49; N, 26.01.

Found: C, 62.58; H, 4.36; N, 25.90.

Example A-303

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidinamine

This compound was synthesized by heating 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to the method of Example A-299 in benzylamine to reflux overnight. The product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidinamine, was obtained as a white solid in 95% yield.

Mp 216-217 ° C;

Elementary analysis:

• 9

- 28199 9999

Calcd for C ₂₀ H ₁₆ FN ₅ : C, 69.55; H, 4.67; N, 20.28. Found: C, 69.73; H, 4.69; N, 19.90.

Example A-304

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 the method of Example A-299 in excess cyclopropylamine in methanol at 50 ° C for 12 hours. The product, N-cyclopropyl-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine, was obtained as a white solid in 26% yield.

Mp 203-204 ° C;

Elementary analysis:

Calcd for C 16 H 14 FN 5: C, 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] -N - [(4-methoxyphenyl) methyl] -2-pyrimidinamine

This compound was synthesized by refluxing 2-chloro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine prepared according to the method of Example A-299 in 4-methoxybenzylamine overnight. The product, 4- [3- (4-fluorophenyl) 1H-pyrazol-4-yl] -N - [(4-methoxyphenyl) methyl] -2-pyrimidinamine, was obtained as an off-white solid in 80% yield.

Mp 183-185 ° C;

Elementary analysis:

Calcd for C ₂₁ H ₁₈ FN ₅ O: C, 67.19; H, 4.83; N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.

Example A-306

nh ₂

4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine

A solution of 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] - N - [(4-methoxyphenyl) methyl] -2-pyrimidinamine prepared as described in 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 removed and the residue was partitioned between ethyl acetate and 1 N ammonium hydroxide. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel chromatography (ethyl acetate) to give 0.14 g of the product, 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine as a pale yellow solid ( 59% yield).

Mp 273-274 ° C;

Elementary analysis:

Calcd. 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 · • · φ · φ · «· • · φ · φ ·

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 as described in Example A-303 (0.15 g, 0.00043 mol), DMAP (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF were added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at ambient temperature overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO ₃ , 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- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] N- (phenylmethyl) acetamide as a white solid (60% yield).

Mp 176-178 ° C;

Elementary analysis:

Calcd. For C 22 H 18 FN 5: C, 68.21; H, 4.68; N, 18.08.

Found: C, 67.67; H, 4.85; N, 17.79.

• 4 • 4

Example A-308 • 4 4 4

4 4 4 4

O

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 as described in Example A-306 (0.26 g, 0.001 mol) in 5 mL pyridine was added ethyl chloroformate dropwise. . After the addition was complete, the clear solution was stirred at ambient 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 give 0.15 g of the product, ethyl [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] 2-pyrimidinyl] carbamate as white solids (46% yield).

Mp 163-165 ° C;

Elementary analysis:

Calcd. For C 16 H 14 FN 5 O 2: C, 58.71; H, 4.31; N, 21.04.

- 286 ·· 4444 • 44 44 4 4

9,9949 · 44 ·

499 4 4 4444

4 · 9444 499444 • 4 4 949 4444

44 94 4944

Found: C, 59.22; Η, 4.51; N, 21.66.

Example A-309

4- [3- (3-methylphenyl)]. 1H-pyrazol-4-yl] pyrimidine

This compound was prepared in the same manner as described in Example A-208 except that 1-methyl-3- (4'-pyrimidinylacetyl) benzene (prepared according to the method of Step 1 of Example A-19) from 4-methyl-pyrimidine and methyl 3-methylbenzoate ) was used instead of 4-fluorobenzoyl-4-pyridinylmethane.

Elementary analysis:

Calcd. For C 14 H 12 N 4 (236.27): C, 71.17; H, 5.12; N, 23.71 Found: C, 70.67; H, 5.26; N, 23.53.

DSC: 151.67 ° C.

Example A-310 ·· · «» ··

4- [3- (4-chlorophenyl) -4-pyrazol-4-yl] pyrimidine

This compound was prepared by the method of Schemes VI and IX by selecting the corresponding pyrimidine starting material instead of the pyridine starting material.

Elementary analysis:

Calcd. For C 13 H 9 N 4 Cl. 0,25ΜΗ Ο _2: C, 59 78; H, 3.67; N, 21.45.

Found: C, 59.89; H, 3.32; N, 21.56.

Melting point (DSC): 218.17 ° C.

Example A-311

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

- 28899 9999 • »« · 0 0 0 ·

0 · 000 »0 0 0» 000 00 0 0000 00 0 0 0 0 0 0 0 0 0 0 0000 00 »0 0 0 0 00 00 00 00 0000 00 00

This compound was prepared by the method of Schemes VI and IX by selecting the corresponding pyrimidine starting material instead of the pyridine starting material.

Elementary analysis:

Calcd 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.

Melting point (DSC): 168.55 ° C.

Example A-312

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

This compound was prepared by the method of Schemes VI and IX by selecting the corresponding pyrimidine starting material instead of the pyridine starting material.

Elementary analysis:

Calcd. For C 13 H 9 N 4 F (240.24): C, 64.99; H, 3.78; N, 23.32 Found: C, 64.94; H, 3.56; N, 23.44.

Melting point (DSC): 191.47 ° C.

Other compounds of the present invention that may be prepared using one or more of the reaction schemes set forth in this application include, but are not limited to:

- 289φφ ····

Následující φ · · omez omez omez omez omez omez omez omez omez omez eny omez eny eny omez omez omez omez omez omez omez omez omez eny omez eny omez omez omez omez omez omez omez omez omez omez ·

4- [3- (4-Chloro-phenyl) -5- (1-piperazinyl) -1H-pyrazol-4-yl] -pyrimidine

1- [5- (4-Bromo-phenyl) -4- (6-pyridinyl) -1H-pyrazol-4-yl] -piperazine

- 29099 9 99 9 »

9 9 9 9 9

9

9 9 9 9 9

9 9 9 9 9

99 99 9999

9 9 9

9 9 ·

9 9 9

9 9 9

9 9 9

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

4- [5- [1-piperazinyl-4- (4-pyridinyl) -1H-pyrazol-3-yl] benzonitrile

• · · *

- 2919 9 ·· • 9 8 ·

9 9

9 9 ·

9 * 9

9999

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

5- (4-Fluorophenyl) -4- (4-pyridinyl) -N-3-pyrrolidinyl-1H-pyrazol-3-amine

5- (4-Chloro-phenyl) -4- (4-pyridinyl) -N-3-pyrrolidinyl-1H-pyrazol-3-amine

9 9 9 9 ·

9 99 99 99

N- [5- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-piperidinamine

3- (4-Fluorophenyl) -5- (1-piperazinyl) -4-pyridinyl) -1H-pyrazole-1-ethanol

- 293 · · A A A A A A A A A A A A A A A A A

AA A A A A A A A A A A A

AA AAAA AA AA

H

3- (4-chlorophenyl) -5- (1-piperazinyl) -4- (4-pyridinyl) 1H-pyrazole-1-ethanol

4- [2-Aminoethyl) -2- (4-fluorophenyl) 4,5,6,7-tetrahydro-3- (4-pyridinyl) pyrazolo [1,5-a] pyrimidin-6-ol

- 294 • 9 99 99 99 • 9 · 9 · 9 9 · 9 9 9 9 9

9 9 9 9 9

9999 98 99

4- [2-Aminoethyl) -2- (4-chlorophenyl) 4,5,6,7-tetrahydro-3- (4-pyridinyl) pyrazolo [1,5-a] pyrimidin-6-ol

3- (4-chlorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-1-ethanol

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

NHCOMe

N- [4- [3- (4-Fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] acetamide

N- [4- [3- (4-Chloro-phenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -acetamide

N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] propanamide

NHcoet

N- [4- [3- (4-Chloro-phenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -propanamide

6- [3- (4-fluorophenyl) 1H-pyrazol-4-yl] 1H-purine

6- [3- (4-Chloro-phenyl) -1H-pyrazol-4-yl] -1H-purine

- 298

0000 »0 0

0 0 0 0 0 0

0 0 0 ·· ·· • 0 0000 • 0 0 0

0 0 0

0 0 0 • 0 0 0 »

NCOMe

Βπ

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

.NCOEt

Rn

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

NCOEt

Bn ^

N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -N- (phenylmethyl) propanamide ·

• ·

- 299Results of p38 biological assays Kinase assays

Cloning of human p38a:

The coding region of human p38α cDNA was obtained by PCR amplification from RNA isolated from human monocytic cell line THP.1. The first strand cDNA was synthesized from total RNA as follows: 2 gg RNAs were dissolved into 100 ng of random hexamer primers in a 10 μΐ reaction volume by heating at 70 ° C for 10 minutes, followed by 2 minutes on ice. The cDNA was then synthesized by adding a mixture containing 1 μ 1 RNAsin (Promega, Madison WI), 2 μΐ 50 mM dNTP, 4 μΐ 5X buffer, 2 μΐ 100 mM DTT and 1 μΐ (200 U) Superscript II AMV reverse transcripts. Random Primer, dNTP and Superscript ™ reagents were all purchased from Life Technologies, Gaithersburg, MA. The reaction mixture was incubated at 42 ° C for 1 hour. Amplification of p38 cDNA was performed by aliquotting the 5 μΐ reverse transcriptase reaction mixture into a 100 μ reakční PCR reaction mixture containing the following: 80 μΐ dHzO, 2 μ 50 mM dNTP, 1 μΐ direct and reverse primers (50 pmol / μΙ), 10 μΐ 10X buffer and 1 μΐ Expand ™ polymerase (Boehringer Mannheim). PCR primers included Bam HI sites at the 5 'and 3' ends of the amplified fragments and were purchased from Genosys. The sequences of forward and reverse primers were 5'GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 'and

5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3 '. PCR amplification was performed in a DNA Thermal Cycler (Perkin Elmer).

- 300 repetitions of 30 cycles of 94 ° C for 1 minute, 60 ° C for 1 minute and 68 ° C for 2 minutes. After amplification, excess primers and unincorporated dNTPs were collected from amplified fragments by Wizard ™ PCR'prep (Promega) and the fragments digested with Bam HI (New England Biolabs). Bam HI digested fragments were ligated into Bam HI digested pGEX 2T plasmid DNA (PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described in T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The ligation reaction mixture was transformed into chemically competent E. coli DH10B cells purchased from Life-Technologies following the manufacturer's instructions. Plasmid DNA was isolated from the resulting bacterial colonies using the Promega Wizard ™ miniprep kit. Plasmids containing the corresponding Bam HI fragments were sequenced in a DNA Thermal Cycler (Perkin Elmer) using Prism ™ (Applied Biosystems Inc).

CDNA clones that encode both human p38α isoforms have been identified (Lee et al. Nature 372, 739). One of the clones that contained the p38a-2 (CSBP-2) cDNA inserted at the cloning site in the PGEX 2T, 3 'GST coding region was designated as pMON 35802. The sequence obtained for this clone exactly matches the cDNA clone described by Lee. et al. This expression plasmid allows the production of the GST-p38α fusion protein.

Expression of human p38α:

The GST / p38α fusion protein was expressed from plasmid pMON 35802 in E. coli, strain DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grown in Luria Broth (LB) medium containing 100 mg / ml ampicillin. Following

- 301days were inoculated with 500 ml of fresh LB into 10 ml of overnight culture and grown in a 2 liter flask at 37 ° C with constant shaking until the culture reached an absorption of 0.8 at 600 nm. Expression of the fusion protein was induced by adding isopropyl b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for three hours at ambient temperature and the cells were harvested by centrifugation. Cell pellets were stored frozen until protein purification.

Purification of D38 kinase-α:

All chemicals were from Sigma Chemical Co. unless otherwise stated. Twenty grams of E. coli cell pellet obtained from five 1 L shake flask fermentations was resuspended in PBS volume (140 mM NaCl, 2.7 mM KCl, mM Na ₂ HPO ₄ , 1.8 mM KH ₂ PO ₄ pH 7.3) to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then divided equally into five 50 ml Falcon conical tubes. Cells were sonicated (Ultrasonics model W375) with a 1 cm probe for 3 x 1 minute (pulse) on ice. The lysed cell material was removed by centrifugation (12,000 xg, 15 minutes) and the purified supernatant was applied to glutathione sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography:

Twelve ml of 50% glutathione sepharose-PBS suspension was added to 200 ml of purified supernatant and incubated batchwise for 30 minutes at ambient temperature. The resin was isolated by centrifugation (600 x g, 5 min) and washed with 2 x 150 ml PBS / 1% Triton X-100, followed by 4 x 40 ml PBS. To cleave p38 kinase from the GST-p38 fusion protein,

302glutathione-sepharose resin resuspended in 6 ml PBS containing 250 units of thrombin protease (Pharmacia, specific activity> 7500 units / mg) and gently stirred for 4 hours at ambient temperature. The glutathione-sepharose resin was collected by centrifugation (600 x g, 5 min) and washed with 2 x 6 ml PBS. The PBS wash fraction and the digested supernatant containing the p38 kinase protein were collected and adjusted to 0.3 mM PMSF.

Mono Q anion exchange chromatography:

The thrombin cleaved p38 kinase was further purified by FPLCanion exchange chromatography. The thrombin digested sample was diluted twice with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchange column equilibrated with Buffer A. The column was eluted with a gradient of 160 mL of 0.1 M-0.6 M NaCl / Buffer A (flow rate 2 mL / min). The p38 kinase peak eluted at 200 mM NaCl and was collected and concentrated to 3-4 mL using a Filtron 10 concentrator (Filtron Corp.).

Sefacryl S100 gel filtration chromatography:

The concentrated Mono Q purified p38 kinase sample was further purified by gel filtration chromatography (Pharmacia HiPrep 26/60 Sefacryl S100 column equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol)). The protein was eluted from the Buffer B column at a flow rate of 0.5 ml / min and the protein was detected by absorption at 280 nm. Fractions containing p38 kinase (detection by SDS-polyacrylamide gel electrophoresis) were collected and frozen at -80 ° C. A typical yield of purified protein from 5 L of E. coli fermentation was 35 mg of p38 kinase.

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

ΟΛΟ · 0 · 0 · 0 · 0 0 0 0 “J U d - ·· ·· ·· ·······

In vitro tests

The ability of compounds to inhibit human p38 kinase alpha was determined using two in vitro assays. In the first method, activated human p38 kinase alpha phosphorylated a biotinylated substrate, PHAS-I (phosphorylated heat and acid-stable protein-insulin-inducible), in the presence of gamma ³² P-ATP ( ³² P-ATP). PHAS-I was biotinylated prior to the assay and represented a substrate trapping agent that was phosphorylated during the assay. p38 kinase was activated by MKK6. Compounds were tested at 10-fold serial dilutions ranging from 100 μΜ to 0.001 μΜ using 1% DMSO. Each inhibitor concentration was tested in triplicate.

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

- 304After incubation, 20 μΐ of the reaction mixture was transferred to a high-capacity streptavidin-coated filter plate (SAM-streptavidin-matrix, Promega) pre-moistened with phosphate buffered saline. The transferred reaction mixture was left in contact with the streptavidin membrane of the Promega plate for 1-2 minutes. After capture of biotinylated PHAS-I with ³² P built-in, each well was washed to remove unintegrated ³² P-ATP three times with 2MNaCl, three times with 2M NaCl with 1% phosphorus, three times with distilled water and finally once with 95% ethanol. The filter plates were air dried and 20 μΐ of scintillant was added. Plates were read. The results are shown in Table 4.

A second assay format was also used, based on the phosphorylation of EGFRP (epidermal growth factor receptor peptide, 21mer) induced by p38 kinase alpha in the presence of ³³ P-ATP. Compounds were tested in 10-fold serial dilutions ranging from 100 μΜ to 0.001 μΜ in 1% DMSO. Each inhibitor concentration was tested in triplicate. Compounds were assayed 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, μg EGFRP (200 μΜ) and 0,05 μθί gamma ³³ P-ATP. Reactions were initiated by the addition of 0.09 μς of activated, purified human GST-p38 kinase alpha. Activation was performed using GST-MKK6 (5: 1, p38: MKK6) for one hour at 30 ° C in the presence of 50 μΜ ATP. After incubation for 60 minutes at ambient temperature, the reaction was stopped. · The reaction was stopped.

Add nr 150 μΐ AG 1x8 resin in 900 mM sodium formate buffer, pH 3.0 (1 resin per volume) 2 volumes of buffer). The mixture was mixed three times with pipetting and the resin was allowed to sit. A total of 50 μΐ of the purified solution was transferred from the reaction wells to Microlite-2 plates. Then, a Microlite 150 μΐ Microscint 40 plate was added to each well and the plate was sealed, shaken and read.

Table 4

Example p38 kinase ic ₅₀ (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

• φ φ φ

- 306 ·· 9 · • Φ «Φ

Φ Φ Φ Φ

Φ Φ Φ Φ

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

TNF cell assays

Method of isolation of human peripheral blood mononuclear cells:

Whole human blood was placed in Vacutainer tubes containing EDTA as an anticoagulant. The blood sample (7 ml) was carefully placed on 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml centrifuge flask. The sample was centrifuged at 450-500 x g for 30-35 minutes at ambient temperature. After centrifugation, the top layer of cells was removed and washed 3 times with phosphate buffered saline with calcium or magnesium. Cells were centrifuged at 400 x g for 10 minutes at ambient temperature. Cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells / ml.

LPS stimulation of human PBM:

PBM cells (0.1 ml, 2 million / ml) were co-incubated with 0.1 ml ·

9 99

9 9 9

9 ·

9 9

9999 ·· 9999

- 30799

9 9 9

9 9 ·

9 9 9

99 compounds (10-0.41 μΜ, final concentration) for 1 hour in a 96-well flat-bottom microtiter plate. Compounds were first dissolved in DMSO and diluted in TCM to a final concentration of 0.1% DMSO. LPS (Calbiochem, 20 ng / ml, final concentration) was then added in a volume of 0.010 ml. The cultures were incubated overnight at 37 ° C. Supernatants were then collected and assayed by ELISA for TNF-α and IL1-b. The lifetime was analyzed by MTS. After collecting 0.1 ml of the supernatant, 0.020 ml of MTS was added to the remaining 0.1 ml of cells. The cells were incubated at 37 ° C for 2-4 hours, after which O.D. at 490-650 nM.

Growth and differentiation of U937 human histiocytic lymphoma cell line:

U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU / ml penicillin, 100 gg / ml streptomycin and 2 mM glutamine (Gibco). Fifty million cells in 100 ml medium were induced for terminal monocytic differentiation by 24 hour incubation with 20 ng / ml phorbol 12-myristate 13-acetate (Sigma). Cells were washed by centrifugation (200 x g for 5 min) and resuspended in 100 ml fresh medium. After 24-48 hours, cells were harvested, 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 compound (0.004-50 μΜ, final concentration) for 1 hour in a 96 well microtiter plate. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in ♦ · 9999

- 3089 · ·· ·· 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 · 9 999 9 9 9 9 culture medium to obtain a final DMSO concentration of 0.1% in the cell assay. LPS (E. coli, 100 ng / ml final concentration) was then added in a volume of 0.02 ml. After 4 hours incubation at 37 ° C, the amount of TNF-α released in the culture medium was measured by ELISA.

The inhibitory capacity was expressed as IC ₅₀ (μΜ). The results of these TNF cell assays are shown in Table 5.

Table 5

Example Human PBM U937 cells IC ₅₀ (μΜ) IC ₅₀ (μΜ) 1 0.5 2 1.6 0.578 4 0.1 0.222 5 0.274 7 0.2 0.201 8 <0.1 9 0.4 10 0.7 1, 687 12 8.5 13 4.8 14 1,2 17 1.1 19 Dec 0.3 0.484 20 May 1,089 21 0,077 22nd 3.2 24 8.2 26 <0.1 0,029 27 Mar: 2.7

·· # ···

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

28 0.1 29 2.2 30 2, 6 31 0.8 1,053 32 2,696 33 0.4 34 0.5 35 0.7 36 1.4 37 1.5 0,099 38 0.2 0.208 39 0.7 0.244 40 0.4 41 1.0 42 0.7 43 <0.1 0.243 44 0.4 0.477 45 <0.1 0.04 46 0.329 47 2,359 48 2.2 0, 522 49 6.8 50 0.9 51 0,074 54 0.2 0.13 55 <0.1 0.228 143 0.301

Test with rats

The efficacy of the novel compounds in blocking TNF production was also evaluated using an LPS-based model.

- 310-

rats. Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and was fasted overnight before testing. Compound administration was typically by oral gavage (although intraperitoneal, subcutaneous, and intravenous administration was also used in several cases) 1 to 24 hours prior to LPS administration. Rats were given 30 gg / kg of LPS [salmonella typhosa, Sigma Co.] by intravenous tail vessel. Blood was collected by cardiac puncture 1 hour after LPS administration. Serum samples were stored at -20 ° C until quantitative analysis of TNF-α was performed with EnzymeLinked-Immuno-Sorbent-Assay (ELISA) [Biosource]. Further details of the experiment are given in Perretti, M. et al., Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated herein by reference.

Test with mice

Mouse model of LPS-induced TNF alpha production:

TNF alpha was induced in 10-12 week old BALB / c female mice by injection into the tail vessel of 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline. One hour later, mice were bled from the retro-orbital cavity and serum TNF concentrations from coagulated blood were quantitated by ELISA. Typically, peak serum TNF levels ranged from 2-6 ng / ml one hour after LPS injection.

Test compounds were administered to fasted mice by oral gavage as a suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 in water at 1-9 9 9-9.

311 hours or 6 hours before LPS injection. A one-hour protocol allowed the determination of compound efficacy at C max plasma levels, while a six-hour protocol allowed the estimation of compound duration of action. Efficacy was determined at each time point as a percentage of inhibition of serum TNF relative to LPS-injected mice given vehicle only.

Further results obtained using the above assays are given in Table 6 below. The results of the p38 assay and the U937 cell assay are expressed as IC ₅₀ (pm). The results of the mouse LPS assay are expressed as percent inhibition.

• «« «

- 3124 ·

4

4 ·

4 44

44 4 4 44 4 44 4444

444 4 4

444 4444 · 4444 44 44

Table β

Example 83 8 ¹ ρ38 * U937 mLPS mLPS ! mLPS 8h 6h dose 1h, 30 mg / kg Α-212 0.49 0.74 0.0967 20 May 10 93 Α-208 0.104 0.049 0.1896 98 30 97 Α-227 0.06 96 Α-228 0.76 0.339 0.4173 32 30 92 Α-229 1.4 0.4622 76 91 ' Α-230 0.42 0.178 96 i Α-231 0.174 0.3225 86 30 94 j Α-232 0.048 96, Α-233 0.044 53 Α-234 0.103 Α-235 0.104 56 Α-236 0.237 94 Α-237 0.093 0.087 60 Α-238 0.177 0.4016 Α-239 0.034 51 30 87 Α-240 0.961 78 30 85 Α-241 0.338 79 30 87 Α-242 0.047 95 30 87 Α-243 0.729 82 Α-244 0.099 AND Α-245 <.001 0.0337 65! Α-246 0.403 0.592 0.4952 Α-247 <0.01 0.166 Α-249 0.432 73 30 86 Α-250 2.873 Α-251 0.637 32 87 Α-252 0.774 1.197 48 30 75 Α-253 <.001 0.0044 61 Α-254 0.081 0.1411 Α-215 2.34 0.2976 38 30 80 Α-256 0.813 0.4562 Α-257 1.081 <.01 0.5167 Α-213 0.22 57 Α-258 0.48 1.2083 68 Α-259 0.17 0.7574 62 Α-210 0.16 0.1983 85 30 93 Α-260 0.23 1.2821 47 30 79 Α-214 0.06 1.4006 70 Α-261 0.008 0.2542 48 30 92 Α-216 0.018 1.8287 27 Mar: 30 91 Α-262 <0.1 0.3267 45 Α-263 <0.01 <0.1 0.5434 49

ΦΦ φφφφ • φ φ • · φ

313 • • * φ · φ φ φ φ φ φ • φ φ φ

Φ φ φ φ • • · · φ φ φ φ φ φ φ

! Example p38 ^x p38 ^J U937 mLPS mLPS mLPS 8h 6h dose 1h, 30 mg / kg A-264 0.2594 61 A-265 <0.1 0.6016 32 A-266 0.5393 0 A-267 0.43 2.6681 80 A-268 <0.01 0.0074 11 A-217 0.697 0.3486 9: A-269 > 10 µM 51 A-270 0.015 0.3466 53! A-271 0.216 4.2144 68 A-272 0.073 0.583 -8 A-273 6.98 > 10 43 A-274 <0.1 0.92 21 30 A-275 10.14 2 > 10 A-276 0.176 0.45 -24 30 A-277 0.026 33 30 A-278 0.285 2.3 62 30 and A-279 0.005 0.7 64 30 1 A-280 0.134 15 Dec 30 -1 1 A-281 0.053 22nd 30 and A-218 0.044 18 30 A-282 0.045 0.0973 30 30 A-283 <0.1 0.7998 -20 30 A-284 0.98 0.5088 -1 A-285 <0.1 0.1795 11 30 A-286 0.057 0.09 29 30 A-287 0.041 0.27 -24 30 A-288 0.017 0.3 40 30 A-289 <0.1 0.14 44 30 A-290 6.0191 4 30 A-291 0.388 1.1309 36 30 A-292 1.15 > 10 A-293 0.73 A-294 0.015 0.5 61 30 A-295 7.66 > 10 94 30 A-296 26 A-297 0.52 0.17 89 30

¹ results of ρ38α in vitro tests based on the PHAS-I test procedure ² results of p38a in vitro tests based on the EGFRP test procedure

- 314φ · φ φ φ φ

Induction and determination of collagen-induced arthritis in mice: Arthritis was induced in mice according to the procedure described by J.M. Stuart, Collagen Autoimmune Arthritis Immunol. 2: 199 (1984), which is incorporated herein by reference. Specifically, arthritis was induced in 8-12 week old DBA / 1 male mice by injecting 50 µg of chicken type II collagen (Cil) (provided by Dr. Marie Griffiths, Utah, Salt Lake City, UT) in complete Freund's adjuvant (Sigma) on day 0 to the root of the tail. The injection volume was 100 μΐ. The response of the animals was enhanced on day 21 by administration of 50 μL of Cil in incomplete Freund's adjuvant (volume 100 μΐ). Arthritis was evaluated several times a week in animals. Any animal showing redness or swelling was rated arthritic. Arthritic pancake scores were performed as described by Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Ball: Factors Influencing Disease Suspension and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15: 180 (1983). The severity of the symptoms was determined using a score of 1-3 for each paw (maximum score of 12 / mouse). Animals showing any redness or swelling of the toes or paws were rated as 1. Greater swelling of the whole paw or deformation was rated as 2. Joint ankylosis was rated as 3. Animals were evaluated for 8 weeks. 8-10 animals per group were used.

Preparation and administration of compounds:

Compounds tested in mice having collagen-induced arthritis were prepared as a suspension in 0.5% methylcellulose (Sigma, St. Louis, MO), 0.025% Tween 20.

9

- 315 • 9 9 9

(Sigma). Compound suspensions were administered by oral gavage in a volume of 0.1 ml b.i.d. Administration was started on day 20 after collagen injection and continued daily until the final evaluation on day 56. Arthritic paw scores were scored as above. The test results are shown in Table 7.

Table 7

Compound% Inhibition of Arthritis

A-210 58.5 at 15 Dec mg / kg A-172 49, 3 at 100 ALIGN! mg / kg A-189 51.6 at 30 mg / kg A-208 97.5 at 60 mg / kg A-208 75.0 at 60 mg / kg

The present invention also relates to 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 adjuvants (collectively called a carrier) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of pharmaceutical compositions adapted for the selected route of administration and at doses effective for the intended treatment. For example, the active compounds and compositions may be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM), or topically. Pharmaceutical compositions for oral administration may be, for example, in the form of tablets, hard or soft capsules, lozenges, dispersible powders, suspensions, or liquids. The pharmaceutical compositions are preferably formulated in a unit dosage form containing

- 316 · certain · quantity · certain amount active ingredient. Examples of such unit doses are tablets or capsules. The active ingredient may also be administered by injection (IV, IM, subcutaneously or by injection) in the form of a composition in which, for example, saline, dextrose or water may be used as a suitable carrier. The pH of the composition may be adjusted, if necessary, with a suitable acid, base or buffer. Suitable bulking and dispersing agents, wetting agents or suspending agents, including mannitol and PEG 400, may also be included in the composition. Suitable parenteral compositions may also include compounds formulated as sterile solids, including lyophilized powders, in vials. An aqueous solution may be added to dissolve the compound prior to injection. The amount of therapeutically active compounds to be administered and the dosage regimen for treating a disease state with the compounds and / or compositions of the present invention depend on a number of factors including the age, weight, sex and medical condition of the subject, severity of inflammation or inflammation related disorder, route of administration. and the frequency of administration of the particular compound employed and can therefore vary within wide limits. The pharmaceutical compositions may contain the active ingredients in an amount that is in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A suitable daily dose may be in the range 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 to 30 mg / kg body weight. The daily dose may be administered at one time or in two to four divided doses. In the case of skin conditions, it may be advantageous to apply a topical formulation containing the compounds of the present invention to the affected area two to four times a day. In case of malfunctions

- 317

ocular tissues or other external tissues, for example mouth or skin, the compositions may preferably be applied as a topical gel, spray, ointment or cream or as a suppository containing the active ingredient in a total amount of, for example, 0.075-30% by weight, preferably 0.2-20% by weight and most preferably 0.4 to 15% by weight. When used in an ointment, the active ingredient may be used in either a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated as an oil-in-water cream. If desired, the aqueous phase of the cream may comprise, for example, at least 30 wt. polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. It may be desirable for topical formulations to include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethylsulfoxide and similar analogs. The compounds of the present invention may also be administered by transdermal devices. Preferred topical administration is achieved by using a patch that is either a reservoir and porous membrane type or a solid matrix type. In both cases, the active ingredient is delivered continuously from the reservoir or microcapsule by a membrane to the adhesive layer permeable to the active ingredient that is in contact with the skin or mucosa of the recipient. When the active ingredient is absorbed through the skin, the recipient receives controlled and predetermined doses of the active ingredient. In the case of microcapsules, the encapsulating agent may also function as a membrane. Transdermal patches may include the compound in a suitable solvent system with an adhesive system such as acrylic emulsion and polyester.

- 318 patch. The oily phase of the emulsion of the present invention may consist of known ingredients and be formed in a known manner. While the phase may comprise only a single emulsifier, it may also comprise a mixture of at least one emulsifier with a fat or an oil, or both a fat and an oil. Preferably, the hydrophilic emulsifier is used together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to use both oil and fat. The emulsifier or emulsifier, with or without the use of a stabilizer or stabilizers, forms the so-called emulsifying wax and the wax together with the oil and fat form the so-called emulsifying base of the ointment, which forms the oily dispersed phase of the cream composition. Emulsifiers and emulsion stabilizers suitable for use in the compositions of the present invention include, but are not limited to, Tween 60, Span 80, ketostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The choice of suitable oils or fats for the formulations is based on the desire to achieve the desired cosmetic properties because the solubility of the active compound likely to be used in pharmaceutical emulsion formulations is very low. Therefore, the cream should preferably be a non-greasy, non-staining, washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight or branched chain alkyl esters, mono- or dibasic, such as diisoadipate, isoketyl stearate, coconut propylene glycol diester, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or branched chain esters may be used. These substances can be used either alone or in combination depending on the properties required. Alternatively, they may also be 9

High melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used. Formulations suitable for topical administration to the eye include eye drops in which the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent of the active ingredient. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of from 0.5 to 20%, preferably from 0.5 to 10% and particularly preferably about 1.5% by weight. For therapeutic purposes, the active compounds of the present invention are usually combined with one or more adjuvants that correspond to the chosen route of administration. For oral administration, the compounds may be admixed with lactose, sucrose, starch powder, cellulose alkanoic acid esters, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and then tableted or encapsulated for preferred administration. Such capsules or tablets may contain controlled-release preparations which may be obtained by dispersing the active compound in hydroxypropylmethyl cellulose. Formulations 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 having one or more of the carriers or diluents mentioned for use in the formulations for 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.

- 320 9 9 9 9 9 9 9 9 different buffers. Other adjuvants and modes of administration are well known to those skilled in the art of pharmacy.

All patent documents mentioned above are incorporated by reference.

Although the present invention has been described based on particular embodiments, the details of these embodiments are not intended to limit the scope of the present invention.

Description of the parallel field synthesis method used to prepare the compounds of Examples B-i, B-ii and B-iii.

Scheme B-1 describes a parallel array of reaction blocks that have been used to prepare the compounds of Examples B-0001 to B1574 and can also be used to prepare the compounds of Examples B-1575 to B-2259 based thereon.

The parallel reactions were carried out in multi-chamber reaction blocks. A typical reaction block can perform 48 parallel reactions in which a unique compound is optionally prepared in each of the reaction vessels B1. Each reaction vessel B1 is made of either polypropylene or pyrex glass and contains a frit B2 at the base of the vessel. Each reaction vessel is connected to the reaction block valve plate B3 via a snap connection or a screw connection. Each container valve B4 is either opened or closed by operating the latch position or by opening or closing the levers B5 in a series of valves of the valve assembly plate. Optionally, the solutions can either be drained or held above the frits of the containers by leaving the valves in the open position and

321 by controlling the back pressure under the valve assembly plate by controlling the inert gas flow through the inert gas inlet valve B6. The parallel reactions carried out in these reaction blocks proceed by incubation in jacketed temperature controlled shaking stations. The temperature control of the reaction chambers is achieved by passing the heat transfer fluid through the shell aluminum plates that are in contact with the outer wall B7 of the reaction block.

Stirring is achieved in the shaking station either by vertical orbital shaking of the vertical reaction block or by side shaking of the reaction block tilted to the side.

Functionalized resins are optionally added to each reaction vessel B1 during or after the reaction. These functionalized resins allow rapid purification of each product in the reaction vessel. Vacuum filtration in the reaction block apparatus by opening the vacuum valve B8 allows separation of the purified products from the resin-separated non-products. Valve B8 is located in the bottom of the BIO chamber of the reaction block, in which quadrant sets of frames with bins B 1 are stored. The desired products are obtained as filtrates in a single collection vessel B9. Removal of solvent from these collection containers yields the desired products.

· • ·

- 322-

Scheme B-2 illustrates various uses of functionalized resins to purify B22 products from reaction vessels prior to filtration from fritted B1 vessels to collecting vessels B9. Said functionalized resins have the following functions

(1) resin-bonded B12 reagents to form resin-bonded B13 reagent by-products;

2) separators B14 or B15 of excess B16 or B17 reactants in the solution phase.

The solution phase reactants B16 or B17 contain inherent

- 32399 99

99

99 9 9

9 9 9 9 9

9,999 99 9

9 9 9 9 9

9999 99 99 reactive functional groups -rfi and -rf ₂ , which allow their chemoselective separation by complementary reactive functional groups -Crfi and -Crf ₂ bound to B14 and B15 resins;

3) separators B18 of by-products B19 of the solution phase. B19 by-products contain molecular recognition moieties -mr ₂ , which allow their chemoselective separation by complementary -Cmr ₂ functional groups bound to B18 resins;

4) B20-terminating reactions which allow the formation of B21 end resins. Resins B20 contain a functional group -Q that mediates the termination of the reaction (e.g., proton transfer) of B22 to form the desired isolatable form of B22. Upon completion of the reaction, resin B20 is converted to resin B21 in which -q represents the terminating functional group to resin B21;

5) separators B23 of chemically labeled B24 reagents and their corresponding B25 reagent by-products. The soluble B24 reagent contains a bifunctional chemical group, tag, which is inert to the reaction conditions, but is used to allow post-reaction separation of B24 reagents with complementary -Ctag functional groups bound to B23 resin. In addition, the soluble reagent by-product B25 formed during the reaction contains the same chemical function -tag, which also allows it to be separated by B23 resin. In addition, some B16 reactants, especially sterically hindered reactants and / or electron deficient nucleophiles, contain a poorly separable functional group (rf1 is a poorly separable functional group in this case). These poorly separable reactants B16 can be converted in situ into more robust separable substances B27 by reacting them with

0 * 0 • 0 »0 00 00 ·· 0 0 0 0 0 0 0 0 0 000 · 0 0 0000 00 0 * 00 000000 0000 000 0 · 00 compartments allowing reagents Β2β. B26s contain highly reactive complementary Crfi functional groups that react with B16 to form B27 in situ. The bifunctional molecular recognition functional group, mr, contained in B26 is also found in situ derivatized B21. Both B26 and B27 are separated by complementary molecular recognition functional groups bound to B28 resin. By analogy, poorly separable byproducts of B19 are present in some reactions in which the molecular recognition function mr ₂ is in this case unable to mediate direct separation of B19 by a complementary functional group bound to B18 resin. A similar use of bifunctional separation permitting reagents B29 converts B19 to a more readily separable B30. The added molecular recognition functional group, mr, present in B30 is readily separable by the complementary functional group, Cmr, bound to B31 resin. In some reactions, multiple spacer resins are used simultaneously to perform the reaction purification. Even resins containing incompatible (mutually reactive) functional groups can be used simultaneously, as these resins capture complementary functionalized solution phase reactants, reagents or by-products from the solution phase faster than the resins are neutralized with each other. Similarly, resins containing reactive or neutralizing reaction-terminating functional groups are able to stop the conversion of the reactants, products or by-products of the solution phase faster than the resins are neutralized with each other.

325-

Scheme B3 describes a modular robotized laboratory environment that was used to prepare the compounds of Examples B0001 to Bxxxx. The chemicals that are used in the robotized laboratory are weighed and then dissolved or suspended in solvents at Station # 1 (Automated Chemistry Prep Station). Thus, solutions or suspensions of known molarity are ready for use in other robotized stations. Station # 1 also optionally barcodes each chemical solution so that its identity can be determined by a barcode reader at this or other robotized stations.

Reactions are initiated at modular Stations # 2 and # 2 of DUP. Station # 2 DUP is defined as a duplicate of Station # 2 and is used to increase the capacity of the robotized lab. The reaction block is mounted at Station # 2 or # 2 of the DUP. Frames containing reactants, reagents, solvents and resin suspensions are also mounted in Station # 2 or # 2 DUP. Pod • φ

32 & ΦΦΦΦ 4 •

Φ Φ

ΦΦΦ

By controlling through the information mapping file, reactions are initiated by transferring solutions of reactants, reagents, solvents, and / or resin suspensions to stored reaction block vessels. Known volumes of solutions, suspensions, or solvents are transferred by pumps that control single cannulae for the passage of the septum and argon feed, high-grade cannulas for delivering resin suspensions, or six-fold cannulas that can deliver the volume of the substance to a series of six reaction vessels. The reaction block and / or frame with the chemical solutions may optionally be cooled below ambient temperature during chemical solution transfer operations. After the transfer of chemical solutions and solvents has been completed by Stations # 2 or # 2DUP, the reaction block may be incubated while it is fixed in the robotized station. However, it is preferred that the reaction block be transferred after the chemical transfer is complete and the temperature of the reaction block returns to ambient temperature. The reaction block is transferred off-line to either the vertical or lateral shaking incubation station # 5.

Automated Weighing / Archiving Station # 3 performs the function of weighing empty collection containers (to obtain the empty weight of the collection containers) and also performs the function of weighing the collection containers containing filtered and purified products (to obtain the gross weight of the collection containers). After weighing the collection containers containing the product (determination of the gross weight of the collection containers) at work station # 3, the products from the collection containers are optionally redissolved in the organic solvent at work station # 3. Solvent transfer is provided by pumps that control the attached simple.

cannulas for septum passage and argon delivery. Each collection vessel containing the product is prepared by the solution of known molarity being rectified and recorded by a chemical information system. These product solutions can then be stored at Station # 2 or # 2DUP for subsequent reaction steps or transferred to Station # 7 or # 7DUP for analytical processing.

Rapid evaporation of the solvent in the collection containers containing the product is achieved by storing the collection container frames at Savant Automated Solvent Evaporation Station # 4, # 4 DUP or # 4 TRIP, where # 4DUP and # 4TRIP are defined as duplicate and triplicate Station # 4 to increase solvent removal capacity in a robotized laboratory. Commercially available solvent removal stations were purchased from Savant Company (model # SC210A Speedvac Unit equipped with a vapor trap model # RVT4104 and a steam cryopump model # VN100).

Stations # 7 and # 7DUP perform analytical processing functions. Station # 7DUP is defined as a duplicate of Station # 7 to increase capacity in a robotic lab. The product containing the collection frames is stored in one of these stations. Each product containing the collection vessel was prepared by rectifying and recording a known molarity solution with a chemical information system. This dissolution function is optionally performed prior to the processing of the collection container frames at Station # 3 described above. Stations # 7 or # 7DUP, under the control of the chemical information file, transfer aliquots from each product vial to a single and identifiable well of the microtiter plate.

32θ _: • is used for making analytical determinations.

One such microtiter plate is prepared in Station # 7 or # 7DUP for subsequent use in an automated Station # 8 or # 8DUP equipped with an HPLC / mass spectrometer. Station # 8DUP is a duplicate of Station # 8 to increase the analytical capacity of the robotized lab. Stations # 8 and # 8DUP are commercially available table LC / wt. Spectrum units purchased from Hewlett Packard (HP1100 HPLC model coupled to the HP1100 MSD Mass Spectrometer (G1946A), also equipped with Model # G1322A Solvent Degassing Unit, Model # G1312A, Model # G1316A Column Heater, Diode Array Detector model The HP unit was supplemented with a commercially available autosampler frame (Gilson Company # 215 autosampler) Stations # 8 or # 8DUP are used to determine product purity and identity by performing high performance liquid chromatography (HPLC) and accompanying atmospheric chemical ionization (atmospheric pressure) pressure chemistry (APCI) or electrospray mass spectrometry to determine molecular weight.

An additional microtiter plate was prepared at Station # 7 or # 7DUP for subsequent use in a commercially available Varian # 10 flow probe (Varian Instruments flow probe NMR, 300 MHz, coupled to a commercially available Gilson 215 autosampler). At this Station # 10, proton, ¹³ C and / or ^19- F NMR spectra are determined.

Additional microtiter plates are optionally deposited at Station # 7 or # 7DUP for the purpose of preparing plates containing the bioassay product. Aliquots of

The 32 µL collection containers containing the product are transferred to these bioassay microtiter plates under the control of a chemical information file. The identity and quantity of each transferred product shall be recorded by a chemical information system for processing by biologists conducting biological testing of the products.

The Fourier Transform Infrared Spectra FT-IR is used for analyzing resins for the identity of the organic functional groups chemically bonded to these resins. The resins, as explained above, contain chemical functional groups used as reagents, chemoselective separators or stopping media for processing and purifying mixtures of crude products contained in reaction block vessels. The robotized laboratory uses a commercially available FT-IR spectrometer purchased from Nicolet Instruments (Model # MagnaIR 560 coupled with an InspectIR microscope to store and adjust resins).

Scheme B-3

The Modular Station Link describes the transfer of chemical frames, reaction blocks, and / or collection vessel frames from one modular Station to another. Chemlib IT consists of software running on the client desktop and software installed on the server.

• 4 4 4 4

4

Automated Chemical Preparation Station # 1

Automated station # 2 for reaction preparation Automated station # 2DUP reaction preparation Off-line reaction incubation station # 5

Automated station # 4TRIP solvent evaporation

Automated weighing / archiving station # 3

Automated station # 4 solvent evaporation Automated station # 4 DUP solvent evaporation Automated Analysis Preparation Station # 7 Automated analysis preparation station # 7DUP to AND FT-IR Station # 11 Station # 10 Floating Probe NMR

Automated Station # 8 HPLC / wt. spect.

Automated Station # 8DUP HPLC / Wt. spect.

The Chemlib IT system is a client / server software program developed to support and document the data processing flow in the above-described robotized lab. This IT system connects a chemist with a robotized synthesis laboratory and processes the data generated within the process.

The software installed on the server stores all electronic data for the robotic chemical unit.

This server is a Silicon Graphics IRIX v6.2 workstation running the Oracle 7 v7.3.3.5.0 database software that stores data. Client desktop to server connection is provided by Oracle TCP / IP Adapter v2.2.2.1.0 and SQL * Net v2.2.2.1.0A. SQL * Net is the Oracle network interface • • · 9 9 ·

331 · »· 9 9 9 · that allows an application running on a client desktop to access data in an Oracle database. The client desktop is Microsoft Windows 95. The client software in Chemlib IT is comprised of 0mnis7 v3.5 and Microsoft Visual C ++ v5.0.

This client-side report is what is referred to as Chemlib. Chemlib communicates with the server to achieve this data through Oracle PL / SQL v2.3.3.4.0. Calling this PL / SQL inside Chemlib creates a network socket to connect to the Oracle SQL * Net driver and TCP / IP Adapter, allowing access to the server data.

A library is defined as a set of a number of wells where each well determines a single compound. Chemlib defines a library in a module called Electronic Spreadsheet. An Electronic Spreadsheet is thus a set of n wells containing components that are required for the synthesis of compounds found in that well or wells.

The chemist starts by putting in the Electronic Spreadsheet those components that are necessary for compound synthesis.

The identity and availability of these components is defined in the Building Block Catalog in Chemlib.

The Building Block Catalog is a catalog of lists of all reagents, solvents and peripherals available in the robotized laboratory. After selecting the components for each compound, the amount of each component to be used is also declared. The amount of each component can be identified by its molarity and volumetric amount (μΐ) or by its solid form (mg). The well in the Electronic Spreadsheet therefore defines a compound that is identified by its components and the amount of each of these • · · 9 9 ·

- 332 ’component.

The assembly or synthesis of these components for each compound in the Electronic Spreadsheet is defined in the WS Sequence module in Chemlib. The Define WS Sequence module identifies the synthesis steps to be performed at robotic stations and any other activity performed manually or offline from the robotic station. This module identifies the components of the Electronic Spreadsheet and the activities that should be performed with these components in a robotized laboratory. In the Define WS module, the Sequence chemist selects from a list of activities to be performed in a robotized laboratory and compiles them in the order in which they occur. The Chemlib system takes over this identified set of activities along with the component data in the Electronic Spreadsheet and compiles and reformats these instructions into terminology for use in a robotic station. This robotic terminology is stored in a 'sequence' file stored in a common server, accessible from a robotic workstation.

The robotized stations perform the synthesis in the reaction block apparatus as described. Each well in the Electronic Spreadsheet is tracked and mapped to a designated location in the reaction block device at the robotized station. The compound or product synthesized in the robotized station in the reaction block is then captured in collection containers.

In the robotized station, the empty weight is first determined and then the gross weight after collection of the products from the reaction block. These weights (tare and gross) are recorded in ·· ····

- 333 * ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The Chemlib system in the Tare / Gross Session module. Module

The Tare / Gross Session then calculates the product or compound yields and their final weight.

The preparation of the compound for analytical analysis and testing is defined in the Analytical WS Setup module in Chemlib. The Analytical WS Setup module identifies the dilution factor for each well in the Electronic Spreadsheet, based on compound product yield and desired molar concentration. This determines the amount, in ml, to be transferred to the robotized station at a specific site on the MTP (microtiter plate) for analysis and / or biological assays. Mass spectrometry and HPLC results for each well are recorded and evaluated in a Chemlib system.

The Dilute / Archive WS module further identifies each compound by mapping its well from the Electronic Spreadsheet module to a specific position in the MX block for long-term storage and archiving as part of the registration process.

All communication between Chemlib and robotic stations is done using ASCII files. These files are stored on the server using the Chemlib system, which is available to the robotized stations. Reports generated by robotic stations are also placed on a server where Chemlib can read these files to record the generated data. Each robotized station consists of robotic hardware from Bohdan Automation, Inc. Mundelein, Illinois and PC under Microsoft Windows, WorkGroup v3.11 and Ethernet software. The PC in the robotized station connects to the unidirectional network that allows the workstation to access

- 334server only as file access.

General Scheme B4

Skeleton C with a primary amine functional group contained in R @ ⁴ is reacted in spatially addressed parallel array reaction block vessels with excess of electrophiles of the formula R ^J -Q wherein Q represents a chlorine atom, a bromine atom or an acid activating group including but this would limit N-hydroxysuccinimide. R ^J -Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C with R ^J -Q is effected in the presence of a tertiary amine base at ambient temperature in a mixture of polar aprotic solvent and / or a halogenated solvent. As illustrated in Scheme B-4, the products of Formula Bi are isolated in purified form by adding carbonyl functionalized resin B32 that covalently separates any unreacted primary amine skeleton C1 as a resin-bound adduct B35, and also adding primary amine functionalized resin B33 that covalently separating any remaining electrophile R ^J -Q from each reaction mixture as resin-bound adduct B34. Resin B33 also separates the by-product HQ from the reaction mixture by transferring a proton from the Base-BQ solution phase. Incubation at ambient temperature, filtration, rinsing the resin cake, and concentration of filtrates give purified Bi products by filtering the resin bound adducts B32, B33,

B34, B35 and B36.

335 * • φ · Φ φ · «φ φ φ φ φ φ φ φ φ φ φ φ φ φ • • • • • •

Scheme Β-5 specifically illustrates the derivatization of a C1 skeleton containing a primary amine to obtain the desired Bi products in the form of a parallel synthesis field. In a reaction block of a parallel synthesis field, the individual reaction products are prepared in each multiple reaction block of the vessels in a spatially addressed shape. A solution of the desired skeleton C1 containing the primary amine (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0 fold stoichiometric excess of a solution of N-methylmorpholine in DMF. To each reaction vessel is then added with electrophiles: either a 2.0 fold stoichiometric excess when R ^J -Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R ^J -Q is a sulfonyl chloride or a 1.25 fold stoichiometric excess, when R ^J -Q is an isocyanate. Excess electrophiles and N-methylmorpholine were used to achieve •

9 9 • · · · · ·

9999 faster and / or more complete conversion of the skeleton C1 to products B0001 to B-0048 compared to reactions that do not use stoichiometric excesses of electrophiles and N-methylmorpholine. The reaction mixtures are then incubated at ambient temperature for 2-3 hours. Each reaction vessel was then charged with a large excess (15-20 fold stoichiometric excess) of the amine functionalized resin B33 and the aldehyde functionalized resin B32. The resin-filled reaction block is then shaken vertically for 14-20 hours in an orbital shaker at ambient temperature to ensure optimal mixing of the vessel with the resin-containing mixture. The excess electrophiles R ^J -Q and any unreacted scaffold amine C is removed from the reaction medium as insoluble adducts B34 and B31. In addition, the N-methylmorpholine hydrochloride salt formed during the reaction is also neutralized to its free base form by reaction of proton transfer to the amine functionalized B33 resin. Simple filtration of insoluble resin adducts B32,

B33, B34, B36 and B37, washing the resin cake with dichloroethane and evaporating the filtrates yield the desired products B-i in pure form.

- 337 «· 99 9 9 99

9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 99 99

Scheme B-6 illustrates a general synthetic route comprising a parallel field reaction of a C-ii backbone containing a secondary amine function with the same R ⁴ substituent. Each reaction vessel is filled with a C-ii skeleton containing a secondary amine, followed by the insertion of a stoichiometric excess or unambiguous electrophile R ^L -Q into each vessel wherein Q represents a chlorine atom, a bromine atom or an acid activating group, including but not limited to -hydroxysuccinimide. R ^L -Q includes acid chlorides, alkyl chloroformate, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates.

• 0 0000

338 · * ·· · 'Όν ·· 00

00 00 0 0 0 0 0 0 0 0 0 0 0 0

0 000 0 0 * 0 0 0 0 0

0000 00 0

The reaction of the scaffold C-ii with R ^L -Q is carried out in the presence of a tertiary amine base at ambient temperature or at elevated temperature in a mixture of polar aprotic solvents and / or in a halogenated solvent. After completion of the solution phase reactions that gave the mixture of crude products in each vessel, the B-ii products are isolated in pure form by adding isocyanate-functionalized resin B38 that covalently separates the remaining secondary amine skeleton C-ii as resin-bound adduct B39. functionalized resin B33 that covalently separates the remaining electrophile R ^L -Q from each reaction vessel as resin bound adducts B40. B33 resin also separates the HQ by-product in each vessel as B36, formed by the Base-HQ solution phase proton transfer. Incubation with these resins, either simultaneously or sequentially, followed by filtration, washing and concentration of the filtrates gives purified products B-ii filtered from the resin adducts B33, B36, B38, B39 and B40.

φφ φφφφ

- 339 »· 4 * · Φ 4 ·· · Φ

ΦΦ ΦΦ

Φ · Φ ·

Φ · ·

ΦΦΦ Φ ΦΦΦ • Φ ΦΦΦΦ

ΦΦ ΦΦ

Φ »Φ

Φ Φ Φ *

Φ Φ Φ φ φ

Φ Φ Φ * ·· ··

Scheme Β-7 illustrates the conversion of a C-2 backbone containing a secondary amine to the desired B-ii products. In the parallel field of the synthesis reaction, the individual binary reaction products are prepared in each of the 48 vessels of multiple reaction blocks. A solution of C-2 skeleton (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0-fold stoichiometric excess of the solution

Of N-methylmorpholine in DMF. To each reaction vessel is then added an electrophile R ^L -Q as a dichloroethane (DCE) solution; either a 2.0 fold stoichiometric excess when R ^L -Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R ^L -Q is a sulfonyl chloride or a 1.25 fold stoichiometric excess when R ^L -Q is an isocyanate . The reaction mixtures were incubated at ambient temperature for 2-6 hours. Each reaction vessel was charged

then filled with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 and the isocyanate-functionalized resin B32. The resin-filled reaction block was shaken vertically for 14-20 hours in an orbital shaker at ambient temperature for optimal mixing of the vessel containing the resin blends. The excess electrophiles R ^L -Q and unreacted scaffold amine C-2 are removed from the reaction medium as insoluble adducts B40 and B39. Resin B33 also separates the HQ by-product in each vessel as B36, formed by transferring a proton from the Base-HQ solution phase. Incubation with these resins, followed by filtration and washing with DMF and / or DCE solvent mixtures, gives pure product solutions in collection containers by filtering out the resin adducts B33, B36, B38, B39 and B40. Concentration of the filtrates gives pure products B-ii.

• ·

Scheme B-8 illustrates another general synthesis method involving a parallel array by reacting a C-ii backbone containing a secondary amine functional group with a substituent R ⁴ . Each reaction vessel is charged with scaffold C-ii containing a secondary amine, followed by insertion of a stoichiometric excess of an optionally straightforward electrophile R ^L -Q into each vessel. The reaction of the scaffold C-ii with R ^L -Q is carried out in the presence of a tertiary amine base at ambient temperature or at elevated temperature in a mixture of a polar aprotic solvent and / or a halogenated solvent.

Excess electrophiles and N-methylmorpholine are used to achieve a faster and / or more complete conversion of the C-ii skeleton to

products B-ii compared to reactions that do not use stoichiometric excesses of electrophiles and N-methylmorpholine. The reaction mixtures were incubated at ambient temperature for 2-8 hours. Each reaction vessel was then charged with the phenylsulfonylisocyanate B41 reagent to allow separation. This reagent B41 reacts with the remaining secondary amine skeleton C-ii and converts C-ii into an in situ derivatized compound B42. Subsequent incubation of these mixtures with a large excess (15-20 fold stoichiometric excess), amine-functionalized resin B33 substance solution phase separates R ^L -Q, HQ, B41, and B42 as the resin-bound adducts B40, B36, B44 and B43. The resin-filled reaction block is shaken vertically for 14-20 hours in an orbital shaker at ambient temperature for optimal mixing of the resin-containing mixture. Filtration of the insoluble resin adducts B33, B36, B40, B43, and B44 and subsequent washing of the resin bed in a DMF and / or DCE vessel yields filtrates containing pure products B-ii. Concentration of the filtrates gives pure products B-ii.

34Λ • ·

Scheme B-9 illustrates the method of Scheme B-8 using a C-2 skeleton. A solution of C-2 skeleton (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels, followed by a 4.0-fold stoichiometric excess of a solution of N-methylmorpholine in DMF. An electrophile R ^L -Q in the form of dichloroethane (DCE) is then added to each reaction vessel.

- 34.4 / * · .. · solution: either a 2.0 fold stoichiometric excess when R ^L -Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R ^L -Q is a sulfonyl chloride or 1, 25 fold stoichiometric excess when R ^L -Q is an isocyanate. The reaction mixtures were incubated at ambient temperature for 2-6 hours. After completion of the solution phase reactions to give a mixture of crude products, each reaction vessel is then charged with a dichloroethane solution of phenylsulfonyl isocyanate B41 allowing separation. This reagent B41 reacts with the remaining secondary amine skeleton C-2, converting C-2 into an in situ derivatized compound B45. Subsequent incubation of mixtures with a large excess (15-20 fold stoichiometric excess), amine-functionalized resin B33 substance solution phase separates R ^L -Q, HQ, B41, and B45 as the resin-bound adducts B40, B36, B44 and B46. The resin-filled reaction block was shaken vertically for 20 hours in an orbital shaker at ambient temperature for optimal mixing of the resin-containing mixture. Filtration of the insoluble resin adducts B33, B36, B40, B44, and B46 and subsequent washing of the resin bed in the DCE vessel yields filtrates containing pure products B-ii. Concentration of the filtrates gives pure products B-ii.

• 9,999 9

99 ··

9,999,999

- 34Λ ·

98 9 ·· 99

Another general synthesis method in the parallel array of reaction blocks is illustrated in Scheme B-10 for derivatizing a carboxylic acid-containing backbone C-iii. The free carboxylic acid functional skeleton C iii reacts in the spatially addressed parallel arrays of reaction block vessels with excess or different

9 9999

99 • 9 9 9 • · · · · · · · · · · · ·

99 primary or secondary amines B47 in the presence of polymer bound carbodiimide reagents B48 and a tertiary amine base in a mixture of a polar aprotic solvent and / or a halogenated solvent. After filtering each mixture of crude products from B48 and B49 resins, each reaction mixture is purified by treatment with reagent B50 allowing separation (tetrafluorophthalic anhydride). Reagent B50 reacts with the remaining excess of amine B47 to form in situ derivatized intermediates B51 that contain a carboxylic acid molecular recognition function. Subsequent incubation of each reaction mixture with a 15-20-fold stoichiometric excess of primary amine functionalized B33 resin separates B51, B50, and each remaining acid skeleton C-iii as resin bound adducts B52, B53 and B54. Filtration of the products in solution phase B-iii from these resin bound adducts and washing of the resin bed with a polar aprotic solvent and / or halogenated solvent yields filtrates containing pure products B-iii. Concentration of the filtrates gives pure B-iii.

«

9

9999 ··> 999

9 9 9

9 9 9

9 9 9

9 «

Scheme B-11 illustrates the conversion of an acid-containing skeleton C-49 to the desired amide products B-III in parallel synthesis. A limiting amount of C-49 scaffolds was added as a solution in dimethylformamide to each reaction vessel containing the polymer bound carbodiimide reagent B48 (5-fold stoichiometric excess). A solution of pyridine (4-fold stoichiometric excess) in dichloromethane was added to this suspension, followed by addition of an excess of dimethylformamide solution of the clear amine B47 (1.5-fold stoichiometric excess) to each vessel. The parallel reaction block is then stirred vertically in an orbital shaker for 16-18 hours at ambient temperature and filtered to separate the solution phase product mixture from the resin bound B48 reagents and the resin bound B49 reagent by-product. The resulting solutions (filtrates) containing a mixture of the desired amide products B-iii, excess amines B47 and any unreacted acid containing the C-49 skeleton are treated with tetrafluorophthalic anhydride B50. B50 converts the excess of amines B47 in each filtrate vessel to its separable semi-acidic forms B51. After a two hour incubation period, excess amine functionalized resin B33 and dichloromethane solvent are added to each reaction vessel. The amine-containing resin B33 converts B51, any remaining B50, and any remaining C-49 into their resin-bound adducts B52, B53 and B55. The resin-filled reaction block was shaken vertically for 16 hours in an orbital shaker at ambient temperature for optimal mixing of the resin mixture. Filtration of insoluble resin adducts B33, B52, B53 and B55 and subsequent washing of the resin bed in the vessel with • · • ·

349-dimethylformamide gives filtrates containing pure products B-iii. Concentration of the filtrates gives pure products B-iii.

Although Schemes B-1 through B-11 describe the use of ·· technology

The 350 parallel arrays of chemical libraries for the preparation of compounds of formulas Bi, B-ii and B-iii are well within the ability of one skilled in the art of chemical synthesis that classical synthetic organic chemistry is capable of preparing compounds Bi, B-ii and B-iii by conventional means. one compound at any time, prepared in conventional glassware and purified by conventional means such as chromatography and / or crystallization).

The general synthesis of the pyridylpyrazole skeletons C-i, C-ii and C-iii is shown in Scheme C-1.

Step A: Picoline is treated with a base selected, but not limited to, n-butyllithium (n-BuLi), lithium di-isopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide (tBuOK), or sodium hydride (NaH). in an organic solvent such as tetrahydrofuran (THF), diethyl ether, t-butyl methyl ether, t-BuOH or dioxane at temperatures from -78 ° C to 50 ° C for 10 minutes to 3 hours. The metal picoline solution is then added to the B56 ester solution. The reaction mixture is left under stirring for 30 minutes to 48 hours, during which time the temperature may be between -20 ° C and 120 ° C. The mixture was then poured into water and extracted with an organic solvent. After drying and solvent removal, pyridyl monoketone B57 is isolated as a crude solid which can be purified by crystallization and / or chromatography.

Step B: A solution of pyridyl monoketone B57 in ether, THF, tBuOH or dioxane is added to a base selected without limitation from n-BuLi, LDA, LiHMDS, tBuOK or NaH.

- 351-

contained in hexane, THF, diethyl ether, t-butyl methyl ether or t-BuOH at a temperature from -78 ° C to 50 ° C for a period ranging from 10 minutes to 3 hours. A suitably substituted activated ester or acid halide of R ⁴ -CO ₂ H is then added as a solution in THF, ether or dioxane to the mono-ketone anion B57 while maintaining the temperature between -50 ° C and 50 ° C. The resulting mixture is left under stirring at the indicated temperature for 5 minutes to three hours. The resulting pyridyl diketone intermediate B58 is used without purification in Step C.

Step C: The reaction of the solution containing pyridyldiketone B58 is quenched with water and the pH adjusted to between 4 and 8 using an inorganic or organic acid selected from the group consisting of HOAc, H ₂ SO ₄ , HCl or HNO ₃ . The temperature during this step is maintained between -20 ° C and ambient temperature. Hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between -20 ° C and 40 ° C for 30 minutes to three hours. The mixture was then poured into water and extracted with an organic solvent. Pyridylpyrazole C 1 or C-ii is obtained as a crude solid which is purified by chromatography or crystallization.

Step: In some cases with pyridylpyrazole C 1 or C 11 alkyl is QC (R ^A ) - (CH ₂ ) _n CO ₂ alkyl wherein Q represents a halogen atom. Ci or C-ii is treated with a base selected from NaH, NaOEt, KOtBu or NEt ₃ in an organic solvent such as THF, methylene chloride, dioxane or DMF at a temperature between -20 ° C and 150 ° C with a reaction time between 30 minutes and 12 hours. The resulting alkylated pyridylpyrazole ester is then hydrolyzed to the acid

- 352-

by treatment with NaOH or LiOH in an aqueous / alcoholic solvent mixture or in a THF / water mixture. Alternatively, the ester functionality is removed by treatment with an organic or inorganic acid when the alkyl residue is tert-butyl. Acidification, followed by extraction with an organic solvent gives C-iii, which can be purified by chromatography or crystallization. In some instances, regioisomeric alkylated C-iv products are also formed. The desired C-iii can be separated from C-iv by chromatographic purification or fractional crystallization.

·· ···· · ·

- 353-

The synthesis of the pyridylpyrazole skeleton C-1 is shown in Scheme C-2.

Step A:

Picolin is added to a solution of LiHMDS in THF at ambient temperature over a period of time ranging from 30 minutes to 1 hour.

The resulting solution was stirred for an additional 30 minutes to 1 hour at ambient temperature. This solution was then added to ethyl p-fluorobenzoate B60 alone at ambient temperature over 1-2 hours. The mixture was then stirred at ambient temperature for 16-24 hours. Thereafter, equal portions of water and ethyl acetate were added to the reaction mixture, and the mixture was partitioned 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 Step B.

Step B:

Pyridyl monoketone B61 is added as a solution in THF to a flask maintained at ambient temperature and containing C-BuOK in THF / t-BuOH co-solvent. A yellow precipitate is formed and stirring is continued at ambient temperature for 1-3 hours. After this time, N-cbz-protected glycine N-hydroxysuccinimide B62 was added dropwise at ambient temperature as a solution in THF over 1-3 hours. This solution, containing crude diketone B63, is used directly in Step C.

Step C:

The solution from step C is treated with water and the pH is adjusted to between 6 and 7 with acetic acid. Hydrazine hydrate as a solution in water is then added dropwise over a period of 30 minutes to 1 hour at ambient temperature. Water and ethyl acetate were then added to the flask and the mixture was then distributed in a separatory funnel. The organic layer was dried, filtered and evaporated to give a crude oil which was purified

- 355 ····

9 9 ·

9 9 9

9

9 9 9

99 silica gel chromatography to give pure C-1Cbz.

Step: D

The Cbz protecting group contained in C-1Cbz is cleaved using hydrogen gas under pressure and Pd-C in a methanol solvent. The resulting amine C-1 is obtained by filtration and concentration.

0

0

356-

A number of C-v pyridylpyrazole skeletons are prepared as shown in Scheme C-3.

Step A:

Picoline is treated with a base selected in a non-limiting manner from n-BuLi, LDA, LiHMDS, CBuOK or NaH in

- 357 • Φ φ φ φ φ φ φ φ · · · ·>>>>>>>>>>> φ φ

An organic solvent such as THF, ether, t-BuOH or dioxane at -78 ° C to 50 ° C for 10 minutes to 3 hours. The metal picoline solution is then added to the solution of the suitably activated CbzNR ^H - (CH 2) n CR ^F (R ^G ) -CO 2 ^H carboxylic acid ester analogue, or BocNR ^H - (CH 2) n CR ^F (R ^G ) -CO 2 H, preferably without the choice was limited to

N-hydroxysuccinimide B64. The reaction mixture is left under stirring for 30 minutes to 48 hours, during which time the temperature may be between -20 ° C and 120 ° C. The mixture was then poured into water and extracted with an organic solvent. After drying and solvent removal, pyridyl monoketone B65 is isolated as a crude solid which can be purified by crystallization and / or chromatography.

Step B:

A solution of pyridyl monoketone B65 in ether, THF, tBuOH or dioxane is added to a base selected without limitation from n-BuLi, LDA, LiHMDS, CBuOK or NaH contained in hexane, THF, ether, dioxane or CBUOH at -78 ° C to 50 ° C for 10 minutes to 3 hours. The anion sometimes precipitates as a yellow solid. A suitably substituted activated ester such as N-hydroxysuccinimide B66 is then added as a solution in THF, ether or dioxane to the monoketone anion while maintaining the temperature between -50 ° C and 50 ° C. The resulting mixture is left under stirring at the indicated temperature for a time ranging from 5 minutes to 3 hours. The resulting pyridyl diketone intermediate B67 is used without further purification in Step C.

Step C:

The reaction in a solution containing pyridyldiketone B67 is terminated

And 8 using a water selected from the group and the pH is adjusted to between an inorganic or organic acid containing HOAc, H ₂ SO ₄ , HCl or HNO ₃ . The temperature during this step is maintained between -20 ° C and ambient temperature. The hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between -20 ° C and 40 ° C for 30 minutes to three hours. The mixture was then poured into water and extracted with an organic solvent. Pyridylpyrazole C-vBoc or CvCbz is obtained as a crude solid which is purified by chromatography or crystallization.

Step: D

The C-vBoc or C-vCbz carbamate protecting groups are removed to give Cv skeletons containing either a free primary amine (R ^H is hydrogen) or a free secondary amine (R ^H is not equal to hydrogen). The Boc protecting carbamate group is cleaved using 1: 1 trifluoroacetic acid (TFA) / methylene chloride at ambient temperature for several hours. The CBZ carbamate protecting group is cleaved using hydrogen gas under pressure and Pd-C in an alcoholic solvent. The resulting amines Cv are then optionally crystallized or purified by chromatography.

• 99

- 35999 9

99

9 9 9

9 9 9

# 9 9999

99

9 9 9 • 100 4

9 9 9

99

The synthesis of C-vi scaffolds is carried out as shown in FIG

Diagram C-4.

Step A • ·

The 360Boc protected pyridylpyrazole B68 is treated with benzaldehyde in methylene chloride at ambient temperature in the presence of a desiccant for 1-24 hours. The solvent was then evaporated and the resulting imine B69 was used in step B without further purification.

Step B:

The pyridylpyrazole imine B69 is dissolved in THF and stirred under a nitrogen atmosphere at a temperature ranging from -78 to -20 ° C. A base such as LDA, n-BuLi or LiHMDS is added dropwise to the mixture, which is then stirred for an additional 10 minutes to 3 hours. Two fifths equivalents of an alkylating agent R ^F -Q are then added to the mixture and stirring was continued for several hours. The reaction is then quenched with acid and allowed to warm to ambient temperature and stirred for several hours until cleavage of Boc and imine functional groups is complete. The pH is adjusted to 12 and then the mixture is extracted with an organic solvent, which is dried and evaporated. The crude pyridylpyrazole is then crystallized and / or chromatographed to yield C-vi.

• · · ·

361-

The synthesis of maleimide-containing skeletons C-vii is performed as shown in Scheme C-5.

Maleimidpyrazole scaffolds C-vii are synthesized as shown in Scheme C-5. The condensation reaction of the primary amine H ₂ NR with maleic anhydride B70, which is substituted in the 3-position with either a bromine atom, a chlorine atom or a triflate group, produces compound B71. The formed maleimide derivative B71 is then reacted with the acetophenone derivative B72 in the presence of a Pd (O) catalyst and a base to give compound B73. The methylene position of B73 is then acylated with acid anhydride B74 or an activated ester of acid B75 to give the di-ketone derivative B76. Diketone B76 is condensed with hydrazine to give the desired compound.

362-maleimide pyrazole skeleton C-vii.

Scheme C-6 illustrates the synthesis of the maleimide pyrazole skeleton C-63 wherein R ⁴ represents a hydrogen atom. The synthesis begins with the condensation reaction of bromomalein anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride to form intermediate B78. Maleimide B78 is then treated with 4'-fluoroacetophenone in the presence of a catalytic amount of Pd ₂ (dba) ₃ and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. B79 is treated with tert-butoxybis (dimethylamino) methane to afford the α-ketoenamine B80. The α-ketoenamine B80 is condensed with hydrazine to form the maleimide pyrazole skeleton B81. The 2,4-dimethoxybenzyl protecting group is optionally removed with ceric ammonium nitrate (CAN) to provide compound C-63.

• · · · · · · · · · · ·

- 363-

Scheme C-7 illustrates the synthesis of maleimide-containing scaffolds C-64 and C-65. These scaffolds C-49 and C-50 are synthesized by the general methods described in Schemes C-5 and illustrated using the N-hydroxysuccinimides B82 and B83 to obtain maleimide-containing pyrazoles B86 and B87. Optional removal of 2,4-dimethoxybenzyl groups by CAN and subsequent removal of Boc-protecting groups with trifluoroacetic acid (TFA) gives scaffolds C-64 and C-65.

·························

- 364- ·. · ´. · ’·’

The various functionalized resins and separation reagents used for the preparation and purification of the parallel-prepared reaction mixtures are described in more detail below, with reference to a commercial source or reference to their preparation literature.

·· ····· ·· · · · ··

B32

Novabiochem 4-benzyloxybenzaldehyde functionalized polystyrene cat. No. 01-64-0182

Prepared by the method of D. L. Flynn et al.,

J. American Chemical Society (1997) 119: 4874-4881

838

O-A

N = C = O

Methylisocyanate functionalized polystyrene by Novabiochem Cat. No. 01-64-0169

Polymer bound EDC, prepared according to M.C. Desai et al., Tetrahedron Letters (1993) 34, 7685

B41

SO ₂ N = C = O

Benzenesulfonylisocyanate, purchased from Aldrich Chemical Company, Cat. No. 23,

229-7

B50

Tetrafluorophthalic anhydride, purchased from Aldrich Chemical Company, Cat. No. 23, 229-7

Experimental methods for the parallel synthesis of a number of amides, carbamates, ureas and sulfonamides B-0001 to B-0048 from skeleton

C-1.

• · · ·

Examples B-0001 to B-0048

200 ml dimethylformamide was added to each reaction vessel (polypropylene syringe tube fitted with a porous frit, sealed at the bottom) in a parallel reaction apparatus. A stock solution of the amine C-1 skeleton in dimethylformamide (0.1 M, 500 mL) was added to each reaction vessel followed by the addition of a stock solution of N-methylmorpholine in dimethylformamide (1.0 M, 200 mL). A stock solution of each electrophile was then added to the corresponding reaction vessels:

(a) 500 ml 0,2 M acid chloride solution in dichloroethane; or

(b) 500 ml of a 0,2 M solution of chloroformates in dichloroethane; or

(c) 313 ml of a 0,2 M solution of isocyanates in dichloroethane; or

d) 375 ml of a 0.2 M solution of sulfonyl chloride in dichloroethane. The parallel reaction apparatus was then orbital shaken (Labline Benchtop Orbital Shaker) at 200 rpm at ambient temperature (23-30 ° C) for 2-3 hours, under a gentle stream of nitrogen. At this point, each reaction vessel was treated with approximately 250 mg of polyamine resin B33 (4.0 meq N / g resin) and approximately 100 mg ° C of polyaldehyde resin B32 (2.9 mmol / g resin). The mixture in each reaction vessel was diluted with 1 mL of dimethylformamide and 1 mL of dichloroethane and the orbital shaking was continued at 200 rpm for 14-20 hours at ambient temperature. Each reaction vessel was then opened and the desired solution phase products were separated from these terminated by-products by filtration and collected in individual conical vessels. Each flask was rinsed twice with dichloroethane (1 mL) and the washings were also collected. The resulting solutions were then evaporated to dryness in a Savant (high vacuum ultracentrifuge, adjustable).

- 367 - · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Φ · Φ · φ · solvents for the condensation of volatile solvent vapors). The resulting amide, carbamate, urea and sulfonamide products were then weighed and characterized. Yields and analytical data of the products obtained in this way are given below.

• ⁴ * ⁴

36fi- ···· ··· ···· '-Z' w '** 0 »44 · · · · · ·

Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-OOO1 1 85 397 398 1 B-0002 94 412 413 B-0003 ^{f f} ~ <Q4 0 i 91 340 341 B-0004 r-m ihA> -d i o A 79 368 369 B-0005 Η »' 92 498 499 B-0006 0 92 416 417 B-0007 HDi Fa. 86 450 451

Example δ. R

B-0008

B-0009

B-0010 ^f- OH

B-0011

B-0012

B-0013

B-0014

B-0015

B-0016 • · · · φ φ φ φ φ φ φ φ φ φ

ΦΦ I ···

-369- * · · · * ⁴ φφ φ ·

o o.

Ř ^ i ^{CF CF CF CF CF CF CF CF CF CF CF CF}

<> φ ·

I Φ φ · Φ Φ

Observed Calculated Mass Mass Spectrum> Yield Spectrum (M + H)

448

449

368

338

402

442

446

352

380

440

498

369

339

403

443

447

353

381

441

499

B-0017 • · ·· * »

- 370

Example #

B-0018

B-0019

I ^f ~ GM

B-0020

B-0021

B-0022

B-0023

B-0024

B-0025

B-0026 · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Observed Calculated mass mass spectrum% yield spectrum (M + H)

_o_i íf— <:

NQ!

'O

439

440

474

475

440

386

417

441

387

418

IF-λ

-2 |

397

398

417

354

426

350

418

427

351

B-0027

φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

- 371 φ φ φ φ • • • φ φ φ φ φ φ φ φ φ φ

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example R ²

Β-0037 • φ «•» »» φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Example δ.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

- 373

Example No. R ² R ^J • · * ·

• · ··· · • · · ·· ·· • · · · 99 99 9 • · · • 9 9 · • · · · ·· ·· • · « • · · * · · «« ♦ ··· 9 9 9 99 99 % yield Calculated wt spectrum Observed wt spectrum (M + H)

By analogy to the methods described above for the preparation of Examples B0001-B0048, the following Examples B 0049 to B-1573 were prepared.

- 374 99 99 9 9 9

9 9 · 9 · 9 9 99 9 9

9 9 9 9 9

9999 98 4 «

• 0 ··· ♦

- 375

Example R ² ·

• 0 •

• 0 00 ·

• 000 «0 00

0 0 ·

0 0 0 0 • 0 0 0

00

Calculated Observed wt wt spectrum % yield spectrum (M + H)

- 376

Example No. R ² 99 9 9 9 9 9 9 99 99 9

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

0 4 4

- 377 • 4 ··

4 4 4 4

4 4 · 4 ·

4 4

4045 44 44

Observed Mass Spectrum (M + H)

Example #

Calculated mass% yield spectrum

- 378 ·· ··

99 9999

Example δ.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

- 379 • · · · ···· · · ··

Example No. R ²

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0096 F— is ď i 410 411 i 0 1

• · · ·

- 380 Example no.

Calculated Observed wt wt spectrum % yield spectrum (M + H)

- 381

A A A A *

A A A A A A

AA AAA AAAA AA AA

Example.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

• ·

382- · ··

Example.

B-0114

B-0115 Ref

X ^ NQ1

B-0116

B-0117! ^F '\ = / < _r

B-0118

B-0119

B-0120

B-0121

B-0122

B-0123 »4 · 4 · · · · · · · · · · · ·

Observed Calculated mass mass spectrum% yield spectrum (M + H) |

Λ fc! ^{F -} O 'Š

453

453

459

454

487

ó: 77

Λ

438

422

439

423

434

435

422

423

414

415 _f - <2h

501

502 r \

100 ALIGN!

450

451 • 9,999

Example #

B-0124

B-0125

B-0126

B-0127

B-0128

B-0129

B-0130

B-0131

B-0132

B-0133

- 383 -

íX /

F-

IF

IF-

rO ⁴

/ I

·· · * ·· ··· · · ···. · · I I I I I I I I I I I I I

I · · · · ·. *........

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

100 ALIGN!

100 ALIGN!

456

457

472

473

476

477

433

482

480

468

434

481

469

-TM

468

469

436

437

--OH h

426

427

Example #

- 384 ₃ ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · 9 ·· ··

Observed Calculated mass mass spectrum% yield spectrum (M + H)

MM • 4

- 385 -

44 • 4 4 4 4 9 ···

4 4 · 4 4 4 4 4 4 4

44 4444 ·· 44

He attaches. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-0144 í ^f— • '1 49 448 449

♦ · · »· · ·« «« «« «« «« »

'.Cl 7- * * ···· ·· «* · *

Job- * ··· ··. «« «· · · · · · ·

Example #

Observed Calculated Mass Mass Spectrum and Yield Spectrum (M + H)

- 387 • 9999

9

9 9 9

9 9 9

9 9 9

9999 999 9999

99 99 99 99 99

Example No. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

- 388 φ

Example No. R ² φφ φφφφ •

φ φ

φ Φ ® ® · · φ φ φ · • • · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

01-0171

- 389 φ φ · · φ φ ’φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Observed Calculated wt Example # 2 J wt spectrum R R % yield spectrum (M + H)

··

- 390 00 »

00

0 0

0 0 ·· ♦ 0

0

0 0 *

0 0 *

0 0 ·

0 0 ·

00

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-0182 50 447 448 B-0183 22nd 455 456 B-0184 63 465 466 8-0185 J-X. ·. Qr · ' 65 471 472 B-O186 vQI> ^H | 1 42 429 430 B-0187 Ρ-θ | > · / ¾ ¹ ....... / .. 62 481 482 B-0188 98 439 440 B-0189 i-o-s '3 \ 21 453 454 B-0190 s ^F_ OH 3 and 57 417 418 B-0191 ! Ί Ί 24 477 478 AND

* «98 9 9

Example. R ²

- 391 99 10 »

9 9

9

9999 99 »9 9 9 9 9 9« I 9 «·· 9999

99

9 9 9

9 9 «

9 9 9

9 99

Calculated Observed wt wt spectrum % yield spectrum (M + H)

B-0192 <<M 35 455 456

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 392 «β ·· · 4 · ·

Example No. R ²

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0219 •

Observed Disconnected Mass ₂ µ Mass Spectrum

Example. R R% yield spectrum (M + H)

B-0193 O γί O 42 378 379 B0194 Ό 0 65 365 366 B-0195 • O-i 93 587 588 B-0196 F-θ - ^ 0 • Μ ... NH Ο 82 365 366 B-0197 / -ν '* ¹ 0 ... i 109 587 588 B-0198 hrO ' O 86 373 374 B-0199 • OH '0 ^: 81 373 374

- 394 - • · • · • · • · • · • · • · · · • · • · • · · • · · · • · · • · • · 9 Examples. R ² J R % yield Calculated wt spectrum Observed wt spectrum (M + H)

- 395 · · 39 39 39 39 39 39 39 39 39 39

R

He attaches. R ²

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0222 o \ - j? ’ 1-ΚλΛ 0 96 486 487 B-0223 -O-s k ΐ i Γ- * 100 ALIGN! 465 466 B-0224 • Ό + - / Br \ XT: Y '° 75 486 509a B-0225 ^mp X2H \ * ° 100 ALIGN! 442 443 B-0226 O V> J ηπ 88 482 483 B-0227 ^{! F} “CH br-ft 73 482 483 B-0228 and : ° \ hI 37 452

• ·

- 397 • · · 9 ·

9 9 • 999 · 9 9 9

9999

Example. R ²

The observed calculated mass mass spectrum

R% yield spectrum (M + H)

- 397 -

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example. R ²

B-O229 ^ff - £ ZH 100 ALIGN! 476 477 B-0230 FrQS! or ^Cl 94 476 477 B-0231 H-O- ^f 0 100 ALIGN! 460 461 B-0232 i-HtJ 90 440 441 B-O233 KM Cl i 99 476 477 B-0234 KM Prb 0 100 ALIGN! 486 487.489 B-023S ^F O ~ 89 486 487.489 B-0236 r-m 100 ALIGN! 476 477 B-0237 ^f- GM HJM 100 ALIGN! 476 477 B-0238 ^F řQ 92 438

9

- 398 Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0239 i ^F ~ CH 0 ^S ci 100 ALIGN! 442 443 B-0240 Hí-íí O 100 ALIGN! 442 443 B-0241 ⁰ 100 ALIGN! 476 477 B-0242 100 ALIGN! 460 461 B-0243 H-p 87 456 457 B-0244 100 ALIGN! 436 437 B-O245 ^r OH ht-b 0 100 ALIGN! 422 423 B-0246 / -CH 100 ALIGN! 452 453 B-0247 ! ^f- O — š AND Ο = ω = ο β gp 100 ALIGN! 476 477 B-0248 i-OH ⁰ f 0 73 468

• · ··· · ·· · · • · · · · ♦ «· 9 9 9 - 399 - 9 9 9 · 999 9 9 99 9 Example # R ^Z J R Observed Calculated Mass Mass Spectrum % yield spectrum (M + H)

Φ · · Φ φ

9 9 9 9 9 9

9 9 ΦΦΦΦ

Φ Φ 9 9 9 9 9

Φ · Φ ΦΦΦ *

ΦΦΦ ΦΦΦ * ΦΦ ΦΦ

Example δ.

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-0259 S-pM 100 ALIGN! 554 555 B-0260 d ^^ CL ^X 91 500 501 B-0261 HQ? ⁰ o 100 ALIGN! 486 487 B-0262 genus 0 100 ALIGN! 481 482 B-0263 i < H ⁵ fO 100 ALIGN! 554 555 B-0264 0 ! $ H s' 5-S—! 0 75 375 376 B-0265 r <B j> —N m45 ^! O 71 459 460 B-0266 100 ALIGN! 412 413 K = H t ¹¹ of%

- 401 -

• A A A A A

A A A A A A

A · · A «· ·

A A A A AA A A AAAA

AA AA · AA AA

Observed

Calculated mass ₂ µ mass spectrum Example No. RR% yield spectrum (M + H) B-0267 0 100 ALIGN! 386 387 ^{! f-} Oh B-0268 Ό 0 89 406 407 IF— B-0269 θ ' 0 84 386 387 •• -Os B-0270 92 440 441 O B-0271 98 428 429 • Os B-0272 57 498 499 O-s B-0273 i ø ^{1 1} kN o! 100 ALIGN! 440 441 • Os

φ φ »» ·

- 402 · · · ♦ · · φφ φφ φφφφφφφφφφφφφ φ φ φφ

ΦΦΦΦ φφφ ΦΦΦΦ φφ φφ φφ φφφφ φφ φφ

Example 6. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0274 ^f CM sk? '’ 94 397 398 B-0275 ¹ Q 1 o 90 422 423 B-0276 ^f -GH ke ?. 100 ALIGN! 408 409 B-0277 o ^ Q ^F and F 88 408 409 B-0278 F 100 ALIGN! 426 427 B-0279 Bye! ! 0 54 440 441 B-02B0 KH Mk 79 414 415 B-0281 CF ₃ i hk 82 458 459 B-0282 KM / k ^! o 1 89 426 427 B-0283 L / 0 ^-04 nr ¹⁰ 0 90 458 459

9 9 * 99

Example.

B-0284

B-0285

B-0286

B-0287

B-0288

B-0289

B-0290

B-0291

B-0292

B-0293

- 403 -

O F

f-T \

Ol! ^f ~ QH

cf ₃ |

Cl

Cl!

i O * · · · · · · · O O O O O O O O O O O O O O O O O O O O «·» »* * * * *

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

458

459

100 ALIGN!

100 ALIGN!

100 ALIGN!

458

459

458

459

458

459

458

459

406

407

386

387

440

390

408

441

391

409 • 9 ··· ·

Example no.

B-0294

404 ci

Cl

B * 0295

B-0296

B-0297 ri

B-0298 r \ | F-

F

B-0299

’O

B-0300

I o

B-0301

Br

B-0302 r \

CF ₃

B-0303

«» · 9 · 99 «· 9 9 ··· 9 9 9 9 9 9 9 99 9 9999 9 9 9999« 9999 999 999 999 # 999

9 * 9 9 99 9

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

440

441

100 ALIGN!

408

409

426

427

390

408

408

406

450

440

378

391

409

409

407

451,453

441

379

- 405 ♦ · »» »

4 «* ·

4 4 · 4 4

4 4 9

4 4

4444

44

4 4 4 • «« 3

4 4 4

4 4 4

44

Observed Calculated wt Example # '2 J wt spectrum R R % yield spectrum (M + H)

B-0304

- 406> 9

99 99 99

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

99 99 99 99

Example No. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-0305 ΛΛ— icr O 70 326 327 B-0306 ir, I Vv \ w br ^J 0 59 340 341 B-0307 iQ-l SA 0 1 59 354 355 B-0308 m t / j ÍCl i Μί 0 1 60 368 369 B-0309 O ^- cr S_i 61 352 353 B-0310 PI Cl ^{7 k} r ^ 0 61 366 367 B-0311 , o! In: 65 356 357

··· ♦

- 407 • *

Example. R ² «· · ^{2 2 2 2 2 2 2 2}

Calculated Observed wt wt spectrum % yield spectrum (M + H)

* · · · · · * * * * * *

• ΦΦΦ

- 408 Φ φ φ · φ φ φ φ φ

φ φ

φ φ φφ

φ φ φ φ φ φ φφ

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example. R ²

B-0322 P = I —— 64 474 475 B-0323 ΛΑΛΑ ςύ p ____........ 58 474 475 B-0324 p-i O 0 Ct 60 422 423 B-0325 Q-1 Cr 64 422 423 0.0326 UV -and_ 58 422 423 8 * 0327 Cl > -v>: 63 378 379 B-0328 o ~ WHOSE 68 389 390 B-0329 p-l 0 > II i * II o; 63 362 363 8 * 0330 cr ^J II o 48 376 377 B-0331 , o. , ‘L V /, 66 424 425

4 4 4 0 4 • 5

- 409 44 44 4 4444 4444 4444 4444 444 4444 444 4444 44 44 4444 44 44

Example no.

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

·· 9999

- 410 • 9 99 99 99 * · · · · ·

9 9 9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-0351

- 411 · ft t ft t t ft t t t t t 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 · · · »« «« «« «« «« «

Example 6. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-0352

397

398 ·· ····

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example #

B-0353 -Oi 71 382 383 B-0354 s - - ·; 35 512 513 B-0355 0 37 352 353 B-0356 ! ^f “CM r 57 404 405 B-0357 H ~ 88 366 367 B-035B Ml? 0 88 410 411 B-0359 100 ALIGN! 324 325

- 413 Example no.

B-0360

O-i

Observed Calculated mass mass spectrum% yield spectrum (M + H)

364

365

B-0361

350

351

B-0362

100 ALIGN!

464

465

B-0363

512

513

B-0364

377

378

B-0365

396

397

B-0366

IF-

100 ALIGN!

354

355

B-0367

/

V / i

416

417

B-0368

454

455

B-0369

440

441 »·········· 4 · · · · · · · · ·

44 4 4 · · ·

- 414 Example no.

Observed Calculated Mass Mass Spectrum> Yield Spectrum (M + H)

- 415 · · · 41 41 41 41 41 41 41

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0380 85 416 417 B-0381 I-° γτΛ 93 430 431 B-0382 M ·, 84 382 383 B-0383 ! ^fh CH '^ l 74 583 584 B-0384 63 438 439 ^{f f} -CM

- 416 ···· · · · · · · · · · · · ·

Example δ. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0385 ! ^f CH HrO ’: 83 440 441 B-0386 ^{, fh} Ch ί rO O 99 422 423 B-0387 47 388 389 B-0388 -o-l 100 ALIGN! 448 449 B-03B9 > 1 i 71 436 437 B-0390 -CH HKr 100 ALIGN! 458 459 B-0391 45 414 415 l | II · * ss ^CF 'on

- 417 Example no.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

• ·

- 417 • ·

Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

- 419 • · ··· ·

Observed Calculated wt 2 J wt spectrum Example no. R R % yield spectrum (M + H)

B-0412 K-CH ' ihr · '· • 0 91 365 366 B-0413 hrd 0? 79 367 368 B-O414 dd 0 85 429 430 B-0415 ^{f f} ^ GM k'O 82 401 402 B-0416 /and 93 429 430 B-0417 hr ^ d •. 'O ¹ 97 429 430 B-0418 ’S í 100 ALIGN! 419 420 B-O419 f-OH , Α ³ 100 ALIGN! 431 432 B-0420 V a 1 36 381 382 B-0421 v ^r 96 353 354

- 420 • 9999 999

9

9 9 · ·

9 9 9 9 9 9 9

99 99

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example #

B-0422 KM \ 100 ALIGN! 461 462 B-0423 iKM ‘Ru 100 ALIGN! 406 407 B-0424 0 76 366 367 B-0425 , ^f <M 21 368 369 B-0426 (KM t c- hr ¹ 0 100 ALIGN! 354 355 B-0427 iKM • o 100 ALIGN! 379 380 B-0428 iKM ·; · /> 1_a- 100 ALIGN! 379 380 B-0429 KM hrH 86 368 369

AA ·· «·

A A

- 421 • A AAAA

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0430 \ -N 0 O 51 500 501 f ^f O í í Q ---------- B-0431 íf— Λ 4 ° X- 76 479 480 B-0432 ^íf- Oh know- γ · ° 90 500 501 B-0433 ^f Oh °, xr ^c ' 96 456 457 B-0434 : ^ρ ΟΗ V \ ί ⁰ / \ »4 * / v 75 496 497 B-0435 OH t-H 52 496 497 B-0436 OH k / á. 73 506

• ·

- 422 φ · · · · · ♦ 42 42 42 42 42 42 42 42 42 42 42 φ φ φ · φφ

Example no.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0437

466

B-0438

100 ALIGN!

490

491

B-0439 |

464

465

B-0440

472

473

B-0441

R

472

473

B-0442

-MM?

«>,

481

482

B-0443

473

474

B-0444

-MM

51S

516

B-0445

490

491

B-0446

464

464 ·· ···· · «

- 423 Example no.

B-0447

B-0448

CI_I

B-0449

B-0450

B-0451

B-0452

ct

B-0453

B-0454

B-0455

B-0456

Ll

9 9 9 9 9 · 9 9 * * * * * * * * * * * * * * * * * * * * * * · ·· · »

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

100 ALIGN!

100 ALIGN!

100 ALIGN!

100 ALIGN!

100 ALIGN!

470

490

474

447

454

496

490

500

500

494

471

491

475

448

455

497

491

501

501

495

- 424 • v ΦΦ ΦΦ t t t t t t t t t t t 424 424 424 424 424 424 424 424 424 424 424 424 424 424 φ · φ

Example δ. R ²

J Vypofitené wt Observed wt spectrum R % yield spectrum (M + H)

B-O457 r <M 93 482 483 B-0458 100 ALIGN! 490 491 B-0459 0 100 ALIGN! 490 491

- 425 ·· · <

. _w <· · ·> φ · · · · ·; · · ♦ · · · φφφφφφ •ΦΦφφφφφφφΦΦΦΦφφφφ · · · ·φ • · · ·

φ •

φ

Example. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-0460 93 450 451 B-0461 ^f ~ OA 84 452 453 B-0462 ^F <n H-Q cr 96 456 457 B-0463 ^F - ^ 1 H-b 66 456 457 B-0464 ^F ~ O ~ ^ Hhť 69 490 491 B-0465 +> p i rO ~ “ Whose 86 490 491 B-0466 ^F O 'i ο i 78 474 475

- 426

Example δ.

B-0467

B-0468

B-0469

B-0470

Oi /

B-0471

B-0472

XI

B-O473

B-0474 zs

ll \

B-0475 E-1

B-0476

M

· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

470

471

450

436

466

490

482

462

530

472

441

451

437

467

491

483

463

532

473

442

- 427 9 · 9 9 · · 9 9 9 9 9

9 ·· · 9 ··· ····················

Example R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-O477 -O-i CQ ___ 79 464 465 B-0478 -KP 92 486 487 B-0479 .1, -0_ ¹ 97 447 448 B-0480 ^f CH i-rCL ^ O 75 561 562 B-0481 and 74 498 499 B-0482 «/ · 57 548 549 B-0483 ^f ~ OH -Q- - 1 83 505 506 B-0484 04 / HKX / <5 ί 100 ALIGN! 568 569 B-0485 o 1 100 ALIGN! 495 496 B-O486 OH d O - <) - o 100 ALIGN! 426 427

- 428 Example. R ² j

R

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

B-0487 1 í Λ 32 389 390 B-0488 100 ALIGN! 568 569 B-O489 _F £ y ^ ’7 '· 91 500 501 B-0490 ^F Oi H-0 40 473 474 B-0491 c _ / ** <>: H-Q 1 73 514 515

• · • ·

- 4 9 Q - · ·· · · tt · · ·· • · · · · ···· · · · · Example δ. R ² Calculated j wt R% yield spectrum Observed wt spectrum (M + H)

- 430 • ·

Example. R ² R ^J

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

• · · · · · · · · · ·

- 431 -

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0508

- 432 9 9 9 9 9 9 ·

9 9 9 9 9 9 9 9 9 9

9 9 ··· ····· »

999 · 9 · 9 999 · • 9 99 99

Attaches R ²

Observed Calculated mass mass spectrum% yield spectrum (M + H)

433 ·· · φ φ φ · · φ φ φ · φ · · · · · · · φ φ φ φ φ φ φ φ »» »» »» »

Example no.

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0519

100 ALIGN!

454

455

B-0520 iF-

i O

422

423

B-0521

440

441

B-0522

404

405

B-0523

F

100 ALIGN!

422

423

B-0524

IF-

100 ALIGN!

422

423

B-0525 ίρ-ΖΛ

,whose

100 ALIGN!

420

421

B-0526

Bi

!] '.

o_i

100 ALIGN!

464

465

B-0527 f- / A

100 ALIGN!

454

455

B-0528

I o

100 ALIGN!

392

393

- 434 • φ φ r · ř »1» φ φ <

Observed Calculated wt Example 6. 2 J wt spectrum R R % yield spectrum (M + H)

B-0529 f 'From' Λ I O I 94 405 406

·· ·· <··

Example No. R ² R ^J % yield

Calculated mass spectrum

Observed Mass Spectrum (M + H)

- 436 9 · · * * * * * * 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 43 * * * * * * • · · »» »

Example #

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0537

100 ALIGN!

364

365

B-0538

350

351

B-0539

464

465

B-0540

512

513

B-0541

377

378

B-0542 ROJ

396

397

B-O543

354

355

B-0544

416

417

B-0545

From

I o rve ·

100 ALIGN!

454

455

B-0546

440

441

- 437 • Φ ·· φφ φφ

4 φ · φ φ 4

Φ Φ Φ 4

ΦΦ Φ Φ Φ φ φ φ φ φ ΦΦ ΦΦ «

Φ Φ Φ Φ Φ Φ 4

ΦΦΦΦΦ ΦΦΦΦΦ 4 ΦΦΦ φ Φ Φ 4

ΦΦ ΦΦΦΦ ΦΦ ΦΦ

Example δ.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

- 438 9999

99 99

9 «999 999

9 9 · 9 9999

9 999 999 · 9 9 9 9 9 9

9999 999 9 · 99

99 99 99 99 99

Observed Calculated Mass ₂ µ Mass Spectrum

Example No. R R% yield spectrum (M + H)

B-0557 70 416 417 B-0558 -Oi 57 430 431 B-0559 74 382 383 B-0560 , ί -'- Ο-! O í 36 583 584 B-0561 51 438 439

- 439 9 9 9 9 9 10 11 12 13 14 15 16 17 · · · · · «· · · · · · ·

Observed Calculated mass mass spectrum% yield spectrum (M + H)

Example #

B-0562 ^ip —I rO ^f 0 ' 88 440 441 B-0563 HrO 68 422 423 B-0564 • Os U_ / ¹ y \ 47 388 389 B-0565 ^f- Qh AvG 0 100 ALIGN! 448 449 B-0566 & II • i '\ 76 436 437 B-0567 Ό O 99 458 459 B-O568 Ό ; o ι> II s! F || O ¹ 0 45 414 415

φ »ΦΦ • Φ Φ Φ

Φ Φ Φ

ΦΦΦΦ

ΦΦΦ • Φ ΦΦΦΦ

- 440 ΦΦΦ φ · φ φ

9 9 9

ΦΦ ΦΦ

ΦΦ ΦΦ • Φ · Φ

Φ Φ Φ Φ

Φ Φ · *

Φ Φ Φ Φ

ΦΦ ΦΦ

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

0000

Example.

0000

00 ·· ·· «0 0

0 0 ·· ······· 0 0 00 00 · 0

- 441 - «» * * · ·· ·········

Observed Calculated mass mass spectrum% yield spectrum (M + H)

• ·

- 442 - • · · · · · · · · · • · · • · · · ·· ·· • · • · • · • · • · • · · · · · • · · · · · · · · · · · · • · · · · • · · · · ··· Observed Calculated wt J wt spectrum Example no. R R % yield spectrum (M + H)

• · · · · · · · · ···

- 443 Observed Calculated mass ₂ µ mass spectrum

Example No. R R% yield spectrum (M + H)

- 444 - • »···· · · • · · · · • · · · · · · · • · · · • · * · • · · · • · · · · · Observed Calculated wt J wt spectrum Example # R R % yield spectrum (M + H)

B-0607 hM 34 500 501 B-0608 IF— 100 ALIGN! 479 480 B-0609 sxr \ A i 82 500 501 B-0610 ^íf- Oh O 100 ALIGN! 456 457 B-0611 ¹ Vv 1 F 1 Mi 76 496 497 B-0612 -CH Μη 69 496 497 B-0613 \ _____ 61 506

• · · · · · · · · · · · · · · ·

Example no.

B-0614

B-0615

B-0616

B-0617

B-0618

B-0619

B-0620

B-0621

B-0622

B-0623

445 ···· ·· · ·

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

Stick·

-Qi

100 ALIGN!

466

490

491

464

465

472

473

/and

Λ /

472

473

481

473

515

490

464

482

474

516

491

465

446 Example 6.

B-0624

·· · · · · · · · · · · · ·

Observed Calculated mass mass spectrum% yield spectrum (M + H)

470

471

B-0625

490

491

B-0626

100 ALIGN!

474

475

B-0627! ^F 2 OH OH

100 ALIGN!

447

448

B-0628 ^f -CN

454

455

B-0629

100 ALIGN!

496

497

B-0630 |

490

491

B-0631

IF-O

500

501

Bi

B-0632;

500

501

B-0633

IF — A u

494

494 ·· • ·

• · • · - 448 - · • · · * · » ® ♦ · φ • 9 9 99 99 9 9 · • Φ • · · • · • · · · Observed Calculated wt 0 J wt spectrum Example # R R% yield spectrum (M + H)

B-0634 γΌη ! 63 462 483 B-0635 KM 95 490 491 B-0636 • MM 100 ALIGN! 490 491

9 »999 • 9

9

- 448 ₄

9 9 9 9 9

99 99 9999

Observed Calculated wt Example 6. 2 J wt spectrum R R % yield spectrum (M + H)

B-0637 0 ._ _t "s-LIV 'TV / I 91 450 451 B-0638 O-i 98 436 437 B-0639 • O-S HHO ^{1 0} \ Cl Cl ' 100 ALIGN! 456 457 B-0640 hOH Td 100 ALIGN! 456 457 B-0641 t-hd -sd 88 490 491 B-0642 Ci: 99 490 491 B-0643 kL / ^ VJ ^F rV - (“í (.............. Cl 92 474 475

• · · · · · · · · · · ·

- 449 • · ····································· 4 9 9 9 9 9 4 4 4 4 9 9 4 4 4 9 9 4 . 4 9 4 9

9 4 99 9 4 4 4 94 9 9

Example no.

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

- 450 99 ···· 99 99 99 99

9 9 9 9 9 99

9 9 «· 9 9 9 9

9999 9 * 9 9 999 999

99 99 99 99 99

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

- 451 • Φ φ · · · · β φ φ φ φ φ φ φ φ

Observed Calculated wt 2 J wt spectrum Example 6. R R % yield spectrum (M + H)

B-0664 $ ii /! ¹ y \ | 30 389 390 B-0665 in 100 ALIGN! 568 569 B-0666 - ^ - 1 ' / * ”» 0! 93 500 501 B-0667 1-1-8 54 473 474 B-0668 66 514 515

- 452 -

β »»

9 9 4

9 9 4

9 β

Example No. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0669 V ³ 0 65 400 401 B-0670 j _F _ -IN O 45 420 421 B-0671 ^f 3JH IN I o 43 400 401 B-0672 0 45 454 455 B-0673 ! ^F Od 41 442 443 B-0674 16 512 513 B-0675 r-CM IN- · 0 39 454 455

• 9

- 453

9 ·

9

9

9

9

9

He attaches. R ²

Calculated Observed wt wt spectrum % yield spectrum (M + H)

* · · «

• ·

- 454 # «·· • * • ♦

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

A A AAAA

A A

AA AA ··

A A A A A A

A A A A A

- 455 AAAA AAA AAAA

AA AA AA AAAA AA ··

Observed Calculated wt 2 J wt spectrum Example. R R % yield spectrum (M + H)

B-0696 S-P? O 57 454 455 B-0697 O 0 F 51 422 423 B-0698 O F! 59 440 441 B-0699 O Mo i O 46 404 405 B-0700 ^! Oi l 2_L 47 422 423 B-0701 ^fh GH I o 46 422 423 B-0702 r- £ M I x ^CI10 43 420 421 B-0703 ^f - £ H ---- br ...... i U ³ 57 464 465 B-0704 O 44 454 455 B-0705 ^f- O4 hr ^ 0 33 392 393

- 456

Example. R ² • 9 9999 • 9

9 9 • 9

9 9

99

9 «99

9 9 9

9 9

9 9

9 9

9999

9 9 9

9 9 9

9 · 9 9

9 9 9

99

Calculated Observed wt wt spectrum % yield spectrum (M + H)

· * 0 0 «0

Example No. R ² R ^J

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0707 o ___ brv / ‘0 76 516 517 B-0708 o. · rrw O 61 498 499 B-0709 ^{! f} CM H ^- <o 37 464 465 B-0710 ^ÍV Q 76 524 525 B-0711 r-CM > Γ i LIMB! 75 512 513 B-0712 r-CH K-h-i 91 534 535 B-0713 r-CH 9 42 490 491

- 458 · 9 · 99 · 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

• 4

4004

- 458 0 4 »0

44 44

4 4

4 4 4 4 4 •

4 0 4 0 4 4 4004 44 44

Example. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

- 460

Example No. R ² ·· φφφφ

Φ Φ ·

ΦΦΦ φ φ · · · φ φ φφ ··

Φ · φ · φ · · · Φ · · · · · · · · · · · · · · · · · · ·

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example. R ²

- 461

Calculated Observed wt wt spectrum % yield spectrum (M + H)

-4 62 ·· ··

Example No. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-0752 1. ^ 1 /Her 84 516 517 B-0753 HIM i ..... p ............ 67 498 499 B-0754 --ΌΗ 1 0 t y \ 31 464 465 B-0755 ίΌΗ r 85 524 525 B-0756 ! ^fh CH > II From, 77 512 513 B-0757 rW ) 4bH 57 534 535 B-O758 Hf [- ^CF '! oi 36 490 491

• ·

- 463 ·· ·· · · · · · ···

Observed Calculated mass, mass spectrum

Example. R R% yield spectrum (M + H)

• ·

- 465 • ·

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

9

Example #

465 • 4 4 4

4 4

4 9 9 4 4 0 0

Observed Calculated Mass Mass Spectrum and Yield Spectrum (M + H)

9 ·

0 · · · ·

4 • • «

466 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example #

Observed Calculated Mass Mass Spectrum and Yield Spectrum (M + H)

9

- 467 -

Observed Calculated wt 2 J wt spectrum Example # R R % yield spectrum (M + H)

B-0797 O-i 90 458 459 B-0798 qo _2_ 90 588 589 B-0799 ^f Oh 0 82 428 429 B-0800 ^F -O- ^ A 1 92 4B0 481 B-0801 H 82 442 443 B-0802 ^f ^ Oh ‘~ Ť 95 486 487 B-0803 ^f- Oh 89 400 401

468 • A A AA A

AA ·· A A A

A A ·

A · ·

A A A AAA

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-0804 0 87 440 441 B-0805 100 ALIGN! 426 427 B-0806 _{! γ} α. O 99 540 541 B-0807 KM 0 96 588 589 B-0808 0 82 453 454 B-0809 -CH O?! -...... f-. ' 92 472 473 B-0810 C · ****** O 98 430 431 B-0811 88 492 493 B-0812 81 530 531 B-0813 í ^f CM Ýř ‘ 98 516 517

9 ···

He does. R ²

- 468 9 · •

• 99

99 • 9 9 ·

9 9 ·

9 9 9 9

9 9 9

Calculated Observed wt wt spectrum % yield spectrum (M + H)

- 470 · β · 470 470 470 470 470 470 470 470

9999

9 9 ·

9 9 · · · · · ·

9 9 9

99

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example. R ²

B-0824 . 82 492 493 B-0825 ί «Μ ' 100 ALIGN! 506 507 B-0826 'CM W i 97 458 459 B-O827 _f - / 2h 100 ALIGN! 659 660 B-0828 ‘Ά5 97 514 515

- 471 · • · 47 47 47 47 47 47

9 9 9

9 99

Observed Calculated wt Example no. '2 J wt spectrum R R % yield spectrum (M + H)

B-0829 •in C 63 458 459 B-830 70 588 5B9 B-0831 to- 0 100 ALIGN! 428 429 B-0832 81 480 481 B-0833 ^f Oh 0- M 0 73 442 443 B-0834 -OH 0 79 486 487 B-0835 TO ⁵ 400 401

• ·

- 473 · «♦ ···

9

99 ·· • 9 9 9 · ·

9 · · * ·· 9999

9 9 9

9 9 9

9 9 9

9 9 9

99

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

- 473 · «» ··· 4

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

·

- 474 • 9 9 9 9 9 9

9 «

9 9 * • 9 «• · · · ·

9 «··

9 9 ♦

9 9 9 · · · · · ·

9 * Κ

Example R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-0856 yvl / 0 75 492 493 B-0857 ! ^F -0-3 .Λ hX i 86 506 507 B-0858 84 458 459 B-0859 Yy i Q J 80 659 660 B-0860 94 514 515 ^ ¾ ¹

·· ····

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example #

B-0861 vO 0 84 583 584 B-0862 f + or .....O............ 96 475 476 B-0863 kr ' ---E-: 69 423 424 B-0864 H 86 437 438 B-0865 O; 62 395 - B-0866 0 81 421 422 ízO ^- ] B-0867 h / X in { 100 ALIGN! 535 536 ~ O-s

• · · · · · · · ·

• · · - 477 - · .. * • · • · · • · • · • « • · · • · • · · · · · Example # R ² j R% yield Calculated wt spectrum Observed wt spectrum (M + H)

B-0868 Uf, 89 583 584 B-0869 100 ALIGN! 448 449 B-0870 o · Fr ³ ; 0 100 ALIGN! 425 426 B-0871 -From 100 ALIGN! 487 488 B-0872 vQJ 78 501 502 B-0873 ^f -0H fy \ 78 471 472 B-O874 ^f - ^ vQ 0 F I 92 475 476 B-0875 Oí Ζτθ 0 J 37 458 459 B-0876 fy * II 0 69 507 508 B-0877 ^f X2H 0 > H I p \ 70 445 L 446 I

- 477 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · ·

Observed Calculated Mass ₂ µ Mass Spectrum

Example. R R% yield spectrum (M + H)

B-0878 O l ť ' * II i O 91 431 432 B-0879 ! -hb: 0 at -—— / 92 511 512 B-0880 ^if CH 'o I ! <H 89 410 411 B-0881 ^f qhs hr; 84 490 491 B-OB82 ^if ~ CM him 85 500 501 B-0883 *%! 85 424 425 B-0884 ^if CH k5 ^ ^z 0 _χ | 86 532 533

• · · · · · ·

- 478 - · .. ·· .. ·

N — NH H .N,

nhch ₃

Example #

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

- 479

4 · 4 · ¹ · ¹

4 4 4 <

• 445 ·· · ·

Observed Calculated Mass ₂ µ Mass Spectrum

Example No. R R% yield spectrum (M + H)

φ φ e · · · φφφ ·

- 480 Example. R ² j

R

Observed Mass Mass Spectrum Yield Spectrum (M + H)

B-0902 ^f ~ CM ó ¹ > II 5 II 0 93 431 432 B-0903 i - ------ ~~ —l 100 ALIGN! 511 512 B-0904 0? ^H 95 410 411 B-0905 '-Oi ςχ. hr- - <------------ - · 89 490 491 B-0906 ^f O4 hjó 69 500 501 B-0907 , < 28 424 425 B-0908 64 532 533 kP 1 \

Example. R ² R ^J % yield

Calculated mass spectrum

Observed Mass Spectrum (M + H)

B-0909 Ol O 83 542 543 B-0910 Ol ίνθ 0 80 434 435 B-0911 O 91 382 383 B-0912 O 100 ALIGN! 396 397 B-0913 Ol H ' 94 354 355 B-0914 Ol O o I 95 380 381 B-0915 io hXK. 0 98 494 495

- 482 »2 48 48 48 48 48 48 48 48

Observed

Example. R ² R ^J % yield Calculated wt spectrum wt spectrum (M + H) B-0916 <3 / 7 I 0 84 542 543 B-G917 79 407 408 B-0918 0 · 0 89 384 385 B-0919 -33 33 91 446 447 B-0920 99 460 461 ^F CW B-G921 ^{ζ ΎθΊ} 0 84 n 430 431 ^f ^ 4 B-0922 3γ! 81 434 435 B-0923 76 417 418 B-0924 0 i 70 466 467 ' ^f O' ^ B-0925 ⁰ ί ϊ ^{11 1} f ^ l 64 404 405

π «· * ·» · 9 9 9

9 9 9

99 ·· • 9

- 483 <

• ·

Example. R

Observed Compound Mass Mass Spectrum i> Yield Spectrum (M + H)

• 0

- 484 ·· ·· «·

· 4

4444

4 ♦ 0 4 ·

4 4 * ·· 4

4 4 0

44

η

Ν

Example i. R ² j

R

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-0933 or Qj 48 447 448 ^f -Ch B-0934 íf ~ 44 429 430 B-0935 ^f OH ^! TO 1 .......... 33 485 486 B-0936 -OH 30 479 - B-0937 0: TO/ 68 367 368 B-0938 ^! KM 72 479 480 B-0939 KM 76 415 416

- 486

9 • »· ·

99

99 9 9 99 »

9,999 99 9

9 9> 999

9999 8 »9 ·

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-0950 64 419 420 B-O951 100 ALIGN! 469 470 ^: ~ Ok kV H ' B-0952 Η ”- / v j 61 469 470 B-0953 -in l <i 67 425 426 B-0954 ? ^f -O3 62 431 432 B-0955 39 461 462 B-0956 in vQ 66 429 430 B-0957 If-Q— 93 429 430 B-0958 _{. Θ} | 86 365 366 B-0959 r-m 73 451 452

IN?

9 »

- 487

Example no.

B-0960

·· ·· ·· ► · φ · φ * φ · · · · · ϊί. i. . »« ···

- .. ....... * ··

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

485

486

B-0961

100 ALIGN!

469

470

B-0962 / v.

100 ALIGN!

419

420

B-0963 ^IF CH

401

402

B-0964

429

430

B-0965

AA90

411

412

B-0966 iF-

Ύ

443

444

B-0967

μΧ,

100 ALIGN!

443

444

B-0968 ^: -CM

100 ALIGN!

477

478

B-0969

477

478

Example no.

B-0970

B-0971

- 488 yr '

HN - '<(lL ·

B-0972

B-0973

OH

B-0974

B-0975

OH

B-0976 o-i

B-0977

B-0978 rCM

Φι

B-0979

/ I · ** ** 9 9 9 9 ♦ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 »» ·. · ·. ·. «.» »» »» »»

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

100 ALIGN!

461

462

469

479

465

443

495

453

467

431

491

470

480

486

444

496

454

468

432

492

- 489

Example. R ²

09-0980

• 9 9 ···

Φ Φ Φ *

Φ Φ Φ ·

Φ Φ * • Φ Φ ·

Φ Φ Φ ·

Φ Φ ·

ΦΦ ΦΦ ·

ΦΦ ΦΦΦΦ

ΦΦ ΦΦ

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

C: Χ.

469

470

Φ ·

Φ Φ

Φ ·

ΦΦ • ♦ ·· ···· • Φ · ♦

- 490 · »490 490 490 - 490

Example No. R ² R% yield

Calculated mass spectrum

Observed Mass Spectrum (M + H)

• 0

- 491

0000 • 0 00 • 0 0 W

0 0 *

0 0 ·

0 0 ·

00

Observed mass Výpočlené j ₂ wt spectrum

Example. R R% yield spectrum (M + H)

A A

- 492

AA AAAA

A A

A A • ·

A A • *.

• · *

A · ·

AA AAAA

Example. R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

- 493 ·· ··· · 9 · · · · ·

9 ·

9999

99

9 9 · · 9 ·

9 9 9

99

Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

Example no.

B-1013

· · · «... *; ί!

- 494 -

A A A β 0 0 0.

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

440

441

B-1014

ÍF-

fc

422

423

B-1015

F— fc

388

389

B-1016

F-f

448

449

B-1017

436

437

B-1018

458

459

B-1019

O

II

T ^Cf · o_

414

415

- 495 ·· φφφφ · · · φ φ> φ φφ φ

φ • · φ

• φ φ

φ φ

φ · φ • φ φ φ φ φ · · · φ φ φ φ «« «φ •

φ φ

φφ

He does. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

• · · · · · · · · ·

496 Example. R ²

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

• · · · · ·

- 497 - • · · • · · · • · · · · · · · · · · Observed Calculated wt Example # 2 J wt spectrum R R% yield spectrum (M + H)

- 498

Example R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-1050 'i 100 ALIGN! 461 462 B-1051 OH ŤOí 88 406 407 B-1052 0 82 366 367 B-1053 21 368 B-1054 hr ⁿ 98 354 355 B-1055 i Ό ί ΙΓ * II O 100 ALIGN! 379 380 B-1056 ¹ Γ * * \ • 8ι ⁸ i 0 85 379 380 B-1057 ^{f f} - ^ hrH 30 368 369

································································

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1058 -04 ⁰ f> lTi 1 35 500 501 B-1059 l + νλ 77 479 480 B-1060 KB 37 500 501 B-1061 0-4 \ Ά 86 456 457 B-1062 ^{, f} Oh ° K Vk. i ⁰ * '·} \ tfr \ 58 496 497 B-1063 ^{! f} Oh 59 496 497 B-1064 -Qh H-o i ⁰ / O HO 58 506 -

• · · · · · · · · · · · · · · · ·

Example no.

B-1065

500 -

B-1066!

B-1067

B-1068 iF- /

B-1069

B-1070

IF-

B-1071

B-1072

B-1073

B-1074 r \

T \]

Observed Calculated mass mass spectrum% yield spectrum (M + H)

466

100 ALIGN!

490

491

100 ALIGN!

100 ALIGN!

464

472

472

481

473

515

490

464

465

473

473

482

474

516

491

465

- 501 · 4 · 99 · 4 · 99 · 4 · 99 9

9 9 9

9 9 9

Example #

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

B-1075

IF ·

100 ALIGN!

470

471

B-1076

490

491

B-1077! F-

ULZVJ

100 ALIGN!

474

475

B-1078

447

448

B-1079

IF-

-l · /

454

455

B-1080

.Cl

100 ALIGN!

496

497

B-1081

II-

100 ALIGN!

490

491

B-1082

100 ALIGN!

500

501

B-1083

at

500

501

B-1084 • F-

494

495

• · • · * · - 502 - · .. · • · · · • * « • · · • · · » • · · · · · · · · · · · • · • · · • · • · · • · • · · · < Observed Calculated wt Example # _2 J wt spectrum R R% yield spectrum (M + H)

B-1085 ^iF dIM 93 482 483 B-1086 ~ Q-i 92 490 491 B-1087 F + Q-4 A <f '0 100 ALIGN! 490 491

• 9 ····

- 503 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1088 0, _, la ' from \ J ~ \ 0! 97 450 451 ^íf- GH B-1089 ^{m /} z GH + d 100 ALIGN! 436 437 B-1090 4 <ý 100 ALIGN! 456 457 AND B-1091 ^μ Γ0 100 ALIGN! 456 457 B-1092 v-Kř whose! 96 490 491 ^t -CH B-1093 + - <Ch 100 ALIGN! 490 491 B-1094 100 ALIGN! 474 475

Example δ.

B-1095

9 9999

9 9

504 - ♦ ·

99 99 999 «

9 9 9

9 «

9 «

9 4

9 9 4

9 9 9

Observed Calculated mass mass spectrum% yield spectrum (M + H)

470

471

^{B-1096! F} -CN

450

451

B-1097

100 ALIGN!

436

437

B-1098! ^fH CM

\

466

467

B-1099

100 ALIGN!

490

491

B-1100

i_I t — p

482

B-1101

\ Λ

462

463

B-1102 ^; Oi /

i.e

H-

530

531

B-1103

472

B-1104 ’Oi

441

442 «

• φ 99 9 ·

- 505

Example. R ² j

R

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

B-1105 ^- Oh ^s - * - Q 100 ALIGN! 464 465 B-1106 ⁼ ~ CM AND ° I ° ΛΑΛ 91 486 487 B-1107 ^íf- Oh ,AND' If __________ 96 447 448 B-110B -O-i  U / Ί Γ Λλ 1 i 0 55 561 562 B-1109 KM . i o ^- i 100 ALIGN! 498 499 B-1110 KM 73 548 549 B-1111 ^f PH ' Μ- / Ί if 0 - I 94 505 506 B-1112 -CH '-ikCky ΑΊ ...AND 100 ALIGN! 568 569 B-1113 HDH s-Ln! ° U 100 ALIGN! 495 496 B-1114 F- HA o ^H I 73 426 427

- 506

Example. R ² • 9 ·

9 9

9 9 9

99 · «9999

9 · 9

9 9

9 9

9999

9 9 9

9 9 9

9 9 9

9 9 9

9 9 9

99

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1115 ii> i r ž \ 30 389 390 B-1116 í ^f X2h I— ¹⁰⁰ A 568 569 B-1117 IN 83 500 501 B-1118 I - C + 55 473 - B-1119 ^f O ~ ^ 70 514 515

999 ·

- 507

9 9 • 9 9

9 «99 99 99

99 9 · 99 ·

9 9 9 9 9

99999 9

9 9 9 9 9 • 9 9999 99 99

Observed Calculated wt 2 J wt spectrum Example # R R % yield spectrum (M + H)

B-1120 ^F ~ O ^- i V ³ 0 84 400 401 B-1121 V ³ 'o 86 420 421 B-1122 ^f O ~ ^ O 90 400 401 B-1123 100 ALIGN! 454 455 O B-1124 ^F ^ 91 442 443 B-1125 // 50 512 513 B-1126 ^f Of Article ^: 0 85 454 455

9

- 507 ₅

9

9 9 9

99

99 9

9

9

9

Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

• · «« · · ·

509 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9................. · »♦ · · ·

Example no.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

A «AAAA • A

Example #

B-1147

F- <i

510

B-1148

O F

B-1149

B-1150

B-1151

B-1152

B-1153

B-1154

B-1155

B-1156

AND

Br

F-fl

A A A AAAA A AA A AAAA

A A A A A A A A A

AAA AAA AAAA

AA AA AAA AAA

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

454

455

422

440

404

422

422

420

464

454

392

423

441

405

423

423

421

465

455

393 • »991

Example R ²

- 511 • φ φ «· φ φ · · · φ φ φ φ φ φ φ φ · · φ φ φ φ φ φ φ φ φ * φ φ φ φ φ φ φ φ φ φ

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-1157 ~ Ch 0 81 405 406

»· ····

Example No. R ² R ^J · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

9 9 9 99 99 9999 99 99

Observed Compound Mass Mass Spectrum Yield Spectrum (M + H)

B-1158 ^f / 0h ύ -'- τ ' 0 54 396 397 B-1159 ^fh CM yp; 42 526 527 B-1160 33 zp 0 27 Mar: 366 367 B-1161 ^F -m ^χλ α. 58 418 419 B-1162 • 33 γρ 62 380 381 B-1163 • 33 58 424 425 B-1164 ^f OH 'V' ¹ 67 338 339

- 513

Example no.

Observed Calculated Mass Mass Spectrum Yield Spectrum (M + H)

·····················

Example no.

- 514 Observed Calculated Mass Mass Spectrum% Yield Spectrum (M + H)

- 515 Example δ. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-1185 -Os 90 430 431 B-1186 O-i O 86 444 445 B-1187 -O-i 'X- 74 396 397 B-1188 ^f CM r-i-O- % 76 597 598 B-1189 OH 60 452 453

- 516 ·· ······································· · * ·· ·· ···· ·· ··

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example No. R ²

B-1190 o-i 0 ._, 44 454 455 B-1191 ^F Od HrO 47 436 437 B-1192 O-i αλλλ AND D-— Λ 50 402 403 B-1193 ^{, F} 0d δ i-pLQ 62 462 463 B-1194 • O-t In II ‘O 49 450 451 B-1195 -O-i η'γΡ 61 472 473 B-1196 ^f OH , 0 1 11 * II u_________0__ 52 428 429

9 9

99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 999 9 9 9 9

Observed Calculated Mass ₂ µ Mass Spectrum

ExampleNo. R R% yield spectrum (M + H)

B-1197 54 454 455 B-1198 ^f Oh AR ... .. 0 I 44 402 403 B-1199 - <M Ά-Ά 0 ^! 67 416 417 B-1200 | F —- <> OI, II I l S "\ i 45 388 389 B-1201 'K-i AND 52 374 375 B-1202 : ^f -O4 0; 100 ALIGN! 466 467 B-1203 ^IF- OX 4Ό o! 91 442 443 B-1204 F - ^^ - 1 o. r HU! 100 ALIGN! 450 451 B-1205 -Oh MM '! i ......................... ..l 83 496 497 B-1206 ! ^fh CM AA! 97 381 382

··

- 518 Example R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1207 H ~. 100 ALIGN! 339 340 B-1208 'blH A ~ - «j 90 429 430 B-1209 ^{íf -CM} '-M 69 393 394 B-1210 ^f ~ CH O Ι _ν Οΐ o I 35 409 410 B-1211 100 ALIGN! 433 434 B-1212 0 * I 63 367 368 B-1213 ^f -Oh ; 0 | Μ AND? Η 78 353 354 B-1214 —Ch ί ^C P ^: nr r 68 429 430 B-1215 i CX. br 65 433 434 B-1216 -CH Him 91 443 444

- 519 99 9 9 9 9 9 9 9 9

99 99 9999

Example. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1217 Γ “θΗ · ! 0 99 379 380 B-1218 ---- ^{O ==} K ti 92 381 382 B-1219 74 443 444 B-1220 hňo 67 415 416 B-1221 -Whose 14 443 444 B-1222 19 Dec 443 444 B-1223 j ... ----------- i 71 433 434 B-1224 100 ALIGN! 445 446 B-1225 with ^F -m i Π 75 395 396 B-122G hrH 0 ' 58 367 368

- 520 -

····

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-1227 KM y! 98 475 476 B-1228 KM Υό 71 420 421 B-1229 0 85 380 381 B-1230 MM t Η 10 382 - B-1231 IF ~ ^^ - > z hr ’ O 66 368 369 B-1232 OH Ϊ HN • '-' 'X ο ° ...... 0 - 100 ALIGN! 393 394 B-1233 iKM 0 96 393 394 B-1234 ^! KM hrH 0 66 382 383

«« 0 · • · 0

- 522 00

0 0

0 0 0 0 0 0 0 0

Example #

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-1235 ^fh Gh rpsXÁ 0 50 514 515 B-1236 KW 100 ALIGN! 493 494 B-1237 91 514 515 B-123B ^f <H sxr " \ Ά 100 ALIGN! 470 471 B-1239 V +. ! 71 510 511 B-1240 -O-i I + hS 27 Mar: 510 511 B-1241 ^f- Oh ! HO with ^{C <} i h -ď! ¹⁰ ^ c, l 73 520

- 521 11 1111

Φ · φ φ • • • • • • • • • • • •

ΦΦΦ · · · ····

11 Φ ΦΦΦΦ Φ · Φ ·

Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-1242 ř + pi! ° ^ ^C '0h' 26 480 481 B-1243 H ~ 0 u -.______ ρ I 100 ALIGN! 504 B-1244 o! 52 478 479 B-1245 : ^f ~ CM 100 ALIGN! 486 487 B-1246 ^íf O4 ! μ «_Ζ ~ Λί ? II \ _Z : O; 56 486 487 B-1247 , db: Hi " I -..... 'C ....... .......... 43 495 496 B-1248 ^Hh 8; 61 487 488 B-1249 U-ΖΛ! pV? ! G V — N I You v 32 529 530 B-1250 i-O4 i C, e "H-tt 10 ' ^{a == /} , 56 504 505 B-1251 0 ___ | s-LTV /! ⁵ inj o I 56 478 479

999 · ·

- 523 Example δ.

B-1252

B-1253! F-

n ~ r

B-1254

B-1255

B-1256

B-1257

✓

B-1258

IF // \

clay-

B-1259

IF ·

/ S

HP

B-1260 r \

I O

B-1261

4/3 • 9 99 99 99

9,999,999

999 98 9 9 9 9 ·

99 ·· ······

999 * 999 9999

99 99 99 99 99

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

100 ALIGN!

484

485

504

505

488

489

461

468

469

510

504

514

514

508

511

505

515

515

509

- 524 99 9999

9 «99 99 99

9 «9 99 · 9 9999

9 99 9 9φ99

9999 99999 9

9999 999 9999

99 99 99 99 99

He does. R ²

Calculated Observed wt wt spectrum % yield spectrum (M + H)

B-1262 KM  < ! -) A 97 496 497 B-1263 = -04 Cf 1 I ii + Ui 100 ALIGN! 504 505 B-1264 / Oj 100 ALIGN! 504 505

- 525 • 9 «999

9

9

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-1265 0, _, i A TÍN 0 100 ALIGN! 464 465 B-1266 79 466 451 -OH H- <5 B-1267 -OH 4d 0 100 ALIGN! 470 471 B-1268 -OH o - H-p Cl 87 470 471 B-1269 Hp ... _______ ...... J? ' 100 ALIGN! 504 505 B-1270 _F 0p hP 0 100 ALIGN! 504 505 B-1271 -OH + Ó4 _ 56 488 489

- 526 Example no.

B-1272

B-1273

B-1274 ^f ~ CH hγμ

B-1275

K5

Xi

B-1276

B-1277

ΖΛ

ku 3— »

B-1276

,ST

Lkx

Xi

B-1279

Ti ”X /

B-1280 r \

B-1281

h-

«0 0 ··· ·· * · · * ·· 00 0 0000 0000 00 0 00 0 0000 00 0000 000000 000

00 00 0000 0 · ··

Observed Calculated mass mass spectrum% yield spectrum (M + H)

100 ALIGN!

100 ALIGN!

484

485

464

465

450

480

504

496

476

544

486

455

451

481

505

511

477

545

456

- 527 ·· ·· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··········································

Example No. R ²

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

B-1282

B-1283

B-1284

B-1285

B-1286

B-1287

B-1288

B-1289

B-1290

B-1291

• • •

- 528 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Observed Calculated Mass ₂ µ Mass Spectrum

Example No. R R% yield spectrum (M + H)

B-1292 35 403 404 Ό Λ li / i y \ ^! B-1293 ! A I 73 582 583 B-1294 In I H - Z3i 49 514 515 B-1295 • ΛΑΛ 48 487 - B-1296 _F ^ | 1 y \ - <i 76 528 529

- 529 -

Observed Calculated wt 2 J wt spectrum Example # R R % yield spectrum (M + H)

B-1297 O ⁰ 62 447 448 B-1298 F- Μ / λ 66 452 453 B-1299 ^f ~ Oh Γ \! —NN—, Jj ^w \ H 65 479 431 B-1300 0 Xj 71 444 445 B-1301 -O-s 0 H Her 'KM 100 ALIGN! 472 473 B-1302 KH c> II, ^ø : / „ 75 410 411 B-1303 L * ΠΛΑ ^M ' ^M 1 74 424 425

Observed Calculated mass ₂ µ mass spectrum

Example No. R R% yield spectrum (M + H)

B-1304 04 / LVk! r 11 430 431 B-1305 } Ί ? AND 2 424 - B-1306 -Λ O 30 433 434 B-1307 AND 100 ALIGN! 522 523 B-1308 ^'F -CH XT! i Ί - * '*' ¹ Λ ...........- J 100 ALIGN! 508 509 B-1309 : η H / X ^N J 100 ALIGN! 448 449 B-131O ^ ^f ~ Oh> . ί X í 1 26 430 431 B-1311 ΗΣΜ -'- δ ------------ IL — nh Í and .................... 0— 45 397 398 B-1312 iPi 14 507 508 B-1313 -04 P oo 67 450 451

- 531 Observed Calculated Mass Mass Spectrum

Example No. R R% yield spectrum (M + H)

B-1314 AND ^ -Oí 69 444 445 B-1315 km Lil! r ~ \ \ ^: 57 450 451 B-1316 Ad H 75 393 394 B-1317 Pdx! 100 ALIGN! 461 462 B-1318 -N l · j Lz i 31 450 451 B-1319 _c dd 23 464 465 B-1320 59 512 513

- 532 -

Observed Calculated wt 2 J wt spectrum Example no. R R % yield spectrum (M + H)

- 533 AAA AAAA

AA A A A A A * AA AA

Observed Calculated Mass 2 J Mass Spectrum

Example. R R% yield spectrum (M + H)

B-1328 w 0 29 425 426 B-1329 r € H 67 450 451 B-1330 After 59 436 437 B-1331 ^f ~ (2h -a ^: F 45 436 437 B-1332 • ΌΗ F 81 454 455 B-1333 OH I 0 23 468 469 B-1334 * 0 53 442 443 B-1335 Okay i 7 * ' hrl i 0 F 81 486 487 B-1336 Okay s-Pi ’ 'O 69 454 455 B-1337 O hl 67 486 487

• ·

- 534 • 9 • 9

Observed Calculated Mass ₂ µ Mass Spectrum

Example No. R R% yield spectrum (M + H)

B-1338 KM l 2 <her L. ... F ί 39 486 487 B-1339 iKM 0 F ⁵ O 81 486 487 B-1340 5r C 49 486 487 B-1341 'KM AND_______ '-'-at O -n 55 486 487 B-1342 KM ........ | Í ^ 51 486 487 B-1343 KM ‘O · 72 434 435 B-1344 i ^f KM hd I__s_i 52 414 415 B-1345 Cl 0 I 43 468 469 B-1346 hr ^ 0 40 418 419 B-1347 KM // . . o .... | 67 436 437

- 535 «9 9

99

I 9 9 9 ø 9 9 9> 9 9 9

The observed calculated mass-mass spectrum

R% yield spectrum (M + H)

Example. R ²

- 536 «· · 99 99 • · 9 9999 9999

999 99 9,999

9999 <99999 «999 999 9999« · 99 99

Example. R ²

Observed

Calculated mass mass spectrum

R% yield spectrum (M + H)

- 537 ··· ················· · · · · · Φ φφφφ

99 99 99 ΦΦΦΦ ΦΦ 99

Observed Calculated Mass Mass Spectrum

Example. R ² R% yield spectrum (M + H)

B-1359 -O ~ i and and 95 552 553 B-1360 ^fh Ck 77 444 445 B-1361 ^ -04 o i 100 ALIGN! 392 393 B-1362 AND h 85 406 407 B-1363 -04 0 100 ALIGN! 364 365 B-1364 -O) h> 99 390 391 B-1365 04 / p ...... 92 504 505

99 99 99 9 9 9 9 9

9 999 «

Example #

B-1366

538 Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-1367

B-1368

IF

B-1369

B-1370

B-1371: ^f ~ C = 4

B-1372

B-1373 iKM

B-1374 f-4

B-1375

I «^ o i \

'· F

100 ALIGN!

100 ALIGN!

100 ALIGN!

100 ALIGN!

100 ALIGN!

552

417

394

456

470

440

444

427

476

414

553

418

395

457

471

441

445

428

477

415

- 539 99 · 9 99 99

9,999,999

9 99 9 9999

9,999 9,999,999 9

9999 999 9999

99 99 99 99 99

Observed Calculated Mass Mass Spectrum

Example. R ² R% yield spectrum (M + H)

B-1376 ! -K ° i <v 87 400 401 B-1377 KM those ’ 100 ALIGN! 480 481 B-1378 / ti 95 379 380 • B-1379 Yď 93 459 460 B-138O 89 469 470 B-1381 KM ά κ ^hn_ 4 ^! ί 0 84 393 394 B-1382 , ^{/ γ} _______o__ 85 501 502

«« »* 99 ·· •« 9 9 9 9 9

9 9 9 9 9 ····

- 540 9 9 9 9 9 9 9 9 9 9 9

99 99 99 99 99

Example #

j

R

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-1383 ΌΗ -in? O 46 416 417 B-1384 in? 0 56 432 433 B-1385 • O-s O 59 426 427 B-1386 ^f- Ch 0 50 427 428 B-1387 O 12 427 428 B-1388 0 ' 66 504 505 B-1389 f-O-i \ -ο- ^α o 48 460 461

* 9,999

- 542 99

99 · 9 9

9 9

9 t 9

9 9

9 «9 9 9 9

99

9 9 9

9 9 9

9 9 9

99

Observed Calculated Mass Mass Spectrum

Example. R ² R% yield spectrum (M + H)

Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

- 542 ·· φφφφ

Φ Φ • ♦ ♦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Observed Calculated Mass Mass Spectrum

Example No. R% Yield Spectrum (M + H)

B-1400 : o 74 440 441 B-1401 Ml 76 462 463 B-1402 -CH 0 65 462 463 B-1403 M 64 445 446 B-1404 M ¹ 0 ^F 70 512 513 B-1405 Ή2Η cr ₃ 57 512 513 B-1406 M i 0 F I 73 512 513 B-1407 corner f ₃ c 1 1 o ¹ 80 512 513 B-1408 ¹ \ = /> ! FjC HyXT i ....... o ............. 2 512 513 B-1409 KH r ^F 1 1 0 62 512 513

9 9 9 • 9

- 543 • 9 · 9

9 9 9 9 9 »·· ······

9 9 9 9 9

9999 98 99

Example No. R

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1410

512

513

B-1411'-Ch

462

463

B-1412

^F '

462

463

B-1413

494

495

B-1414

462

463

B-1415

462

463

B-1416 * ^fh Ch

494

495

B-1417

494

495

B-1418

i o

494

495

B-1419

494

495

- 544 • 9 9 · · ·· ·

9 · 9 9 9 9

Example No. R ² j

R

Observed computed mass mass spectrum% yield spectrum (M + H)

B-1420 ! ^fH CM 0 72 378 379 B-1421 ^f -CH 74 406 407 B-1422 0 68 394 395 B-1423 57 408 409 Oi 0 B-1424 ^f OH 0 77 422 423 B-1425 ^{-0f -0H} Λ- ° ^Λ 0 26 408 409 B-1426 ! ^f -O ~ I Ύν * O AND 41 406 407 B-1427 O 37 404 405 B-1428 ^f ^ h ^! to 60 456 457 B-1429 1H-2H I CF ₃ i r 2 418 419

- 545 · · 54 54 - 545 · 54 54 54 54

Example.

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-1430

442

443

B-1431

428

429

B-1432

429

430

B-1433

/%

462

463

B-1434

-trii

O

466

467

B-1435 iF-

481

482

B-1436

504

505

- 546 - • · • · · • 9 • · · 9 · · • 9 · · · · Example # R ² J R% yield Calculated wt spectrum Observed wt spectrum (M + H)

9

9

9

- 547

9,999,999

9,999,999 ·

9 # 999

9999 999 999 999 • 9 99 99 9999 9 9 9 9

He does. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1447 í ^f O3 ⁰ -J ³ '' VS-0 i 73 506 507 B-1448 Cl- ^Cl Cl ^Cl 76 530 531 B-1449 ^f 3ZH 1 ^Cl 1 L fX 1 / —h ~ V / ~ ^ci ! 0 82 530 531 B-1450 ? ^f -O3 . Cl k-j-o i el 1 83 530 531 B-1451 ! ^f O3 1 Cl ( IN 74 530 531 B-1452 M-qp • Cl 76 530 531 B-1453 , ° _ZI μΎ i _________5 '1 73 530 531 B-1454 i ^f O3 and\-?- ’0 81 498 499 B-1455 ! ^f O3 83 498 499 B-1456 F- i kPI 1 o 1 78 498 499

···· · · · φφ φφ · · ·φ · · · ·φφφφφφφΦΦΦφφφφφφ * * φφφφφφφφφφφφφφφφφφφφφφ

Observed Calculated Mass ₂ µ Mass Spectrum

Example. R R% yield spectrum (M + H)

B-1457 ^m -OH 74 496 497 B-1458 F ~ v- | A> B2 540 541 B-1459 iv-bbl 80 476 477 B-1460 r + OM ° CF 3 78 530 531 B-1461 ' ^F -Od CN i 0 | 82 487 488 B-1462 -OH ! o ^ s = o 71 540 541 B-1463 ^IF- Oi. PQ! i CFjl 78 546 547 B-1464 “ΌΊ X-I-6 about: 83 480 481 B-1465 ^F “C = ^ - k? π; t A I o 84 496 497 B-1466 í ^f <M k B A p T-V ^ Br I o 80 540 541

• · · and • · ·

- 549 Attached.

B-1467

ÍFΛΛ

B-1468

OH »· ·« • • * * * *

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1469

B-1470

B-1471

B-1472

B-1473

B-1474

B-1475

B-1476

II

O

Ό

CF ₃ l

-gh ^{f IF-CM} O ^f ^ · r \

FA

íf-

476

530

487

477

531

488 et al

-sII O

Br.

480

481

496

497

540

541

if

I O!

um θι

II i s— (

476

477

530

487

540

531

488

541

- 550 • · · 9 9

9

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 99 9 99 9

He attaches. R ²

Observed Calculated Mass Mass Spectrum

R% yield spectrum (M + H)

B-1477 79 546 547 * o!

• A

A A · A

- 551 · A A AA AA A AA A AAAA A AAAA A AAAA

AA AAAA AA AA

Observed Calculated mass mass spectrum% yield spectrum (M + H)

Example no.

«*

• 9 · 9 - 552 ^-: .J • · · · 9 9 9 · * 9 9 • 9 «9 9 9 · 9 · 9 9 Observed Calculated wt J wt spectrum Example no. R R% yield spectrum (IW + H)

· ♦ 4 44 4

- 553 • * 4 4 4 • • 444 4 4 4 4 4

4 44 · · «4 4 • 444 4 444 44 4 ··· 4 · 4 4444

4 »4 4 44 44 44 44 4 4

Example R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

* · ··· · •

- 554 ι:

Observed Calculated wt 2 J wt spectrum Example no. R R % yield spectrum (M + H)

- 555 • «

J Calculation of read mass Observed wt spectrum R % yield spectrum (M + H)

Example. R ²

B-1515 ° i ’A 68 496 497 B-1516 1 ^of i 1 8 Á 27 Mar: 429 430 B-1517 dZL d 92 466 467 B-1518 ; $ η 1 in/ o 1 33 379 380 B-1519 γΟί L ¹ i d 'O i 50 393 394 B-1520 Γ O ¹ γ · - <1 c 82 435 436 B-1521 loi 86 509 510 B-1522 ΗΟΊ Ad 12 405 406 B-1523 Vaq ¹ l., * 1 59 459 460 B-1524 ^f CH ^v d 81 459 460

- 556 9 9 99 9 9 * · φ

ΦΦΦ φ φ φ φ • φ φ φ φφ φφ

99

9 9 Φ

Φ Φ Φ Φ

9 Φ Φ Φ Φ · · 9 9 9

Observed Calc

- 557 φφ «φφφ

ΦΦ φ • * * · φ φ φ φ φ β β β β φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Example R ²

J Calculated wt Observed wt spectrum R % yield spectrum (M + H)

B-1526 you et 0 0 0 'i 73 410 411 B-1527 Cl ¹ o ”1 AND and 66 520 521 B-1528 91 467 468 B-1529 pr ' Cl 73 432 433 B-1530 cy E" ! Oh 91 443 444 B-1531 pr · Cl Ιγν-χ O 74 422 423 B-1532 ...... J 66 438 439

- 558

ΦΙ ··· '·

ΦΦ φ · · · · φ φ φ · · · · · · φ φ φ φ φ φ · · · · · ΦΦΦΦΦΦ ΦΦΦΦΦΦ φ

Observed Calculated mass mass spectrum% yield spectrum (M + H)

Example no.

♦ · · «

9 9 9

9 9

9 9

9 9

9

- 559 ·

99

9 9 9

9

9 9 9

9 9 9

Calculated Observed wt wt spectrum % yield spectrum (M + H)

Example. R ²

• 9 9 «

9 9 9

9 9

9 ·

9 9

9 9 9 * 99

- 560 «» 9999

99

9 9 ·

9 9 9

9 9 • 9 99

Example No. R ²

J Out of focus wt Observed wt spectrum R % yield spectrum (M + H)

- 561

A A AAAA

A * A

AAA A A A

A A A A

AA AA

AND·

A A

A A

A A

A A

A A

Observed Calculated Mass Mass Spectrum

Example. R R% yield spectrum (M + H)

B-1563 ! and Q-> ...... Cl, ............... 'V / I CJ! 72 512 513 B-1564 AND p et í íi / ' r 1 \ 57 445 446 B-1565 AND F 9 Cl Π v 64 482 483 B-1566 and and P ', Cl N 1 ΎΊ O 71 395 396 B-1567 and AND O hrH 0 ’ 54 409 410 B-1568 7 Cl. í o • 0 76 451 452 B-1569 7 Cl 70 525 526 B-1570 pl Cl______ ¹ ϊγΜ í 0 79 421 422 B-1571 pd I! [τ ^!> φ! 60 475 476 B-1572 91 Cl 77 475 476

** • *

- 562 R

Example. R ²

Observed Calculated mass mass spectrum% yield spectrum (M + H)

B-1573 C/' c ... ! O 55 435 436

The proton NMR data for selected examples from B-0001 to B-1573 are shown in the following table.

• 0 · ♦

- 563 <1 0 0 ·· 00 00> 0 0 000 9 9 * 00 · 00 0 9000

0 0000 00000 00 0000 900 009 0

99 99 0999 00 00

Board no. 1 H NMR (solvent) d ppm B-0120 (DMF-d7) d 8.53 (bd, J = 4.99Hz, 2H), 7.44-7.24 (m, 1H). 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) 8-0244 (CDCl 3 / CD 3 OD) d 8.38 (d, J = 5.38 Hz, 1 H), 7.62-7.32 (m, 9H), 7.04-6.95 (m, 4H), 6.86-6.80 (m, 2 H). 4.52 (q, J = 6.96Hz, 1 H), 1.40 (d, J = 6.88Hz, 3H) B-0256 (DMF-d7) d 8.45 (bd, J = 2.85, 2H), 7.87 (brs, 4H), 7.76-7.75 (m, 2H). 7.537.33 (m, 5H), 7.18-7.13 (br. 4H) B-0426 (DMF-d7), 1.32 (br, 3H), 1.67 (br, 3H), 4.17 (br, 2 H), 5.12 (br, 1 H), 7.50 (m, 6 H), 8.77 (m, 2 H), 13.54 ( br, 1H). B-0438 (DMSO). 1.14 (t, J = 6.9Hz, 3H). 4.54 (m, 1H); 6.99 (br. 2H). 7.21 (br. 4H); 7.45 (s, 1H). 7.61 (q, J = 8.7Hz, 2H), 8.52 (d, J = 5.2Hz, 2H). B-0466 (DMF-d7), 1.61 (brd, J = 30.6Hz, 3H), 4.61 (br, 1H), 7.25 (m, 6H), 7.65 (m, 3H), 8.59 (br. 2H), 13.34 (brd, J (34.8 Hz, 1H). B-0473 (CD3OD), 1.53 (d, J = 7.2Hz, 3H), 4.59 (q, J = 7.2Hz, 1H), 6.B8 (d, J = 4Hz, 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, 1 H), 4.98 (br, 1 H), 7.38 (m, 6 H), 7.85 (m, 2 H). 8.45 (br. 1H). 8.75 (d, J = 6.0 Hz, 2H). B-0479 (Methanol-d4), 1.57 (d, J = 5.6Hz, 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, 1 H). 7.42 (br. 2H). 7.54 (br. 2H); 7.66 (br. 3H). 8.82 (s, 2H). B-0566 (CD3OD). 1.38 (d, J = 7.2Hz, 3H). 4.15 (br. 2H); 4.50 (br. 1H); 7.04 (br, 2H); 7.18 (br, 2H). 7.30 (m, 7H). 8.45 (m, 2H). B-0569 (CD 3 OD), 1.56 (br, 3H). 4.66 (q, J = 6.7Hz, 1H); 7.17 (m, 8H); 7.56 (m, 2H); 8.47 (s, 2H). B-0574 (Methanol-d4), 1.49 (br. 3H), 3.86 (br, 3H). 4.60 (br. 1H); 6.92 (br. 2H). 7.19 (br. 2H); 7.31 (br. 2H). 7.76 (m, 4H). 8.60 (br. 2H). B-0639 (DMF-d7). 1.58 (brd, J = 30.0 Hz, 3H); 4.62 (br, 1H); 7.25 (m, 6H). 7.60 (m, 4H), 8.59 (br. 2H), 13.30 (brd, J = 12.3 Hz). B-0643 7.18 (m, 2H), 7.32 (dd, J = 6.0, 4.4 Hz, 1H), 7.70 (dd, J = 9.0, 5.8 Hz, 1H), 8.43 (dd, J s 4.8, 3.2 Hz, 2H). B-0650 (CD3OD), 1.58 (br, 3H), 4.62 (q, J = 6.6Hz, 1H), 6.93 (br, 1H). 7.17 (m. 5H). 7.31 (br. 2H); 8.51 (br. 2H). B-0656 (CDCl 3 / CD 3 OD) d 8.48 (d, J = 5.30 Hz, 2H). 7.72-7.59 (m, 4H); 7.14-7.10 (m, 2H); 7.03-6.97 (m, 4H); 4.60 (q. J = 7.57Hz, 1H); 1.43 (d, J = 7.26Hz, 3H) B-0663 (CD 3 OD), 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, 1 H), 3.43 (q, J = 6.1 Hz, 2 H), 7.02 (m, 2 H). 7.14 (m. 2H). 7.41 (m, 2H). 8.59 (d, J = 5.6 Hz, 2H). B-1169 1.6 Hz, 1H), 7.04 (t, J = 8.6 Hz, 2H), 7.14 (m, 2H), 7.36 (m, 2H), 8.39 (d, J = 1.8 Hz, 1H). 8.60 (m, 2 H). B-1171 6.83 (br, 1H), 7.02 (t, J = 8.7Hz, 2H), 7.15 (d, J = 5.6Hz, 2H), 7.40 (m, 2H), 8.59 (d, J, 5.0 Hz, 2H).

4404 • 4

- 564 40 40 · 0

4,040 04 04 4

4,440 0,0009 • 4,444 4,040 04 4

4444 444 4444

04 44 0004 4 · 44

Board no. 1 H NMR (solvent) d ppm B-1179 (CDCl3), 1.94 (br, 2H), 2.53 (s, 3H), 2.85 (1, J = 6.2Hz, 2H), 3.65 (br, 2H), 6.15 (br. 1H); 7.04 (m, 3H). 7.22 (m, 3H). 7.41 (br. 4H). 8.60 (br. 2H). B-1183 (CDCl 3), 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 (br, 2H), 7.18 (br, 5H), 7.35 (m, 6H), 8.54 (d, J = 5.8 Hz, 2 H). 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, 2 H). 2.63 (br. 2H); 3.00 (br. 2H); 3.65 (br. 1H); 5.69 (m. 2H). 7.16 (br. 4H), 7.35 (br. 2H), 8.54 (br, 2H). B-1216 (DMSO), 1.75 (m, 2H), 2.14 (s, 6H), 2.66 (br, 2H), 3.1O (br, 2H), 7.04 (br, 3H), 7.18 (br. 4Hk, 7.35 (m, 2H)) 7.47 (br. 1H), 8.54 (d, J = 4.8Hz, 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-d 6), 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 (br. 2H). B-1361 (DMSO-d6), 0.99 (br, 6H), 1.73 (br, 2H), 2.89 (br, 2H), 3.03 (m, 1H), 4.04 (br, 2H), 4.44 (m, 1H), 7.18 (br, 2H) 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 (CDCl 3), 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, 1 H), 2.99 (m, 1 H). 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 (CDCl 3), 1.89 (s, 4H), 2.65 (m, 1 H). 2.96 (m, 1 H), 3.06 (m, 1 H), 3.43 (s, 3 H), 3.93 (d, J = 13.2 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1 H), 4.18 (d, J = 13.5 Hz, 1 H), 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). |

- 565 AA AAAA A A A A A A A

A A A ·

AA AA AAAA

A A A A

A A A A ·

A A A A A A A

By analogy to the above procedures for preparing Examples B-0001 to B-0048, the following Examples B.1574 to B-2269 were prepared.

- 566 • Φ φ φ «<<<· · · · · · · · · · · · φ φ φ φ φ φ φ φ φ φ φ φ · · · · · · · «

Examples Β-1574 to Β-1597 were prepared from C-27 backbone

Example No. R ² R ^L

B-1574 6-? ⁰ i ^iU G B-1575 Ή ·· “Π _ B-1576 OH B-1577 Br OH ! ⁰ B-1578 Br ^; B-1579 ^B \ * Η B-1580 Br ^, BR i BR ¹

- 567 ·· 9999

99 99 99 • 9 · 9 9 9 9 9 · 9 9 ··· · · · 9 9 9 9 · · 9 ··· 99 ···

9999 9 9 9 9999 ·· 99 9999 99 99

15-1581 Βι ^ Β-1582 Br ^ Β-1583 Br ^ j Β-1584 b-p ή IN Β-1585 b + X Β-1586 and_ <i AND Β-1587 Oh i ^p rP: O ^ ^o! Β-1588 She knows ir 15-1589 in Β-1590 Br ^ i Β-1591 tn j < _r oi '/ * O i

- 568 99 9900 99 99

9 9 9 9

9 9 9 9 9

9 9 9 9 9

99 99 9999

99

9 9

B-1592 Ch : γ W B-1593 m iV ⁰ ! ' _χ NH: B-1594 Ή i + ó, B-1595 ffl B-1595 Ή H Λ i ^h H ₀ i B-1597 Ή 0 ί

- 568 ₅ • · • ·

·· · ··· ·· ··

Examples B-1598 to B-1621 were prepared from C-28 backbone

Example. R ² R ^L

B-1598 H ₃ C OH · , 0! dí B-1599 h ₃ c ^ i 0 to..! B-1600 h ₃ C! cm ! 0 V ¹ B-1601 H ₃ C i Yh 0 idl B-1602 H, C CM i O TO B-1603 H ₃ C i Od : o B-1604 h ₃ c CM db ! BR!

- 570 • 9 9 99 ·································

Example No. R ² r ^l

B-1605 h ₃ or X I ° X, B-1606 h ₃ c CM Czech IC _N '! B-1607 H ₃ Cl 2 Λλ B-1608 h ₃ c Ch X B-1609 h ₃ c ^ Id i! 0-3 B-1610 h ₃ c X i < t oi B-1611 H ₃ C Ci δ ° B-1612 h ₃ c OH AND I fVS AND 3i B-1613 H ₃ C CH OA 0 B-1614 H ₃ C CH i X ~ o I gssU

• ·

- 571 • · · · ·······

Example. R ² R ^L

• ·

9 9 9

9

9

9

9,999 99 · 9

Examples Β-1622 to 1645 were prepared from C-38 backbone

He does. R ² R ^L

B-1622 'X B-1623 ^f Ch x, i B-1624 i ° I B-1625 ‘CM ^ Pxi B-1626 OH ¹ 0 vk B-1627 r-CM 0 X B-1628 xi

- 573 ·· ··

Example. R ² R ^L

- 574 • · · · ΑΑ ·

Example. R ² R ^L

B-1639 • OH i «X! ι-o --o · i a; and B-1640 • O-s fd B-1641 ΌΗ i <z ^! > / NH! B-1642 ^f O4 Vxi ¹ B-1643 kl Χ \ Π ^ř Vi B-1644 v, ^H X ₀ B-1645 Ό V Λ, , ~ s 1

0

- 575 ·· 0 «• · · · · · · · · · · · · ·

0 0 0 · 0 ·

00 · 0 000 *

Examples Β-1646 to Β-1669 were prepared from the C-39 backbone

Example. R ² R ^L

B-1646 ^ifh GH B-1647 ^'F OH B-1648 ^f <H I 0 νγ B-1649 KB d / x- B-1650 ^{if <} GM , O; Kj B-1651 ^f o ..... '' ^x \! B-1652 ^f ~ CH Λ ⁷ _____

• «# ·

- 576 tt tt tt tt tt tt tt · ·· ··

Example. R ² R ^L

B-1653 -33 I ^{0 1} B-1654 ^r O! IU 1 i <3, \ = SN B-1655 -33 ^: θ! Ό \ · B-1656 33 B-1657 X; B-1658 ΌΗ i - <i B-1659 From B-1660 From B-1661 iQ3: ° B-1662 ^F Od i <-0 s ^ °

• 9,999

- 577 99 99 99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99

Attaches R ² R ^L

B-1663 [> \ cť \\ ^S o B-1664 -Oi . <ol B-1665 CH ^ij C ° -NH; and B-1666 CH - B-1667 • ΌΗ {O ^H jnn iyl B-1666 '^ \ A 1 C i B-1669 OH PC ; and

* · 9999

- 578 99 99 99 99

9 9 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99

Examples B-1670 to B-1693 were prepared from a C-65 backbone

Example #

B-1670 3 ÍQ B-1671 O to F B-1672 ^íf O4 O! j ^ i B-1673 L B-1674 AND 0 B-167S HCM ⁰ i Pi B-1676 i ^F ^

- 579 φ φ • · · φ φ • • • · · • · · · · · · · ·

He attaches. R ² R ^L

Β-1677 ^f ~ CH ΒΊ678 ! ^f -04 i 0 Β-1679 -Οη ' o! Β-1680 ^íf Oh f] Β-1681 Β-1682 • OH Β-1683 ^F M ^7: ιζζη Β-1684 i-CH ! -X ^! I / TV- ^ o! 'I Β-1685 -OH iOJr Β-1686 i XJ i ~ -o ₀ I

- 580 • · · · ··············

Example. R ² R ^L

B-1687 ί-τΌο ' ^s > ^! '/% ¹ B-1688 GR cA ^s o B-1689 _χ ΝΗ B-1690 -Oh Κά B-1691 ~ O4 i 1 ' Apl B-1692 ΗΝ-ς 0 B-1693 r ^ í ^HN \:

• · · · · · · · · ·

from the C-66 skeleton

Examples B-1694 to B-1717 were prepared

Example. R ² R ^L

B-1694 ^f -OX X ' B-1695 1 0 B-1696 ^f ~ OX B-1697 B-1698 o ^ / B-1699 OH 1 0 X B-1700 X BR I

- 582 Example No. R ² R ^L

B-1701 i ^F Od L. ____ ï B-1702 Ί ° B-1703 0 \ B-1704 ! O B-1705 B-1706 , _F -O— B-1707 B-1708 Μ, B-1709 ΟΟ-Λ ° B-1710 ^f 0H and b ^ 1 °

- 583 Example No. R ² R ^L

B-1711 '/' o i B-1712 O S V ° 30 B-1713 ^NH B-1714 Ή B-1715 ^F Od 0 H t--, i ΜφΙ B-1716 'Oi Ά Λ hn ~ 4: O B-1717 • Ol ^. Λ i

- 584 · 58 58 · 58 58 58 58 58

Examples Β-1718 to Β-1741 were prepared from the C-69 backbone

Attaches R ² R ^L

B-1718 ^F- O '1 B-1719 • KDH and; B-1720 l 0 to B-1721 ^f -Oh i 0 B-1722 B-1723 KM 1 θ i AND B-1724 AND 1 BR '

- 585 ·· ·· ··

Example. R ² R ^L

B-1725 = y2k B-1726 ~ CH - I ίφ ° Z-O B-1727 hOH 0 I Μ / γ B-1728 I o db B-1729 ~ QH B-1730 B-1731 ^f Od ió ^ oj B-1732 ! -Kí í í ^N xK i B-1733 O-Y B-1734 I-X is 25 °

- 586 9 999

9 9 9 9 9

98 9 · 9999

Example. R ² R ^L

B-1735 -OH Ixko • o ! /% B-1736 ^f -O3 and B-1737 P NH ' • B-1738 - _P - | B-1739 I · J-J rp B-1740 -in p _p; ^H P i 0 0 ¹ B-1741 O) 3 ^: 0 i

- 588 «99« 9 9

99

99 99 99

99 9 9

9 9 9 9 9

9,999 99 9

9 9 9 9 9

9999 98 99

Examples B-1742 to B-1765 were prepared from a C-70 backbone

Example. R ² R ^L

B-1742 ΌΗ B-1743 ^f O4 B-1744 Oi 0 AND B-1745 isj; TO B-1746 0. B-1747 iKH 1 θ K B-1748 i ^F ~ CH Jr___

99 · 9

9 ·

- 588 Example R ² R ^L

B-1749 ^f O- ^ i o I ha B-1750 f-CH i 0 \ = N B-1751 • Ό3 O-J B-1752 OH  ° I hr B-1753 i ^F ~ θ— SU! Čk B-1754 -03 ! <' i- (H B-1755 -HP B-1756 O i - <i and B-1757 ^f- CH íGP B-1758 -03 ¹ y Sf °

- 588 0 · ··

9999

Example. R ² R ^U

B-1759 ^f ~ QH O WITH B-1760 ^f Oh J-O's * ⁸⁰ B-1761 -Oh % nh! B-1762 _f 7A-i V —— /> | iY ~ 6 B-1763 ^f ~ OH ! o h ί B-1764 Λ hn-4 - i 0 i B-1765 A ^HN Á!

• 9999 • 9

9

- 590 99 99 • 9 9 9 9 9

9

9 9 9 9 9

9 9 9 9

9 9 9 99 9999

Examples B-1766 to B-1789 were prepared from C-71 backbone

- 591 Example No. R ² R ^L 9 9 99 99 99 9 9 999 999 9

991 99 9 «999 ···· 9 9 9 9999

99 ·· 9900 «9 99

· «····

- 592 A AA AA AA A AAAA A * A

AAA A A A AAA

A · A ··· AAA A *

AAAA AAA AAAA

AAAA AA AAAA

Example. R ² R ^L

B-1783 Xo : / \ i i 'O i B-1784 --O? X- _O : g-SO B-1785 / ^NH i B-1786 ^F -m ÍYtJ B-1787 ^f ~ C = M ^! · U ry B-1788 ^ zOd όΛ . ΗΝ-ς 'o her B-1789 ^F- Od i ^HN \;

- 593

9999 · * ·· ·· · «9 9 9 9 9 9 9 9 9 • 9 9

9 9999 99 99 99 9 9 9 9 999 99 99 9

99 99 99 99 99

Examples B-1790 to B-1813 were prepared from a C-72 backbone

Example No. R ² R ^L

B-1790 43 _jp ..... i B-1791 ~ Ch i ⁰ ! B-1792 B-1793 Yeah P B-1794 to B-1795 i θ d B-1796 ^f X2H ^{1 0} 1 d BR i

• · · · · · · · · · · · · · · ·

- 594 ·································

Example No. R ² R ^L

B-1797 rCH o! % B-1798 KM AND 62 " ________ B-1799 i 0 i B-1800 KM I O 1 , σ i B-1801 / KM y B-1802 ! ^f -OH quarry B-1803 KM í f; ίζχΗ B-1804 ÍKM * / r \ K ^ _o i ΐ'κΖ; B-1805 KM iO / i B-1806 KM | , i S = * ° Mn

• • •

- 595 Attaches R ² R ^L

B-1807 > Λ O B-1808 O....... S M TL-wf B-1809 _f ) h -V ^; X ^NH : • B-1810 vii B-1811 ^f ~ CM B-1812 ^f -CH X l · - HN-O i '0 B-1813 OH X i ^HN Á!

· · · · · · · · · · · · · · · · · · ·

Examples B-1814 to B-1837 were prepared from C-73 backbone

Example. R ² R ^L

B-1814 B-1815 Ό B-1816 O i X B-1B17 ρ-θ— B-1818 33 ki B-1819 KM ! ⁰ I N B-1820 iKM I 0 i b ¹ BR i

9 • 9 · 9

- 598 • · 9 9 9

99 99 99 99

Example No. R ² R ^L

B-1821 Oh J-r AND B-1822 Os Rb! B-1823 ^{-0f -0H} WE ! 'and B-1824 ^{f f} -Oi B-1825 Y 8-1826 ^{! f} XM ! θΧ B-1827 rCH i ^ o | B-1828 í ^f OM I <í M i B-1829 OH cc% ° B-1830 OH ¹ X lX * o

- 598 ·· ··

Example No. R ² R ^L

B-1831 and '/'O B-1832 - <□ 'you' · and B-1833 '0 ° / NH B-1634 iY-chi B-1835 Okay 0 M f B-1835 A /, ^HN k 'o B-1837 And ^{x ΗΝ} Λ

• * · ·· ·

Examples B-1838 to B-1861 were prepared from C-33 backbone

- 600 • 9 9

9 9

9 9

9 9 9

9 9

9 9 • 9 9999

Example. R ^Z R ^L

B-1845 'KM B-1846 AND IN B-1847 OH i 0! B-1848 KM B-1849 o-s B-1850 KM -θΚ. B-1851 OH B-1852 iKM i · <i! ^N M ί B-1853 iOÁi B-1854 OH I K! i sK MM

- 601 99

9 «9

99

9 9 9

9 9

9999

99

9 9 9

9 9 9

9 9 9

9 9 9

9 9 9

Example No. R ^Z R ^L

B-1855 ^f OH oX \ ^S o B-1856 CH I A °! B-1857 Ι-Πγ ⁰ / ^NH i B-1858 Ch YtÓ B-1859 ^f ~ CH - · hl Γγ B-1860 ^fh CM Λ x HN-4 ¹ 0 B-1861 ^f OH X

- 602 · Φ Φ Φ

11 ΦΦ · · · · · · · · · · · · · · · · · · · · · · • • • • • • • •

Examples Β-1862 to

18-1885 was prepared from the skeleton C-45

Example No. R ² r ^l

- 603 φ φ φ φ φ φ «« φ φ φ * * · · · · · φ φ φ φ φ φ φ φ φ φ

Example No. R ² R ^L

Β-1869 ^c -CM Μ, Β-1870 ΚΜ C Β-1871 Ο 1 CD 'ί Β-1872 ^ø - € M 1 ο Ή Β-1873 ΌΗ Β-1874 ^f ~ Ch Β-1875 Oi ibM Β-1876 Β-1877 -CM : ΟΛ Β-1878 ΌΗ i - ^r ^ Sol i i 1

φ · · · φ φ φ φ φ φ φ φφ φ

ΦΦΦ φ ΦΦΦ · · · φ φ φ φ φ φ φ φ φ φ φ φ

- 604 9 9 9999

Example. R ² r ^l

Β-1879 Β-1880 ^ρ ΌΗ I χ ° ° ° Β-1881 / ^NH i Β-1882 <Η VxS Β-1883 ^ρ ΟΜ '· - k pp Β-1884 ^f ~ Oh Λ Λ i “Λ ¹ Β-1885 ^f OH ? Γ 1% ρ ^ην_ % *

• «

9 9

9

- 605 «·· 9

99

9

9

9999

Examples B-1886 to B-1909 were prepared from a C-42 backbone

- 606 Attached. R ² * 9 ΦΦΦΦ φφ φ φ φ φφ

Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Β-1893 Ι0Μ 0 Β-1894 ί! ó ¹ Β-1895 0Μ Β-1896 ! ^f_ 04 1 0 1 Β-1897 Β-1898 ! <i 1-00 Β-1899 ^{'F-0- F F} 1! 1900-1900 '0 1 -0! i jTV ^ o 'M i Β-1901 0M ! O8 Β-1902 l ι · ~ ν * ο i

11 • 11 1

1 • ·

- 607 Example R ² r ^l

1 111

11 1

11

111 11 1112

11 11

B-1903 C? _O , _S ? O B-1904 ^f ~ CM ! / i Even with * °! B-1905 ^f - £ M b ·: : / NHj B-1906 vúi B-1907 ^f W i - Li i + b B-1908 f- (2h λ A ^HN Á i B-1909 ^f -Oh I ^x hn-4 i I oi

- 608

999

9 9

9 9 9

99

99

9 9 9

9 9

9 9

9999

98 • 9 9 9

9 9 9

9 9 9

9 9 9

99

Examples B-1910 to B-1933 were prepared from a C-44 backbone

- 609 Example No. R ² r ^l

9 · 99 ·

99

9 9 9

9 9

9 9

9999

9 9 9

99

B-1917 ! ^fH CH B-1918 B-1919 ^f - £ M I O I · ’\ Α \ 'and B-1920 ^! o! ¥ B-1921 K i TALLOW B-1922 B-1923 B-1924 • <h B-1925 ^fh ÍM From B-1926 i X_ _o s »° | -— / * o

·

- 610 · 999 9 9999

999 ·· 9 9999 • 999 999 9999

99 99 * 999

Example. R ² R ^L

B-1927 >> - \ 1 cF \\ ^s O B-1928 '-Aoi B-1929 AM A ³ _{x x} nh; B-1930 OH YOU B-1931 O upJai ř v B-1932 'o B-1933 AM

- 611 «· · 9 ♦ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99 99

Examples B-1934 to 1957 were prepared from C-41 backbone

Example No. R ² r ^l

B-1934 ^íf KH B-1935 KM B-1936 ' ⁰ I 3! B-1937 km O 'va B-1938 ^f Oh i ⁰ i Mm B-1939 KM i ° I X! B-1940 ^'3/1 BR!

- 613 «0 0000 0 0 ·

00 • 0 · 0 • 0 00 0 0 0 • 0 0 ·

00 • · e

000 ·

0 0 00 00

000 ·

Example. R ² R ^L

- 613 -

Example No. R ² R ^L

• · • ·

Examples B-1958 to B-1981 were prepared from C-43 backbone

9

- 615 Attached. R ² R ^L

B-1965 ! O | B-1966 r-CH 1 z-o B-1967 in i 0 i Me B-1968 corner B-1969 3 B-1970 IF —— <> i + qA B-1971 B-1972 ^{| f} OH ! V | -Υ = B-1973 ^f ^ '0 / B-1974 ^f OH ! ν S i S ^ ° sn

- 616 • 0

Example. R ² R ^L

B-1975 i-F-loloi '/ * O' B-1976 -Cm i dd B-1977 ~ O4 / γ ° ' ^! / ^NH ί B-1978 KB foils B-1979 w I I Η / B-1980 ά - ^Λ -% 0 B-1981 ^F- 0 ~ i , ..... r

9

9

- 617

99

Examples B-1982 to B-2005 were prepared from a C-30 backbone

Example. R ² r ^l

B-1982 O/ 3 B-1983 CM B-1984 'CV I 0 i 'IN B-1985 ísCH B-1986 isCM B-1987 CM i O TO B-1988 BR I

- 618 A AAAA

Example. R ² R ^L

B-1989 From 1 ........... ..... ï 1 '......... B-1990 From i o; ' x, and \ s = »N i B-1991 sOd B-1992 iodine in B-1993 From d ¹ BOTTLE B-1994 Ch 0k ^o ! B-1995 From B-1996 ship ^{! IN} sO B-1997 ship OZ B-1998 From -/in

9 9 9 9

619 99 99 99

98 9 9 9 · 9

9 9 · 9 · 9

999 · 9 9

Attaches R ² R ^L

B-1999 Ox XJ gtfíU, ; / »O i B-2000 O-s i - <ol ^f d ° i B-2001 Ox P ¹ / ^NH B-2002 Ox Yo B-2003 Ox X i 1 B-2004 isQx x X ΗΝ-ς O B-2005 OX !

- 620 · · 620 620 620 620 620 620 620 - 620

4,444 94 · ·

Examples B-2006 to B-2029 were prepared from a C-60 backbone

- 621 Example.

B-2013

1

and

B-2014

“1 o ^u U i! <? \ = a> N i

B-2015

 in

B-2016 iF

B-2017

KM

B-2018

B-2019 ^; F-

 ιό ^ Ί

B-2020

B-2021

B-2022 B-2022 B-2022

l r / °

<MI

Γ

X.

If

- 622 99 9999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

9999 »10 99

φ φ φ # # # # # · ·

Examples of 20-2030 to Β-2053 were prepared from the skeleton C-36. r ² _R ^J

B-2030 From B-2031 -CM B-2032 B-2033 ^f CH B-2034 -CM O i Me B-2035 O X B-2036 -CH Ή BR

- 624 ** 99 · * 9 9 9 «φ φφφφ •« · Φ

99 ΦΦ • 99

9999

Φ · Φ ·

Φ φ Φ • · Φ

Φ Φ ·

9 9 Φ

ΦΦ ΦΦ

- 625 · 25 25 6 6 6 · · 6 · 6

Example No. R ² r ^j

B-2047 ^f -OK ó ^ W ^S o B-2048 ^f Oh ^: K _o ; KK B-2049 -KM / ^NH : B-2050 -CH —R — i i ^ V ί 5 ·, B-2051 -KK X B-2052 KM ! λ Λ IK ^; B-2053 -CH i »K Λί  —Σ;

• · · · · · · · · · ·

Examples B-2054 to B-2077 were prepared from C-34 backbone

Example. R ² R ^J

627 ·· · ·

Example No. R ² _R ^J

B-2061 ^f ~ CW I. ....____ ï AND...... B-2062 Ό4 B-2063  o < 0 AND· B-2064 ^f- OH B-2065 ^mp 0- ^ AND B-2066 ^{: f} -Oí B-2067 r <H | <ίΛ B-2068 B-2069 --O-S oA B-2070 ! ^f <H i QSSOÍ Ysí

- 628 A ··· ··· ··· «

AA ·· ·· AAAA AA ··

Example. R ² r ^j

B-2071 O WITH B-2072 f-04 OR ο ^ \\ ^ς o B-2073 O 'X ° .NH i AND B-2074 iVli B-2075 OS H-p B-2076 OH ooi i O Í B-2077 STEED R

* · · · · · · · · · · · · Β ·

Examples Β-2078 to Β-2101 were prepared from the C-57 backbone

Přfkladč. R ² r ^j

Example. R ² • 9

9 9 9 ··

9

9 9 9 9 9 • 9 9 # 9 9 · · · ·

9 · φ

9 9

9 *

- 631 • 99 • 9 9 9 9 9 9

9

9 9 9 9 9

9 9 9 9 9

9,999 9,999

Example. R ²

·

- 632

Examples B-2102 to B-2125 were prepared from C-52 backbone

Example #

- 633 Example. R ² φ φ φ φφ φ φ

- 634 Example. R ² R ^J · * · * * «*

- 635 • 99 · 9 · 9 · 9 · 9 · 9 · · 9 «f * ·

9 φ · 9 9 9 9 9 ♦ ·· 9999 999 99 9 ••• 9 999 ♦ ··· • 9 99

Examples Β-2126 to Β 2149 were prepared from C-56 skeleton

Example. R ² _R ^J

- 636 Example. R ² r ^j ·· 9999

9 «99 99 99

9 9 9 9 9

9 9 9 9 9

9 9 9 9 9

99 99 9999

9 · ·· ·

- 637 99 9999 »9 · 9

I 9 9 9 9 ·

9999

9 9 • 9

9 9

9999

99

9 9 9

9 9 ·

9 9 9

9 9 9

99

Example. R ²

- 638 • 9,999> 9 9 »9 4» 9 9 I

99 • 99 99 99

99 9 9 99 9 • 9 9 9

9,999 99 9

9 9 9 9 9

9999 98 99

Examples B-2150 to B-2173 were prepared from C-32 backbone

»0

- 639 • * 0 · »0 0 0 0 · 00 0 0 · · · 0 0« 000 00 0 0ft * 0 ·· 0000 00009 0 • 000 · 09 0 099 • 0 ·· 00 0000 ·· 0 «

- 640 • φ φ · Φ ·

Φ · φ φ φ φ φ φ φ φ • • Φ φ · · · · φ φ φ φ φ φ φ · · · φ φ φ »φ φ φ φ φ φ »··

»· 8 ··· * ·

- 641 99

9

9

9 • 9 99

9 9 9

9 9 9

9 9 9

Examples Β-2174 to Β-2197 were prepared from the C-64 backbone

Example # R ² R ^J B-2174 ^f KM < and ^{! Í} o B-2175 and 0 ^ιΛ α, B-2176 corner 0 B-2177 -OH j- L in B-2178 iKM O TO B-2179 ÍKM 0 B-2180 ^F O- ^ />

* · 99

- 642 9 9

9 · • 9 · · ···

9

9999

Example £. R ² R ^J 21-2181 r-CM ί ⁰ Μ Β-2182 ~ Ο-ί ο-ζ Μ ⁵ SE Β-2183 ίΚΜ i 0 i 3λ _; 8-2184 Β-2185 AND Β-2186 33 θΜ>) 21-2187 ΜΜ Άΐ Β-2188 ΜΜ ί 3 | _ν / γΟΜο Β-2189 ΜΜ 03 / Β-2190 ΜΜ Μ οΜ \ ^s ο

φ® ΦΦΦΦ

- 643 ΦΦ φφ · · φ · · · · φ φ · · φ φ · · φ

ΦΦΦ · φφφ φφ φφ φφ φφφφ φ φ ♦ *

Example δ. R ² R ^J Β-2191 -CM Μ \\ ^ς Β-2192 -X íf AND AND ^ ο; « Β-2193 ίΉ! / ^ΝΗ ί Β-2194 ^f- Oh hoo Β-2195 ί 0 ^Μ _X Β-2196 -From X Μ. ^ην Λ, '0 ι Β-2197 ^ 0Η χ; ην- < _ο

φ φ · · • φ φ φ · · · r r r r r r r r r r r r r r - - - - - - - - -

Examples Β-2198 to Β-2221 were prepared from the C-22 backbone

- 645 φ · · · · · · φ φ φ • • · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

- 646 · * 4 «» · · * * 64 64 64 64 64 64 64 64 64 64 64 64

fe • ·

9 ··

- 647

Examples B-2222 to B-2245 were prepared from C-29 backbone

• • •

- 648 -

Pflkladč. R ² R ^J

B-2229 Of fy. B-2230 O F B-2231 Oh B-2232 sOf IN B-2233 Fri LF B-2234 ω - 9 θΑ B-2235 Of F fy OF B-2236 sOf B-2237 OF

• ·

649 ·· · 9

Examples B-2246 to B-2269 were prepared from skeleton C-35

- 651 • A • A *

A. A. A

Φ · · · φ ·

652 • · • φφ · φ · φ · Φ ₄ · ₄

• Φ Φ • • • • • • • • •

- 653 • · • φ • φ • · φ φ

• 00 · 0

- 654 ♦ 0 · 0 0 0 • 0 0 0 0 · 0 0 0 0 • 00 0 0 · 00 0000

Examples B-2270 to B-2317

In a parallel reaction block containing 48 fritted vessels, each reaction vessel was filled with 250 mg of polymer bound carbodiimide B48 (1.0 mmol / g resin) and a C-49 skeleton solution in dimethylformamide (0.1 M, 500 μΐ). A solution of pyridine in dichloromethane (0.2 M, 100 μΐ) was added to each suspension, followed by a solution of the individual amine B47 (0.2 M, 375 μΐ) in dimethylformamide. The reaction mixture was stirred in a Labline benchtop orbital shaker at 250 rpm. for 16 to 20 hours at ambient temperature. The reaction mixtures were 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 and dimethylformamide (350 μΐ) was added to each conical vessel to dissolve the residue. A solution of terephthalic anhydride (1.0 M, 150 μΐ) in dimethylformamide was added to the reconstituted conical flasks and incubated for 2 hours at ambient temperature. Next, polyamine polymer B33 (4.0 meq N / g resin) and 1.0 mL dichloromethane were added to the reaction mixture in each conical vessel. After stirring the reaction mixture for 16 hours at 250 rpm. in an orbital shaker at ambient temperature, the mixtures were filtered through a polypropylene tube filled with a porous frit. The polymers were washed twice in dimethylformamide (1.0 mL each) and the filtrates and washes were collected in conical vessels. 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 yields for the products obtained in this way are given below.

Example δ.

B-2270

B-2271

B-2272

B-2273

B-2274

B-2275

B-2276

99 9

9 99 9 9 · 9 9 9 9 9 9 9 9 99 φ 9999

........ Σ J Í Í

IN

X _o

N — R

• 9 9 4

99 • 9 9 9 • 9 99 99

- .1

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

352

353

432

433

400

396

397

434

435

443

364

365

- 656 Example δ.

Ν-R • * φφφφ • 9 Φ · ♦ 9 · φ φ φ φ φ φ φ φ φ · 9 · · φ φ ♦ · φ · · · φ ·

Calculated mass% yield spectrum

B-2277

 ; _JL,

490

B-2278

460

B-2279

420

B-2280

B-2281

B-2282

B-2283

B-2284

B-2285

B-2286

 and

435

-NH

401

HN o

HIVE,

/

-NH

and.

390

394

423

450

506 ·· 99 • φ φ · • 9 9 9

9 9 9

9 9 9

9 φ 9

Observed Mass Spectrum (M + H)

461

436

402

413 “• M + Na

417 *

M + Na · ♦ · ·

- 657 ····················· ^B

--R ^C

K 'Calculated mass q% yield spectrum

Example #

Observed Mass Spectrum (M + H)

B-2287 i ^F "" ^ - M «d 5 437 438 B-2288 8 435 436 i ₀ 0! j B-2289 i r \ ! o ΔΎ / ~ 4 450 451 B-2290 '-Os I 8 pL0j 9 456 457 B-2291 í ^f O ~ l · jOi ? and Η I 9 415 416 B-2292 ! o Γ \; _with li /! 5 368 369 B-2293 5 ^f ~ O ~ ^ | pL _N k 5 366 367 B-2294 ! ^F CM .... ° i 5 381 382 B-2295 rOHi 16 410 411 B-2296 ! ^f -CM ¹ 4 483 -

\

Example δ.

Μ,

658 N — FT

B-2297

B-2298

; f- <i

B-2299

A if

«I, ^u !

B-2300

Pi

B-2301 r \

iJ-Out

B-2302

B-2303

B-2304

B-2305! ^F OH —g—

If

B-2306

N i tt * 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99

9999

Calculated mass% yield spectrum

490

537

507

442

396

459

482

395

460

466

99

9 9 9

9 9 9

9 9 9

9 9 9

99

Observed Mass Spectrum (M + H)

508

397

396

467

- 659 • 9,999 «

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

Example 6.

- 660

1 119

1 »11

1111 1118 11

11 19 11 11 11 11 1111

91 10 1 »11 ·

1912 19 »1 r ^b ic

N - R Observed

In analogy to the above procedures for preparing Examples B-2270 to B-2317, the following Examples B-2318 to B-2461 were prepared.

• · · · · · · ·

- 661 -

• · · · ·

662

R ² r ^b N — R ^c 0 % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2325 ° τγ ~~ o AND 41 382 383 ^f_ Oh B-2326 0 M ČQ 71 440 441 B-2327 Q- < 36 464 465 • p-ί B-2328 NH 'P i „,, ____ H 32 467 468 • PH B-2329 0 »V ^ NH ^! ζ> I ig ~~ ^> ₀ . 34 465 466 B-2330 0 ', ^ηΧΎη:! </ 26 364 365 ^f OM B-2331 0 I 38 464 465 B-2332 ύ! ί-Λ H : o i 'HOi 33 483 484 PH B-2333 0 · ΥΥ i 36 378 379 ^F ^

• I - £ O _ · · · · ··· ·

ΌΌΟ ·· ·· ·· ···· ··

R ’ _r b N — R ^c K i 0 % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2334 _f _ £ 2h • A „i 44 428 429 B-2335 o Ά _ΝΗ í O 27 Mar: 406 407 B-2336 ^f W o \ A _NH from 41 428 429 B-2337 ^F- Od Oh, i IA. γ ^ν ί I 27 Mar: 423 424 B-2338 'From Oh Onh and Oh! ^N --o 33 469 470 B-2339 HB idzA He. 52 518 519 B-2340 ⁰ ! χΆ A 64 442 443 B-2341 HB i 0 i A <^;AND' 41 350 351 B-2342 ^ Od o! 'i OVh i cY ' 34 414 415

- 666 9 9 • ·

• ·

- 665 -

R ’ r ^b N - R ^C * 0 % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2352 - AND χ · NH 0 __O. 41 482 483 B-2353 0 '0 57 438 439 B-2354 0 X 1 N H φ- ' r Γ 63 484 485 B-2355 ‘Ď ......... ? -NH O 28 536 537 0 B-2356 29 408 409 ^F_ Od 0 5 B-2357 0 Ύ * 0 Ν -Ν _x __ 41 436 437 ^fh CH B-2358 88 ...... 41 451 452 B-2359 0 1 0 57 502 503 B-2360 0 0ΝΗ 0 0 46 496 497 l ^F 0K

- 666 · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

R ^s r ^b Ň - R ^c 0 % yield Calculated wt spectrum Observed wt spectrum (M + H) Β-2361 0 ° ^H Λ W 13 476 477 Β-2362 'Κ-! i 0 H- ° i O 46 493 494 Β-2363 ^f_ Oh Γ / O R r 57 396 397 Β-2364 ^f_ Oh 0 X 1 -NH ! ,.-IN- O 61 438 439 23-2365 Κη ~ 0 i ΌΧη ^! - ° vV 0 ¹ 72 424 425

• 9 9 9 9

99 • 9

9 9 9

9 ·

9 ·

9

9 9 *

9 9 9

9 9 9

Observed

Calculated mass mass spectrum% yield spectrum (M + H)

B-2366 Oh O 34 380 381 B-2367 0 Cl MM 52 480 481 B-2368 <= - From 35 407 407 B-2369 ^F ^ 31 435 436 B-2370 -OH i ¹ M 33 414 415 B-2371 •From 0 , k 28 388 367 B-2372 KM i ⁰ Ύ í í i Y; 37 422 423

• · · · · ·

- 668 -

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

- 669 - · * ·· · «· 0 · * 0 0 0

0 0 0 · · 0 • 0 0 4 · 4 4

4 4 4 0 40 4444 0 0 0 4 0 04 l

X

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

·· A A · ·

AA

- 670 · · 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 670 · · · · · ·

R

Calculated mass% yield spectrum

Observed Mass Spectrum (M + H)

671 • 999 9 * 99

9 9 9999 999 ·

999 99 9,999

9 99 * 9 * 9 99 *

9999 999 999 *

99 99 9900 99 9 ·

- 672 · ·> * * * * *

Observed mass spectrum (M + H) κ

% yield

Calculated mass spectrum

B-2409 0 i - ^s · 0 47 448 449 B-2410 ^F Od 73 542 543 B-2411 Ξ € Β o! \ ^Λ Ν O ' 81 489 490 B-2412 0 i ^ Si, ^{1 :} Y 'i 54 409 410 B-2413 Ho and H ^'N_ \ l> ^{ο Ρ'.} 37 493 494

- 673 · * 0000

00 • 0 0

0 0

0 0 0 0000

R ² r ^b N - R ^c H % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2414 X 14 473 474 • 04 B-2415 F ^: Φ Cl 19 Dec 421 422 • 04 B-2416 0: ' ^v <Xnh O 13 388 387 B-2417 ó ^; V ^ NH • v 29 414 415 0-4 B-2418 . — Δ ---- i Φ ______WITH_.' 6 420 421 O B-2419 0 'ν ^ ΝΗ i X ^CF · 10 454 - B-2420 5 442 443 i Λ -'77 O

- 674 • 9,999

99 9 9999 999

99 «9 9 · 9 999

9999 99999 9

9999 999 9999 • 9 99 99 9

- 675 ₆ φ «« φ φ φ φ

· ♦ φ φ «· · · · · φ φ φ φ

φ φ

φφ

R * r ^b Ň — R ^c K i % yield Calculated wt spectrum Observed wt spectrum (M + H) Β-2430 ^f KM o ό ^ νη; jMx - OjN ^s ^ 'NO 15 Dec 476 477 Β-2431 KM 0 ...... I ‘ΧΜ'ΝΗ Μ '| I] 6 446 447 Β-2432 -Ob ’0 To me cM 37 404 405 Β-2433 -Ob O HER 'V'NH, i O 8 428 429 24-2434 OH 0 13 476 477 Β-2435 Ob O I Ay O 23 442 443 Β-2436 KM Λ i 'Όνη i 'Φ i 5 486 487 Β-2437 ! ^f KM ; 'SC' ^U '»I' 4 ' 4 492 493 24-2438 Mh o 'X'; · ηΟνη ^! ,-C; 58 422 423

• 9 · 9

- 676 -

R ¹ R ^{and —} — R ^c '0 % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2439 'F ^ nh Φ CF, 12 454 455 AM B-2440 . ... ₀ - X = NH HN - $ ... fy °. .: 8 521 522 OH B-2441 TZsT A ° 0 6 443 444 OH B-2442 lóA 37 514 515 B-2443 _.G---------- 15 Dec 518 - OH B-2444 AŽ? 52 520 - B-2445 ΪΑ 33 517 518 ' ^f AM B-2446 5 ¹ F M 6 70 500 501 • Oh B-2447 v ^{.: lr} p: v 56 488 489 Íf—

• · • ·

- 677 ·· · ···

0 · 0 · 0

- 679 0 0 0 0

0 0 0

0 ·

0 0

0 0 0 0000

R ’ r ^b N - R ^c 'K % yield Calculated wt spectrum Observed wt spectrum (M + H) B-2457 ^f Kh AND" 0¾ 55 540 - B-2458 ^f -K-] 0: ^χΑ -, 0 22nd 488 489 B-2459 O V, NH 'Ol. WITH CF 8 486 487 B-2460 '· O αΛνη pí 13 534 535 B-2461 KB ₀ i.xy, ₀ A _f 13 542 -

• 9 • 9 9 9 9 • 9

679 Example C-1

5-Aminomethyl-4- (4-pyridyl) -3- (4-fluorophenyl) pyrazole

1- (4-Fluorophenyl) -2- (4-pyridyl) -1-ethanone.

4-picoline (40 g, 0.43 mol) was added to the LiHMDS solution (0.45 mol, 450 mL, 1.0 M solution in THF) over 30 minutes at ambient temperature (slight exotherm was observed). The resulting solution was stirred for 1 hour. This solution was added to ethyl 4-fluorobenzoate (75.8 g, 0.45 mol, anhydrous) over 1 hour. The mixture was stirred overnight (16 hours). Water (200 mL) was added and the mixture was extracted with EtOAc (2x200 mL). The organic layer was washed with brine (1 x 100 mL) and dried over Na ₂ SO ₄ . The organic layer was filtered and the solvent was removed leaving an oily solid. Hexane was added to the oil and the resulting solid was filtered and washed with hexane (cold). A yellow solid (50 g, 54%) was isolated:

1 H NMR (CDCl ₃ ) δ 8.58 (d, J = 5.7 Hz, 2H), 8.02 (dd, J = 5.5, 8.0, 2H), 7.12-7.21 ( m, 4H), 4.23 (s, 2H);

¹⁹ F NMR (CDCl 3) δ -104.38 (m);

LC / MS, t _r = 2.14 minutes (5 to 955 acetonitrile / water over 15 minutes at 1 mL / min, at 254 nm at 50 ° C), M + H = 216;

• • •

- 680 High resolution mass spectrum calculated for C ₂₃ H ₂₀ N ₄ O ₂ F (M + H): 216, 0825.

Found: 216.0830 (Δ mmu = 0.5).

N-benzyloxycarbonyl-5-aminomethyl-4- (4-pyridyl) 3- (4-fluorophenyl) pyrazole.

A 1 flask equipped with a mechanical stirrer, an N ₂ inlet and an additional funnel was charged with 557 mL (0.56 mol) of 1 M tBuOK in THF and 53 mL (0.56 mol) of t-BuOH. Ketone 1 (60 g, 0.28 mol) was dissolved in 600 mL THF and added to the stirred mixture at ambient temperature. A yellow precipitate formed and the mixture was stirred for 1 hour. N-Benzyloxycarbonyl-glycinyl N-hydroxysuccinimide (128.6 g, 0.42 mol) was dissolved in 600 mL of THF and added dropwise at ambient temperature over 1 hour. The mixture was stirred for an additional 5 minutes and 150 mL of water was added. The pH was adjusted to 6.7 with 70 mL of AcOH. Hydrazine monohydrate (41 mL in 100 mL water) was added via additional funnel. The mixture was stirred for 1 hour and was diluted with 500 mL water and 500 mL ethyl acetate. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3x300 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give 157 g of a crude reddish oil.

The oil was suspended in CH ₂ C1 ₂ and filtered to remove any insoluble material (DCU, hydrazone monoketone). The solution was divided into two portions and each portion was chromatographed (Biotage 75L, 3% EtOH / CH ₂ Cl ₂ then 6% EtOH / CH ₂ Cl ₂ ). The corresponding fractions were concentrated (some contamination with monoketone and hydrazone) from each section to give a yellow solid. The solid was suspended in ethyl acetate and heated to boiling for 10 minutes.

• · · · · · · · · · · ·

- 682 ·· · ·

The solution was allowed to cool to ambient temperature overnight. The precipitate was filtered to give 30 g of a white solid (27% yield 2):

^{Χ Η} NMR (DMF-d7) δ 13.36 (s, 1H), 8.57 (d, J = 5.8 Hz, 2H), 7.16 to 7.52 (m, 11H), 5.11 (s, 2H), 4.48 (d, J = 5.4 Hz, 2H); ¹⁹ F NMR (DMF-d7) δ -114.9 (m), -116.8 (m) (split fluorine signal due to pyrazole tautomers);

LC / MS, t _r = 3.52 minutes (5 to 25% acetonitrile / water over 15 minutes at 1 mL / min, at 254 nm at 50 ° C), M + H =

03;

High resolution mass spectrum calculated for C 21 H 20 N 4 O 2 F (M + H): 403, 1570.

Found: 403.1581 (Δ mmu = 1.1).

5-Aminomethyl-4- (4-pyridyl) -3- (4-fluorophenyl) pyrazole.

To a 1 L Parr bottle was added 7 g (17.4 mmol) of 2 and 180 mL of MeOH and 90 mL of THF to give a clear solution. The bottle was flushed with nitrogen and 1.5 g of 10% Pd / C (wet Degussa type E101) was added. The Parr bottle was pressurized to 40 psi (H ₂ ) and stirred. Hydrogen consumption was 5 psi after hours. The bottle was pressurized to 42 psi and stirred overnight. The bottle was purged with N ₂ and the contents filtered through Celite. Celite was washed with MeOH (3x50 mL) and the filtrate was concentrated to give 4.5 g off-white solid (94%) ^X H NMR (DMSO-d ₆₎ δ 8.52 (d, J = 4.63 Hz, 2H), 1.36 (dd, J = 5.64, 8.1 Hz, 2H), 7.16-7.30 (m, 4H), 3.79 (s, 2H);

¹⁹ F NMR (DMSO-d ₆ ) δ -114.56 (m);

LC / MS, t _r = 1.21 min (5 to 95% acetonitrile / water over 15 min at 1 mL / min, at 254 nm at 50 ° C), M + H = • 9 • 99 9

- 682,269 m / z;

High resolution mass spectrum calculated for C ₁₅ H ₄ N ₄ F (M + H): 269.1202.

Found: 269.1229 (Δmmu at 2.7).

The following pyridylpyrazoles (C-2 to C-21, Table C-1) were prepared as described for Example C-1 above.

Table C-1.

Example C. Structure MW (M + H) Calculated and found ¹ H NMR (solvent), ppm C-2 N-NH 323.1672 (DMF-d 6): 8.77 (t, J = F-' 1 t___nh O N 323.1670 4.4 Hz, 2H); 7.60 (m, 2H); 7.44 (t, J = 4.4Hz, 2H); 7.35 (m, 2H), 3.22 (bd, 2H), 3.01 (septet, .delta. = 5.3) Hz, 1H), 2.74 (m, 2H). 1.95 (m. 4H)

• · φ φ · ♦

- 683 · φ>> 68 68 68 68 68

φφφφ ·· φ · · • • · · <

C-3 F- Ο N-NH -FF O N NH, CH ₃ 282.127 (M) 282.1245 (El,)) (DMF-d 2): 3.77 (br s, 2H), 7.64-7.62 (m, 2H); 7.50 (br s, 2H); 7.38-7.34 (m. 2H), 4.40-4.37. 1H), 1.56 (brs, 3H) C-4 Ό N-NH FF ^ NH3 282.127 (DMF-d _7): 8.77 (br s, F' čh ₃ (M) 2H), 7.64-7.62 (m, 2H); O N 282.1147 7.50 (br s, 2H), 7.38-7.35 (El,)) (m, 2H), 4.40-4.37 m 1H), 1.57 (brs, 3H) C-5 fy N-NH 323.1672 (DMSO-d6): 8.56 (br. 2H); F' 323.1687 7.32 (m, 2K), 7.18 m t} N 4H), 2.91 (m, 2H), 2.71 (m, 2H) 1.88 (m, 1 H), 1.65 (m, 2H); 1.40 (m, 2H); C-6 FY N-NH b i. <- ^{NH 1} 359 (DMSO-d6): 8.46 <d, J = F Fi 359 4.6 Hz (2H), 7.32-7.13 (m, u J) IN 7H), 6.98-6.96 (m, 4H); 4.06 (t, J = 7.0Hz, 1H). 2.98-2.95 (m. 2H) C-7 FV N-NH F Ϊ. z * ^nh 2 359 (DMSO-d _6): 8.46 (d, J = F 359 5.4 Hz (2H), 7.32-7.28 (m, řii »] N 2H), 7.20-7.12 (m, 5H >, 6.98-6.96 (m. 4H); 4.06 (t, J = 7.0 Hz, 1 H), 2.98- 2.94 (m. 2H) C-8 -θ ' N-NH FF- .NHj 313.1465 (DMSO-d6): 13.83 (bs, F' (Fl ^ OCHj 313.1492 1H), 8.61 (d, J = 5.7Hz, N 2H), 8.33 (bs, 1 H), 7.33 (m. 6H); 4.44 (m. 1H); 3.63 (m, 2H); 3.27 (s, 3H).

- 684 C-9 et seq

C-11 φφ

N-NH

νη ₂

OCH,

313.1465 313.1457

F

N-Nri

C-12

F

N-NH

C-13

F

354

354

283.1359

283.1363 (DMSO-d 6): 8.55 (dd, J =

1.5 Hz, 4.4 Hz, 2K), 7.37- 7.32 (m. 2H); 7.26 (dd, J = 1.6, 4.4 Hz , 2H) , 7.22- 7.16 (m, 2H). 4.06 (z, J = 6.5 Hz, 1H 3.49 (d, I - 6.6 Hz, 2H) 3.20 (2H, 2H)

(DMSO-d ₆ ): 13.03 (bs, 1H), 8.50 (dd, J = 1 '). 6, 2. ' 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, 1 H), , 2.45 (d, J = 4.5Hz, 3H) 1.97 (t, J = 7.4Hz, 2H) , 1.85 (dt, J = 7.3, 7.1Hz) , 2H)

(DMSO-d 6): 13.03 (bs,

1H), 8.50 (dd, J = 1. 6, 2.7 Hz, 2K) 7.58 (bq, J = 4.3 Hz, 1H) , 7.3 (m, 2K),

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 (DMSO-d6): 5.0 Hz, 2H),

7.1 Hz, 2H) 8.53 (d, J = 7.37 - 7.32 (m,

2H), 7.21-7.17 (m, 4H), 2.83 (d, J = 6.0 Hz). 2H), 2.77 (d, J = 6.0Hz, 2H) 297.1515 (DMSO-d 6): 8.53 (d, J =

297.1515 (5.4 Hz, 2H). 7.34 (dd, J =

5.8, 8.2 Hz, 2H), 7.18 ·

- 686 • ·

9 9

9 • 9 9

99

(dd, J = 5.8, 9.8 Hz, 4K, 2.68 (t, J = 7.3 Hz, 2H) 2.52 <m, 2H), 1.64 (m. 2H)

C-14

C-15

C-16

C-17

234.0829

284.0806

285

285

329, 331

339

339 (CD ₃ OD): 8.74 (br, 2H)

7.77 (br. 2H), 7.45-7.58 (br, 3H), 7.30-7.40 (br, 2H), 4.43 (5, 2H) (DMSO-d6): 8.53 (br, 2K)

7.56 (br, 2H), 7.26 (m, 4H), 3.75 (br, 2H) _(DKSO-d6):

4.4 Hz, 2H) 7.42 7.9 Hz, 2 H !, 7.34 8.5 Hz, 2H>, 7.24 4.6 Hz, 2H) 3.76 (DMSO-d _6): 8.53 4.3 Hz, 2H) 7.33 7.19 4.6: 7.14 7.3:

8.53 (d, J =

3.23 (m, 2H); 2.88 (m, 2H)

3H), 1.92 (m, 3H), 1.70 (m, 1 H)

C-18

Cl

N-NH

339

339

(DMSO-d _6): 8.57 (d, J = 4.6 HZ, 2H) 7.41 (d, J = 8.3 Hz, 2H) 7.29 (d, J = 8.5 Hz, 2H) 7.20 (d, J =

C-19

Br

N-NH

383,385 383,385

Ηε 4.8, 2H), 3.18 (bd, 2H), 2.88 (m, 1H), 2.75 (m, 2H), 1.82 (br, 4H) (DMSO-d _6): 8.56 (br, 2H) 7

7.52 (br. 2H); 7.14-7.29 (m. 4H); 2.99 (br. 2H);

- 686 · * * 9 9 9 9 9 9 9 9

9 9 9 9 9 9 ·· 99 99 9999

9 9 9

9 9 9

9 9 9

9 9 9

9 9 9

99

2.71 (br, 1R), 2.51 (br, 2 H>, 1.68 (br, 4H)

The following pyridylpyrazoles (C-22 to C-40, Table C-2) were prepared using the general schemes C-1 and C-2 and the experimental procedure described in Example C-1 above.

Table C-2

Ciripc. No. Struccure C-22 N-NH C' O brS N C-23 Ό N-NH ^ NH _? F Yk L, j N = / C-24 O N-NH L. F' Vnh l J N = /

• · · · · ·

- 687 -

• 9 ···

- 690 99

9 ·

9

9 9 9

9 <· ·

9 9 • 9 99 9999

· • · ·

• 9 • 9

- 689 99 99 99 99

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

9999 98 99

C-45 N-NH _H- R '-NH C-46 N-NH _u C-47 N-NH O C-48 N-NM _H F ^{N XCH 3}

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 NaOH. Ammonium tetrabutyl hydroxide (0.5 mL of 1 M aqueous solution) was added to the stirred mixture. To this mixture was added t-butyl bromoacetate (2.10 g, 10.8 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The mixture was poured onto 200 ml of CH ₂ C1 ₂ and 200 ml H ₂ O • · »· *

- 690 -

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 Na ₂ SO ₄ and filtered. The solvent was removed to give an off-white solid. This solid was triturated with hexane and the resulting solid collected by filtration. The solid was washed with hexane to give 3.4 g of a white solid (90%).

Step B

The alkylated pyrazole (3.7 g, 10.1 mmol) from Step A was treated with 57 mL of 4 N HCl in dioxane. The solution was stirred at ambient temperature for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in THF. The solution was treated with propylene oxide (10.3 mmol) and stirred for 1 hour at ambient temperature. The solvent was removed to give an oil. The residual solvent was expelled with several portions of EtOH. The resulting solid was triturated with Et ₂ O and the title compound C-49 was isolated by filtration to give 3.0 g of an off-white solid (95%).

Mass Spectrum: M + H Calc: 312; found 312.

¹ H NMR (DMSO-d ₆ ): 8.81 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 5.8 Hz, 2H), 7.40 (m, 2H) 7.23 (t, J = 8.5Hz, 1H), 5.16 (s,

2H), 2.40 (s, 3H).

Example C-50 »9« ···

- 694 99 »9

9 9 9 • 9 9 9 9

9 9 9 9 9

99 99 9999 · 9

9 9 9 '

9 9 9

9 9 9

9 9 9

99

Following the procedure described in Example C-49 above, Example C-50 was also prepared starting from 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine.

Mass Spectrum: M + H calculated: 298; found 298.

¹ H NMR (DMSO-d ₆ ): 8.75 (d, J = 6.4 Hz, 2H), 8.68 (s, 1H),

7.78 (d, J = 6.6 Hz, 2H), 7.52 (dd, J = 5.4, 8.5 Hz, 2H),

7.31 (t, J = 8.9 Hz, 2H), 5.16 (s, 2H).

Example C-51

Starting from N-Boc-piperidinyl, the analogue of Example C-2, Example C-51, was also prepared as described in Scheme C-1.

Example C-52 ·· ····

692 • φ φ ·· · -

Ν-ΝΗ

Ν

Η

Step A: Picoline was treated with a base selected from, but not limited to, n-BuLi, LDA, LiHMDS, tBLOK, or NaH, in an organic solvent such as THF, ether, t-BLOH or dioxane at -78 ° C to 50 ° C for 10 minutes to 3 hours. The picoline solution was then added to the Ν-Cbz- (L) -phenylalaninyl solution

N-hydroxysuccinimide. The reaction 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, the pyridyl monoketone was isolated as a crude solid which can be purified by crystallization and / or chromatography.

Step B: A solution of pyridyl monoketone in ether, THF, tBuOH, or dioxane was added to the base selected without being limited to n-BuLi, LDA, LiHMDS, tBuOK.

9 or NaH contained in hexane, THF, ether, dioxane or tBuOH at -78 ° C to 50 ° C for 10 minutes to 3 hours. Formic and acetic anhydride was then added as a solution in THF, ether, or dioxane to the monoketone anion while maintaining the temperature between -50 ° C and 50 ° C. The resulting mixture was allowed to stir at this temperature for 5 minutes to several hours. The resulting pyridyl diketone was used immediately without purification in Step C.

Cbz

Step C: The solution containing the pyridyl diketone was poured in water and the pH was adjusted to between 4 and 8 using an inorganic or organic acid selected from HOAc, H ₂ SO ₄ , HCl, or HNO ₃ . The temperature during this step was maintained between -20 ° C and ambient temperature. Hydrazine or hydrazine hydrate was then added to the mixture while maintaining the temperature between -20 ° C and 40 ° C for 30 minutes to several hours. The mixture was then poured into water and extracted with an organic solvent. The N-Cbz-protected pyridylpyrazole was obtained as a crude solid, which was purified by chromatography or crystallization.

- 694

Step: D

The CBZ protecting group was cleaved using hydrogen gas under pressure and in the presence of Pd-C in an alcoholic solvent, giving the C-52 skeleton after filtration and concentration.

The following compounds C-53 to C-59 in Table C-3 were prepared using the general method described above for the preparation of C-52.

- 695 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Table C-3

Example # Structure C-53 N-NH h ₂ n -γ-Η ÍJ k j N

- 696 ·· ··

C-54 H ₂ Nv a N-NH 3/1 and '0 N ^z Boc C-55 ^H 2 ^N x hon N-NH 7 / V O N ^z Boc C-56 h ₂ n-nh H < y ó N C-57 h ₂ n H 4 Ai N C-58 H ₂ N _x N-NH <.nh-Boc O rH 1¾. 9 N C-59 h ₂ n N-NH NH-Boc O Λ N

Example C-60

Step A:

The Boc protected pyridylpyrazole was treated with benzaldehyde in methylene chloride at ambient 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.

Step B:

The pyridylpyrazolimine was dissolved in THF and stirred under a nitrogen atmosphere at a temperature ranging from -78 to -20-C. A base such as LDA, η-BuLi, or LiHMDS was added dropwise to the mixture, which was then stirred for an additional 10 minutes to 3 hours. Two equivalents of methyl iodide were then added to the mixture and stirring was continued for several hours. The reaction was then quenched with acid and the mixture was allowed to warm to ambient temperature and stirred for several hours until cleavage of Boc and imine functionality was complete. The pH was adjusted to 12 and then the mixture was extracted with an organic solvent, dried and the solvent was evaporated. The crude pyridylpyrazole was then crystallized and / or chromatographed to give purified C-60.

• «

StepB

1) Base

2) Mel

3) Acid, Η_ρ

Example C-61

Example C-61 was 60, using 1,4-dibromobutane instead of methyl iodide prepared as described in Example C.

Example C-62

Example C-62 was prepared as described in Example C 60 using 1,3-dibromoethane instead of methyl iodide.

·· · ♦ ·· •

- 699

Example C-63

The synthesis of compound C-63 begins with the condensation reaction of brom77ale anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride. Maleimide B78 was then treated with 4'-fluoroacetophenone in the presence of a catalytic amount of Pd ₂ (dba) ₃ and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. B79 was then treated with tert-butoxybis (dimethylamino) methane to give the α-ketoenamine B80. acetoenamine B80 was condensed with hydrazine to form the N-protected maleimidpyrazole B81. The 2,4-dimethoxybenzyl group was cleaved by ceric ammonium nitrate (CAN) to give the title compound C-63.

NH _and NH _? and

B81

MeO

C-63 •

700> ♦ · · * * * *>>>>>>>>>>>

Example C-64

nh ₂

Using the method described in Schemes C-6 and C-7, Example 64 was prepared.

Example C-65

Using the method described in Schemes C-6 and C-7, Example 65 was prepared.

Example C-66

- 701 999 9 • 9 99 • 9 9

9 9 ·· 9999 ·· ··

9 9 • 9 9 9 9

9 9 • 9 99

Using the method described in Schemes C-6 and C-7, Example C-66 was synthesized using

N-2,4-dimethoxybenzyl-4-bromopyridone instead of B78.

Example C-67

Using the method described in Schemes C-6 and C-7, Example C-67 was synthesized using

N-2,4-dimethoxybenzyl-4-bromopyridone instead of B78, using N-Boc-glycyl N-hydroxysuccinimide instead of B82.

Example C-68 · φφφφ

- 702-ϊ ϊ 'φ • Φ φ

V Φ · φ φ φ φ φ * φ φ φ • φ φφ

νη ₂

Using the method described in Schemes C-6 and C-7, Example C-68 was synthesized using

N-2,4-dimethoxybenzyl-4-bromopyridone instead of B78.

Example C-69

Using the method described in Schemes C-6 and C-7, Example 69 was prepared using N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-70 φφ φφφφ

ΦΦ φ φ

- 703 φ φ · · · · · · · · • • • · · · · ·

Using the method described in Schemes C-6 and C-7, Example 70 was prepared using N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-71

Using the method described in Schemes C-6 and C-7, Example 71 was prepared using N-methyl-3-bromo-maleimide instead of B78.

Example C-72

- 704 •

Using the method described in Schemes C-6 and C-7, Example 72 was prepared using N-methyl-3-bromo-maleimide instead of B78 and N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Example C-73

Using the method described in Schemes C-β and C-7, Example 73 was prepared using N-methyl-3-bromo-maleimide instead of B78 and N-Boc-nipecotyl N-hydroxysuccinimide instead of B83.

Biological data of the compounds of Examples B-0001 to B-1513 and Examples B-2270 to B-2462 are shown in the following tables.

In vitro inhibition data of P38 alpha kinase are shown in the column labeled:

0 0 0

0

- 704 0 · 0 ·

0 0 ·

IC ₅ op38 alpha kinase μΜ or% conc. (μΜ)

An in vitro whole cell assay to measure the ability of compounds to inhibit TNF production in human U937 cells stimulated with LPS is shown in the column labeled:

IC50 U937 cells, μΜ or% conc., (ΜΜ)

An in vivo determination of the ability of compounds to inhibit LPSstimulated TNF release in mice is shown in the column labeled:

Mouse LPS model,% TNF inhibited dose pre-dosing time.

wherein the dose is reported in milligrams per kilogram (mg / kg) administered by oral gavage and the duration of the dosages. is the time before the test compound was administered prior to LPS administration.

The in vivo determination of the ability of compounds to inhibit LPSstimulated TNF release in rat is shown in the column labeled:

Rat LPS model,% TNF inhibited dose pre-dosing time.

wherein the dose is reported in milligrams per kilogram (mg / kg) administered by oral gavage and the duration of the dosages. is the time before the test compound was administered prior to LPS administration.

- 706 - * .. · · ..

Example # IC ₆₀ p38 alpha kinase mM or% conc. (μΜ) IC _{50 of} U937 cells, mM or% inhibitor conc., (ΜΜ, Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0001 53.0%@1.0uM 40.0% 01.OUM B-0002 71.0%@1.0uM 28.O% 01O.OuM B-0003 70.0% ®1.0uM 76.0% IO.OuM B-0004 80.0% ®1.0uM 4.61 UM B-OOO5 9S.O% 01.OuM 2.97uM B-OOO6 82.0%@1.0uM 8 0% @ IO.OuM B-0007 74.0% @ 1.0µM 85.0% ®10.0uM B-OOO8 42.0% ®1.0uM 65.0% ®10.0uM B-0009 0.04 µM 0.72UM B-OOIO 0.52 µM 0.65UM B-0011 0.03 µM 4.47UM B-OO12 33.0% © 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-OO15 82.0% ®1.0uM 80.0% ®10.0uM B-0016 94.0°/o@1.0uM 3.98uM B-0017 56.0% ®1.0uM 79.0% ®10.0uM B-OO18 6O.O% 01.OuM 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 70.0% © 1.0uM 44.0®1.0uM B-0023 89.0% © 1.0uM 77.0% ®10.0uM B-0024 94.0% ®1.0uM 52.0% ®1.0uM B-OO25 89.0%@1.0uM 79.0% ®10.0uM B-0026 94.0% © 1.0uM 3.27uM B-0027 93.0% © 1.0uM 11.0uM B-0028 69.0% ®1.0uM 45.0% ®10.0uM B-OO29 91.O% 01.OuM 5B.O% 01O.OUM B-0930 92.0% ®1.0uM 75.0% 010.0µM B-0031 94.0% ®1.0uM 100.0% ®10.0uM B-0032 94.0% ®1.0uM 78.0% ®10.0uM B-0033 100.0% © 1.0uM IO.OuM B-0034 94.0% © 1.0uM IO.OuM B-0035 94.0% ®1.0uM 10.0uM B-0036 92.0% ®1.0uM 8.24uM B-0037 91.0% ®1.0uM B8.O% 01O.OuM B-0038 71.0% ®1.0uM 84.0% ®10.0uM B-0039 B9.O% 01.OuM 72.0% ®10.0uM B-0040 93.0% ®1.0uM 2.3uM B-0041 65.0% ®1.0uM 66.0% ®10.0uM B-OO42 94.0% ®1.0uM 2.76uM

- 707 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example # IC ₆₀ p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0043 0.22 µM 0.54uM B-0044 0.14 µM 0.19uM B-0045 94.0% 91.0µM 1.01 UM B-0046 96.0% <81, From M 54.0% 91.0µM B-0047 94.0% 91.0µM 74.0% 910.0µM B-0048 94.0% 91.0µM 76.0% 910.0µM B-0049 88% 91.0 µM 33.0% 91.0µM B-OO50 73% 91.0µM 34.0% 91.0µM B-OO51 3.3uM 2.15UM 46% 9100trig / kg @ -6h 79% 9 3 mg / kg -44h B-0052 92% 91.0µM 15.0% 91.0µM 6 * 0053 95% 91.0µM 34.0% 91.0µM B-0054 90% 91.0µM 30.0% 91.0µM B-OO55 93% 91.0µM > 1.0uM B-0056 96% 91.0µM 21.0% 91.0µM B-0057 96% 91.0µM 29.0% 91.0µM B-0058 79%@1.0uM 18.0% 91.0µM B-0059 83% 91.0µM 35.0% 91.0µM B-0060 73% 91.0µM 22.0% 91.0µM B-0061 62%@1.0uM 27.0% 91.0µM B-0082 94% 91.0µM 36.0% 91.0µM B-0063 96% 91.0µM 40.0% 91.0µM B-0064 90% 91.0µM 4.0% 91.0µM B-0065 83% 91.0µM 21.0% 91.0µM B-0066 94% 91.0µM 28.0% 91.0µM B-0067 91%@1.0uM 1.0% 91.0µM 8-0068 72% 91.0µM 22.0% 91.0µM B-0069 96% 91.0µM 37.0% 91.0µM B-0070 92% 91.0µM 30.0% 91.0µM B-0071 86% 91.0µM 31.0% 91.0µM B-0072 77% 91.0µM 32.0% 91.0µM B-0073 91% 91.0µM 24.0% 91.0µM B-0074 92% 91.0µM . 42.0% 91.0µM B-0075 91% 91.0µM 35.0% 91.0µM B-OO76 58% 91.0µM 21.0% 91.0µM B-0077 0.8uM 10.0uM B-0078 80%@1.0uM 20.0% 91.0µM B-0079 93% 91.0µM 13.0% 91.0µM B-0080 73% 91.0µM 73.0% 91.0µM B-0081 92% 91.0µM 13.0% 91.0µM B-0082 47% 91.0µM 27.0% 91.0µM B-0083 0.22uM 6.51 µM B-0084 56% 91.0µM 30.0% 91.0µM

9 9 9 9 9 9 9 9

9,999,999 9

9 9 9 9 9

9999 98 99

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0085 83% ®1.0uM 21.O% 01.OuM 8 * 0086 91%@1.0uM 37.0% ®1.0uM B-0087 0.5SuM 2.26uM 38% ®30mg / kg® -6h B-0088 96% ®1.0uM 9.0% ®1.0uM B-0088 0.04uM 3.33uM B-0090 98% ®1.0uM 52.0% ®1.0uM B-0091 96%@1.0uM 40.0% © 1.0uM B-0092 97% ®1.0uM 34.0% ®1.0uM 8-0093 3.18 UM 1.25UM 30% ®30 mg / kg® «6h B-0094 96% ®1.0uM 50.0% © 1.0uM B-0095 98%@1.0uM 38.0% ®1.0uM B-0096 91% ®1.0uM 21.7% © 1.0uM B-0097 73.0% © 10.0uM 40.0% © 1.0uM B-0098 66.0%@10.0uM 11.7% © 1.0uM B-0099 45.0% © 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 55.0% @ 1.0uM 2.78uM B-0105 78.0%@1.0uM 5.0uM B-0106 62.0% ®1.0uM 5.0uM B-0107 0.27UM 5.0 µM B-0108 61.0% ®1.0uM 4.85UM B-0109 45.0% ®1.0uM 18.7% © 1.0uM B-0110 67.0% © 1.0uM 13.0% ®1.0uM B-0111 57.0% ®1.0uM > 1.0uM B-0112 100.0% © 1.0uM 1.12uM B-0113 75.0%@1.0uM 43.0% ®1.0uM B-0114 45.0% ®1.0uM 3.92UM B-0115 50% © 1.0uM 2.0% ®1.0uM B-0116 74.0% © 1.0uM 33.0% © 1.0uM B-0117 0.46 µM 1.78 µM 30% @ 30'g'kg @ -6h B-0118 1.18 UM 129 µM B-0116 89.0% ®10.0uM 2.78uM B-0120 0.008 uM 0.21 uM 77% ® 100 mg / kg ® -6h 70% @ 3 mg / kg®-4 hr 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 71.0% © 10.0uM 17.0% ®1.0uM B-0126 66.0% ®1.0uM 1.57uM

- 709 «· · ·

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0127 82.0% @ 1 .OuM 0.96uM B-0128 78.0%@1.0uM 1.81UM B-0129 51.0%@1.0uM 31.0%@1.0uM B-0130 69.0% @ 1.OuM 58.0%@1.0uM B-0131 43.0%@1.0uM 46.0%@1.0uM B-0132 75.0% ® 1.OuM 8.0% ® 1.OuM B-0133 51.0% ®1.0µM 42.0%@1.0uM B-0134 60.0% ® 1.OuM 2.17uM B-0135 78.0% ® 1.OuM 58.0% @ 1.OuM B-0136 77.0% ®1.0uM 44.0%@1.0uM B-0137 41.0%@1.0uM 37.0% ® 1.OuM B-0138 50.0% @ 1.0 UM 32.0% @ 1.OuM B-0139 54.0% ®10.0uM 17.0% ® 1.OuM B-0140 67%@10.0uM 9.0% ® 1.OuM B-0141 78.0% @ 1.0 UM 10.0% ®1.0uM B-0142 85.0% ® 1.OuM 12.0% ® 1.OuM B-0143 42.0% ®1.OuM 3.63uM B-0144 86.0% ®1.0uM 43.0% ® 1.OuM B-0145 54.0% @ 10.0uM 13.0% @ 1.0uM B-0146 77.0% ®10.0uM 27.0% @ 1.0uM B-0147 44.0% @ 1.OuM 22.0% @ 1.OuM B-0148 50.0% © 1.0uM > 1.0uM B-0149 1.15 µM 10.0 UM B-0150 27.0% ®10.0uM 34.0% @ 1.0uM B-0151 43.0% ®1.OuM 30.0% ®1.0uM B-0152 51.0% ®1.0µM 25.7% © I.OuM B-0153 58.0% @ 1.0uM 20.0% @ 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.OuM B-0157 48.0% 910.0UM 9.0% ®1.0uM B-0159 58.0% OlO.OuM 40.0% © 1.0uM B-0159 54.0% OlO.OuM 1.0% @ 1.0uM B-0160 59.0% OlO.OuM 25.0% @ 1.0uM B-0161 72.0% ®1O.OuM 12.0% @ 1.0uM B-0162 23% ®1.0uM 2.05 µM B-0153 20.0% OlO.OuM 5.0% @ 1.0uM B-0164 37.0% ®10.0uM 21.0% © 1.0uM B-0165 70.0% @ 10.0uM 18.0% @ 1.0uM B-0166 45.0% ®10.0uM 36.0% @ 1.0uM B-0167 40.0% ®1.0µM 37.0% ®1.0uM B-0168 45% @ 1.OuM 2.36 µM

· AAA · A

- 710 • A A · ·

A · A

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Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC _S0 U937 cells, mM or% inhibitor conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0169 43.0% AI.OuM 21.0% AI.OuM B-0170 43.0% AI.OuM 30.0% AI.OuM B-0171 61.0% A10.0µM 21.0% AI.OuM B-0172 16.0% A10.0µM 11.0% AI.OuM B-0173 33.0% A10.0µM 48.0% AI.OuM B-0174 54.0% AlO.OuM 43.0% AI.OuM B-017S 41.0% ®10.0uM 31.0% AI.OuM B-0176 50.0% AI.OuM 30.0% AI.OuM B-0177 70.0% AlO.OuM 27.0% AI.OuM B-0178 12.0% AlO.OuM 35.0% AI.OuM B-0179 27.0% AlO.OuM 37.0% AI.OuM B-0180 34.0% AlO.OuM 23.0% AI.OuM B-0181 5.0% AI.OuM 2.0% AI.OuM B-0182 39.0% AlO.OuM 40.0% AI.OuM B-0183 12.0% AlO.OuM 34.0% AI.OuM B-0184 66.0% AlO.OuM 17.0% AI.OuM B-0185 65.0% AlO.OuM 25.0% AI.OuM B-0186 40.0% AI.OuM 25.0% AI.OuM B-0187 4.0% AlO.OuM 14.0% AI.OuM B-0188 70.0% AlO.OuM 35.0% AI.OuM B-0189 42.0% AlO.OuM 9.0% AI.OuM B-0190 59.0% AlO.OuM 31.0% AI.OuM B-0191 40.0% AI.OuM 29.0% AI.OuM B-0192 12.0% AlO.OuM 47.0% AI.OuM B-0193 0.54 µM 6% A1.0µM B0194 1.31 µM 22% AI.OuM B-0195 1.03 µM 55% Al.OuM B-0196 2.24 µM > 1.0uM B-0197 2.0 UM 14% AI.OuM B-0198 1.2 µM 2% A1.0µM B-0199 1.34 µM 3% A1.0µM B-0200 1.31 µM 16% Al.OuM B-0201 0.29 µM 59% Al.OuM B-0202 0.55 UM 2.26 uM B-0203 0.16 µM 65% Al.OuM B-0204 0.21 uM 48% Al.OuM B-0205 0.096 µM 54% A1.0UM B-0206 5.76 µM 14% AI.OuM B-0207 0.12 µM 52% A1.0µM B-O2O8 0.067 uM > 1.0uM B-0209 0.29 µM 8% Al.OuM B-0210 0.057 uM 67% A1.0µM

• 4 · ♦ * · »711 - ·· ·« ► ♦ * <

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Example 6. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0211 0.25 µM 30% 41.0µM B-0212 0.12 UM 28%@1.0uM B-0213 0.31 µM 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 UM 18%@1.0uM B-0219 0.91 µM 18%@1.0uM B-0220 0.13 µM 40%@1.0uM B-0221 2.4 µM > 1.0uM B-0222 0.4uM. 29.0%@1.0uM B-0223 0.2uM 1.0% 41.0µM B-0224 <0.1 µM 93.0% 41.0µM B-0225 0.047UM 37.0% 41.0µM B-0226 0.074U M 20.0%@1.0uM B-0227 0.045uM 1.0%@1.0uM B-0228 0.15uM 44.0% 41.0µM 8-0229 <0.1 µM 61.0% 41.0µM B-0230 0.041 uM 30.0% 41.0µM B-0231 0.055uM 40.0% 1.0µM B-0232 0.048uM 24.0% 41.0µM B-0233 O.O95UM 43.0% 41.0µM B-0234 0.11uM 68.0% 41.0µM B-023S 1.31 µM 90.0% 41.0µM B-0236 0.077UM 46.0% 41.0µM B-0237 0.13uM 60.0% 41.0µM B-023B 0.47UM 82.0% 41.0µM B-0239 5.73UM 84.0% 41.0µM B-0240 0.2UM 70.0% 41.0µM B-0241 0.1 UM 45.0% 41.0µM B-0242 <0.1 µM 78.0% 41.0µM B-0243 0.039UM 53.0% 41.0µM B-0244 0.02uM 57.0% 41.0µM B-0245 0.13uM 24.0% 41.0µM B-0246 <0.1 µM > 1.0uM B-0247 0.082UM 75.0% 41.0µM B-0248 <0.1 µM 11.0% 41.0µM B-0249 <0.1uM 75.0% 41.0µM B-0250 0.28uM 36.0% 41.0µM B-0251 0.31 µM 1.0% 41.0µM B-0252 0.041 uM 54.0% 41.0µM

♦ ♦ 9 »

- 712

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0253 0.061 uM 74.0% 91.0µM B-0254 0.12uM 59.0% 91.0µM B-0255 0.32uM 68.0% 91.0µM B-0256 <0.1 µM 88.0% 91.0µM B-0257 1.71uM 11.0% 91.0µM B-0258 0.37uM 63.0% 91.0µM B-0259 0.35uM 58.0% 91.0µM B-0260 0.56UM 23.0% 91.0µM B-0261 0.49uM 23.0% 91.0µM B-0262 0.41 µM 89.0% 91.0µM B-0263 0.62uM 64.0% 91.0µM B-0264 0.14uM 18.0% 91.0µM B-0265 0.92uM 24.0% 91.0µM B-0266 0.25uM 24.0% 91.0µM B-0267 0.48uM 11.0% 91.0µM B-0268 3.39uM 19.0% 91.0µM B-0269 9.81uM 19.0% 91.0µM B-0270 5.79uM 13.0% 91.0µM B-0271 7.55uM 12.0% 91.0µM B-0272 1.81uM 48.0% 91.0µM B-0273 5.03uM 13.0% 91.0µM B-0274 2.68uM 25.0% 91.0µM B-0275 2.67 µM 33.0% 91.0µM B-0276 1.25uM 26.0% 91.0µM B-0277 0.68uM 34.0% 91.0µM B-0278 1.26uM 36.0% 91.0µM B-0279 1.39uM 33.0% 91.0µM B-0280 0.86UM 18.0% 91.0µM B-0281 7.37uM 24.0% 91.0µM B-02B2 0.75UM 38.0% 91.0µM B-0283 6.66uM 29.0% 91.0µM B-02B4 0.083uM 65.0% 91.0µM B-02B5 4.57uM 29.0% 91.0µM B-0286 0.33uM 50.0% 91.0µM B-0287 4.0UM 22.0% 91.0µM B-0288 4.46uM 26.0% 91.0µM B-0289 0.15uM 55.0% 91.0µM B-0290 0.66uM 44.0% 91.0µM B-0291 1.33uM 20.0% 91.0µM B-0292 0.22uM 28.0% 91.0µM B-0283 0.66uM 53.0% 91.0µM B-0294 0.68UM 45.0% 91.0µM

·· »···

- 713 φ ···

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) I-IC ₅₀ U937 cells, Mouse LPS model, mM or% inhib% TNF inhibited dose @ conc., (ΜΜ) pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0295 0.82uM 45.0%@1.0uM B-0286 8.03UM 36.0%@1.0uM B-0297 0.78uM 30.0%@1.0uM B-0298 0.58uM 48.0%@1.0uM B-0299 0.B7UM 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%@1.0uM B-0305 B-0306 B-0307 B-0308 B-0309 B-0310 B-0311 8-0312 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

9999

- 714 • 9999

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0337 B-0338 B-0339 B-0340 B-0341 B-0342 B-0343 B-0344 B-0345 B-0348 B-0347 B-0348 B-0349 B-0350 B-0351 B-0352 B-0353 1.37uM 55% @ I.OuM B-0354 I.OuM 0.66UM 51% @ 30 mg / kg (R) -6h 54% @ 3 mg / kg @ -4 hr B-0355 0.75uM 3 0.0% @ I.OuM B-0356 0.66uM 24.0% @ I.OuM B-0357 1.46uM 0.56uM B-0358 0.37uM 17.0%@1.0uM B-0359 0.45uM 47.0% @ I.OuM B-0360 1.6uM 19.0% ® I.OuM B-0361 0.33uM 46.0% ® I.OuM B-0362 0.52uM 27.0% ® 1.0UM B-0363 4.67uM 24.0% @ 1.0uM B-0364 1.44uM 27.0%@1.0uM B-0365 0.96uM 27.0% ® 1.0UM B-0368 0.7uM 46.0%@1.0uM B-0367 I.OuM 23.0% ® 1.0uM B-0368 I.OuM 0.64UM 37% @ 30mg / kg @ -6h B-0369 0.16uM 56.0% ® 1.0uM B-0370 O.65uM 28.0% ® I.OuM B-0371 0.49uM 28.0% @ I.OUM B-0372 0.35uM 29.0% @ I.OuM B-0373 0.45uM 18.0% ® I.OuM B-0374 1.38UM 12.0% ® 1.0µM B-0375 I.OuM 19.0% @ I.OuM B-0376 2.99uM 12.0% @ I.OuM B-0377 1.29uM 36.0% @ I.OuM B-0378 1.1 µM 36.0% @ I.OuM

- 715 -

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₆₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. 8-0379 0.53uM 25.7% © 1.0uM B-0380 1.41 UM 32.O% 01.OuM B-0381 0.22uM 50% © 1.0uM B-0382 0.41 UM 32.O% 01.OuM B-0383 1.43uM 10O.O% 01.OuM B-0384 4.02uM 16.O% 01.OuM B-0385 0.057UM 0.9uM 30% 03C mg / kg® -6h 0% 3 3 mg / kg® -4h B-0386 0.13uM 54.O% 01.OuM B-0387 0.41uM 52.O% 01.OuM B-0388 <0.1 µM 36.O% 01.OUM B-0389 0.01 UM 0.05UM 60% @ 3mgikg® -4h B-0390 0.089uM. 55.O% 01.OuM B-0391 0.86uM 1B.O% 01.OuM B-0392 0.13uM 57.O% 01.OuM B-0393 0.043uM 66.O% 01.OuM B-0394 0.13UM 45.O% 01.OuM B-0395 0.087uM 48.O% 01.OuM B-0396 0.097uM 0.44UM B-0397 0.17uM 41.O% 01.OuM 8-0398 0.054uM 66.O% 01.OUM B-0399 0.14uM 39.O% 01.OuM B-0400 0.16uM 25.O% 01.OuM B-0401 0.46UM 52.O% 01.OuM 8-0402 0.14uM 1.51uM B-0403 1.77uM 2.42UM B-0404 0.31 UM 48.O% 01.OuM B-0405 0.79uM 3O.O% 01.OuM B-0406 0.54uM 35.O% 01.OuM B-0407 0.76uM 27.O% 01.OuM B-0408 0.5uM 50.O% 01.OuM B-0409 0.53uM 3O.O% 01.OuM B-0410 0.38uM 44.0%@1.0uM B-0411 0.62uM 50.O% 01.OuM B-0412 0.24uM 48.O% 01.OuM B-0413 0.18uM 55.O% 01.OuM B-0414 2.54uM 25.O% 01.OuM B-0415 0.42UM 43.O% 01.OuM B-0416 0.32uM 34.O% 01.OuM B-0417 0.91 UM 28.O% 01.OuM B-0418 0.22uM 27.O% 01.OuM B-0419 0.85uM 41.0% 21.0µM B-0420 0.83uM 49.O% 01.OuM

- 716 • 99 99 99 99 • 99 99 99 99

9 «9 9 9 9

9,999 99 · · 9 <9 9 9 9

9 · 999 * 99

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0421 0.46uM 57.0% 91.0µM B-0422 <0.1 µM 40.0% 91.0µM B-0423 0.18uM 33.0% 91.0µM B-0424 0.083uM 32.0% 91.0µM B-0425 0.26uM 54.0% 91.0µM B-0426 0.055uM 0.74uM 41% 93 mglkg (R) -4h B-0427 0.63uM 39.0% 91.0µM B-042B 0.99uM 27.0% 91.0µM B-0429 0.27UM 45.0% 91.0µM B-0430 0.29UM 75.0% 91.0µM B-0431 0.21 uM 64.0% 91.0µM B-0432 <0.1 µM 89.0% 91.0µM B-0433 <0.1 µM 92.0% 91.0µM B-0434 0.12uM 65.0% 91.0µM B-0435 0.3uM 61.0% 91.0µM B-0436 1.11uM 71.0% 91.0µM B-0437 0.58UM 59.0% 91.0µM B-0438 <0.1 µM 91.0% 91.0µM B-0439 2.12uM 65.0% 91.0µM B-0440 0.66uM 63.0% 91.0µM B-0441 0.8uM 58.0% 91.0µM B-0442 <0.1 µM 91.0% 91.0µM B-0443 2.01UM 71.0% 91.0µM B-0444 1.01 µM 51.0% 91.0µM B-0445 <0.1 µM 83.0% 91.0µM B-0446 0.78uM 80.0% 91.0µM B-0447 0.19uM 71.0% 91.0µM B-0448 0.4uM 79.0% 91.0µM B-0449 0.83uM 81.0% 91.0µM B-0450 0.26uM 81.0% 91.0µM B-0451 0.071 uM 83.0% 91.0µM 42% 930 mg / kg (R) -6h B-0452 0.7UM 75.0% 91.0µM B-0453 0.47uM 75.0% 91.0µM B-0454 0.11uM 80.0% 91.0µM B-0455 <0.1 µM 95.0% 91.0µM 36% @ 3 mg / kg R4h B-0456 1.81 µM 67.0% 91.0µM B-0457 0.089uM 81.0% 91.0µM B-0458 0.033uM 70.0% 91.0µM B-0459 0.099uM 76.0% 91.0µM B-0460 0.061 uM 92.0% 91.0µM B-0461 0.025uM 96.0% 91.0µM B-0452 <0.1 µM 97.0% 91.OuM

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- 717 I ·· · A · A · A · A · A · ·

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC _{50 of} U937 cells, mM or% inhibitor conc., (ΜΜ, Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0463 0.052uM 95.0% 91.0µM B-0464 <0.1 µM 91.0%@1.0uM B-0465 0.084uM 98.0% 91.0µM B-0466 <0.1 µM 98.0% 91.0µM 0% @ 3mg / kg® -4h B-0467 <0.1 µM 77.0% 91.0µM B-0468 0.031 µM 93.0% 91.0µM B-0469 0.056UM 92.0% 91.0µM B-0470 0.063uM 92.0% 91.0µM B-0471 0.027UM 97.0% 91.0µM B-0472 0.19uM 54.0% 91.0µM B-0473 0,004uM 95.0% 91.0µM B-0474 0.024UM. 86.0% 91.0µM B-0475 0.21 uM 74.0% 91.0µM B-0475 0.56UM 69.0% 91.0µM B-0477 1.48uM 96.0% 91.0µM B-047B 0.034UM 87.0% 91.0µM B-0479 0.031 µM 90.0% 91.0µM 15% @ 3 mg / kg (R) -4h B-0480 0.12uM 88.0% 91.0µM B-0481 0.014uM 95.0% 91.0µM 56% @ 3 mg / kg (R) -4h B-0482 0.97uM 68.0%@1.0uM B-0483 0.57uM 68.0% 91.0µM B-0484 0.28uM 62.0% 91.0µM B-0485 0.04uM 9S.0% 91.0µM B-0486 0.24uM 80.0% 91.0µM B-0487 0.11uM 89.0% 91.0µM 54% @ 3 mg / kg (R) -4h B-0488 0.62UM 88.0% 91.0µM B-0489 0.3uM 80.0% 91.0µM B-0490 0.91 µM 74.0% 91.0µM B-0491 0.43UM 66.0% 91.0µM B-0492 0.069uM 42.0% 91.0µM B-0493 0.3uM 36.0% 91.0µM B-0494 0.13uM . 30.0% 91.0µM B-0495 0.12uM 25.0% 91.0µM B-0496 0.83uM 16.0% 91.0µM B-0497 0.44uM 31.0% 91.0µM B-0498 0.33uM 11.0% 91.0µM B-0499 0.39uM 37.0% 91.OuM B-0500 0.26uM 41.0% 91.0µM B-0501 0.049UM 52.0% 91.0µM B-0502 0.065uM 48.0% 91.0µM B-0503 0.16uM 73.0% 91.0µM B-0504 0.4uM 43.0% 91.0µM

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Example no. IC ₉₀ p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0505 0.28uM 45.7% © 1.OuM B-0506 0.94UM 45.0% © 1.0uM B-0507 0.18uM 75.O% 01.OuM B-0508 2.OuM 48.O% 01.OuM B-0509 0.1 µM 86.O% 01.OuM B-0510 0.69UM 61.O% 01.OuM B-0511 0.007uM 9O.O% 01.OuM B-0512 1.0uM 53.O% 01.OuM B-0513 0.72UM 52.O% 01.OuM B-0514 0.14uM 87.O% 01.OuM B-0515 0.42uM 62.0% © 1.0uM B-0516 0.37uM. 84.O% 01.OuM B-0517 0.094uM 52.O% 01.OuM B-0518 0.1 luM 64.O% 01.OuM B-0519 0.043uM 87.O% 01.OuM B-0520 0.4UM 67.O% 01.OuM B-0521 1.37uM 52.O% 01.OuM B-0522 0.15uM 75.O% 01.OuM B-0523 0.19uM 83.O% 01.OuM B-0524 0.4uM 76.0% © 1.0uM B-0525 0.16 µM 76.O% 01.OuM B-0526 0.031 UM 87.O% 01.OuM B-0527 1.09uM 63.O% 01.OuM B-0528 0.14uM 7O.O% 01.OuM B-0529 0.11uM 73.O% 01.OuM B-0530 5.53uM 50% © 1 .OuM B-0531 0.5uM 48.O% 01.OuM B-0532 0.45UM 1.01uM 41% @ 30 mg / kg (R) -6h B-0533 1.23uM 47.O% 01.OuM B-0534 0.41 µM 54.O% 01.OuM B-0535 0.44UM 0.87uM B-0536 0.46uM 0.15uM B-0537 3.44uM 51.O% 01.OuM B-0538 1.13UM 45.0% 01.OuM B-0539 2.84uM 21.O% 01.OuM B-0540 3.62UM 54.O% 01.OuM B-0541 3.24uM 28.O% 01.OuM B-0542 1.5SUM 50.O% 01.OuM B-0543 1.56UM 43.O% 01.OuM B-0544 1.12uM 27.O% 01.OuM B-0545 1.06uM 41.O% 01.OuM B-0545 1.04uM 18.O% 01.OuM B-0547 1.24uM 21.O% 01.OuM B-0548 1.77uM 28.O% 01.OuM 0-0549 2.22uM 22.O% 01.OuM

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99

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0550 2.41 µM 14.0%@1.0uM B-0551 1.08UM 56.0%@1.0uM B-0SS2 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.B5UM 33.0%@1.0uM B-0556 D.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 0.3uM 5% @ 3mg / kg @ -4h B-0563 0.18uM 0.13uM B-0564 0.82uM 58%@1.0uM B-0565 0.23 UM 0.59uM B-0566 <0.1 µM 0.17UM 0% @ 3 mg / kg® -4 µl B-0567 0.14uM 0.28UM B-056B 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 0.13 µM 0.66uM 37% @ 3mg / kg®-4h B-0575 0.032UM 0.17UM B-0576 0.068UM 0.39UM 65% @ 3 mg / kg @ 4h B-0577 0.091 uM 66.0%@1.0uM B-0578 1.88UM 47.0%@1.0uM 8-0579 0.11uM 79.0%@1.0uM B-0580 2.23UM 0.84uM B-0581 0.28UM 2.17UM B-0562 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% @ 30 mg / kg (R) -6h B-0588 0.81 uM 51.0%@1.0uM B-0587 1 6.84UM 38%@1.0uM B-0588 12.8UM 42%@1.0uM B-0589 1.71 µM 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

- 720 ·· ·· · 9 9 9 «

9999 999 9999

9 4 99 9900 9 · 99

Example no. IC _S0 ρ38 kinase alpha mM or% Inhib @ conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. 05-0599 4.16uM 21.0% 91.0µM 06-0600 0.002UM 28.0%@1.0uM 06-0601 0.089uM 1.31 µM 43% 93 mg / kg -44h 0-0602 0.97uM 61.0% 91.0µM Β-Ο6-3 0.09UM 51.0%@1.0uM 0-0604 0.3uM 20.0%@1.0uM 0-0605 0.18uM 47.0%@1.0uM 0-0606 0.17UM 53.0%@1.0uM 0-0607 2.79uM 70.0% 91.0µM 0-0608 0.059UM 73.0%@1.0uM 0-0609 <0.1 µM 87.0% 91.0µM 06-0610 <0.1 µM 88.0% 91.0µM 06-0611 0.65uM 60.0% 91.0µM and 06-0612 0.18uM 60.0% 91.0µM and Β-0613 0.17uM 76.0%@1.0uM 06-0614 0.76UM 70.0%@1.0uM 0% @ 3mg / kg © -4h 06-0615 0.08uM 83.0% 91.0µM 06-0616 0.38uM 87.0% 91.0µM 06-0617 0.045UM 92.0% 91.OuM 06-0618 0.37uM 80.0% 91.0µM Β-0619 <0.1 µM 88.0% 91.0µM 06-0620 1.59uM 58.0% 91.0µM 06-0621 0.36uM 68.0% 91.OuM 06-0622 0.076uM 78.0% 91.0µM 06-0623 0.12uM 76.0% 91.0µM 06-0624 0.085uM 54.0% 91.0µM 06-0625 0.023UM 88.0% 91.0UM 06-0626 <0.1 µM 8S.0% 91.OuM 06-0627 0.25uM 69.0% 91.0µM 06-0628 0.023UM 72.0% 91.0µM 06-0629 0.2uM 79.0% 91.0µM 06-0630 0.06UM 77.0% 91.0µM Β-0631 0.065uM 81.0% 91.0µM 06-0632 <0.1 µM 79.0% 91.0µM 06-0633 0.6uM 80.0% 91.0µM 06-0634 0.6uM 40.0% 91.0µM 06-0635 0.15uM 55.0% 91.0µM 06-0636 <0.1 µM 86.0% 91.0µM Β-0637 0.11uM 92.0% 91.0µM 06-0638 0.25uM 89.0% 91.0µM 06-0639 0.051 uM 93.0% 91.0µM 50% 9 3 mg / kg -44h 06-0640 0.36uM 94.0% 91.0µM 06-0641 0.58uM 65.0% 91.0µM 06-0642 0.49uM 90.0% 91.0µM 06-0643 0.069UM 85.0% 91.0µM 0% 93 mg / kg -44h Β-0644 O.OSBuM 89.0% 91.QuM 06-0645 0.58uM 80.0% 91.0µM 06-0646 0.26uM 94.0% 91.0µM 06-0647 1.61 µM 76.0% 91.0µM

- 726 ₇

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0648 <0.1 µM 82.0% © 1.0uM B-0649 0.83uM 39.0%@1.0uM B-0650 Ο.ΟΟβυΜ 95.0% ®1.0uM 8% 03 mg / kg (R) -4h B-0651 1.7BUM 80% © 1.0uM B-0652 0.19uM 83.O% 01.OuM B-0653 2.01 µM 74.O% 01.OuM B-0654 5.97uM 78.O% 01.OuM B-0655 1.25UM 76.0%@1.0uM B-0656 0.007UM 94.0% © 1.0uM 28% @ 3 mg / kg (R) -4h B-0657 0.17uM 83.O% 01.OuM B-0658 1.14UM 91.0%@1.0uM B-0659 2.64UM 88.0% © 1.0uM B-0680 0.088UM 92.0%@1.0uM B-0661 <0.1 µM. 89.0% © 1.0uM B-0662 <0.1 µM 95.0%@1.0uM B-0663 0.88UM 74.0%@1.0uM B-0664 0.39uM 8O.O% 01.OuM B-066S 0.47UM 72.O% 01.OuM B-0666 0.17uM 73.O% 01.OuM B-0667 0.83UM 75.O% 01.OuM B-0668 0.27UM 78.O% 01.OuM B-0669 0.89uM 34.O% 01.OuM B-0670 3.15uM 32.O% 01.OuM B-0671 6.38UM 36.O% 01.OUM B-0672 ^r 6.59UM 32.O% 01.OuM B-0673 8.54UM 48.O% 01.OuM B-0674 2.81 UM 42.O% 01.OuM B-0675 5.42UM 3.O% 01.OuM B-0676 2.09UM 22.O% 01.OuM B-0677 1.63uM 25.O% 01.OuM B-0678 0.38UM 52.O% 01.OuM B-0679 0.062uM 45.O% 01.OuM B-0680 0.42UM 67.O% 01.OuM B-06B1 1.96UM 17.O% 01.OuM B-0682 0.76UM 39.O% 01.OuM B-0683 13.0UM 32.O% 01.OuM B-0684 0.54uM 68.O% 01.OuM B-0685 15.4UM 33.O% 01.OuM B-0686 0.42uM 59.O% 01.OuM B-0S87 10.1UM 15.O% 01.OuM B-0688 0.66UM 58.O% 01.OuM B-0689 14.6uM 27.O% 01.OuM B-O690 27.1 µM 36.O% 01.OuM B-0691 0.16uM 48.O% 01.OuM B-0692 0.38uM 29.O% 01.OuM B-0693 0.39UM 28.O% 01.OuM B-0694 0.62UM 21.O% 01.OuM B-0695 0.23UM 32.O% 01.OuM B-0696 0.085UM 35.O% 01.OuM

• ·

- 722 -

Example no. IC _S0 p38 alpha kinase mM or% Inhib @ conc. (μΜ) ICgg U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0697 0.4SUM 44.0% 91.0µM B-0698 2.33uM 43.0% 91.0µM B-0699 0.34uM 31.0% 91.OuM B-0700 0.24UM 56.0% 91.0µM B-0701 0.39uM 45.0% 91.0µM B-0702 0.036UM 39.0% 91.0µM B-0703 0.12uM 39.0% 91.0µM B-0704 2.19UM 29.0% 91.0µM B-0705 0.44uM 21.0% 91.0µM B-0706 0.44UM 32.0% 91.0µM B-0707 1.7uM B-07QB 2.1 µM B-0709 0.S4UM 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 3.4 µM B-0720 1.3uM B-0721 3.8uM B-0722 0.07uM > 1.0uM B-0723 0.47uM B-0724 0.06uM 17.0% 91.0µM B-0725 9.7uM B-0726 1.4uM B-0727 0.51 µM B-0728 20.0uM B-0729 0.87UM B-0730 0.25uM 11.0% 91.0µM B-0731 0.87UM > 1.0uM B-0732 14.0uM B-0733 32.0uM B-0734 0.S2UM B-0735 1.0uM B-0736 26.0uM B-0737 2.6UM B-073B 2.7uM B-0739 4.1 µM B-0740 4.4uM B-0741 26.0uM B-0742 2.2UM B-0743 1.2uM B-0744 23.0UM B-0745 6.0uM

- 723

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0746 0.01 UM 22.0%@1.0uM B-0747 1.1 µM B-0748 1.2uM B-0749 4.4uM B-0750 0.92uM B-0751 1.6uM B-0752 0.33uM B-0753 0.37uM B-0784 0.55UM B-0755 2.3uM B-0756 0.94uM B-0757 0.54uM 16.0%@1.0uM B-075B 1.5uM B-0759 0.3uM 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-076S 0.3uM 29.0% ®1.0uM B-0786 0.95 µM 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. OuM B-0774 1.5 µM B-0775 0.6uM > 1.0uM B-0776 0.9uM > 1 .OuM B-0777 21 .OuM B-077B 51 .OuM B-0779 0.5uM B-0780 1.1 µM B-0781 48.0uM B-0782 22.0UM B-0783 8.OuM B-0784 7.OuM B-0785 23.OuM B-0786 24.0uM B-0787 1.5uM B-0788 1.2uM B-0789 33.0UM B-0790 1.0uM 4.0% ®1.0uM B-0791 0.3uM > 1.0uM B-0792 1.1UM B-0793 0.3uM B-0794 2.9uM 2.0%@1.0uM

- 724 · · * * * * 7 7 7 7 7 7 7 7 7 7 7 7 7 7 · · · ·

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0795 1.9uM 11.0%@1.0uM B-0796 1,4uM B-0797 1.04uM - B-079B 1.73uM - B-0799 - > 1.0uM B-0800 1.01 UM > 1.0uM B-0801 0.67uM > 1.0uM B-0802 - > 1.0uM B-0803 0.057U M 53.0%@1.0uM B-0804 0.3uM 32.0%@1.0uM B-0805 0.71 uM > 1.0uM B-0806 3.2BuM > 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 3.41 µM • B-0825 - - B-0826 1.74UM - B-0827 15.6UM - B-0828 7.9UM - B-0829 0.61 UM 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.OuM B-0843 0.61 uM > 1 .OuM

- 724 • ·

Example ¢. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Krys! LPS model, % TNF inhibited dose pre-dosing time. B-0844 0.4uM 25.0% @ 1.OuM B-0845 1.78uM - B-0848 1.8uM - B-0847 0.73UM 21.0%@1.0uM B-0848 1.56uM B-0849 1.25uM - B-0850 1.81uM - B-0851 0.91 UM 39.0% @ 1.OuM B-0852 1.02uM - B-0853 - 38.0% @ 1.OuM B-0854 - 25.0% @ 1.OuM B-0855 - 8.0% ® 1.OuM B-0856 - 38.0%@1.0uM B-0857 6.25uM - B-0858 2.1 µM 50% @ 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.OuM B-0863 0.81 UM 25.0% @ 1.OuM B-0864 0.39uM 40,% @ 1.0µM B-0865 0.66uM 45.0% @ 1. OuM B-0866 1.38uM 28.0%@1.0uM B-0867 0.62uM > 1.0uM B-0868 3.28uM 7.9% @ 1.OuM B-0B69 4.19uM > 1.0uM B-0870 3.13uM > 1 .OuM B-0871 1.9uM > 1.0uM B-0872 3.13uM 3.0% ® 1. OUM B-0873 6.92UM > 1.ÓuM 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.OuM B-0878 O.SSuM 20.0% ® 1.OuM B-0879 0.87uM 1.0% ®1.0uM B-0880 O.ISuM 40.0% ® 1.OuM B-0881 1.36uM > 1.0uM B-0882 1.48uM 9%@1.0uM B-0883 1.06uM > 1 .OuM B-0884 1.89uM - B-0885 B-0886 B-0887 B-0888 B-0889 B-0890 B-0891 B-0892

• · · φ

- 726 • Φ · Φ Φ · ···· ··· φφ φφφ »»φφφφφφφ • • • • φφφφφφφφφφφφφφφφφφφφφ φφφφ

Example no. IC ₅₀ ρ38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. 08-0893 08-0894 08-0895 Β-0Β96 Β-0897 08-0898 08-0899 Β-0900 09-0901 Β-0902 Β-0903 Β-0904 Β-0905 Β-0906 Β-0904 Β-0908 09-0909 Β-0910 09-0911 09-0911 Β-0913 09-0913 Β-0915 09-0916 09-0917 Β-0917 09-0919 09-0920 Β-0921 09-0922 Β-0923 Β-0924 Β-0925 Β-0926 Β-0927 09-0928 Β-0929 09-0930 09-0931 Β-0933 09-0933 47.0% 91.0µM 37.0% 91.0µM 09-0934 67.0% 91.0µM 36.0% 91.0µM 09-0935 Bg.O% 91.0µM 54.0% 91.0µM Β-0936 69.0% 91.0µM > 1.0uM Β-0937 64.0% 91.0µM 1.74UM 09-0938 51.0% 91.0µM 29.0% 91.0µM 09-0939 78.0% 91.0µM 14.0% 91.0µM Β-0940 56.0% 91.0µM 22.0% 91.0µM Β-0941 81.0% 91.0µM 25.0% 91.0µM 1

- 727 ··

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0942 82.0% @ I.OuM 2.0% @ I.OuM B-0943 63.0% ®10.0uM 24.0% ® I.OuM B-0944 45.0% ® I.OuM 27.0%@1.0uM B-0945 96.0% ® I.OuM 0.93uM B-0946 76.0% ® I.OuM 31.0% ® I.OuM B-0947 69.0% @ I.OuM 34.0% @ I.OuM B-0948 68.0% ® I.OuM 1.81uM B-0949 90.0% ® 1.0uM 17.0% @ I.OuM B-0950 81.0% ®1.0uM 0.58uM B-0951 82.0% @ 1.0µM 20.0% ® 1.OuM B-0952 44.0% ® I.OuM 21.0% ® I.OuM B-0953 63.0%@1.0uM 25.0% ® 1.OuM B-0954 62.0%@1.0uM 0.52uM B-0955 50.0% @ 1.0UM 0.54UM B-0956 56.0% @ I.OuM 1.33uM B-0957 79.0% ® 1.0UM 22.0% @ I.OuM B-0958 74.0% @ I.OuM 0.38uM B-0959 83.0% @ I.OuM 39.0% @ I.OuM B-0960 48.0% ® I.OuM 4.0% ® 1.OuM B-0961 79.0% ® I.OuM 23.0%@1.0uM B-0962 85.0% ® I.OuM 2.71 µM B-0963 76.0% @ I.OuM 39.0%@1.0uM B-0964 94.0% @ I.OuM 5.OuM B-0965 74.0% ® I.OuM 1.1uM B-0966 50.0% @ I.OuM 5.0% @ 1.OuM B-0967 80.0% @ I.OuM 29.0% @ I.OuM 8-0968 35.0% @ I.OuM 26.0% ® I.OuM B-0969 62.0% @ 1.0uM 35.0% ® I.OuM B-0970 76.0% @ 10.OuM 0.88uM B-0971 61.0% ® I.OuM 39.0% @ I.OuM B-0972 85.0% ® I.OuM 2.0% ® 1.0UM B-0973 66.0% ®10.0uM 48.0% @ I.OuM B-0974 56.0% ® 1.OuM 47.0% ®1.0uM B-0975 82.0%@1.0uM 33.0% ® 1.OuM B-0976 79.0% ® I.OuM 36.0%@1.0uM B-0977 60.0% ® I.OuM 25.0% ® 1.OuM B-0978 59.0% ®1.OuM 36.0%@1.0uM B-0979 56.0% ®10.0uM 23.0% ® 1.OuM B-0980 68.0% ® 1.OuM 31.0%@1.0uM B-0981 62.0% ® I.OuM 57.0% @ 1.OuM B-0982 65.0% ® I.OuM 23.0% ®1.0uM B-0983 75.0%@1.0uM 0.8UM B-0984 60.0% ® I.OuM 51.0% ® I.OuM B-0985 86.0% ® 1.0UM 0.75UM B-0986 70.0% ®1.0υΜ 71.0% ® I.OuM B-0987 78.0% ® I.OuM 79.0% ® 1.OuM B-0988 72.0% ® I.OuM 65.0%@1.0uM B-0989 85.0% ® I.OuM 0.85uM B-0990 - 26.0% ® I.OuM

9

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Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₆₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0991 58.0% AI.OuM 33.0% A1.0UM B-0992 77.0% A1.0µM 45.0% AI.OuM B-0993 57.0% AI.OuM 73.0% AI.OuM B-0994 55.0% A1.0µM 43.0% A1.0UM 8-0995 53.0% A1.0µM 14.0% A1.0µM B-0996 54.0% A1.0µM 27.0% AI.OuM B-0997 69.0% A1.0µM 22.0% A1.0µM B-0998 67.0% A1.0µM 25.0% AI.OuM B-0999 61.0% A1.0µM 24.0% AI.OuM B-1000 55.0% A1.0µM 42.0% AI.OuM B-1001 63.0% A1.0µM 31.0% AI.OuM B-1002 70.0% A1.0µM 41.0% AI.OuM B-1003 74.0% A1.0µM 29.0% AI.OuM B-1004 79.0% A1.0µM 45.0% AI.OuM B-1005 58.0% A1.0µM 23.0% AI.OuM B-1006 69.0% AI.OuM 38.0% AI.OuM B-1007 52.0% A1.0µM 34.0% A1.0µM B-1008 54.0% A1.0µM 23.0% AI.OuM B-1009 80.0% A1.0µM 55.0% A1.0UM B-1010 75.0% AI.OuM 1.0uM B-1011 72.0% 21.0µM 17.0% AI.OuM 8-1012 - 20.0% AI.OuM B-1013 85.0% A1.0µM 7.0% AI.OuM B-1014 88.0% A1.0µM 20.0% AI.OuM B-1015 77.0% A1.0µM 34.0% A1.0UM B-1016 58.0% A1.0µM 10.0% A1.0µM B-1017 96.0% A1.0µM 58.0% A1.0µM B-1018 88.0% A1.0µM 34.0% AI.OuM B-1019 82.0% AI.OuM 66.0% AI.OuM B-1020 87.0% A1.0µM 36.0% A1.0µM B-1021 82.0% AI.OuM 35.0% A1.0µM B-1022 84.0% A1.0µM 53.0% A1.0µM B-1023 93.0% A1.0µM 70.0% A1.0µM 8-1024 89.0% AI.OuM 57.0% A1.0µM B-1025 61.0% AI.OuM 23.0% A1.0UM B-1026 87.0% A1.0µM 53.0% AI.OuM B-1027 58.0% AI.OuM 18.0% A1.0µM B-1028 70.0% A1.0µM 17.0% A1.0µM B-1029 69.0% AI.OuM 54.0% AI.OuM B-1030 76.0% A1.0µM 60.0% AI.OuM B-1031 69.0% A1.0µM 42.0% AI.OuM B-1032 76.0% AI.OuM 37.0% AI.OuM B-1033 86.O% A1.OUM 34.0% A1.0µM B-1034 66.0% A1.0µM 39.0% A1.0µM B-1035 75.0% AI.OuM 52.0% A1.0µM B-1036 68.0% A1.0µM 68.0% A1.0UM B-1037 - 41.0% A1.0µM B-1038 57.0% A1.0µM 0.57UM B-1039 1 » 1.33UM

• ·

- 729 -

Example # IC ₅ of p38 alpha kinase mM or% conc. (μΜ) IC _S0 U937 cells, mM or% inhibitor conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-0991 58.0% 91.0µM 33.0% 91.0µM B-0992 77.0% 91.0µM 45.0% 91.0µM 8-0993 57.0% 91.0µM 73.0% 91.0µM B-0994 55.0% 91.0µM 43.0% 91.0µM B-0995 53.0% 91.0µM 14.0% 91.0µM B-0996 54.0% 91.0µM 27.0% 91.0µM B-0997 69.0% 91.0µM 22.0% 91.0µM B-0998 67.0% 91.0µM 25.0% 91.0µM B-0999 61.0% 91.0µM 24.0% 91.0µM B-1000 55.0% 91.0µM 42.0% 91.0µM B-1001 63.0% 91.0µM 31.0% 91.0µM B-1002 70.0% 91.0µM 41.0% 91.0µM B-1003 74.0% 91.0µM 29.0% 91.0µM B-1004 79.0% 91.0µM 45.0% 91.0µM B-1005 58.0% 91.0µM 23.0% 91.0µM B-1006 69.0% 91.0µM 38.0% 91.0µM B-1007 52.0% 91.0µM 34.0% 91.0µM B-1008 54.0% 91.0µM 23.0% 91.0µM B-1009 80.0%@1.0uM 55.0% 91.0µM B-1010 75.0% 91.0µM 1.0uM B-1011 72.0% 21.0µM 17.0% 91.0µM B-1012 - 20.0% 91.0µM B-1013 85.0% 91.0µM 7.0% 91.0µM B-1014 88.0% 91.0µM 20.0% 91.0µM B-1015 77.0% 91.0µM 34.0% 91.0µM B-1016 58.0% 91.0µM 10.0% 91.0µM B-1017 96.0% 91.0µM 58.0% 91.0µM B-1018 88.0% 91.0µM 34.0% 91.0µM B-1019 82.0% 91.0µM 66.0% 91.0µM B-1020 87.0% 91.0µM 36.0% 91.0µM B-1021 82.0% 91.0µM 35.0% 91.0µM B-1022 84.0% 91.0µM 53.0% 91.0µM B-1023 93.0% 9l, OuM 70.0% 91.0µM B-1024 B9.0% 91.0µM 57.0% 91.0µM B-1025 61.0% 91.0µM 23.0% 91.0µM B-1026 87.0% 91.0µM 53.0% 91.0µM B-1027 58.0% 91.0µM 18.0% 91.OuM B-1028 70.0% 91.0µM 17.0% 91.0µM B-1029 69.0% 91.0µM 54.0% 91.0µM B-1030 76.0% 91.0µM 60.0% 91.0µM B-1031 69.0% 91.0µM 42.0% 91.0µM B-1032 76.0% 91.OuM 37.0% 91.0µM B-1033 86.0% 91.0µM 34.0% 91.0µM B-1034 66.0% 91.0µM 39.0% 91.0µM B-1035 75.0% 91.0µM 52.Q% 91.0µM B-1036 68.0% 91.0µM 68.0% 91.0µM B-1037 - 41.0% 91.0µM B-1038 57.0% 91.0µM 0.57UM B-1039 - 1.33UM

• · «·

- 730 -

Example # IC ₉₀ p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-1040 72.0% 91.0µM 0.38UM B-1041 70.0% 91.0µM 73.0% 91.0µM B-1042 79.0% 91.0µM 12.0% 91.0µM B-1043 64.0% 91.0µM 53.0% 91.0µM B-1044 94.0% 91.0µM 0.93UM B-1045 78.0% 91.0µM 25.0% 91.0µM B-1046 72.0% 91.0µM 66.0% 91.0µM B-1047 72.0% 91.0µM 58.0% 91.0µM B-1048 67.0% 91.0µM 19.0% 91.0µM B-1049 67.0% 91.0µM 65.0% 91.0µM B-1050 - 0.54uM B-1051 68.0% 91.0µM 41% 91.0µM B-1052 69.0% 91.0µM 66% 91.0µM B-1053 78.0% 91.0µM 0.4uM B-1054 79.0% 91.0µM 55.0% 91.0µM B-1055 89.0% 91.0µM 63.0% 91.0µM B-1056 89.0% 91.0µM 0.76uM B-1057 85.0% 91.0µM 0.72uM B-1058 0.66uM 43.0% 91.0µM B-1059 0.18uM 24.0% 91.0µM B-1060 0.1 luM 32.0% 91.0µM B-1061 0.03UM 19.0% 91.0µM B-1062 <0.1 µM 26.0% 91.0µM B-1063 0.16uM 44.0% 91.0µM B-1064 O.39uM 50.0% 91.0µM B-1065 0.56uM 40.0% 91.0µM B-1066 <0.1 µM 39.0% 91.0µM B-1067 1.6uM 32.0% 91.0µM B-1068 0.48uM 24.0% 91.0µM B-1069 0.22UM 27.0% 91.0µM B-1070 <0.1 µM 44.0% 91.0µM B-1071 <0.1 µM 48.0% 91.0µM B-1072 0.38uM 2B.0% 91.0µM B-1073 <0.1 µM 21.0% 91.0µM B-1074 0.23UM 33.0% 91.0µM B-1075 0.03uM 29.0% 91.0µM B-1076 0.08uM 31.0% 91.0µM B-1077 <0.1 µM 38.0% 91.0µM B-107B 0.26uM 48.0% 91.0µM B-1079 <0.1 µM 40.0% 91.0µM B-1080 0.19uM 28.0% 91.0µM B-1081 <0.1 µM 37.0% 91.0µM B-1082 <0.1 µM 54.0% 91.0µM B-1083 <0.1 µM 23.0% 91.0µM B-1084 0.43uM 29.0% 91.0µM B-1085 <0.1 µM 29.0% 91.0µM B-1086 <0.1 µM 42.0% 91.0µM B-1087 0.05uM 32.0% 91.0µM B-1088 0.73uM 49.0% 91.0µM

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Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ, IC _{50 of} U937 cells, mM or% inhibitor conc., (ΜΜ, Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-10BB <0.1 µM 39.0% 91.puM B-1090 <0.1 µM 90.0% 91.0µM B-1091 <0.1 µM 73.0% 91.0µM B-1092 0.27uM 85.0% 91.0µM B-1093 0.33uM 36.0% 91.0µM B-1094 0.013uM 69.0% 91.0µM B-1095 <0.1 µM 70.0% 91.0µM B-1096 <0.1 µM 32.0% 91.0µM B-1097 <0.1 µM 44.0% 91.07µM B-1098 <0.1 µM 82.0% 91.0µM B-1099 0.26uM 74.0% 91.0µM B-1100 Ď.22UM 56.0% 91.0µM B-1101 0.026UM 82.0% 91.0µM B-1102 0.035uM 83.0% 91.0µM B-1103 0.094UM 90.0% 91.0µM B-1104 0.12uM 69.0% 91.0µM B-1105 <0.1 µM 64.0% 91.0µM B-1106 <0.1 µM 86.0% 91.0µM B-1107 0.057UM 84.0% 91.0µM B-1108 0.22UM 81.0% 91.0µM B-1109 0.054UM 80.0% 91.0µM B-1110 0.47uM 64.0% 91.0µM B-1111 0.19uM 64.0% 91.0µM B-1112 0.58uM 43.0% 91.0µM B-1113 <0.1 µM 72.0% 91.0µM B-1114 0.069UM S1.0% 91.0µM B-1115 0.024UM 89.0% 91.0µM B-1116 0.41 µM 81.0% 91.0µM B-1117 0.13uM 73.0% 91.0µM B-1118 0.33UM 91.0% 91.0µM B-1119 0.35uM 80.0% 91.0µM B-1120 0.47UM 9.0% 91.0µM B-1121 3.58UM 29.0% 91.0µM B-1122 1.84uM 32.0% 91.0µM B-1123 2.93UM 27.0% 91.0µM B-1124 1.49uM 52.0% 91.0µM B-1125 0.S6uM 41.0% 91.0µM B-1126 1.5uM > 1.0uM B-1127 0.71 uM 7.0% 91.0µM B-1128 2.55UM 26.0% 91.0µM B-1129 1.07UM 46.0% 91.0µM B-1130 0.5uM 29.0% 91.0µM B-1131 0.076UM 34.0% 91.0µM B-1132 0.72uM 11.0% 91.0µM B-1133 0.38uM 33.0% 91.0µM B-1134 1.7 luM 33.0% 91.0µM B-1135 0.23uM 38.0% 91.0µM B-1136 1.17uM 40.0% 91.0µM B-1137 0.038UM 3S.0% 91.0µM

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Example no. IC ₆₀ p38 alpha kinase mM or% conc. (μΜ) IC _S0 U937 cells, mM or% inhibitor conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. - Rat LPS model, % TNF inhibited dose pre-dosing time. B-1138 1.62uM > 1.0uM B-1139 0.041 uM 29.0% ®1.0uM 8-1140 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% ®1.0µM B-1144 0.44uM 72.0% ®1.0uM B-1145 1.07UM 71.0% ®1.0uM B-1146 0.47uM 61.0% ®1.0uM B-1147 O.OSSuM 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% ®1.0uM B-1154 0.085UM 46.0% ®1.0uM B-1155 3.22UM 30.0% ®1.0uM B-1156 0.27UM 78.0% ®1.0uM B-1157 0.26UM 66.O% 01.OuM B-1158 74% ®1.0uM 0.68uM 53% ®30 mg / kg® -6h B-1159 66.0% ®1.0uM 1.03uM 60% 030 mg / kg (R) -6h B-1160 79.0% ®1.0uM 0.38uM B-1161 64.0% 21.0µM 0.93uM 40% 030 mg / kg (R) -6h 45% 03 mg / kg (R) -4h B-1162 79.0% ®1.0uM 0.59UM 40% 30 30 mg / kg® -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% ® 30 mg / kg ® -6h 50% 3 3 mg / kg® -4h B-1167 70.0% ®1.0uM 1.06UM B-1168 66.0% ®1.0uM 0.63uM B-1169 8O.O% 01.OuM 0.11UM B-1170 82.0% ®1.0uM 0.57UM B-1171 78.0% ®1.0uM 0.23UM B-1172 68.0% ®1.0uM 1.9SUM 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 02.0% ®1.0µM 1.61 µM B-1179 86.0% ®1.0uM 0.41 µM B-1160 78.0% ®1.0uM 0.53uM B-1181 79.0% ®1.0uM 67% © 1.0uM B-1182 72.0% ®1.0uM 0.65uM B-1183 77.0% ®1.0uM 0.2UM B-1184 69.0% ®1.0uM 0.63uM B-1185 71.0% ®1.0uM 0.79UM B-1186 B3.O% 01.OuM 60% ®1.0uM

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Example no. IC ₅₀ ρ38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. 11-1187 76.0% 91.0µM 1.89uM Β-1188 - 36.0% 91.0µM 11-1189 68.0% 91.0µM 0.83UM 11-1190 78.0% 91.0µM 62.0% 91.0µM Β-1191 74.0% 91.0µM 57.0% 91.0µM 11-1192 84.0% 91.0µM 0.47UM Β-1193 69.0% 91.0µM 65.0% 91.0µM • Β-1194 87.0% 91.0µM 0.58uM 11-1195 52.0% 91.0µM 60.0% 91.0µM 11-1198 74.0% 91.0µM 68.0% 91.0µM 11-1197 77.0% 91.0µM 45.0% 91.0µM 11-1198 92.0% 91.0µM 0.46uM 11-1199 87.0% 91.0µM 49.0% 91.0µM Β-1200 95.0% 91.0µM 0.64uM Β-1201 84.0% 91.0µM 0.51 UM Β-1202 71.0% 91.0µM 58.0% 91.0µM Β-1203 84.0% 91.0µM 58.0% 91.0µM Β-1204 68.0% 91.0µM 59.0% 91.0µM Β-1205 74.0% 91.0µM 46.0% 91.0µM Β-1206 81.0% 91.0µM 0.34uM Β-1207 90.0% 91.0µM 58.0% 91.0µM Β-1208 82.0% 91.0µM 51.0% 91.0µM Β-1209 86.0% 91.0µM 55.0% 91.0µM Β-1210 82.0% 91.0µM 57.0% 91.0µM Β-1211 88.0% 91.0µM 59.0% 91.0µM Β-1212 90.0% 91.0µM 57.0% 91.0µM Β-1213 84.0% 91.0µM 0.62UM Β-1214 76.0% 91.0µM 58.0% 91.OuM 12-1215 66.0% 91.0µM 0.23uM Β-1216 88.0% 91.0µM 0.18uM Β-1217 B7.0% 91.0µM 0.46uM Β-1218 88.0% 91.0µM 76.0% 91.0µM 12-1219 85.0% 91.0µM 37.0% 91.0µM Β-1220 81.0% 91.0µM 53.0% 91.0µM Β-1221 82.0% 91.0µM 44.0% 91.0µM Β-1222 65.0% 91.0µM 9.0% 91.0µM Β-1223 80.0% 91.0µM 61.0% 91.0µM Β-1224 82.0% 91.0µM 74.0% 91.0µM Β-1225 89.0% 91.0µM 73.0% 91.0µM Β-1226 89.0% 91.0µM 0.18uM Β-1227 83.0% 91.0µM 0.22uM Β-1228 90.0% 91.0µM 0.72uM Β-1229 87.0% 91.0µM 0.65UM Β-1230 90.0% 91.0µM 0.25uM Β-1231 94.0% 91.0µM 0.56uM Β-1232 81.0% 91.0µM 54.0% 91.0µM Β-1233 85.0% 91.0µM 0.36uM Β-1234 89.0% 91.0µM 0.49uM Β-1235 0.04uM 76.0% 91.0µM

- 734 ·· »··· • * · 0 0 0 ♦ 0 0 0 0 0

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Example ¢. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Rat LPS model,% TNF inhibited dose pre-dosing time. B-1236 0.1uM 53.0%@1.0uM B-1237 0.22uM 40.0% © 1.0uM S-1238 0.14uM 16.O% 01.OuM B-1239 <0.1uM 38.O% 01.OuM B-1240 <0.1 µM 59.O% 01.OuM 8-1241 0.04uM 81.O% 01.OuM B-1242 0.08uM * 83.O% 01.OuM B-1243 0.04uM 47.O% 01.OuM B-1244 0.26uM 44.O% 01.OuM B-124S 0.49uM 42.O% 01.OuM B-1246 0.27uM 4O.O% 01.OuM B-1247 <0.1 µM 58.O% 01.OuM B-1248 <0.1 µM 68.O% 01.OuM B-1249 0.24uM. 6O.O% 01.OuM and B-1250 0.14uM 18.O% 01.OuM B-1251 0.41 µM 38.O% 01.OuM B-1252 0.17uM 46.O% 01.OuM B-1253 0.15uM 57.O% 01.OuM B-1254 0.16uM 68.O% 01.OuM B-1255 12.9uM 75.O% 01.OuM B-1256 0.12UM 41.O% 01.OuM B-12S7 1.48uM 4O.O% 01.OuM B-1258 0.07UM 56.O% 01.OuM B-1259 <0.1 µM 0.48UM B-1280 0.11uM 48.O% 01.OuM B-1261 0.74UM 44.O% 01.OuM B-1262 <0.1 µM 63.O% 01.OuM B-1263 1.05UM 57.O% 01.OuM B-1264 0.32uM 47.O% 01.OuM B-1265 0.43UM 51.O% 01.OuM B-1266 <0.1 µM 58.O% 01.OuM B-1267 <0.1 µM 73.O% 01.OuM B-1268 <0.1 µM 79.O% 01.OuM B-1269 0.46uM 84.O% 01.OuM B-1270 0.47uM 83.O% 01.OuM B-1271 0.13uM 74.O% 01.OuM B-1272 0.014uM 38.O% 01.OuM B-1273 <0.1 µM 36.O% 01.OuM B-1274 <0.1 µM 41.O% 01.OuM B-1275 <0.1 µM 50.O% 01.OuM 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%@1.0uM 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

-Itf • ♦

Example # IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-1285 0.057UM 80.0% 41.0µM B-128S 0.15uM 78.0% 21.0µM B-1287 0.2SUM 55.0% 41.0µM B-1288 0.15uM 74.0% 41.0µM B-1289 0.73UM 35.0% 41.0µM B-1290 0.26uM 75.0%@1.0uM B-1291 0.097UM 55.0% 41.0µM B-1292 0.01 µM 74.0% 41.0µM B-1293 0.31 µM 48.0% 41.0µM B-1294 0.013UM 54.0% 41.0µM B-1285 0.079uM 74.0% 41.0µM B-1296 0.038UM 48.0% 41.0µM B-1297 0.02uM > 1.0uM B-1298 0.055uM 20.0% 41.0µM B-1299 0.091 uM ' > 1.0uM B-1300 0.071 uM 1B.0% 41.0µM B-1301 0.12uM 15.0% 41.0µM B-1302 0.023UM 11.0% 41.0µM B-1303 0.08UM > 1.0uM B-1304 0.11uM 10.0% 41.0µM B-1305 0.64uM 9.0% 41.0µM B-1306 0.11UM > 1.0uM B-1307 0.009uM 16.0% 41.0µM B-1308 <0.1 µM > 1.0uM B-1309 0.04SUM > 1.0uM B-1310 0.12uM 11.0% 41.0µM B-1311 0.05UM 57.0% 41.0µM B-1312 0.35uM > 1.0uM B-1313 0.035UM 37.0% 41.0µM B-1314 0.045UM 24.0% 41.0µM B-1315 0.055uM 12.0% 41.0µM B-1316 0.026UM 36.0% 41.0µM B-1317 0.01 SuM 9.0% 41.0µM B-1318 <0.1 µM 1.0% 41.0µM B-1319 0.24uM > 1.0uM B-1320 0.047uM 43.0% 41.0µM B-1321 0.47UM 66.0% 41.0µM B-1322 0.12uM 87.0% 41.0µM B-1323 0.013uM 85.0% 41.0µM B-1324 0.16uM 83.0% 41.0µM B-1325 0.27uM 95.0% 41.0µM B-1326 0.092UM 84.0% 41.0µM B-1327 0.13uM 65.0% 41.0µM B-1328 0.032uM 86.0% 41.0µM B-1329 0.66uM 54.0% 41.0µM B-1330 0.053uM 85.0% 41.0µM B-1331 0.004uM 85.0% 41.0µM B-1332 0.007UM 81.0% 41.0µM B-1333 0.45uM 76.0% 41.0µM

• 00®

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Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-1334 0.13uM 73.0% @ 1.OuM B-1335 0.097uM 63.0% @ 1.OuM B-1336 0.072uM 82.0% ® 1.OuM B-1337 0.4uM 90.0%@1.0uM B-1338 0.18uM 73.0% ® 1.OuM B-1339 0.12UM 67.0% ® 1.OuM B-1340 0.043UM 63.0%@1.0uM B-1341 0.42UM 52.0% ®1.0uM B-1342 0.25uM 59.0% ® 1.OuM B-1343 0.065UM 83.0% @ 1.OuM B-1344 0.014uM .86.0% ® 1.OuM B-1345 0.27uM 73.0%@1.0uM 0-1346 0.043UM 86.0%@1.0uM B-1347 0.021 uM 85.0% ® 1.OuM B-1348 0.009UM 69.0% @ 1.OuM B-1349 0.037UM 86.0%@1.0uM B-1350 0.019uM 78.0%@1.0uM B-1351 0.068uM 78.0% ® 1.OuM B-1352 0.013uM 76.0%@1.0uM B-1353 0.062uM 80.0%@1.0uM B-1354 0.013uM 82.0% ® 1.OuM B-1355 0.07 µM 75.0%@1.0uM B-1356 0.059uM 91.0%@1.0uM B-1357 0.18uM 84.0% @ 1.OuM B-1358 0.16uM 76.0%@1.0uM B-1359 0.005 85.0% ® 1.OuM B-1360 0.11 0.15UM 54% @ 3 mg / kg (R) -4h B-1361 0.03 0.29uM 0-1362 0.003 O.29UM B-1363 0.009 0.28uM 51.0% @ 30 mg / kg® 6H 53% @ 3 mg / kg (R) -4h B-1364 0.009 0.27UM 53.0% @ 30mg / kg® · 6.0H 17% ® 3 mg / kg ® -4h B-1365 0.17 88.0% ® 1.OuM B-1366 0.04 0.27uM B-1367 <0.1 0.22uM B-1368 0.031 0.33uM 44.0 %@30 mg / kg® « B-1369 <0.1 0.29uM B-1370 <0.1 0.77uM B-1371 0.06 82.0% ® 1.OuM B-1372 <0.1 0.41 UM 50.0% @ 30 mg / kg® - 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% @ 30 mg / kg® -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

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9 9

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Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibited dose pre-dosing time. Krys! LPS model, % TNF inhibited dose pre-dosing time. B-1381 0.055 0.73uM B-1382 <0.1 0.44uM 8-1383 0.0012 0.15uM B-1384 0.57 0.37uM B-138S <0.1 0.1 luM B-13B6 <0.1 0.25uM B-1387 <0.1 0.1 µM B-1388 0.57 1.38uM B-1389 0.06 0.57uM B-1390 <0.1 70.0% © 1.0uM B-1391 0.016uM 82.O% 01.OuM B-1392 0.059UM 82.O% 01.OuM B-1393 3.17uM 8O.O% 01.OuM B-1394 0.32uM. 78.0%@1.0uM B-1395 1.48 61.O% 01.OuM B-1396 1.55 73.O% 01.OuM B-1397 0.92 85.0%@1.OuM B-1398 0.67 83.O% 01.OuM B-1399 0.14 74.O% 01.OUM B-1400 0.024 83.O% 01.OuM B-1401 0.033 7S.O% 01.OuM B-1402 0.12 76.O% 01.OuM B-1403 4.54 71% 01.OuM B-1404 0.6 70% 01.OuM B-1405 0.28 70% 01.OuM B-1406 1.39 56.O% 01.OuM B-1407 0.4 70.0% © 1.0uM B-1408 0.27 69.O% 01.OuM B-1409 <0.1 71.0% © 1.0uM B-1410 <0.1 69% 01.OuM B-1411 <0.1 81.O% 01.OuM B-1412 0.097 8O.O% 01.OuM B-1413 0.016 78.O% 01.OuM B-1414 0.025 83.O% 01.OuM B-1415 1.41 79.O% 01.OuM B-1416 0.14 81.O% 01.OUM B-1417 0.069 69.O% 01.OuM B-1418 1.01 82.O% 01.OuM B-1419 0.3 84.O% 01.OuM B-1420 <0.1 82.O% 01.OuM B-1421 0.014 75.O% 01.OuM B-1422 0.58 68.O% 01.OuM B-1423 1.58 84.O% 01.OuM B-1424 0.86 76.O% 01.OUM B-1425 0.09 83.O% 01.OuM B-1426 0.19 8O.O% 01.OuM B-1427 <0.1 84.O% 01.OuM B-1428 <0.1 86.O% 01.OuM B-1429 <0.1 87.O% 01.OUM

• ···

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Example no. IC ₆₀ p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, TNF% inhibited dose pre-dosing time. Rat LPS model, % TNF inhibited dose pre-dosing time. B-1430 0.75uM 35.0% 0 I.OuM B-1431 0.36UM 58.0% 0 I.OuM B-1432 0.11uM 51.0% 0 I.OuM B-1433 0.26uM 21.0% 01.0µM B-1434 0.19uM 28.0% 0 I.OuM B-1435 1.8uM 45.0% ®1.0uM B-1436 I.OuM 20.0% 01.0µM B-1437 0.3uM 22.0% @ 1.0uM B-1438 2.01 µM 27.0%@1.0uM B-1439 1.7uM 17.0% 01.0µM B-1440 0.87UM 3.0% 01.0µM 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 0.3uM 25.7% © I.OuM B-1445 0.43UM 27.0% 01.0µM B-1446 0.77UM 37.0% © 1.0uM B-1447 0.5uM 34.0% ®1.0uM B-1448 1.43UM 21.7% © 1.0UM B-1449 1.61 µM 50.0% B-1450 2.1uM 49.0% ®1.0uM B-1451 2.88UM 50% 01.0µM B-1452 2.41 µM 47.0% ®1.0uM B-1453 2.53uM 50% © 1.0uM B-1454 1.6uM 12.0% ®1.0uM B-1455 1.21 uM 8.07 «© I.OuM B-1456 1.29uM > 1.0uM B-1457 0.43uM 43.08 «© 1.0uM B-145B 0.95uM 65.07 «®1.0µM B-1459 0.67uM 46.0% 01.OUM B-1460 0.96uM 29.07 «© I.OuM B-1461 0.4uM 40.0% © 1.0uM B-1462 0.22uM 50.06 «01.0uM B-1463 2.34uM 26.07 «01.OUM B-1464 1.18UM 27.08 «© 1.0uM B-1465 3.23uM 31.0% 0I.OuM B-1466 1.69uM > 1.0uM B-1467 1.22uM 1.07 «0I.OuM B-1488 1.61uM 10.0% ®1.0uM B-1469 0.37UM 15.0% ® 1.0uM B-1470 0.6uM 28.07 «© I.OuM B-1471 0.85uM 25.0% ®1.0µM B-1472 0.93uM 12.0% ®1.0uM B-1473 1.24uM 14.06 «®1.0uM B-1474 1.23UM 31.06 «®1.0uM B-1475 2.1 UM 24.O% 01.OuM B-1475 0.047UM 42.0% ®1.0uM B-1477 2.5UM 34.07 «0I.OuM B-1478

- 739 9999 • 9 • 9 • 9

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Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. Krysf LPS model, % TNF inhibited dose pre-dosing time. B-1479

- 740 ·· φφφφ

Φ φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Example # IC ₅₀ ρ38 alpha kinase mM or% conc. (μΜ) IC _S0 U937 cells, mM or% inhibitor conc., (ΜΜ) Mouse LPS model, % TNF inhibited dosing time pred. (LPS model, TNF inhibit dose 5) pre-dosing time. Β-2270 0.72uM 31% ®10.0uM Β-2271 0.93UM 38%@10.0uM Β-2272 0.26uM 53.0%@10.0uM Β-2273 1.92UM 39.0%@10.0uM Β-2274 0.26uM 59.0% ®10.0uM Β-2275 2.16uM 53.0% ®10.0uM Β-2276 11.5uM 37.0% @ 10.OuM Β-2277 14.9uM 44.0% ®10.0uM Β-2278 0.8uM 51.0% @ 10.OuM Β-2279 0.32uM 36.0%@10.0uM Β-2280 0.4uM 57.0%@1Q.0uM Β-2281 0.81uM 60.0%@10.0uM Β-2282 0.91 µM 41.0% @ 10.OuM Β-2283 0.04UM 53.0% @ 10.OuM Β-2284 4.61uM 62.0%@10.0uM Β-2285 2.29uM 49.0%@10.0uM Β-2286 0.017uM 0.78UM 30% @ 30mpk @ -1h Β-2287 2.56uM 61.0% @ 10.OuM Β-2288 6.51 µM 46.0% @ 10.OuM Β-2289 3.0uM 30.0% @ 10.OuM Β-2290 2.37uM 59.0%@10.0uM Β-2291 0.019uM 41%@10.0uM Β-2292 8.82uM 57.0%@10.0uM Β-2293 2.11uM 56.0% @ 10.OuM Β-2294 1.68uM 50.0%@10.0uM 22-2295 1.79uM 56.0% @ 10.OuM Β-2296 17.3uM 63.0%@1Q.0uM Β-2297 3.59uM 57.0%@10.0uM Β-2298 0.29uM 4.22uM 22-2299 1.97uM 62.0%@10.0uM Β-2300 0.07uM 43.0% @ 11. OuM Β-2301 0.18uM 44.0%@10.0uM Β-2302 1.0uM 58.0% ® 1.OuM Β-2303 0.01 luM 54.0%@10.0uM Β-2304 1.41UM 50.0% @ 11. OuM Β-2305 0.54uM 60.0% @ 11. OuM Β-2306 5.88uM 39.0% @ 11. OuM Β-2307 2.29uM 69.0% @ 11. OuM Β-2308 0.66uM 56.0%@10.0uM Β-2309 0.29UM 47.0%@10.0uM

• 9 ··· ♦

- 741 ·· ·· · · · · · · ·

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model,% TNF inhibited dose ⁰ pre-dosing time. ( - <LPS model, ti TNF inhibit dose S> time pred. B-2310 0.12uM 1.2uM 50% 93C mg / kg © -6h B-2311 7.18uM 60% 910.0µM B-2312 2.93uM 43.0% 910.0µM B-2313 42.3uM 58.0%@10.0uM B-2314 -fl.OuM 66.0% 910.0µM B-2315 0.49uM 36.0% 910.0µM B-2316 0.46uM 58.0% 910.0µM B-2317 1.0uM 60.0% 910.0µM B-2318 73.0% 910.0µM 25.0% 910.0µM B-2319 75.0% 910.0µM 40.0% 910.0µM B-2320 44.0% 910.0µM 35.0% 910.0µM B-2321 69.0% 910.0µM 27.0% 910.0µM B-2322 76.0% 910.0µM 38.0%@10.0uM B-2323 69.0% 910.0µM 46.0% 910.0µM B-2324 56.0% 910.0µM 36.0% 910.0µM B-2325 60.0% 910.0µM 51.0% 910.0µM B-2326 76.0% 910.0µM 33.0% 910.0µM B-2327 76.0% 910.0µM 23.0% 910.0µM B-2328 65.0% 910.0µM 28.0% 910.0µM B-2329 72.0% 910.0µM 53.0% 910.0µM B-2330 81.0% 910.OuM 37.0% 910.0µM B-2331 74.0% 910.0µM 44.0% 910.0µM B-2332 70.0% 910.0µM 47.0% 910.0µM B-2333 58.0% 910.0µM 36.0% 910.0µM B-2334 81.0% 910.0µM 45.0% 910.0µM B-2335 82.0% 910.0µM 50.0% 910.0µM B-2336 48.0% 910.0µM 35.0% 910.0µM B-2337 46.0% 910.0µM 59.0% 910.0µM B-2338 73.0% 910.OuM 50.0% 910.0µM B-2339 84.0% 910.0µM > 10.0uM B-2340 35.0% 910.0µM 12.0% 910.0µM B-2341 75.0% 910.0µM 50.0% 910.0µM B-2342 83.0% 910.0µM 46.0% 910.0µM B-2343 43.0% 910.0µM 27.0% 910.0µM B-2344 71.0% 910.0µM 50.0% 910.0µM B-2345 64.0% 910.0µM 38.0% 910.0µM B-2346 45.0% 910.0µM 48.0% 910.0µM B-2347 49.0% 910.0µM 50.0% 910.0µM B-2348 76.0% 910.0µM 48.0% 910.0µM B-2349 75.0% 910.0µM 27.0% 910.0µM

♦ Φ φφφφ

- 742 -

· Φ • • • · · · · · · · • • • • • φ •

Example no. IC ₅₀ ρ38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) LPS model mice, % TNF inhibitor @ dose? @ time pref. ( - (features LPS model, TNF inhibited dose 2 &gt; 23-2350 38.0% 910.0µM 56.0% 910.0µM Β-2351 77.0% 910.0µM 1.0% 910.0µM 23-2352 37.0% 910.0µM 19.0% 910.0µM Β-2353 38.0% 910.0µM 33.0% 910.0µM Β-2354 65.0%@10.0uM 25.0% 910.0µM Β-2355 84.0%@10.0uM 50.0% 910.0µM Β-2356 77.0% 910.0µM 45.0% 910.0µM Β-2357 47.0%@10.0uM 41.0% 910.0µM Β-2358 17.0% 910.0µM 52.0% ®10.0uM 23-2359 76.0% 910.0µM 35.0% 910.0µM Β-2360 45.0%@10.0uM > 10.0uM Β-2351 19.0%@10.0uM 46.0% 910.0µM Β-2362 60% 9100.0µM 39.0% 910.0µM Β-2363 44.0% 910.0µM 1.0% 910.0µM Β-2364 47.0% 910.OuM 4.0%@10.0uM 23-2365 82.0% 910.0µM 43.0% 910.0µM Β-2366 70.0% 910.0µM 59.0% 910.0µM Β-2367 46.0% 910.0µM 40.0% 91.0µM Β-2368 65.0% 910.0µM 55.0% 910.0µM Β-2369 32.0% 910.0µM > 10.0uM Β-2370 73% 9100.0µM 20.0% 910.0µM Β-2371 54.0% 910.0µM 36.0% 910.0µM Β-2372 55.0%@100.0uM > 10.0uM Β-2373 50.0% 9100.0µM 6% 910.0µM Β-2374 35.0% 910.0µM 20.0% 910.0µM Β-2375 62.0% 9100.0µM > 10.0uM Β-2376 32.0% 910.0µM 17.0% 910.0µM Β-2377 34.0% 910.0µM 17.0% 910.0µM 23-2378 48.0% 910.0µM 61.0% 910.0µM Β-2379 73.0% 9100.0µM 45.0% 91.0µM Β-2380 81% 9100.0µM 53.0% 910.0µM 23-2381 68% 9100.0µM 2.0% 910.0uM Β-2382 51.0% 910.0µM 24.0% 910.0µM Β-23-3 63.0% 910.0µM 35.0% 910.0µM Β-2384 49% 9100.0µM 10.0% 910.0µM Β-2385 79.0% 910.0µM 19.0% 910.0µM Β-2386 38.0% 910.0µM 19.0% 910.0µM 23-2387 50.0% 9100.0µM > 10.0uM Β-2388 42.0% 910.0µM 24.0% 910.0µM Β-2389 39.0% 910.0µM 29.0% 910.0µM

- 743 ♦ 0000

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₉₀ U937 cells, mM or% inhib. Conc., (ΜΜ) AND- Mouse LPS model, Rat LPS model, % TNF inhibits the% TNF inhibits the dose @ time pref. g prep. B-2390 34.O% 01O.OuM 27.O% 01.OuM B-2391 4O.O% 01O.OuM 59.O% 01O.OuM B-2392 63.O% 01O.OuM 46.O% 01O.OuM B-2393 43.O% 01O.OuM > 10.0uM B-2394 37.O% 01O.OuM 22.O% 01O.OuM B-2395 32.O% 01O.OUM 28.O% 01O.OUM B-2396 75.O% 01O.OuM > 10.0uM B-2397 83.O% 01O.OuM 22.O% 01O.OuM B-239B 55% 0100.OuM 10O.O% 01O.OuM B-2399 69.O% 01O.OuM 18.O% 01O.OuM B-2400 6O.O% 01O.OuM 4O.O% 01O.OuM B-2401 79.O% 01O.6uM 44.O% 01O.OuM B-2402 43.O% 01O.OuM 52.O% 01O.OuM B-2403 72% 0100.OuM 52.O% 01O.OuM B-2404 60% © 100.0uM 52.O% 01O.OuM B-2405 47% 0100.OuM > 10.0uM B-2406 45.O% 01O.OuM 24.O% 01O.OuM B-2407 47%@100.0uM 27.O% 01O.OuM B-2408 39.O% 01O.OUM 10O.O% 01O.OuM B-2409 78.O% 01O.OuM 26.O% 01O.OuM B-2410 33.O% 01O.OuM 32.O% 01O.OuM B-2411 25% © 100.0uM 13.O% 01O.OuM B-2412 4O.O% 01O.OuM 31.O% 01O.OuM B-2413 75.O% 01O.OuM 37.O% 01O.OuM B-2414 86.O% 01O.OuM 38.O% 01O.OuM B-2415 94.O% 01O.OuM 50O.O% 01O.OuM B-2416 8S.O% 01O.OuM 43.O% 01.OuM B-2417 83.O% 01O.OuM 18.O% 01O.OuM B-2418 88.O% 01O.OuM 34.O% 01O.OuM B-2419 86.O% 01O.OuM 66.O% 01O.OuM B-2420 7O.O% 01O.OuM 34.O% 01O.OuM B-2421 89.0% 210.0µM 38.O% 01O.OuM B-2422 9O.O% 01O.OuM 17.O% 01O.OuM B-2423 85.O% 01O.OuM > 10.0uM B-2424 86.O% 01O.OuM 43.O% 01O.OuM B-2425 79.O% 01O.OuM 42.O% 01O.OuM B-2426 88.O% 01O.OuM 53.O% 01O.OuM B-2427 87.O% 01O.OuM 59.O% 01O.OuM B-2428 82.O% 01O.OuM 50O.O% 01O.OuM B-2429 92.O% 01O.OuM 32.O% 01O.OuM

· · · · · · · · ·

- 744 ························ • · · ·

ΑΑ At

Example no. IC _{50 of} p38 alpha kinase mM or% conc. (μΜ) IC ₅₀ U937 cells, mM or% inhib. Conc., (ΜΜ) Mouse LPS model, % TNF inhibited dose pre-dosing time. - Krys! LPS model, % TNF Inhibits Dose Pre-dos. B-2430 90.0% A10.0µM 61.0% A10.0µM B-2431 85.0% 210.0µM 68.0% A10.0µM B-2432 86.0% 210.0µM 40.0% A10.0µM B-2433 94.0%@10.0uM 84.0% A10.0µM B-2434 92.0% A10.0µM 63.0% A10.0µM B-2435 84.0% A10.0µM 4.0% A10.0µM B-2436 80.0% A10.0µM 54.0% A10.0µM B-2437 82.0% A10.0UM 41.0% A10.0µM B-2438 75.0% A10.0µM 40.0% A10.0µM B-2439 80.O% A10.0uM 44.0% A10.0µM B-2440 77.0% A10.0µM 78.0% A10.0µM B-2441 86.0% A10.0µM 46.0% AlO.OuM B-2442 86.0% A10.0µM > 10.0uM B-2443 84.0% A10.0µM 44.0% A10.0µM B-2444 89.0% A10.0µM 7.0% A10.0µM B-2445 94.0% A10.0µM 15.0% A10.0µM B-2446 90.0% A10.0µM 28.0% A10.0µM B-2447 94.0% A10.0µM > 10.0uM B-2448 75.0% A10.0µM 30.0% A10.0µM B-2449 86.0% A10.0µM 42.0% A10.0µM B-2450 87.0% A10.0µM 46.0% AI.OuM B-2451 87.0% A10.0µM 45.0% A10.0µM B-2452 89.0% A10.0µM 33.0% A10.0µM B-2453 91.0% A10.0µM > 10.0uM B-2454 88.0% A10.0µM 40.0% A10.0µM B-2455 87.0% A10.0µM 54.0% A10.0µM B-2456 86.0% A10.0µM 53.0% A10.0µM B-2457 90.0% A10.0µM 18.0% A10.0µM B-2458 B3.0% A10.0µM 36.0%@10.0uM B-24S9 82.0% A10.0µM 81.0% AlO.OuM B-2460 80.0% A10.0µM 79.0% A10.0µM B-2461 67.0% A10.0µM 59.0% A10.0µM

Represented by:

Dr. Otakar Švorčík

JUDr. Otakar Švorčík attorney

Claims (25)

PATENTOVÉ Claims A compound of formula 1 (X) wherein: R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheteroc carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylakylene, · · · · · · · · · · · · · · · · · Aryloxycarbonylalkylene, heterocyclyloxycarbones lalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylakylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene; or R ¹ has the general formula o II »26 in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclylalkyl. - 747 alkylheterocyclylarylene, aralkylheterocyklyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylaikylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylalkylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxyarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, sulfyclylthioarylene, heterocyclylthiarylene, heterocyclylthiarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, and φφφφ · φφφφ · φφφ · · alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxykarbonylheterocykly1, a1koxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, alkoxykarbonylaminoalkylamino and heterocyclylsulfonyl; • · • · 749 wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from the group consisting of halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: C (CH ₂ ): 1 i., 1 H / (III) in which: j is an integer from 0 to 8; and m is 0 or 1; and 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; and R ³² 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 ³⁵ , -C (O) OR ³⁵ , -SO ² R ³⁶ , -C (O) NR ³⁷ R ^38, and -SO ² NR ³⁹ R ⁴⁰ ; - 750 • A AAAA AA AA AA AA AA AA AA * AAAA AAAAAA AAAA AAA AAAA AA AA AA AAAA AA AA wherein R ³⁵ , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents hydroxy; ao _e R 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 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, - 751 99 9999 » 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 9 9 99 9 9 99 aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheteroclycyclyl, aralkylheteroclyl , alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , 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 hydrido; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not - 752 φφ φφφφ ΦΦ φ φ «« φ φ φ ΦΦΦ · · φ φ φ ΦΦΦΦ φ φ φ φ methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl methyl s methyl methyl s methyl or a pharmaceutically acceptable salt or tautomer thereof. A compound according to claim 1 wherein: R ¹ is selected from the group consisting of hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino , lower arylamino, lower alkylaminoalkylene and lower heterocyclylalkylene; or R ¹ has the general formula R ²⁵ AND II 7 C — N (II) in which: i is 0, 1, or 2; and R ²⁵ is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene and lower heterocyclylcarbonylaminoalkylene; and R ²⁶ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene and lower alkylaminoalkyl; a ···················· R ²⁷ is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylfenylen, lower alkylphenylalkyl, lower fenylalkylfenylen, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyklylfenylen, lower fenylalkylheterocyklyl, lower alkoxyalkylene, lower alkoxyfenylen, lower alkoxyfenylalkyl, lower alkoxyheterocyklyl, lower alkoxyalkoxyfenylen, lower fenoxyfenylen, lower fenylalkoxyfenylen, lower alkoxyheterocyklylalkylen, lower fenoxyalkoxyfenylen, lower alkoxycarbonylalkylene , lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenyla minokarbonylalkylen lower alkoxyfenylaminokarbonylalkylen, lower aminocarbonylalkylene, arylaminokarbonylalkylen lower alkylaminokarbonylalkylen, lower fenylkarbonylalkylen, lower alkoxykarbonylfenylen, lower fenoxykarbonylfenylen, lower alkylfenoxykarbonylfenylen, lower fenylkarbonylfenylen, lower alkylfenylkarbonylfenylen, lower alkoxykarbonylheterocyklylfenylen, lower alkoxykarbonylalkoxyfenylen, lower heterocyklylkarbonylalkylfenylen, lower alkylthioalkylene, cykloalkylthioalkylen lower alkylthiofenylen lower fenylalkylthiofenylen lower heterocyclylthiophenylene, lower phenylthioalkylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene; • · Wherein said lower alkyl, lower cycloalkyl, aryl group is selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalkylphenylene, and lower alkylsulfonyl, each of which is optionally, haloalkyl, lower alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ⁴⁶ R ⁴⁷ wherein R ⁴⁶ is lower alkoxycarbonyl and R ⁴⁷ is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle, wherein said heterocycle is optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, aryl selected from the group consisting of phenyl , biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower 755 alkoxycarbonylamino; wherein said aryl radicals selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and R ² is selected from hydrido, halo, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- or 6-membered heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino , lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl , alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy and lower heterocyclylthio; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, lower alkyl, lower alkynyl, phenyl, 5- or 6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower - 756 alkylaminoalkylamino, lower alkynylamino, lower amino (hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl and phenylsulfonyl; or R ² has the formula: R ³⁰ AND -C (CH3). AND R ³¹ R ³ is> 33 (III) in which: j is 0, 1 or 2; and m 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 the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene and heterocyclylcarbonylaminoalkylene; and 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 ; wherein R ³⁵ is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, - 757 alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylalkylene, aralkoxybenzyloxy, aralkoxybenzyloxy; wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl, halo, haloalkyl, alkoxy, haloalkyl, alkoxy, amino, nitro and cyano; or R ³⁵ is CHR ⁴⁸ R ⁴⁹ wherein R ⁴⁸ is arylsulfonylamino or alkylarylsulfonylamino and R ⁴⁹ is selected from the group consisting of aralkyl, amino, alkylamino and aralkylamino; or R ³⁵ represents -NR ⁵⁰ R ⁵¹ wherein R ⁵⁰ represents alkyl and R ⁵¹ represents aryl; and wherein R ³⁶ is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoalkylene, alkylcarbonylyhino, alkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino alkylsulfonylarylene, alkylsulfonylaralkyl and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylamino-heterocyclyl groups and Alkylsulfonylarylene are optionally substituted with one or more radicals selected independently from the group consisting of alkyl, halogen, hydroxy, haloalkyl , alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ is selected from the group consisting of hydrogen and alkyl; and wherein R ³⁸ is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyalkylene, aryloxyarylene, aryloxyarylene, aryloxyarylene, aryloxy alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl and aminosulfonylaralkyl; wherein said aryl, heterocyclyl, aralkyl and heterocyclylalkylene groups are optionally substituted with one or more radicals selected independently from the group consisting of alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; or R ³⁸ represents -CR ⁵² R ⁵³ wherein R ⁵² represents alkoxycarbonyl and R ⁵³ represents 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 are as defined for R ²⁶ and R ²⁷ in claim 1; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; or R ² is selected from the group consisting of - 759 • · · · AND CCH ₃ is _k (VI) (VII) (VIII) wherein k is an integer from 0 to 3; and R ⁵⁶ is hydrogen or lower alkyl; and R ⁵⁷ is hydrogen or lower alkyl; or R ⁵⁶ and R ⁵⁷ together form a lower alkylene bridge; and R ⁵⁸ 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 (O) NHR ⁶¹ ; wherein R ⁵⁹ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl and aralkyl groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, 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; - 760 9 alkylaminoarylene, alkylsulfonylarylene and arylsulfonyl heterocycles; wherein said aryl, heterocyclyl and aralkyl groups are optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶¹ is selected from the group consisting of alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals selected independently from alkyl, halogen, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro and cyano; and R ³ is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl and wherein R ⁴³ is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl, and lower aryloxyalkyl; and wherein the R ³ pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halogen, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, - 761 cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower aikinylamino, lower aminoalkyl, arylamino, lower arylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyfenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower fenylalkylheterocyklylamino, lower alkylaminocarbonyl, lower alkoxyfenylalkylamino hydrazinyl, lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² is lower alkylcarbonyl or amino, and R ⁶³ represents lower alkyl or lower phenylalkyl; and R ⁴ is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl and naphthyl and 5- or 6-membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from the group consisting of lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halogen, lower alkyl, lower alkynyl lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 2 wherein R ¹ is selected from the group consisting of hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, 9 9 · 9 9 9 9 9 9 - 769 9 9 9 9 • 9 9 9 9 9 9 9 9 9 fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethinyl, propargyl, 1-propynyl, 2-propynyl, 2-propynyl, 2-propynyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, cyclic aminoethyl, dimethylaminoethyl, dimethylaminoethyl, dimethylaminoethyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl and methylthiomethyl; and R ² is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazolyl, imidazoline, morpholinyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, Ν, Ν-dimethylamino, N-ethylamino, N, N-diethylamino, N, N-propylamino, Ν, Ν-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, φφφφφ - 763 φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ cyk cyk cyk cyk cyk cyclohexyl, cyclohexyl, cyclopropenyl, cyclopropenyl, cyclopropenyl, , aminoethyl, aminoethylamino, aminopropylamino, N, N-dimethylaminoethylamino, N, N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylethoxycarbonylaminoethylamino, 1,1-dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl and 1,1-dimethylethoxycarbonylpiperazinylcarbonyl; wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from the group consisting of fluorine atom, chlorine atom, bromine atom, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl and 1,1-dimethylethylcarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and R ³ is selected from pyridinyl, pyrimidinyl and purinyl; where R ³ is optionally substituted with one or more radicals selected independently from methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl , aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, 99 ΦΦ ·· - 764 9 Φ 9 9 9 9 9 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 9 9 99 99 9.9 9999 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methyl-aminocarbonyl, ethylaminocarbonyl, ethylaminocarbonyl, ethylaminocarbonyl, ethylaminocarbonyl, -hydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl, ethyl or phenylmethyl; and R ⁴ is selected from the group consisting of hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, isoxazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups in R ⁴ are optionally substituted with one or two 99 · 999 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 more radicals selected independently from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethinyl, methoxy , ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 3 wherein R ¹ represents hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl; R ² is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N, N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl and piperazinylamino; wherein the phenyl, piperidinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, ethyl and trifluoromethyl; R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl; R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; • Φ · φ »· 9 · 9 9 9 766 wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy , trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 4 wherein R ¹ represents hydrido or methyl; R ² is selected from hydrido, methyl or ethyl; R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl; R ⁴ is selected from phenyl optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 2 wherein R ¹ is selected from the group consisting of hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, 4 4 4 4 4 9 4 4 4 4 4 4 5 · • · - Ί6Ί 9 4 9 ♦ · * • · 4 9 4 4 · 4 4 4 · · · · · · · · · · 4 9 · 4 4 · 9 44 4444 fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, piperazinyl, 2-propynyl, 2-propynyl, 2-propynyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, ethylaminoethyl, ethylaminoethyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl and methylthiomethyl; and R ² has the formula: 'I - C-CCH ₂ 3 • R ³¹ >3' R ³² OF N, 33 (III) in which: j is 0, 1 or 2; and m is 0; and R ³⁰ and R ³¹ are independently selected from the group consisting of hydrogen and lower alkyl; R ³² is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower - 768 ·· ·· · · · · · · · · · · · · · · · · · 99 · » 99 ·· · · · · 9 9 9999 9 9 9 9 9 9 · 9 99 99 * 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 ; wherein R ³⁵ is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene , lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, lower heterocyclylcarbonyl, , lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene and lower alkylthioalkylene; wherein said aryl selected from the group consisting of phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene and lower alkylcarbonylheterocyclyl groups; selected independently from the group consisting of lower alkyl, halogen, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or R ³⁵ represents CHR ⁴⁸ R ⁴⁹ wherein R ⁴⁸ represents • · 769 phenylsulfonylamino or lower alkylphenylsulfonylamino and R ⁴⁹ is selected from the group consisting of lower phenylalkyl, amino, lower alkylamino and lower phenylalkylamino; or R ³⁵ is -NR ⁵⁰ R ⁵¹ wherein R ⁵⁰ is lower alkyl and R ⁵¹ is aryl selected from phenyl, biphenyl and naphthyl; and wherein R ³⁶ is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl , carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylene; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl and lower alkylsulfonylphenylene are optionally substituted with one or more radicals independently selected from lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ is selected from the group consisting of hydrogen and lower alkyl; and wherein R ³⁸ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl selected from the group consisting of: - 770 · 99 9 9 t t 99 · 99 99 t t 99 99 99 99 99 99 9999 9 9 9 9 9 9 9 9 9 Including phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxycarbonylene, lower alkoxycarbenylene, lower alkoxyphenyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl and lower aminosulfonylphenylalkyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl and lower heterocyclylalkylene are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; or R ³⁸ represents -CR ⁵² R ⁵³ wherein R ⁵² represents lower alkoxycarbonyl and R ⁵³ represents lower alkylthioalkylene; or R ³⁷ and R ³⁸ together with the nitrogen atom to which they are attached form a 4-8 membered heterocycle; R ³⁹ and R ⁴⁰ are as defined for R ²⁶ and R ²⁷ in claim 2; or R ² is selected from the group consisting of (VI) (VII) (VIII) wherein k is an integer from 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, and -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 alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and - 772 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 heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene and lower phenylsulfonylheterocyclyl; wherein said aryl groups selected from phenyl, biphenyl and naphthyl, lower heterocyclyl and lower phenylalkyl are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, 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 with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and R ³ is selected from pyridinyl, pyrimidinyl and purinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl , ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, - 773 dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, nbutoxy, methylamino, ethylamino, dimethylamino, prophylamino, 2-dimethylamino, diethylamino, 2-dimethylamino, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylethylethyl -ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents Me ⁶² thylcarbonyl or amino and R ⁶³ represents methyl, ethyl or phenylmethyl; and R ⁴ is selected from the group consisting of hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, isoxazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and The heterocyclyl in R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine, methyl ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 6 wherein R ¹ represents hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl; R ² has the formula: , 30 -C-CCHPjka i H I c , 33 (III) in which: j is 0, 1 or 2; and m is 0; and R ( ³⁰⁾ is hydrogen; and R ³¹ is elected that file, include alkyl; and R ³² is elected that file, include alkyl; and R ³³ is elected that file, include -C (O) OR ³⁵ , -SO ₂ R ³⁶ , -C (O) NR ³⁷ R ³⁸ and lower hydrogen, lower hydrogen, lower alkyl, -C (O) R ³⁵ , SO ₂ NR ³⁹ R ^40; Wherein R ³⁵ is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen and lower haloalkyl; and wherein R ³⁶ is selected from the group consisting of lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ³⁷ represents a hydrogen atom; and wherein R is selected from the group consisting of lower alkyl, phenyl and lower alkylphenylene; wherein R ³⁹ and R ⁴⁰ are as defined for R ²⁶ and R ²⁷ in claim 2; or R ² is selected from the group consisting of - 775 - • · ??? (VI) (VII) (VIII) wherein k is an integer from 0 to 1; and R ⁵⁶ represents a hydrogen atom; and R ⁵⁷ represents a hydrogen atom; and R ⁵⁸ is selected from the group consisting of -C (O) R ⁵⁹ and -SO 2 R ⁶⁰ ; wherein R ⁵⁹ is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halogen, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro and cyano; and wherein R ⁶⁰ is selected from the group consisting of lower alkyl; and R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl; and - 777 - R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups in R ⁴ are optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 7 wherein R ¹ represents hydrido or methyl; and R ³ is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R ³ is optionally substituted by one or more radicals chosen independently from the group comprising fluorine, bromine, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxy, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, , hydroxy and methylcarbonyl; and R ⁴ is selected from phenyl optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 wherein R ¹ is hydrido. • · · ·· · The compound of claim 2 wherein R ¹ is hydrido. The compound of claim 3 wherein R ¹ is hydrido. The compound of claim 6 wherein R ¹ is hydrido. The compound of claim 3 wherein R ¹ is methyl or ethyl. The compound of claim 6 wherein R ¹ is methyl or ethyl. The compound of claim 2 wherein R ² is hydrido. The compound of claim 3 wherein R ² is hydrido. The compound of claim 2 wherein R ⁴ is optionally substituted phenyl. The compound of claim 3 wherein R ⁴ is optionally substituted phenyl. The compound of claim 6 wherein R ⁴ is optionally substituted phenyl. • · · · · · - 779 ·· ·· ·· ·· ·· · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99 99 99 The compound of claim 2 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl. The compound of claim 3 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl. The compound of claim 2 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl; and R ⁴ represents optionally substituted phenyl. A compound according to claim 3 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl; and R ⁴ represents optionally substituted phenyl. A compound of formula IX wherein: Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocyclyl, lower - 780 ·································· Aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl , lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxyycycloalkyl, lower carboxyycycloalkyl lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and R ⁴ is selected from the group consisting of hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5 or β-membered heterocyclyl and aryl selected from phenyl, biphenyl, naphthyl; wherein R ⁴ is optionally substituted at a substitutable position by one or more radicals selected independently from the group consisting of halogen, lower alkyl, lower alkoxy, 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9999 99 99 aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 24 wherein wherein R ¹ is selected from the group consisting of hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R ² is selected from the group consisting of hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morphol pyridinyl, carboxymethylamino, methoxyethylamino, 9 «99 99 99 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9999 99 99 (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl; and R ⁴ is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, chlorolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, 783-methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof. 26. Compound hydrido. according to claim 24 ve which R ¹ represents 27. Compound hydrido. according to claim 25 ve which R ¹ represents 28. Compound lower alkyl. according to claim 24 ve which R ¹ represents 29. Compound lower alkyl. according to claim 25 ve which R ¹ represents 30. Compound hydrido. according to claim 24 ve which R ² represents 31. Compound hydrido. according to claim 25 ve which R ² represents 32. Compound according to claim 24 ve which R ¹ and R ² is selected independently from the file, including i hydrido, methyl and ethyl. 33. Compound according to claim 25 ve which R ¹ and R ² is selected independently from the group consisting of hydrido, methyl and ethyl. - 784 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The compound of claim 25 wherein Z represents a carbon atom. A compound of formula X wherein: Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower 785 heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylcarbonylheterocyclyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and R ⁴ is selected from the group consisting of 5- or 6-membered heteroaryl and aryl selected from the group consisting of phenyl, biphenyl and naphthyl; wherein R ⁴ is optionally substituted with one or more radicals independently selected from halogen, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower • 9 · · · · · · 786 alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 35 wherein wherein R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; and R ² is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, Ν, Ν-dimethylamino, N-ethylamino, N, N-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, methoxy, carboxymethylamino) (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl and 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl; and • · «· - 787 · · 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 78 «· · · · · · R ⁴ is selected from phenyl, quinolyl, diphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylethylamino, phenylmethylamino, fluoromethylamino, phenylmethylamino, phenylmethylamino, , hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 35 wherein R ¹ is lower alkyl. A compound according to claim 36 wherein R ¹ represents - 788 lower alkyl. 39. Compound hydrido. according to claim 35 ve which R ² represents 40. Compound hydrido. according to claim 36 ve which R ² represents 41. Compound according to claim 35 ve which R ¹ represents methyl or ethyl; and R ² is selected from the group consisting of hydrido, methyl and ethyl. The compound of claim 36 wherein R ¹ is methyl or ethyl and R ² is selected from the group consisting of hydrido, methyl and ethyl. The compound of claim 35 wherein Z represents a carbon atom. 44. Compound of formula XI (XI) • 9 9 ·· - 789 99 99 99 99 • 99 9 9 9 9 9 9 9 9 9 · 9,999,999 9 9 9 9 9 9 9 9 • 9 9999 99 9 · in which Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxyycycloalkyl, lower carboxyycyckyalkyl, lower carboxyycyckyalkyl lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from halogen, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and R ⁴ is selected from the group consisting of 5- or 6-membered heteroaryl and aryl selected from the group consisting of phenyl, biphenyl and naphthyl; Wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy , lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 44 R ¹ is selected from the group consisting of methyl, ethyl, hydroxyethyl and propargyl; and 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-diethylamino, N-propylamino, N- Phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl 99 99 9 9 9 9 9 · carboxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl- ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl and benzodioxolyl; wherein R ⁴ is optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R ⁵ is selected from the group consisting of fluorine atom, chlorine atom, bromine atom, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino , hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, 792 · ♦ ·· ·· · · * · 9 9 » 9 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9999 99 99 methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 44 wherein R ¹ is lower alkyl. The compound of claim 45 wherein R ¹ is lower alkyl. The compound of claim 44 wherein R ² is hydrido. The compound of claim 45 wherein R ² is hydrido. A compound according to claim 44 wherein R ¹ is methyl or ethyl and R ² is selected from hydrido, methyl and ethyl. The compound of claim 45 wherein R ¹ is methyl or ethyl and R ² is selected from the group consisting of hydrido, methyl and ethyl. The compound of claim 44 wherein Z represents a carbon atom. ·· »· - 793 ·· ···· 53. A compound of formula IX Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R ² is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycyckyalkyl, lower carboxyycycloalkyl, lower carboxyycyckyalkyl lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl and lower alkoxycarbonylheterocyclylcarbonyl; 9 · 794 wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals selected independently from the group consisting of halogen, lower alkyl, keto, aralkyl, carboxy , lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R ² represents -CR ⁵⁴ R ⁵⁵ wherein R ⁵⁴ represents phenyl and R ⁵⁵ represents hydroxy; and R ⁴ is phenyl, which is optionally substituted with one or more radicals selected independently from halogen, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R ⁵ is selected from the group consisting of halogen, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower arylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents lower alkylcarbonyl or amino and R ⁶³ represents lower alkyl or lower phenylalkyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 53 wherein R ¹ is selected from the group consisting of hydrido, methyl, ethyl, hydroxyethyl and propargyl; • 0 00 0 0 0 0 0 0 · 0 0 0 0 0 0 0 0 0 0 0 0 0 «0000 - 795 9 · 0000 • 0 • 0 0 0 0 0 0 0 0 0 • 0 0 0 0 0 0 0 • 0 0 0 00 ·· 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-diethylamino, N-propylamino, N- phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonyl, (1,1-dimethyl) ethylcarbonyl, ethylcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl and pyridinyl groups are optionally substituted with one or more radicals selected independently from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl , ethoxycarbonyl and (1,1-dimethyl) ethoxycarbonyl; R ⁴ is phenyl optionally substituted with one or more radicals selected independently from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy ; and R ⁵ is selected from fluorine, chlorine, bromine, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, AAAA - 796 AA AA AA AA AAAA AAAA AAA AA AAAA * AA AAAA A A A A A ♦ AAAA A A A AAAA AA AA AA AAAA AA AA hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluoromethylamino, fluoromethylamino, fluoromethylamino, fluoromethylamino, fluoromethyl , methylcarbonyl, hydrazinyl and 1-methylhydrazinyl, or -NR ⁶² R ⁶³ wherein R ⁶² represents methylcarbonyl or amino and R ⁶³ represents methyl or benzyl; or a pharmaceutically acceptable salt or tautomer thereof. A compound according to claim hydrido or lower alkyl. 53 ve which R ¹ represents A compound according to claim hydrido or lower alkyl. 54 ve which R ¹ represents A compound according to claim hydrido. 53 ve which R ¹ represents The compound of claim hydrido. 54 ve which R ¹ represents A compound according to claim hydrido. 53 ve which R ² represents A compound according to claim 54 ve which R ² represents hydrido. ·· ···· 9 · ♦ + + + + + + + + + + + + + + + + + + + + + + + + + · » A compound according to claim 53 wherein R ⁴ represents phenyl substituted with one or more fluorine, chlorine or bromine atoms. A compound according to claim 54 wherein R ⁴ is phenyl substituted with one or more fluorine, chlorine or bromine atoms. The compound of claim 53 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl. A compound according to claim 54 wherein R ¹ and R ² are independently selected from the group consisting of hydrido, methyl and ethyl. A compound according to claim 53 wherein Z represents a carbon atom. 66. Compound of Formula IX (IX) Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of hydrido, lower alkyl, 798 φ «φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ · · · · · · · · nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší nižší hydroxy nižší nižší nižší nižší nižší nižší nižší nižší nižší; and R ² is selected from the group consisting of hydrido and lower alkyl; and R ⁴ is selected from phenyl and benzodioxolyl; wherein the phenyl is optionally substituted with one or more halogen radicals; and R ⁵ is selected from the group consisting of hydrido, halogen and alkylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 66 wherein Z represents a carbon atom; and R ¹ is selected from hydrido, methyl, hydroxyethyl, propargyl; and R ² represents hydrido; and R ⁴ is selected from phenyl and benzodioxolyl; wherein the phenyl is optionally substituted with one or more radicals selected independently from the group consisting of chlorine, fluorine and bromine; and R ⁵ is selected from the group consisting of hydrido, fluoro and 1-methylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 67 wherein Z represents a carbon atom; and R ¹ is selected from the group consisting of hydrido and methyl; and R ² represents hydrido; and R ⁴ is selected from phenyl optionally substituted with one or more radicals selected independently from chloro, fluoro and bromo; and ·· ···· - 799 ·· ················· · · · φφφ · · φ Φ φ φφ ·· ΦΦΦΦΦΦ ΦΦΦ φ φφ ΦΦ ΦΦ ΦΦΦΦ ΦΦ ΦΦ R ⁵ is selected from hydrido and fluoro; or a pharmaceutically acceptable salt or tautomer thereof. 69. A compound according to claim 1, selected from the group consisting of compounds, tautomers thereof, and pharmaceutically acceptable salts thereof; 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-methyl-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [5-methyl-3- [4- (methylthio) phenyl] -1H-pyrazol-4-yl] pyridine; 4- [3- (4-Chloro-phenyl) -5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [3-Methyl-5- (3-methyl-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [5- (2,5-Dimethyl-phenyl) -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-phenoxy-phenyl) -1H-pyrazol-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; 1-hydroxy-4- (3-methyl-5-phenyl-6-pyrazol-4-yl) pyridinium; 5- (4-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-800 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-Chloro-phenyl) -5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5-methyl-3- (2,4-dimethyl-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [5- (4-Chloro-phenyl) -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-Bromo-phenyl) -5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [3- (2-Fluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-Fluorophenyl) -5-methyl-4-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; • · · · - 801 · · 8 8 8 8 8 8 8 8 8 8 8 8 8 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-ethoxy-phenyl) -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-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (3-Chloro-4-methoxy-phenyl) -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-Chloro-phenyl) -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-methyl-phenyl) -1H-pyrazol-4-yl] -pyrimidin-2-amine; 5- [5- (4-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyrimidin-2-amine; 5- [5- (4-Fluoro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyrimidin-2-amine; 5- [5- (4-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyrimidin-2-amine; 5- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine; 4- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine; 4- [5- (3-Methyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine; 4- [5- (2-Methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-802 2-amine; 4- [5- (4-Chloro-phenyl) -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-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-amine; 5- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -2-methoxy-pyridine; 2-methoxy-5- [3-methyl-5- (3-methyl-phenyl) -1H-pyrazol-4-yl] -pyridine; 2-methoxy-5- [5- (4-methoxy-phenyl) -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-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; 4- [5- (3-Chloro-phenyl) -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-Methyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; 4- [5- (4-Chloro-phenyl) -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-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridin-2-ol; 5- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine - 803 Λ · 2-methanamine; 4- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine-2-methanamine; 4- [5- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-methanamine; 4- [5- (2-methylphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-methanamine; 4- [5- (4-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine-2-methanamine; 4- [5- (4-Fluorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine-2-methanamine; 4- [5- (4-Methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine-2-methanamine; 5- [5- (3-Chloro-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine-2-carboxamide; 4- [5- (3-Chloro-phenyl) -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-Chloro-phenyl) -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-Methoxy-phenyl) -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; • · 804 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-5-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4- [5- (3-Chloro-5-methoxy-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (1-Cyclohexadien-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-methyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (3-Methoxy-4-methyl-phenyl) -3-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (3-Methoxy-5-methyl-phenyl) -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-carboxamide; 1- [4- (3-Methyl-5-phenyl-1H-pyrazol-4-yl) -pyridin-2-yl] -ethanone; N, N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2-yl) pyridin-2-amine; - 805 · · · · · · · φ · φ · φ · φ · · · · · · · · · · · · · · · · · · · · · · Φ ·· φφ φφφφ ·· «φ 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; 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl) pyrimidin-2-amine; N, N-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; - 806 · 9 9 9 9 9 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 4- [3- (3-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -pyridine; 4- [3- (4-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -pyridine; 4- [3- (3-Chloro-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [3- (4-Chloro-phenyl) -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-Chloro-phenyl) -1-methyl-pyrazol-4-yl] -2-methyl-pyridine; 5- (4-chlorophenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine dihydrate; 5- (3-fluorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; N, N-dimethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; N-ethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3amine; N, N-diethyl-5- (3-methylphenyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -N, N-diethyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] morpholine; 5- (4-chlorophenyl) -N-propyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 5- (4-chlorophenyl) -N- (phenylmethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine hydrate (2: 1); 5- (4-chlorophenyl) -N- (2-methoxyethyl) -4- (4-pyridinyl) -1H-pyrazol-3-amine monohydrate; • · 807 1,1-dimethylethyl 4- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -piperazine trihydrochloride; 1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methyl-piperazine; 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; 1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -piperazine; N- [5- (4-chlorophenyl) -4- [2- (phenylmethyl) aminol-4-pyridinyl] -1H-pyrazol-3-yl] -1,3-propanediamine trihydrochloride; 1- [5- (4-Chloro-phenyl) -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) -1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl [3 - [[5- (4-chlorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate; 1- [5- (4-Chloro-phenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] - 808 - 4-ethylpiperazine; N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 1,2-ethanediamine; 4- [3- (2,5-Difluorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3-ethyl-phenyl) -5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [3- (3-Chloro-phenyl) -5-ethyl-1H-pyrazol-4-yl] -pyridine; 4- [3-ethyl-5- (3-ethyl-phenyl) -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) -4-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) -1H-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-methyl-phenyl) -1H-pyrazol-4-yl] -pyridine 5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-3-carboxylic acid; 9 99 9 9 9 9 9 · 9 9 - 809 9 9 9 99 9999 9 9 9 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-3-yl] 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-Chloro-phenyl) -1,5-dimethyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (4-Chloro-phenyl) -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-Chloro-phenyl) -1-ethyl-5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [3- (4-Chloro-phenyl) -2-ethyl-5-methyl-1H-pyrazol-4-yl] -pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (2-Chloro-phenyl) -1H-pyrazol-4-yl] -pyridine; 3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanol; 3- (4-fluorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-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-methanol; 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-pyridinyl) -1H-pyrazole-5-methanol; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] - 810 • · · · · · 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99 99 99 4-morpholinethanamine; 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] -N- (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) -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-Chloro-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [3- (1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-Chloro-phenyl) -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-Chloro-phenyl) -1-methyl-1H-pyrazol-4-yl] -pyridine; 4- [5- (3-Chloro-phenyl) -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-pyrazoleAA AAAA - 811 • AA A A A A AAA A · AAAA 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-Bromo-phenyl) -1H-pyrazol-4-yl] -pyridine; 4- [3- (3,4-Difluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (4-Bromo-phenyl) -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-Chloro-phenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine-methanamine; N- [4- [3- (4-Fluoro-phenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -2-pyridine-methanamine; 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; • 0 00 ·· 812 2-fluoro-4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 4- [3- (3,4-Difluoro-phenyl) -1H-pyrazol-4-yl] -2-fluoro-pyridine; 4- [3- (4-Fluoro-phenyl) -1H-pyrazol-4-yl] -3-methyl-pyridine; 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-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] -N- [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-pyrazole-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) -N, N-dimethyl-1H-pyrazole-1-ethanamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] -1H-pyrazole-1-ethanol; • · ··· · - 813 * 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 99 99 99 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) -4-pyrazol-4-yl] -N - [(4-fluorophenyl) methyl] -2-pyridinamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl] N, N-dimethyl-1H-pyrazole-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] -N-4-piperadinyl-2-pyridinamine; N, N-diethyl-3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazole-1-ethanamine; 4- [1- [2- (diethylaminolethyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N - [(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-pyrazole-1-ethanol; N, N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazole-1-ethanamine; N - [(4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) 1- [2- (4-morpholinyl) ethyl] -1H-pyrazol-4-yl] -2-pyridinamine; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-morpholinepropanamine; Ν '- [5- (4-Fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] • - 814 · φ φ φ • »• · · • · · · · φ φ φ φ φ φ φ Ν, Ν-dimethyl-1,3-propanediamine; 5- (4-fluorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine; 3- (4-fluorophenyl) -4- [2 - [[(4-fluorophenyl) methyl] amino] -4-pyridinyl] -4-pyrazole-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] glycine methyl ester; N- [5- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] glycine; 4- [3- (4-Fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyrido; 4- [5- (4-Fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyrido; 4,4 '- (1H-pyrazole-3,4-diyl) bis [pyridine]; 4- [3- (3,4-dichlorophenyl) -4-pyrazol-4-yl] pyridine; N- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-piperidinamine; 2-chloro-4- [3- (4-fluorophenyl) -4-pyrazol-4-yl] 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] -N-methyl-2-pyrimidinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) -2-pyrimidinamine; N-cyclopropyl-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N - [(4-methoxyphenyl) methyl] -2-pyrimidinamine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine; »0000 - 815 • 0 · 0 00 00 00 »000 · 0000 • 00 00 0 0 0 0 0 0 0 000 0 000 00 0 0000 000 000« 00 00 00 0000 00 00 N- [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-methylphenyl) -1H-pyrazol-4-yl] pyrimidine; 4- [3- (4-Chloro-phenyl) -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 according to claim 1, selected from the group consisting of compounds, tautomers thereof, and pharmaceutically acceptable salts thereof, of the class consisting of: - 816 · 9 • 9 9 9 99 ················· 9 9 <9 9 9 9 9 9 9 • * 9 99 99 Ο · · · · · · · · · · · · · · · · · · · - 818 ·· ·· N • · · · · · · · · · · · - 820 • · · · · · · · Ν · • · · - 822 ♦ · · · · 8 8 8 8 8 8 4 · · · ··· · · · · 4 4 · · · · · · · 4 4 ·· - 823 9 * 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 «9 99 99 9999 99 99 9 9 • 9 9 9999 9 999 9 * 0090 The compound of claim 1 which is 4- [5- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 3- (4-fluorophenyl) 4- (4-pyridinyl) -1H-pyrazole-1-ethanol or a pharmaceutically acceptable salt or tautomer thereof. 74. The compound of claim 1 which is 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] 2- (1-methylhydrazino) pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] piperazine or a pharmaceutically acceptable salt thereof, or - 825 9 9 9 9 9 9 9 91 99 99 9999 tautomer. The compound of claim 1 which is 4- [3-cyclopropyl-5- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 4-methylpiperazine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyrimidine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 2-fluoro-4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (3,4-difluorophenyl) -1-methyl-ΙΗ-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (4-bromophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. • 4 · » - 827 4 4 · 4 «4 44 4 4 4 4 4444 «4 4 4 4 · * · 4 4 4 4 4 4 4 4 4 4 4 4 • 44 83. The compound of claim 1 which is 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-fluoropyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (1,3-benzodioxol-5-yl) -1-methyl-1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. A compound according to claim 1 which is 4- [3- (3-fluorophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 4- [3- (3-Fluorophenyl) -1-methyl-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. The compound of claim 1 which is 5- (4-fluorophenyl) N-2-propynyl-4- (4-pyridinyl) -1H-pyrazol-3-amine or a pharmaceutically acceptable salt or tautomer thereof. 88. A substituted pyrazole that specifically binds to the ATP binding site of p38 kinase. 89. A compound according to claim 88 having the general formula: »· · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 in which R ¹ represents a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a molecular weight of less than about 360 atomic mass units; and R ² represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue that binds to a p38 kinase at said ATP binding site of the p38 kinase; and R ³ represents a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a functional group forming a hydrogen bond acceptor; and R ⁴ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 360 atomic mass units; 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; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not methylsulfonylphenyl; ♦ 0 ·· ·· - 827 44 «0 ·· ·· 4 4 4 4 4 4 4 4 5 6 7 8 9 10 0,000,000,000,000,000,000,000,000,000,000,000,000,000 * or a pharmaceutically acceptable salt or tautomer thereof. 90. The compound of claim 89 wherein R ² is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclic radical which is linked to the side chains of Lyss ₂ G1U69 Leu ₇₃ Ι1θ8 _2, Leu _4, Leuioi Thrio and ₃ in that the ATP binding site of p38 kinase wherein said residue is substantially within the hydrophobic cavity formed during said p38 kinase binding at the ATP binding site. A compound according to claim 89 wherein R ³ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a functional group forming a hydrogen bond acceptor which forms a hydrogen bond with the NH backbone of the Meti ₀ 6 p38 kinase. The compound of claim 89 wherein R ¹ is a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 250 atomic mass units. 93. A compound according to claim 89 wherein R ⁴ is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclic residue having a molecular weight less than about 250 atomic mass units. The compound of claim 89 wherein R ¹ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 360 atomic - 829 • 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 · · · 9 9 9 9 9 9 · 99 weight units; and R ² is hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclic radical wherein said radical binds with sidechains of Lys _52, Glu ₆ 9, Leu ₇₃ Ile ₈₂ r Leu ₈₄ Leuioi and Thri ₀₃ in said ATP binding site of p38 kinase, said the residue is substantially within the hydrophobic cavity formed during said p38 kinase binding at the ATP binding site; and R ³ represents a hydrocarbon radical, a heterosubstituted hydrocarbon radical or a heterocyclic radical having a functional group forming a hydrogen bond acceptor which forms a hydrogen bond with the NH backbone of the Metio6 p38 kinase; and R ⁴ represents a hydrocarbon residue, a heterosubstituted hydrocarbon residue, or a heterocyclic residue having a molecular weight of less than about 360 atomic mass units. 95. A compound according to claim 94 wherein R ¹ and R ⁴ are independently selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclic, and have a combined molecular weight less than about 360 atomic mass units. 96. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group of claim 1; or a pharmaceutically acceptable salt thereof. 97. The pharmaceutical composition of claim 96, wherein said compound is selected from the group of claim 3; or theirs 100 · # »· - 832 - UJ 09 9 99 99 0 9 9 9 9 09 1 0 0 · 9 0 0 0 90 * 9 * 0 9 9 9 9 9 9 0 9 * 9 0099 90 99 pharmaceutically acceptable salts. 98. The pharmaceutical composition of claim 96 wherein said compound is selected from the group of claim 4; or a pharmaceutically acceptable salt thereof. 99. The pharmaceutical composition of claim 96 wherein said compound is selected from the group of claim 5; or a pharmaceutically acceptable salt thereof. 100. The pharmaceutical composition of claim 96, wherein said compound is selected from the group of claim 6; or a pharmaceutically acceptable salt thereof. 101. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group of claim 24; or a pharmaceutically acceptable salt thereof. 102. The pharmaceutical composition of claim 101 wherein said compound is selected from the group of claim 25; or a pharmaceutically acceptable salt thereof. 103. A pharmaceutical composition comprising a therapeutically effective amount of a compound, said compound selected from the group of claim 25; or their ·· · * «♦ - 831 «· · · ♦ 9« 4 pharmaceutically acceptable salts. 104. The pharmaceutical composition of claim 103, wherein said compound is selected from the group of claim 36; or a pharmaceutically acceptable salt thereof. 105. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group of claim 44; or a pharmaceutically acceptable salt thereof. 106. The pharmaceutical composition of claim 105, wherein said compound is selected from the group of claim 45; or a pharmaceutically acceptable salt thereof. 107. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of compounds of claim 53; or a pharmaceutically acceptable salt thereof. 108. The pharmaceutical composition of claim 107, wherein said compound is selected from the group of claim 54; or a pharmaceutically acceptable salt thereof. 109. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group of claim 66; or φ φ φ φ φ φ φ φ φ φ φ φ φ · · φ φ φ φ φ φ φ φ Q - their pharmaceutically acceptable salts. 110. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group of claim 69; or a pharmaceutically acceptable salt thereof. 111. The pharmaceutical composition of claim 110 wherein said compound is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. 112. A method of treating a TNF-mediated disorder comprising treating a subject having or susceptible to said disorder with a therapeutically effective amount of a compound of Formula I wherein: R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, 9 9 9 9 833 • 9 »9 0 t · · 0 • 0 99 heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy , mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkylsulfonyl, alkenylsulfonyl, alkylsulfinyl, alkynylsulfonyl, alkenylsulfonyl, , alkoxycarbonylalkylene, aryloxycarbonylakylene, heterocyclyloxycarbonylakylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylakylene, alkylcarbonylarylene, alkylcarbonylarylene, alkylcarbonylarylene, alkylcarbonylarylene, alkylcarbonylarylene, flax, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or R ¹ has the general formula H (II) - 834 · 9 9 9 · 9 9 8 8 8 9 9 9 9 9 9 99 9999 9 9 9 9 9 99 99 in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, , alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylalkylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylaikylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylalkylarylen , alkylthioa alkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, - 835 · # # # # # 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 # # 8 # # # # # Arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylakylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and · * Α · 836 R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, alkoxykarbonylaminoalkylamino and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from the group consisting of halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkyinylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: H Z c N (III) 44 4 ·· 4 44 44 44 • · 4 «··· 4 * 44 443 44 4 43 · « 4 444 444 44 4 44 ο Ί 4444 444 4444 0-3 / - 44 44 44 4444 44 44 in which: j is an integer from 0 to 8; and m is 0 or 1; and 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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents hydroxy; and R ³ is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl; - 838 9 »99 44 99 · 95 ·· »9 ·« 994 · · 94 ·· · 9 · 9 · · 4 9 9 ·· » 4999 999 9999 99 99 99 9944 99 99 wherein R ⁴³ is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl and aryloxyalkyl; and wherein the R ³ pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, akynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, amyloxycarbonyl, aryloxycarbonyloxy, aryloxy alkylaminoalkylamino, hydroxyalkylamino, arylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halenesulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ in which R ⁴⁴ represents alkylcarbonyl or and R ⁴⁵ is alkyl or - 839 * · ········ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl, alkylaminocarbonyl 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 hydrido; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof. 113. A method of treating a p38 kinase mediated disorder comprising treating a subject having or susceptible to said disorder with a therapeutically effective amount of a compound of Formula I with a single compound. 9 9 In which R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheteroc carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino arylamino, heterocyclylamino, alkylsulfinyl, alkysulfinyl, alkanesulfinyl, alkenylsulfinyl, alkenylsulfinyl, alkenylsulfinyl, alkenylsulfinyl , alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, heterocyclylsulfonyl ylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, 841 alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or R ¹ has the general formula _n 25 I o II in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, , alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylakylene, aryloxyalkoxyarylene, • - 842 alkoxykarbonylaikylen, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylalkylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylalkylarylen, alkylthioalkylene, cykloalkylthioalkylen, alkylthioarylen, aralkylthioarylen, heterocyklylthioarylen, arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or • · R26 _r 27 _S P _O G _u θ nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted by one or more radicals chosen independently from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene , alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, aíkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, alkoxykarbonylaminoalkylamino and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from the group consisting of halogen, keto, amino, alkyl, alkenyl, - 844> 32> 33 (III) alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: ^R30 I-cch ;; AND R ³¹ in which: j is an integer from 0 to 8; m is 0 or 1; and 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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl; - 845 • 9 9 9 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents 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 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, alkylaminoalkylamino, hydroxyalkylamino, - 846 aa aa ···· ·· • • AAAAAA AAA · and aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulphonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , 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 hydrido; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof. - 847 φ · φφφφ 114. A method for treating inflammation, characterized in that it comprises treating a subject having or susceptible to inflammation with a therapeutically effective amount of a compound of formula I R ¹ (I) wherein R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylhetero carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl. - 848 acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyklyloxykarbonylarylen, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyklylkarbonylalkylen, alkylkarbonylarylen, arylkarbonylarylen, heterocyklylkarbonylarylen, alkylkarbonyloxyalkylen, arylcarbonyloxyalkylene, heterocyklylkarbonyloxyalkylen, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R ¹ has the general formula 26 (II) I - c-CH ₂ d, H in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, - 849 00 9000 • · • · aralkylarylen alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyklyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylalkylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocykly1, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylalkylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylaryIkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylalkylarylen, alkylthioalkylene, cykloalkylthioalkylen, alkylthioarylen, aralkylthioarylen, heterocyklylthioarylen, arylthioalklylarylene, arylsulfonylaminoalkylen, alkylsulfonylarylene groups, alkylaminosulfonylarylen; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, 850-alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; &lt; tb &gt; ______________________________________ &lt; tb &gt; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, 49 »·» ♦ - 851 • 9 99 9 9 • 9 99 ». 9 9 9 • 9 9 9 • «· 9 • 4 4994 R ^{J, i} / -N \ _R33 ^m (III) H t C1-R alkoxycarbonylaminoalkylamino and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: _R @ 30 - c-cCH3 R ³¹ in which: j is an integer from 0 to 8; m is 0 or 1; and 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; and R ³² 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, «9 ···· - 852 <· · 99 99 99 85 85 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 * 99 99 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents 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 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino; - 853. . . ·· ... • · ·......... · ·. Cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, hydroxyalkylamino, hydroxyalkylamino, hydroxyalkylamino, hydroxyalkylamino, hydroxyalkylamino, hydroxyalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , 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 hydrido; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and • · · · · · · 854 further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof. 115. A method of treating arthritis comprising treating a subject having or susceptible to arthritis with a therapeutically effective amount of a compound of Formula I R R (I) wherein R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheteroc carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkyloxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, - 855 arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, -alkynylsulfinyl, arylsulfinyl, heterocyklylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclicsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyklyloxykarbonylarylen, alkylcarbonylalkylene, arylkarbonylaikylen, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or R ¹ has the general formula "25 I-C-CCH ₂ ), H C — N, 26 (II) in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and R ²⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, - 856 - 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, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylalkylene, alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylalkylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylaikylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylalkylarylen, alkylthioalk ylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalkylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said groups alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, alkyl optionally substituted with one or more thioalkynylene, aryl or thioalkynylene are optionally 857 is alkyl, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of alkyl and nitro; or R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene , alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclyl · alkylamino, aralkylamino, aminoalkyl , aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, 858 heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylamino, alkoxycarbonylamino, alkoxycarbonylamino; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: R ³⁰ I - _{C -} CH CH _{P 1} L -> 32 -N> 33, 3 · * (III) in which: j is an integer from 0 to 8; m is 0 or 1; and 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; and R ³² is selected from the group consisting of hydrogen, alkyl, 859 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents 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 R ³ of the pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from the group consisting of · · φ φ ♦ - 860 φ φ φ φ φ Φ ♦ ♦ halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, alkyl, amino, alkyloxy, heterocyclylalkoxy, amino, , cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, aminoalkylamino, aralkybetalamino, aralkylamino, aralkybenzoary , haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy; provided that R ³ does not represent 2-pyridinyl if R ⁴ • φ »» »· · - 861 represents a phenyl ring containing a 2-hydroxy substituent and when R ¹ represents hydrido; further provided that R ² is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when ^R4 is hydrido; and further provided that R ^{4 is} not methylsulfonylphenyl; or a pharmaceutically acceptable salt or tautomer thereof. 116. A method of treating a p38 kinase mediated disorder comprising treating a subject having or susceptible to said disorder with a therapeutically effective amount of a compound of Formula I wherein: Z represents a carbon atom or a nitrogen atom; and R ¹ is selected from the group consisting of hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and R ² is selected from the group consisting of hydrido and lower alkyl; - 860 0 · 0 00 0 00 »0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 »00 00 0 0 0 0 0 0 0 0 00 00 ·· 0 · ·· R ⁴ is selected from phenyl and benzodioxolyl; wherein the phenyl is optionally substituted with one or more halogen radicals; and R ⁵ is selected from the group consisting of hydrido, halogen and alkylhydrazinyl; or a pharmaceutically acceptable salt or tautomer thereof. 117. The method of claim 112, wherein the TNF-mediated disorder is selected from the group consisting of disorders related to bone resorption, graft-rejection reaction of the host, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease states. , adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory diseases, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 118. The method of claim 112, wherein the TNF-mediated disorder is inflammation. 119. The method of claim 112, wherein the TNF-mediated disorder is arthritis. 120. The method of claim 112, wherein the TNF mediated disorder is asthma. 121. The method of claim 112, wherein said compound is 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine or a pharmaceutically acceptable salt or tautomer thereof. 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · · · · 99 99 99 99 99 99 863 122. The method of claim 112, wherein said compound is 1- [5- (4-chlorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4-methylpiperazine or a pharmaceutically acceptable salt thereof. salt or tautomer. 123. The method of claim 113, wherein the disorder is a p38α kinase-mediated disorder. 124. The method of claim 113 wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption related disorders, host graft rejection reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease conditions, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory diseases, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. The method of claim mediated by p38 kinase is 113, characterized by inflammation. that disorder 126. The method of claim 113, wherein the mediated p38 kinase is arthritis. 127. The method of claim 113, wherein the mediated p38 kinase is asthma. that disorder that disorder 128. The method according to claim 116, wherein: 9 9 9 9 9 9 9 9 9 9 999 99999 9 9 99 999 9999 99 99 99 99 99 99 The 864 disorder is a p38α kinase-mediated disorder. 129. The method of claim 116, wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption related disorders, host graft rejection reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease conditions, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory diseases, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. The method of claim mediated by p38 kinase is 116, characterized by inflammation. that disorder 131. The method of claim 116, wherein the p38 kinase mediated disorder is arthritis. 132. The method of claim 116, wherein the mediated p38 kinase is asthma. that disorder 133. A process for the preparation of pyrazoles of formula (I) wherein: R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheteroc carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylaryonylene, aryloxycarbonylene, aryloxycarbonylene, aryloxycarbonyl nylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, - 866 · alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene and heterocyclylcarbonyloxyarylene; or R ¹ has formula C_N> 27 (II) R ²⁵ I - C-CCH ₂ 3, H in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, , alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylakylene, aryloxyalkoxyarylene, 867 alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylaikylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylaminokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylkarbonylarylen, alkoxykarbonylheterocyklylarylen, alkoxykarbonylalkoxyarylen, heterocyklylkarbonylalkylarylen, alkylthioalkylene, cykloalkylthioalkylen, alkylthioarylen, aralkylthioarylen, heterocyklylthioarylen, arylthioalklylarylene , arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from alkyl and nitro; or • 0 - 868 00 0000 R ²⁶ and R ²⁷ together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is optionally substituted with one or more radicals selected independently from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, alkoxykarbonylaminoalkylamino and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals selected independently from the group consisting of halogen, keto, amino, alkyl, alkenyl; 9 · - 869 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -N, 33 (III) alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl and aralkylsulfonyl ; or R ² has the formula: R @ ³⁰ - c-cCH3 R ³¹ in which: j is an integer from 0 to 8; m is 0 or 1; and 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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, - 870 000 00 0 00 ·· 0 0 0 · 0 0 000 * 0 0 • 0 ·· · 9 0 0 * · * 00 00 * 0900 * 9 09 aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents 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 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, alkoxycarbonyloxy, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, aryloxycarbonyl, alkylaminoalkylamino, hydroxyalkylamino, Aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halogenenesulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; and R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof, comprising the step of forming an acylhydrazone and condensing to form the substituted pyrazoles. 134. The process of claim 133 wherein the acylhydrazone is formed by reacting the ketone with an acylhydrazide. 135. The method of claim 133, wherein the condensation is carried out at a temperature of from about 25 ° C to about 200 C. • Φ ···· - 872 φφφφ 136. A process for preparing the pyrazoles of formula (I) wherein: R ¹ is selected from the group consisting of hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylhetero carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkinoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino arylamino, heterocyclylamino, alkylsulfinyl, alkysulfinyl, alkanesulfinyl, alkenylsulfinyl, alkenylsulfinyl, alkenylsulfinyl, alkenylsulfinyl , alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, φφ φ - 873 alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylakylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonyloxyonylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene, arylcarbonyloxyalkylene; or R ¹ has the general formula R ²⁵ -c-CCH _23i H (II) in which: i is an integer 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 heterocyclylcarbonylaminoalkylene; and 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, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, alkylheterocyclyl, • • · ♦ 0 0 0 0 0 0 0 0 0 · 0 0 0 · 0 »· 0 alkoxyarylene, alkoxyaralkyl, alkoxyheterocyklyl, alkoxyalkoxyarylen, aryloxyarylen, aralkoxyarylen, alkoxyheterocyklylalkylen, aryloxyalkoxyarylen, alkoxycarbonylalkylene, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocykly1karbonylalkylen, aminoalkyl, alkylaminoalkylene, arylaminokarbonylalkylen, alkoxyarylaminokarbonylaikylen, aminocarbonylalkylene, arylaminokarbonylalkylen, alkylamínokarbonylalkylen, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxykarbonylarylen, arylkarbonylarylen, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxyarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalkylarylene, arylsulfonylamino, arylsulfonylamino, arylsulfonylamino, arylsulfonylamino; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, optionally substituted with one or more thioalkykylene groups are optionally, halogen, haloalkyl, alkoxy, keto, amino, nitro and cyano; or R ²⁷ is -CHR ²⁸ R ²⁹ wherein R ²⁸ is alkoxycarbonyl and R ²⁹ is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene and aralkylthioalkylene; 9 - 875 9 9 9 9 99 99 99 99 9 9 9 9 9 • 9 9 Wherein said aralkyl and heterocyclyl groups are optionally substituted with one or more radicals selected independently from the group consisting of alkyl and nitro; or R26 _ar 27 _S p _O j _US nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted by one or more radicals chosen independently from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl and alkoxy; and R ² is selected from the group consisting of hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl , aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylen, alkylaminoarylen, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, karboxycykloalkyl, karboxycykloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxykarbonylheterocyklyl, alkoxykarbonylheterocyklylkarbonyl, alkoxyalkylamino, alkoxykarbonylaminoalkylamino and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, - 876 φ φ φφφφ Φ φ φ φ φ φ φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ · · · · · φ φ φ φ φ φ φ φ φ φ φ cycloalkyl and cycloalkenyl are optionally substituted with one or more radicals selected independently from halogen, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkyinylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl alkoxycarbonyl, alkylsulfonyl, arylsulfonyl and aralkylsulfonyl; or R ² has the formula: R ³⁰  H R ³² 1 1 / - C-CCH _2V C -N R ³ j R ³¹ R m (III) in which: j is an integer from 0 to 8; and m is 0 or 1; and 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; and R ³² 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 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 , R ³⁶ , R ³⁷ , R ³⁸ , R ³⁹ and R ⁴⁰ are independently selected from «φ • • φ φ φ φ φ φ • • φ φ φ φ φ φ φ φ φ φ φ φ · · · souboru φ souboru φ souboru souboru souboru souboru souboru souboru souboru souboru souboru, including a hydrocarbon, a heterosubstituted hydrocarbon and a heterocyclyl; and R ³⁴ is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl and arylaminocarbonyl; or R ² represents -CR ⁴¹ R ⁴² wherein R ⁴¹ represents aryl and R ⁴² represents 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 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals selected independently from halogen, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkyinylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aaa · a ·· · - 878 a * aa aaa aaa aaa aaa aaa aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocroalkyl, aralkylheterocroalkyl, aralkylheterocycloalkyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR ⁴⁴ R ⁴⁵ wherein R ⁴⁴ represents alkylcarbonyl or amino and R ⁴⁵ represents alkyl or aralkyl; R ⁴ is selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl wherein R ⁴ is optionally substituted with one or more radicals selected independently from the group consisting of halogen, alkyl, alkenyl, alkynyl , aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, alkylamryinocarbonyl, alkylamryinocarbonyl, alkylaminocarbonyl , arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino and hydroxy; or a pharmaceutically acceptable salt or tautomer thereof, comprising the step of treating the substituted ketone with an acylhydrazide to obtain pyrazole. 137. The process of claim 136, wherein the process is carried out in an acidic solvent. 138. The method of claim 137, wherein the acidic - 879 • 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 99 9999 99 99 the solvent is acetic acid. 139. The process of claim 137 wherein the acidic solvent is an organic solvent containing an acid.