Substituted pyrazoles as p38 kinase inhibitors

Information

  • Patent Application
  • 20070078146
  • Publication Number
    20070078146
  • Date Filed
    May 05, 2004
    20 years ago
  • Date Published
    April 05, 2007
    17 years ago
Abstract
A class of pyrazole derivatives is described for use in treating p38 kinase medicated disorders. Compounds of particular interest are defined by Formula IA wherein R1, R2, R3 and R4 are as described in the specification.
Description
FIELD OF THE INVENTION

This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.


BACKGROUND OF THE INVENTION

Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38α, p38β and p38γ, and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-α) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.


TNF-α is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.


TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.


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


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


TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.


Various pyrazoles have previously been described. U.S. Pat. No. 4,000,281, to Beiler and Binon, describes 4,5-aryl/heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group. WO 92/19615, published Nov. 12, 1992, describes pyrazoles as novel fungicides. U.S. Pat. No. 3,984,431, to Cueremy and Renault, describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U.S. Pat. No. 3,245,093 to Hinsgen et al, describes a process for preparing pyrazoles. WO 83/00330, published Feb. 3, 1983, describes a new process for the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO 95/06036, published Mar. 2, 1995, describes a process for preparing pyrazole derivatives. U.S. Pat. No. 5,589,439, to T. Goto, et al., describes tetrazole derivatives and their use as herbicides. EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides. Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.


Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec. 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole is specifically described. WO 97/01551, published Jan. 16, 1997, describes pyrazole compounds as adenosine antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specifically described. U.S. Pat. No. 5,134,142, to Matsuo et al. describes 1,5-diaryl pyrazoles as having anti-inflammatory activity.


U.S. Pat. No. 5,559,137 to Adams et al, describes novel pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases. Specifically, 3-(4-fluorophenyl)l-1(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole is described. WO 96/03385, published Feb. 8, 1996, describes 3,4-substituted pyrazoles, as having anti-inflammatory activity. Specifically, 3-methylsulfonylphenyl-4-aryl-pyrazoles and 3-aminosulfonylphenyl-4-aryl-pyrazoles are described.


Laszlo et al., Bioorg. Med. Chem. Letters, 8 (1998) 2689-2694, describes certain furans, pyrroles and pyrazolones, particularly 3-pyridyl-2,5-diaryl-pyrroles, as inhibitors of p38 kinase.


The invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.







DESCRIPTION OF THE INVENTION

A class of substituted pyrazolyl compounds useful in treating p38 mediated disorders is defined by Formula IA:
embedded image


wherein


R1 is selected from hydrido, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, alkoxyaryl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or


R1 has the formula
embedded image

wherein:


i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from hydrido, halogen, mercapto, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, heterocyclylheterocyclyl, heterocyclylalkylheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino, aryl(hydroxyalkyl)amino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, N-alkyl-N-alkynyl-amino, aminoalkyl, aminoaryl, aminoalkylamino, aminocarbonylalkylene, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, cycloalkyl, cycloalkenyl, aminoalkylthio, alkylaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, alkoxy, heterocyclyloxy, alkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, arylthio, heterocyclylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, carboxyalkyl, alkoxyalkyl, alkoxyalkylthio, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoalkylamino, heterocyclylsulfonyl, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or


R2 is R200-heterocyclyl-R201, R200-aryl-R201 or R200-cycloalkyl-R201 wherein:


R200 is selected from:

  • —(CR202R203)y—;
  • —C(O)—;
  • —C(O)—(CH2)y—;
  • —C(O)—O—(CH2)y—;
  • —(CH2)y—C(O)—;
  • —O—(CH2)y—C(O)—;
  • —NR202—;
  • —NR202—(CH2)y—;
  • —(CH2)y—NR202—;
  • —(CH2)y—NR202—(CH2)z—;
  • —(CH2)y—C(O)—NR202—(CH2)z—;
  • —(CH2)y—NR202—C(O)—(CH2)z—;
  • —(CH2)y—NR202—C(O)—NR203—(CH2)z—;
  • —S(O)x—(CR202R203)y—;
  • —(CR202R203)y—S(O)x—;
  • —S(O)x—(CR202R203)y—O—;
  • —S(O)x—(CR202R203)y—C(O)—;
  • —O—(CH2)y—;
  • —(CH2)y—O—;
  • —S—;
  • —O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkylene, alkoxyarylene, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkylene, amino, aminoalkyl, alkylamino, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, or alkylsulfonylamino; and


R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and


y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6; and


z is 0, 1 or 2; or


R2 is —NHCR204R205 wherein R204 is alkylaminoalkylene, and R205 is aryl; or


R2 is —C(NR206)R207 wherein R206 is selected from hydrogen and hydroxy, and R207 is selected from alkyl, aryl and aralkyl; or


R2 has the formula:
embedded image

wherein:


j is an integer from 0 to 8; and


m is 0 or 1; and


R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and


R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or


R2 is —CR41R42 wherein R41 is aryl, and R42 is hydroxy; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

groups are optionally substituted with one or more radicals independently selected from halo, keto, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, haloarylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, heterocyclylalkylamino, alkylheterocyclylalkylamino, aralkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, haloalkylsulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;


provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; and


further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and


further provided that R4 is not methylsulfonylphenyl or aminosulfonylphenyl; and


further provided that R1 is not methylsulfonylphenyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


In a subclass of interest, R2 is as defined above, and


R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or


R1 has the formula
embedded image

wherein:


i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, allcoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

groups are optionally substituted with one or more radicals independently selected from halo, keto, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, haloarylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyaralkylamino, aminosulfinyl, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, heterocyclylalkylamino, alkylheterocyclylalkylamino, aralkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarboiiyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


In the various embodiments of the present invention, the novel compounds generically disclosed herein preferably do not include those substituted pyrazoles disclosed in WO98/52940 published on Nov. 26, 1998.


A subclass of compounds useful in treating p38 mediated disorders is defined by Formula I:
embedded image


wherein


R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or

    • R1 has the formula
      embedded image


wherein:

    • i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or


R2 has the formula:
embedded image


wherein:


j is an integer from 0 to 8; and


m is 0 or 1; and


R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and


R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or


R2 is —CR41R42 wherein R41 is aryl, and R42 is hydroxy; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
embedded image


wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;


provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Compounds of Formula I and/or IA would be useful for, but not limited to, the treatment of any disorder or disease state in a human, or other mammal, which is excacerbated or caused by excessive or unregulated TNF or p38 kinase production by such mammal. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula I and/or 1A or a pharmaceutically acceptable salt thereof.


Compounds of Formula I and/or IA would be useful for, but not limited to, the treatment of inflammation in a subject, as an analgesic in the treatment of pain including but not limited to neuropathic pain, and for use as antipyretics for the treatment of fever. Compounds of the invention would be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus. The compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including atherosclerosis, myocardial infarction, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection.


The compounds are also useful for the treatment of influenza, multiple sclerosis, leukemia, lymphoma, diabetes, systemic lupus erthrematosis (SLE), neuroinflammation, ischemia including stroke and brain ischemia, brain trauma, brain edema, skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.


Compounds of the invention would be useful for the prevention or treatment of benign and malignant tumors/neoplasia including cancer, such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcimoma, and other known cancers that affect epithelial cells throughout the body.


The compounds of the invention also would be useful for the treatment of certain central nervous system disorders such as Alzheimer's disease and Parkinson's disease.


Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.


The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, DMARD's, immunosuppressive agents, NSAIDs, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.


As used herein, the term “TNF mediated disorder” refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.


As used herein, the term “p38 mediated disorder” refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38.


As TNF-β has close structural homology with TNF-α (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-α and TNF-β are inhibited by the compounds of the present invention and thus are herein referred to collectively as “TNF” unless specifically delineated otherwise.


A preferred class of compounds consists of those compounds of Formula I wherein


R1 is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; or


R1 has the formula
embedded image


wherein:


i is 0, 1 or 2; and


R25 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and


R27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene; wherein said lower alkyl, lower cycloalkyl, aryl 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 phenylthioalklylphenylene, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR46R47 wherein R46 is lower alkoxycarbonyl, and R47 is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from lower alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and


R2 is selected from hydrido, halogen, 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 alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein the aryl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, 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 alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, and phenylsulfonyl; or


R2 has the formula:
embedded image


wherein:


j is 0, 1 or 2; and


m is 0;


R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R33 is selected from hydrogen, alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40;


wherein R35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene., heterocyclylalkylene, alkylarylene, alkylheterocyclyli, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene; wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or


R35 is CHR45R49 wherein R48 is arylsulfonylamino or alkylarylsulfonylamino, and R49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or


R35 is —NR50R51 wherein R51 is alkyl, and R51 is aryl; and


wherein R36 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and


wherein R37 is selected from hydrogen and alkyl; and


wherein R38 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl, and aminosulfonylaralkyl; wherein said aryl, heterocyclyl, aralkyl, and heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or


R38 is —CR52R53 wherein R52 is alkoxycarbonyl, and R53 is alkylthioalkylene; or


R37 and R38 together with the nitrogen atom to which they are attached form a heterocycle; and


R39 and R40 have the same definition as R26 and R27 in claim 1; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; or


R2 is selected from the group consisting of
embedded image


wherein


k is an integer from 0 to 3; and


R56 is hydrogen or lower alkyl; and


R57 is hydrogen or lower alkyl; or


R56 and R57 form a lower alkylene bridge; and


R58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, —C(O)R59, —SO2R60, and —C(O)NHR61;


wherein R59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and


wherein R60 is selected from 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 independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and


wherein R61 is selected from alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and
embedded image


wherein R43 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl; and


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; and


R4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6-membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


A class of compounds of particular interest consists of these compounds of Formula I wherein


R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and


R2 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, liydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, 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-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 independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1-dimethylethylcarbonyl; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; and


R3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R3 is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl, ethyl or phenylmethyl; and


R4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobeiizofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


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


R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;


R2 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;


R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or-more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;


R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


A class of compounds of specific interest consists of those compounds of Formula I wherein


R1 is hydrido or methyl;


R2 is selected from hydrido, methyl or ethyl;


R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;


R4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


Still another class of compounds of particular interest consists of those compounds of Formula I wherein


R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and


R2 has the formula:
embedded image


wherein:


j is 0, 1 or 2; and


m is 0; and


R30 and R31 are independently selected from hydrogen and lower alkyl;


R32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, lower alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40;


wherein R35 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 alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene; wherein said aryl selected from 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 substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or


R35 is CHR48R49 wherein R48 is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R49 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or


R35 is —NR50R51 wherein R50 is lower alkyl, and R51 is aryl selected from phenyl, biphenyl and naphthyl; and


wherein R36 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 alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


wherein R37 is selected from hydrogen and lower alkyl; and


wherein R38 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 alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower aminosulfonylphenylalkyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or


R38 is —CR52R53 wherein R52 is lower alkoxycarbonyl, and R53 is lower alkylthioalkylene; or


R37 and R38 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle;


R39 and R40 have the same definition as R26 and R27 in claim 2; or

    • R2 is selected from the group consisting of
      embedded image


wherein


k is an integer from 0 to 2; and


R56 is hydrogen or lower alkyl; and


R57 is hydrogen or lower alkyl; and


R58 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, —C(O)R59, —SO2R60, and —C(O)NHR61;


wherein R59 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, loewr phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


wherein R60 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 selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


wherein R61 is selected from lower alkyl, aryl selected from phenyl, biphenyl and napthyl, lower alkylphenylene, and lower alkoxyphenylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


R3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R3 is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl, ethyl or phenylmethyl; and


R4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


Still another class of compounds of particular interest consists of those compounds of Formula I wherein


R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;


R2 has the formula:
embedded image


wherein:


j is 0, 1 or 2; and


m is 0; and


R30 is hydrogen; and


R31 is selected from hydrogen and lower alkyl; and


R32 is selected from hydrogen and lower alkyl; and


R33 is selected from lower alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40;


wherein R35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and


wherein R36 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


wherein R37 is hydrogen; and


wherein R38 is selected from lower alkyl, phenyl, and lower alkylphenylene;


wherein R39 and R40 have the same definition as R26 and R27 in claim 2; or

    • R2 is selected from the group consisting of
      embedded image


wherein


k is an integer from 0 or 1; and


R56 is hydrogen; and


R57 is hydrogen; and


R58 is selected from —C(O)R59 and —SO2R60;


wherein R59 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and


wherein R60 is selected from lower alkyl; and


R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and


R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


Still another class of compounds of specific interest consists of those compounds of Formula I wherein


R1 is hydrido or methyl; and


R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and


R4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


In one embodiment of the present invention, the compounds of Formula I and/or 1A satisfy one or more of the following conditions:


R1 is hydrido or lower alkyl; more preferably, R1 is hydrido or methyl; and still more preferably, R1 is hydrido;


R2 is hydrido or lower alkyl; more preferably, R2 is hydrido or methyl; and still more preferably, R2 is hydrido;


R2 comprises a piperidinyl, piperazinyl or cyclohexyl moiety;


R3 is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl; or


R4 is substituted or unsubstituted phenyl; and preferably, R4 is phenyl substituted with halo.


In addition, where R3 is substituted pyrimidinyl, preferably at least one R3 substitutent is attached to the carbon atom positioned between two nitrogen atoms of the pyrimidinyl ring.


A family of specific compounds of particular interest within Formula I and/or 1A consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:

  • 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-(3-methyl-5-phenyl-1H-pyrazol-4-y]pyridine;
  • 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-methyl-3-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-methyl-3-[4-(methylthio)phenyl]-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorohpenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(2,5-dimethylphenyl)-3-methyl-1H-pyrazol-4yl]pyridine;
  • 4-[5-(1,3-benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-[(1,1′-biphenyl)-4-yl]-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 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; 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-fluordphenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]pyridine;
  • 4-(5-cyclohexyl)-3-methyl-1H-pyrazol-4-yl)pyridine;
  • 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-methylphenyl)-3-propyl-1H-pyrazol-4-yl]pyridine;
  • 4-[(3-methyl-5-phenyl-1H-pyrazol-4-yl)methyl]pyridine;
  • 4-[3,5-bis(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[4-methyl-2-(2-trifluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(2-chlorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-methyl-3-(2,4-dimethylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3,5-dimethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3,5-dimethoxyphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-methyl-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine;
  • N,N-dimethyl-4-[5-methyl-4-(4-pyridinyl)-1H-pyrazol-3yl]benzenamine;
  • 4-[3-(2,3-dihydrobenzofuran-5-yl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-bromophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
  • 4-(3-ethyl-4-phenyl-1H-pyrazol-4-yl)pyridine;
  • 4-[5-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl}pyridine;
  • 4-[3-ethyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3,4-difluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-ethoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
  • 4-[3-methyl-5-(3-thienyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(2,4-dichlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-chloro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • ethyl 3-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazole-5-propanoate;
  • 4-[3-(4-fluorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • 2-methoxy-5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • 2-methoxy-4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 2-methoxy-4-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • 2-methoxy-4-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • 4-[5-(3-chlorophenyl)-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-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(benzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(1-cyclohexyen-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(1,3-cyclohexadien-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-(5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine;
  • 4-[5-(4-methoxy-3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-methoxy-4-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-methoxy-5-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-furyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
  • 2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
  • methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyri-dine-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-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-4yl)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-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
  • 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2-methylpyridine;
  • 4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]-2-methylpyridine;
  • 5-(4-chlorophenyl)-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-3-amine;
  • N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • 5-(4-chlorophenyl)-N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-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;
  • 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
  • 1,1-dimethylethyl 4-(5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
  • N-[5-(4-chlorophenyl)-4-[2-(phenylmethyl)amino]-4-pyridinyl]-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(phenylmethyl)piperazine;
  • 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride;
  • 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]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-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-ethylpiperazine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-ethanediamine;
  • 4-[3-(2,6-difluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-5-(1-methylethyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine;
  • 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
  • 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
  • 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone;
  • 1-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone;
  • Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-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-methylphenyl)-1H-pyrazol-4-yl]pyridine
  • 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid;
  • 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
  • 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine;
  • 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-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-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(2-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
  • 3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-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-butanol;
  • 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile;
  • 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;
  • 3-(4-fluorophenyl)-1-methyl-α-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol;
  • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine;
  • 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]pyridine4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(1,3-benzodioxol-5-y)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-methylpyridine;
  • 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-methylpyridine;
  • 4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 2-methyl-4-[1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 2-methyl-4-[1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
  • 4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
  • 4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine;
  • 4-[3-(4-bromophenyl)-1H-pyrazol-4yl]pyridine;
  • 4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • (E)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-phenylethenyl)pyridine;
  • (S)-4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(2-methylbutyl)-2-pyridinamine;
  • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyridinamine;
  • N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
  • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
  • 2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
  • N-[1-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
  • N-[(3-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
  • 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine;
  • 2-fluoro-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine;
  • 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methylpyridine;
  • 4-[3-(3,4-difluorophenyl)-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-morpholineethanamine;
  • 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;
  • 4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine;
  • 4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-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-(diethylamino)ethyl]-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;
  • 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-pyrazol-3-amine;
  • 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;
  • 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]pyridine;
  • 4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine;
  • 4,4′-(1H-pyrazole-3,4-diyl)bis[pyridine];
  • 4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine;
  • 2-Chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]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;
  • Ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate;
  • 4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidine;
  • 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyrimidine;
  • 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, dihydrate;
  • methyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate, monohydrate;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, monosodium salt dihydrate;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(methylsulfonyl)piperazine, monohydrate;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-(2-propynyl)-1H-pyrazol-3-yl]piperazine, trihydrochloride monohydrate;
  • 4-[3-(4-fluorophenyl)-5-(1H-imidazol-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]pyridine;
  • 4-[3-(4-fluorophenyl)-1H-pyazol-4-yl]-N-2-propynyl-2-pyrimidinamine;
  • N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(2-methoxyphenyl)-2-pyrimidinamine;
  • 1-[5-(3-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
  • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine, trihydrochloride;
  • N-[5-(4-fluorophenyl)-4-(pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine;
  • ethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate, monohydrate;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-methoxyphenyl)piperazine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-phenylpiperazine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-propynyl)piperazine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
  • 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-[(phenylmethyl)amino]-4-pyridinyl-1H-pyrazol-3-yl]amino]propyl]carbamate;
  • 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
  • ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate; 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone;
  • 4-[3-(4-fluorophenyl)-5-[(1-methyl-4-piperidinyl)methyl]-1H-pyrazol-4-yl]pyridine;
  • 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate;
  • 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine;
  • 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperazine;
  • 4-[3-(4-fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-3H-pyrazol-3-yl]-4-piperidineamine, trihydrochloride, monohydrate;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-N,1-dimethyl-4-piperidinamine, dihydrate
  • 1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine;
  • 1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine;
  • 1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine;
  • 1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine;
  • 1-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methylpiperazine;
  • 1-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanol;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanamine;
  • 4-[5-[4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanol;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazineethanamine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-methylpiperazine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-dimethylpiperazine;
  • 1-[5-(4-fluorophneyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-methylpiperazine;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-dimethylpiperazine;
  • 5-(4-chlorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine;
  • 5-(4-chlorophenyl)-N-(1-methyl-3-pyrrolidinyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • 5-(4-fluorophenyl)-4-(4-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazol-3-amine;
  • 5-(4-fluorophenyl)-N-(1-methyl-3-pyrrolidinyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-pyrrolidinamine;
  • 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-3-pyrrolidinamine;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-pyrrolidinamine;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-3-pyrrolidinamine;
  • 5-(4-chlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • 5-(4-fluorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-piperidinamine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-3-piperidinamine;
  • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-piperidinamine;
  • N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-3-piperidinamine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol;
  • 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine;
  • 4-[3-(4-chlorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine;
  • 4-[3-(4-fluorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine;
  • 1-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperidinol;
  • 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl-4-piperidinol;
  • 4-[3-(4-chlorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine;
  • 4-[3-(4-fluorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(methylethyl)-4-piperidinamine;
  • N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-propyl-4-piperidinamine;
  • ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate;
  • 5-(4-fluorophenyl)-N-methyl-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
  • (βR)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene ethanol;
  • (βS)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;
  • (βS)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene ethanol;
  • (βR)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;
  • N-[2-(1-ethyl-2-piperidinyl)ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
  • N2, N2-diethyl-N1-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1-phenyl-1,2-ethanediamine;
  • N-(1-ethyl-4-piperidinyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(4-piperidinylmethyl)-2-pyridinamine;
  • 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-3-methyl-1-butanol;
  • (2S)-2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-4-methyl-1-pentanol;
  • N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-1,4-pentanediamine;
  • (2R)-1-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-2-propanol;
  • N4-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N1,N1-diethyl-1,4-pentanediamine;
  • (2S)-1-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-2-propanol;
  • 1-[5-(3,4-dichlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)-N-[2-(1-piperidinyl)ethyl]-2-pyridinamine;
  • N,N-diethyl-N′-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,2-ethanediamine;
  • 4-[3-(4-fluorophenyl)-1-(2-propenyl)-1H-pyrazol-4-yl)pyridine, monohydrochloride;
  • 8-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-dioxa-8-azaspiro[4.5]decane;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-piperidinone;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinol;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,3,6-hexahydropyridine;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-4-piperidinamine, trihydrochloride;
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine, trihydrochloride;
  • 4-[3-(4-fluorophenyl)-5-(4-(1-pyrrolidinyl)-1-piperidinyl]-1H-pyrazol-4-yl]pyridine, trihydrochloride;
  • ethyl 4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-piperidinecarboxylate;
  • 1-methyl-4-[5-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
  • 1-[5-(3,4-difluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
  • 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine;
  • N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,4-pentanediamine;
  • 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[3-(2-methyl-1-piperidinyl)propyl]-2-pyridinamine;
  • ethyl 4-[5-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
  • N,N-diethyl-N′-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine;
  • N1,N1,-diethyl-N4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-pentanediamine;
  • N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-methyl-1-piperazinepropanamine(2E)-2-butenedioate (1:1);
  • N-(2-[1,4′-bipiperidin]-1′-ylethyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;
  • N-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethyl]-N,N′,N′-trimethyl-1,3-propanediamine;
  • N,N,N″-triethyl-N′-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethyl]-1,3-propanediamine;
  • 3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1,2-propanediol;
  • trans-4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]cyclohexanol;
  • 4-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]cyclohexanone; and
  • 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-diethyl-4-piperidinamine, trihydrochloride.


Within Formula I there is another subclass of compounds of high interest represented by Formula IX:
embedded image


wherein


Z represents a carbon atom or a nitrogen atom; and


R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and


R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; and


R4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R4 is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and


R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A preferred class of compounds consists of those compounds of Formula IX


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and


R4 is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and


R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula I there is another subclass of compounds of high interest represented by Formula X:
embedded image


wherein


Z represents a carbon atom or a nitrogen atom; and


R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and


R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; and


R4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and


R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A preferred class of compounds consists of those compounds of Formula X


R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and


R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and


R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and l-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula I there is another subclass of compounds of high interest represented by Formula XI:
embedded image


wherein


Z represents a carbon atom or a nitrogen atom; and


R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and


R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; and


R4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and


R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A preferred class of compounds consists of those compounds of Formula XI


R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;


R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and


R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A preferred class of compounds consists of those compounds of Formula IX wherein


Z represents a carbon atom or a nitrogen atom; and


R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and


R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or


R2 is —CR54R55 wherein R54 is phenyl and R55 is hydroxy; and


R4 is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and


R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A class of compounds of specific interest consists of those compounds of Formula IX wherein


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;


R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, 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)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethylethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;


R4 is phenyl that is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and


R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Another class of compounds of specific interest consists of those compounds of Formula IX wherein

    • Z represents a carbon atom or a nitrogen atom; and


R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and


R2 is selected from hydrido and lower alkyl; and


R4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and


R5 is selected from hydrido, halo and alkylhydrazinyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Still another class of compounds of specific interest consists of those compounds of Formula IX wherein;


Z represents a carbon atom; and


R1 is selected from hydrido, methyl, hydroxyethyl, propargyl; and


R2 is hydrido; and


R4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and


R5 is selected from hydrido, fluoro, and 1-methylhydrazinyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A preferred class of compounds of specific interest consists of those compounds of Formula IX wherein


Z represents a carbon atom; and


R1 is selected from hydrido and methyl; and


R2 is hydrido; and


R4 is selected from phenyl that is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and


R5is selected from hydrido and fluoro; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA there is another subclass of compounds of interest represented by Formula IXA:
embedded image


wherein


Z represents a carbon atom or a nitrogen atom; and


R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and


R2 is selected from hydrido, lower alkylamino, lower alkynylamino, arylamino, lower aralkylamino, lower heterocyclylalkylamino, lower aminoalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower carboxyalkylamino, and lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, wherein the aryl group is optionally substituted with one or more radicals independently selected from halo, keto, lower alkyl, aralkyl, carboxy, lower alkoxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or


R2 is R200-heterocyclyl-R201 or R200-cycloalkyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—NR202—;


—NR202—(CH2)y—;


—(CH2)y—NR202—;


—O—(CH2)y—;


—(CH2)y—O—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, halogen, hydroxy, carboxy, keto, lower alkyl, lower hydroxyalkyl, lower haloalkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, aryl, heterocyclyl, lower aralkyl, lower heterocyclylalkylene, lower alkylcarbonyl, lower hydroxyalkylcarbonyl, lower cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, lower alkoxy, lower alkoxyalkylene, lower alkoxyarylene, lower alkoxycarbonyl, lower carboxyalkylcarbonyl, lower alkoxyalkylcarbonyl, lower heterocyclylalkylcarbonyl, lower alkylsulfonyl, lower alkylsulfonylalkylene, amino, lower aminoalkyl, lower alkylamino, lower aralkylamino, lower alkylaminoalkylene, aminocarbonyl, lower alkylcarbonylamino, lower alkylcarbonylaminoalkylene, lower alkylaminoalkylcarbonyl, lower alkylaminoalkylcarbonylamino, lower aminoalkylcarbonylaminoalkyl, lower alkoxycarbonylamino, lower alkoxyalkylcarbonylamino, lower alkoxycarbonylaminoalkylene, lower alkylimidocarbonyl, amidino, lower alkylamidino, lower aralkylamidino, guanidino, lower guanidinoalkylene, and lower alkylsulfonylamino; and


R202 and R203 are independently selected from hydrido, lower alkyl, aryl and lower aralkyl; and


y is 0, 1, 2 or 3; and


R4 is selected from aryl selected from phenyl, biphenyl, naphthyl, wherein said aryl is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy; and


R5 is selected from hydrido, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower hydroxyalkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower hydroxycycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or —NR62R63 wherein R62 is lower alkylcarbonyl or amino, and R63 is lower alkyl or lower phenylalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


When the substituent at the 4-position of the pyrazole ring is a substituted pyridinyl, at least one of the substituents preferably is attached to a ring carbon atom adjacent the nitrogen heteroatom of the pyridine ring. When the substituent at the 4-position of the pyrazole ring is a substituted pyrimidinyl, at least one of the substituents preferably is attached to the carbon ring atom between the nitrogen heteroatoms of the pyrimidine ring. When R2 comprises a substituted piperidinyl or piperazinyl moiety, at least one of the substituents preferably is attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine or piperazine ring.


A subclass of compounds of specific interest consists of those compounds of Formula IXA wherein;


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from hydrido, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-butylamino, N-propargylamino, N-phenylamino, N-benzylamino, aminoethylamino, aminopropylamino, aminobutylamino, methylaminoethylamino, dimethylaminoethylamino, ethylaminoethylamino, diethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, ethylaminopropylamino, diethylaminopropylamino, morpholinylmethylamino, morpholinylethylamino, morpholinylpropylamino, piperidinylmethylamino, piperidinylethylamino, piperidinylpropylamino, piperazinylmethylamino, piperazinylethylamino, piperazinylpropylamino, carboxymethylamino, carboxyethylamino, methoxyethylamino, ethoxyethylamino, ethoxymethylamino, (1,1-dimethyl)ethylcarbonylaminopropylamino, and (1,1-dimethyl)ethylcarbonylaminoethylamino, wherein the phenyl, morpholinyl, piperidinyl, and piperazinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, ethyoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and


R2 is R200-piperidinyl-R201, R200-piperazinyl-R201, or R200-cyclohexyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, butoxy, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, methylamidino, benzylamidino, guanidino, guanidinomethylene, guanidinoethylene, and methylsulfonylamino; and


R202 and R203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl; and


y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, benzyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, ethylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IXA there is another subclass of compounds of interest represented by Formula XA:
embedded image

wherein:


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from hydrido, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-butylamino, N-propargylamino, N-phenylamino, N-benzylamino, aminoethylamino, aminopropylamino, aminobutylamino, methylaminoethylamino, dimethylaminoethylamino, ethylaminoethylamino, diethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, ethylaminopropylamino, diethylaminopropylamino, morpholinylmethylamino, morpholinylethylamino, morpholinylpropylamino, piperidinylmethylamino, piperidinylethylamino, piperidinylpropylamino, piperazinylmethylamino, piperazinylethylamino, and piperazinylpropylamino, wherein the phenyl, morpholinyl, piperidinyl, and piperazinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, and methoxy; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of particular interest consists of those compounds of Formula XA wherein:


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is selected from hydrido, methylaminopropylamino, dimethylaminopropylamino, ethylaminopropylamino, diethylaminopropylamino, morpholinylmethylamino, morpholinylethylamino, morpholinylpropylamino, wherein the phenyl and morpholinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and methoxy; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of specific interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is selected from hydrido, methylaminopropylamino, dimethylaminopropylamino, ethylaminopropylamino, diethylaminopropylamino, morpholinylmethylamino, morpholinylethylamino, and morpholinylpropylamino; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of high interest consists of those compounds of Formula XA wherein:


R1 is selected hydrido; and


R2 is selected from hydrido, dimethylaminopropylamino, diethylaminopropylamino, morpholinylethylamino, and morpholinylpropylamino; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, diethylaminoethylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA there is another subclass of compounds of interest represented by Formula XA:
embedded image


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200-piperidinyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, butoxy, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, methylamidino, benzylamidino, guanidino, guanidinomethylene, guanidinoethylene, and methylsulfonylamino; and

    • R202 and R203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl; and
    • y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of particular interest consists of those compounds of Formula XA wherein:


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200-piperidinyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluororoethyl, fluoropropyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-benzylamino, methylaminomethylene, aminocarbonyl, methoxycarbonylamino, ethoxycarbonylamino, or methylsulfonylamino; and


R202 is selected from hydrido, methyl, ethyl, phenyl and benzyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of specific interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-piperidinyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, methylsulfonyl, ethylsulfonyl, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, N-benzylamino, methylaminomethylene, aminocarbonyl, methoxycarbonylamino, and ethoxycarbonylamino; and


R202 is selected from hydrido, methyl phenyl and benzyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of high interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-piperidinyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, methyl, methoxyethyl, methylcarbonyl, hydroxymethylcarbonyl, methoxymethylcarbonyl, methylsulfonyl, amino, N,N-dimethylamino, and N,N-diethylamino; and


R202 is selected from hydrido and methyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, diethylaminoethylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IXA there is another subclass of compounds of interest represented by Formula XA:
embedded image


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200-piperazinyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, butoxy, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, methylamidino, benzylamidino, guanidino, guanidinomethylene, guanidinoethylene, and methylsulfonylamino; and


R202 and R203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl; and

    • y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of particular interest consists of those compounds of Formula XA wherein:


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200piperazinyl-R201 wherein:


R200 is selected from:


—(CR202R203)—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, methoxymethylene, methoxyethylene, ethoxyethylene, methoxyphenylene, ethoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethlylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino,
embedded image
N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, and methylsulfonylamino; and


R202 and R203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl; and


y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of specific interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-piperazinyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethynyl, propynyl, propargyl, phenyl, benzyl, piperidinyl, piperazinyl, and morpholinyl; and


R202 is selected from hydrido, methyl, ethyl, phenyl and benzyl; and


y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of high interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-piperazinyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, methyl, cyclopropyl, propargyl, and benzyl; and


R202 is selected from hydrido and methyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA there is another subclass of compounds of interest represented by Formula XA:
embedded image


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200-cyclohexyl-R201 wherein:


R200 is selected from:


—(CR202R203)—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, hydroxy, carboxy, keto, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, chlorobutyl, fluoromethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, propargyl, butynyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, butoxy, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, methylamidino, benzylamidino, guanidino, guanidinomethylene, guanidinoethylene, and methylsulfonylamino; and


R202 and R203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl; and


y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, propyl, benzyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of particular interest consists of those compounds of Formula XA wherein:


R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and


R2 is R200-cyclohexyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, hydroxy, carboxy, keto, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, chloromethyl, chloroethyl, chloropropyl, fluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, benzyl, piperidinyl, piperazinyl, morpholinyl, piperidinylmethylene, piperazinylmethylene, morpholinylmethylene, methoxy, ethoxy, propoxy, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonyl, ethylsulfonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylamino-carbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, and ethoxycarbonylaminomethylene; and


R202 and R203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl; and

    • y is 0, 1 or 2; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and


R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of specific interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-cyclohexyl-R201 wherein:


R200 is selected from:


methylene;


—NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, amino, aminomethyl, aminoethyl, aminopropyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N,N-dipropylamino, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, and ethoxycarbonylaminomethylene; and


R202 is selected from hydrido, methyl, phenyl and benzyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


A subclass of compounds of high interest consists of those compounds of Formula XA wherein:


R1 is hydrido; and


R2 is R200-cyclohexyl-R201 wherein:


R200 is selected from:


methylene;


NR202—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of amino, aminomethyl, N,N-dimethylamino, and N-isopropylamino; and


R202 is selected from hydrido and methyl; and


R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and


R5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, and diethylaminoethylamino; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA is another subclass of compounds of interest wherein:


R1 is selected from hydrido, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, alkoxyaryl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or


R1 has the formula
embedded image

wherein:

    • i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from mercapto, heterocyclylheterocyclyl, heterocyclylalkylheterocyclyl, N-alkyl-N-alkynyl-amino, aminocarbonylalkylene, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, aminoalkylthio, alkylaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or


R2 is R200-heterocyclyl-R201, R200-aryl-R201, or R200-cycloalkyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—C(O)—;


—C(O)—(CH2)y—;


—C(O)—O—(CH2)y—;


—(CH2)y—C(O)—;


—O—(CH2)y—C(O)—;


—NR202—;


—NR202—(CH2)y—;


—(CH2)y—NR202—;


—(CH2)y—NR202—(CH2)z—;


—(CH2)y—C(O)—NR202—(CH2)z—;


—(CH2)y—NR202—C(O)—(CH2)z—;


—(CH2)y—NR202—C(O)—NR203—(CH2)z—;


—S(O)x—(CR202R203)y—;


—(CR202R203)y—S(O)y—;


—S(O)x—(CR202R203)y—O—;


—S(O)x—(CR202R203)y—C(O)—;


—O—(CH2)y—;


—(CH2)y—O—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkylene, alkoxyarylene, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkylene, amino, aminoalkyl, alkylamino, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, or alkylsulfonylamino; and


R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and


y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6; and


z is 0, 1 or 2; or


R2 is —NHCR204R205 wherein R204 is alkylaminoalkylene, and R205 is aryl; or


R2 is —C(NR206)R201 wherein R206 is selected from hydrogen and hydroxy, and R207 is selected from alkyl, aryl and aralkyl; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

groups are optionally substituted with one or more radicals independently selected from halo, keto, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, haloarylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, heterocyclylalkylamino, alkylheterocyclylalkylamino, aralkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA is another subclass of compounds of interest wherein:


R1 is selected from hydrido, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, alkoxyaryl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or


R1 has the formula
embedded image


wherein:


i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from hydrido, halogen, mercapto, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, heterocyclylheterocyclyl, heterocyclylalkylheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino, aryl (hydroxyalkyl) amino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, N-alkyl-N-alkynyl-amino, aminoalkyl, aminoaryl, aminoalkylamino, aminocarbonylalkylene, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, cycloalkyl, cycloalkenyl, aminoalkylthio, alkylaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, alkoxy, heterocyclyloxy, alkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, arylthio, heterocyclylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, carboxyalkyl, alkoxyalkyl, alkoxyalkylthio, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoalkylamino, heterocyclylsulfonyl, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or


R2 is R200-heterocyclyl-R201, R200-aryl-R201, or R200-cycloalkyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—C(O)—;


—C(O)—(CH2)y—;


—C(O)—O—(CH2)y—;


—(CH2)y—C(O)—;


—O—(CH2)y—C(O)—;


—NR202—;


—NR202—(CH2)y—;


—(CH2)y—NR202—;


—(CH2)y—NR202—(CH2)z—;


—(CH2)y—C(O)—NR202—(CH2)z—;


—(CH2)y—NR202—C(O)—(CH2)z—;


—(CH2)y—NR202—C(O)—NR203—(CH2)z—;


—S(O)x—(CR202R203)y—;


—(CR202R203)—S(O)x—;


—S(O)x—(CR202R203)y—O—;


—S(O)x—(CR202R203)y—C(O)—;


—O—(CH2)y—;


—(CH2)y—O—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkylene, alkoxyarylene, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkylene, amino, aminoalkyl, alkylamino, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, or alkylsulfonylamino; and


R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and


y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6; and


z is 0, 1 or 2; or


R2 is —NHCR204R205 wherein R204 is alkylaminoalkylene, and R205 is aryl; or R2 is —C(NR206)R207 wherein R206 is selected from hydrogen and hydroxy, and R207 is selected from alkyl, aryl and aralkyl; or


R2 has the formula:
embedded image

wherein:


j is an integer from 0 to 8; and


m is 0 or 1; and


R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, alkyl, —C(O)R35,


—C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40, wherein


R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and


R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or


R2 is —CR41R42 wherein R41 is aryl, and R42 is hydroxy; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image

groups are substituted with one or more radicals independently selected from keto, haloarylamino, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxyarylamino, alkylsulfonylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, alkylheterocyclylalkylamino, heterocyclylheterocyclylalkylamino, and alkoxycarbonylheterocyclylamino; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or


a pharmaceutically-acceptable salt or tautomer thereof.


Within Formula IA is another subclass of compounds of interest wherein:


R1 is selected from hydrido, hydroxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, alkoxyaryl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or


R1 has the formula
embedded image

wherein:


i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from hydrido, halogen, mercapto, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, heterocyclylheterocyclyl, heterocyclylalkylheterocyclyl, alkylamino, alkenylamino, alkynylamino, arylamino, aryl(hydroxyalkyl)amino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, N-alkyl-N-alkynyl-amino, aminoalkyl, aminoaryl, aminoalkylamino, aminocarbonylalkylene, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, alkylcarbonylaminoalkylene, aminoalkylcarbonylaminoalkylene, alkylaminoalkylcarbonylamino, cycloalkyl, cycloalkenyl, aminoalkylthio, alkylaminocarbonylalkylthio, alkylaminoalkylaminocarbonylalkylthio, alkoxy, heterocyclyloxy, alkylthio, cyanoalkylthio, alkenylthio, alkynylthio, carboxyalkylthio, arylthio, heterocyclylthio, alkoxycarbonylalkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, carboxyalkyl, alkoxyalkyl, alkoxyalkylthio, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylene, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoalkylamino, heterocyclylsulfonyl, aralkythio, heterocyclylalkylthio, aminoalkoxy, cyanoalkoxy, carboxyalkoxy, aryloxy, aralkoxy, alkenyloxy, alkynyloxy, and heterocyclylalkyloxy; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or


R2 is R200-heterocyclyl-R201, R200-aryl-R201, or R200-cycloalkyl-R201 wherein:


R200 is selected from:


—(CR202R203)y—;


—C(O)—;


—C(O)—(CH2)y—;


—C(O)—O—(CH2)y—;


—(CH2)y—C(O)—;


—O—(CH2)y—C(O)—;


—NR202—;


—NR202—(CH2)y—;


—(CH2)y—NR202—;


—(CH2)y—NR202—(CH2)z—;


—(CH2)y—C(O)—NR202—(CH2)z—;


—(CH2)y—NR202—C(O)—(CH2)z—;


—(CH2)y—NR202—C(O)—NR203—(CH2)Z—;


—S(O)x—(CR202R203)y—;


—(CR202R203)Y—S(O)x—;


—S(O)x—(CR202R203)y—O—;


—S(O)x—(CR202R203)y—C(O)—;


—O—(CH2)y—;


—(CH2)y—O—;


—S—;


—O—;


or R200 represents a bond;


R201 represents one or more radicals selected from the group consisting of hydrido, halogen, hydroxy, carboxy, keto, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylcarbonyl, hydroxyalkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, haloarylcarbonyl, alkoxy, alkoxyalkylene, alkoxyarylene, alkoxycarbonyl, carboxyalkylcarbonyl, alkoxyalkylcarbonyl, heterocyclylalkylcarbonyl, alkylsulfonyl, alkylsulfonylalkylene, amino, aminoalkyl, alkylamino, aralkylamino, alkylaminoalkylene, aminocarbonyl, alkylcarbonylamino, alkylcarbonylaminoalkylene, alkylaminoalkylcarbonyl, alkylaminoalkylcarbonylamino, aminoalkylcarbonylaminoalkyl, alkoxycarbonylamino, alkoxyalkylcarbonylamino, alkoxycarbonylaminoalkylene, alkylimidocarbonyl, amidino, alkylamidino, aralkylamidino, guanidino, guanidinoalkylene, or alkylsulfonylamino; and


R202 and R203 are independently selected from hydrido, alkyl, aryl and aralkyl; and


y and z are independently 0, 1, 2, 3, 4, 5 or 6 wherein y+z is less than or equal to 6; and


z is 0, 1 or 2; or


R2 is —NHCR204R205 wherein R204 is alkylaminoalkylene, and R205 is aryl; or


R2 is —C(NR206)R207 wherein R206 is selected from hydrogen and hydroxy, and R207 is selected from alkyl, aryl and aralkyl; or


R2 has the formula:
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wherein:


j is an integer from 0 to 8; and


m is 0 or 1; and


R30 and R31 are independently selected from hydrogen, Alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and


R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or


R2 is —CR41R42 wherein R41 is aryl, and R42 is hydroxy; and


R3 is selected from maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
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wherein the R3 maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
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groups are optionally substituted with one or more radicals independently selected from halo, keto, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, haloarylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxyalkylene, alkenoxyalkylene, aryloxyalkyl, alkoxyalkylamino, alkylaminoalkoxy, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyarylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylsulfonylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, aryl(hydroxyalkyl)amino, alkylaminoalkylaminoalkylamino, alkylheterocyclylamino, heterocyclylalkylamino, alkylheterocyclylalkylamino, aralkylheterocyclylamino, heterocyclylheterocyclylalkylamino, alkoxycarbonylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;


provided that R3 is other than maleimidyl or pyridonyl having the structures:
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respectively, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


Another group of compounds of interest consists of compounds of Formula IB:
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wherein:

    • R1 has the same definition as previously set forth in the description of compounds of Formula IA. In anther embodiment, R1 is selected from hydrido, alkyl, hydroxyalkyl and alkynyl. In still another embodiment, R1 is hydrido;
    • R2 is selected from at least one of the following four categories:
    • (1) piperidinyl substituted with one or more substituents selected from hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkylene, alkoxyalkenylene, alkoxyalkynylene, and hydroxyacyl, wherein said hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkylene, alkoxyalkenylene, alkoxyalkynylene, and hydroxyacyl substitutents may be optionally substituted with one or more substituents selected from cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl, wherein said cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from alkylene, alkynylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy; or one or more substituents selected from hydroxycycloalkyl, alkoxycycloalkyl, and hydroxycycloalkylcarbonyl, wherein said hydroxycycloalkyl, alkoxycycloalkyl, and hydroxycycloalkylcarbonyl substitutents may be optionally substituted with one or more substituents selected from cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl, wherein said cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from alkylene, alkynylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy. In another embodiment, R2 is piperidinyl substituted with one or more substituents selected from optionally substituted hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkylene, alkoxyalkenylene, alkoxyalkynylene, hydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, and hydroxyalkynylcarbonyl; or one or more substituents selected from optionally substituted hydroxycycloalkyl and hydroxycycloalkylcarbonyl. In still another embodiment, R2 is piperidinyl substituted with one or more substituents selected from optionally substituted hydroxyalkyl, hydroxyalkenyl, alkoxyalkylene, alkoxyalkenylene, hydroxyalkylcarbonyl, and hydroxyalkenylcarbonyl, and hydroxycycloalkylcarbonyl. In still another embodiment, R2 is piperidinyl substituted with at least one substituent selected from optionally substituted lower hydroxyalkyl, lower hydroxyalkylcarbonyl and hydroxycycloalkylcarbonyl. In still another embodiment, R2 is piperidinyl substituted with 2-hydroxyacetyl, 2-hydroxy-proprionyl, 2-hydroxy-2-methylpropionyl, 2-hydroxy-2-phenylacetyl, 3-hydroxyproprionyl, 2-hydroxy-3-methylbutyryl, 2-hydroxyisocapropyl, 2-hydroxy-3-phenylproprionyl, 2-hydroxy-3-imidazolylproprionyl, 1-hydroxy-1-cyclohexylacetyl, 2-hydroxy-1-cyclohexylacetyl, 3-hydroxy-1-cyclohexylacetyl, 4-hydroxy-1-cyclohexylacetyl, 1-hydroxy-1-cyclopentylacetyl, 2-hydroxy-1-cyclopentylacetyl, 3-hydroxy-1-cyclopentylacetyl, 2-hydroxy-2-cyclohexylacetyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, methoxymethylene, methoxyethylene, methoxypropylene, methoxyisopropylene, ethoxymethylene, ethoxyethylene, ethoxypropylene, and ethoxyisopropylene. In each of the above embodiments, when R2 is piperidinyl, the piperidinyl ring may be substituted with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine ring. In each of the above embodiments, the piperidinyl ring may be monosubstituted at the distal nitrogen; and
    • (2) cyclohexyl substituted with one or more substituents selected from optionally substituted hydroxyalkyl, alkylaminoalkylene and cycloalkylamino. In another embodiment, R2 is cyclohexyl substituted with one or more substituents selected from optionally substituted lower hydroxyalkyl, lower alkylaminoalkylene and cycloalkylamino. In still another embodiment, R2 is cyclohexyl substituted with one or more substituents selected from optionally substituted lower hydroxyalkyl, lower dialkylaminoalkylene and cycloalkylamino. In still another embodiment, R2 is cyclohexyl substituted with one or more substituents selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methylaminomethylene, methylaminoethylene, methylaminopropylene, ethylaminomethylene, ethylaminoethylene, ethylaminopropylene, propylaminomethylene, propylaminoethylene, propylaminopropylene, dimethylaminomethylene, dimethylaminoethylene, dimethylaminopropylene, diethylaminomethylene, and di-isobutylamino. In each of the above embodiments, when R2 is cyclohexyl, the cyclohexyl ring may be substituted with at least one substituent attached to the 4-position carbon atom of the cyclohexyl ring heteroatom of the piperidine ring. In each of the above embodiments, the cyclohexyl ring may be monosubstituted at the 4-position carbon atom; and
    • (4) piperidinylamino substituted with one or more alkynyl substituents. In another embodiment, R2 is piperidinylamino substituted with optionally substituted lower alkynyl. In still another embodiment, R2 is piperidinylamino substituted with optionally substituted ethynyl, propynyl and butynyl. In still another embodiment, R2 is piperidinylamino substituted with optionally substituted propargyl. In still another embodiment, R2 is 4-propargylpiperidinylamino. In each of the above embodiments, when R2 is piperidinylamino, the piperidinyl ring may be substituted with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine ring. In each of the above embodiments, the piperidinyl ring may be monosubstituted at the distal nitrogen; and
    • R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
      embedded image


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl, purinyl, maleimidyl, pyridonyl, thiazolyl, thiazolylalkyl, thiazolylamino,
embedded image


groups may be optionally substituted with one or more substituents independently selected from hydrogen, aryl, alkylamino, alkylthio, alkyloxy, aryloxy, arylamino, arylthio, aralkoxy, wherein said aryl, alkylamino, alkylthio, alkyloxy, aryloxy, arylamino, arylthio, aralkoxy substituents may be optionally substituted with one or more alkylene, alkenylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy. In another embodiment, R3 is optionally substituted pyridinyl or pyrimidinyl. In still another embodiment, R3 is unsubstituted pyridinyl or pyrimidinyl; and

    • R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more substituents independently selected from halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl, wherein said haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, alkyl, alkenyl, and alkynyl substituents may be optionally substituted with one or more alkylene, alkenylene, alkynylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy. In another embodiment, R4 is selected from optionally substitutend cycloalkyl, cycloalkenyl, aryl, and heterocyclyl. In still another embodiment, R4 is optionally substituted phenyl. In still another embodiment, R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from chloro, fluoro, bromo and iodo. In still another embodiment, R4 is phenyl optionally substituted at the meta or para position with one or more chloro radicals; or
    • a pharmaceutically-acceptable salt or tautomer thereof. Within each of the above embodiments, R2 may be located at the 3-position of the pyrazole ring with R4 located at the 5-position of the pyrazole ring. Alternatively, R2 may be located at the 5-position of the pyrazole ring with R4 located at the 3-position of the pyrazole ring.


Still another group of compounds of interest consists of the compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
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The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH2—) radical. Where used, either alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, “cyanoalkyl” and “mercaptoalkyl”, the term “alkyll” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. The term “alkynyl” embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about six carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. The term “cycloalkyl” embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term “cycloalkyl” embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “cycloalkylalkylene” embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are “lower cycloalkylalkylene” which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The term “cycloalkenyl” embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called “cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term “halo” means halogens such as fluorine, chlorine, bromine or iodine. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms “alkoxy” and “alkyloxy” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkylene, acyl, carboxy, and aralkoxycarbonyl. The term “heterocyclyl” embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term “heteroaryl” embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term “heterocycle” also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl group” may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino. The term “heterocyclylalkylene” embraces heterocyclyl-substituted alkyl radicals. More preferred heterocyclylalkylene radicals are “lower heterocyclylalkylene” radicals having one to six carbon atoms and a heterocyclyl radicals. The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term “alkylthioalkylene” embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkylene radicals are “lower alkylthioalkylene” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl. The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms, attached to a divalent —S(═O)— radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyland hexylsulfinyl. The term “sulfonyl”, whether used alone or linked to other terms such as “alkylsulfonyl”, “halosulfonyl” denotes a divalent radical, —SO2—. “Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals. The term “halosulfonyl” embraces halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl, and bromosulfonyl. The terms “sulfamyl”, “aaminosulfonyll” and “sulfonamidyl” denote NH2O2S—. The term “acyl” denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, β-hydroxybutyric, galactaric and galacturonic acids. The term “carbonyl”, whether used alone or with other terms, such as “alkoxycarbonyl”, denotes —(C═O)—. The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO2H. The term “carboxyalkyl” embraces alkyl radicals substituted with a carboxy radical. More preferred are “lower carboxyalkyl” which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term “alkoxycarbonylalkyl” embraces alkyl radicals substituted with a alkoxycarbonyl radical as defined above. More preferred are “lower alkoxycarbonylalkyl” radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonyl-ethyl and ethoxycarbonylethyl. The term “alkylcarbonyl”, includes radicals having alkyl, hydroxylalkyl, radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl. The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with one or more substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro. The terms benzyl and phenylmethyl are interchangeable. The term “heterocyclylalkylene” embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals (also can be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly), such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals (also can be called heteroarylalkylene), such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “aryloxy” embraces aryl radicals attached through an oxygen atom to other radicals. The term “aralkoxy” embraces aralkyl radicals attached through an oxygen atom to other radicals. The term “aminoalkyl” embraces alkyl radicals substituted with amino radicals. More preferred are “lower aminoalkyl” radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term “alkylamino” denotes amino groups which are substituted with one or two alkyl radicals. Preferred are “lower alkylamino” radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino” denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical. The term “aminocarbonyll” denotes an amide group of the formula —C(═O)NH2. The term “alkylaminocarbonyl” denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above. The term “alkylcarbonylamino” embraces amino groups which are substituted with one alkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are “lower alkylcarbonylamino” having lower alkylcarbonyl radicals as defined above attached to amino radicals. The term “alkylaminoalkylene” embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.


The “hydrocarbon” moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.


The heterosubstituted hydrocarbon moieties described herein are hydrocarbon moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, sulfur, or a halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.


The additional terms used to describe the substituents of the pyrazole ring and not specifically defined herein are defined in a similar manner to that illustrated in the above definitions. As above, more preferred substituents are those containing “lower” radicals. Unless otherwise defined to contrary, the term “lower” as used in this application means that each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms; each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each. cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring cycloalkyl or cycloalkenyl radical, respectively; each aryl radical of a pyrazole ring substituent comprising one or more aryl radicals is a monocyclic aryl radical; and each heterocyclyl radical of a pyrazole ring substituent comprising one or more heterocyclyl radicals is a 4-8 membered ring heterocyclyl.


The present invention comprises the tautomeric forms of compounds of Formulae I and IX (as well as the compounds of Formulae (IA and IXA). As illustrated below, the pyrazoles of Formula I and I′ are magnetically and structurally equivalent because of the prototropic tautomeric nature of the hydrogen:
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The present invention also comprises compounds of Formula I, IA, IX, IXA, X, XA and XI having one or more asymmetric carbons. It is known to those skilled in the art that those pyrazoles of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.


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


The present invention further encompasses substituted pyrazoles that specifically bind to the ATP binding site of p38 kinase. Without being held to a particular theory, applicants hypothesize that these substituted pyrazoles interact with p38 kinase as set forth below. As the substituent at the 3-position of the pyrazole ring approaches the ATP binding site of p38 kinase, a hydrophobic cavity in the p38 kinase forms around the 3-position substitutent at the binding site. This hydrophobic cavity is believed to form as the 3-position substituent binds to a specific peptide sequence of the enzyme. In particular, it is believed to bind to the sidechains of Lys52, Glu69, Leu73, Ile82, Leu84, Leu101, and the methyl group of the Thr103 sidechain of p38 kinase at the ATP binding site (wherein the numbering scheme corresponds to the numbering scheme conventionally used for ERK-2). Where the 3-position substituent is aryl or heteroaryl, such aryl or heteroaryl may be further substituted. It is hypothesized that such ring substituents may be beneficial in preventing hydroxylation or further metabolism of the ring.


The substituent at the 4-position of the pyrazole ring is one that is a partial mimic of the adenine ring of ATP, although it may be further elaborated. Preferably, it is a planar substituent terminated by a suitable. hydrogen bond acceptor functionality. It is hypothesized that this acceptor hydrogen bonds to the backbone N—H of the Met106 residue while one edge of this substituent is in contact with bulk solvent.


Substitution at the 5-position of the pyrazole ring is well tolerated and can provide increased potency and selectivity. It is hypothesized that such substituents extend out in the direction of the bulk solvent and that suitable polar functionality placed at its terminus can interact with the sidechain of Asp109, leading to increased potency and selectivity.


Similarly, substitution on the nitrogen atom at the 1- or 2-position of the pyrazole ring is well tolerated and can provide increased potency. It is hypothesized that a hydrogen substituent attached to one of the ring nitrogen atoms is hydrogen bonded to Asp165. Preferably, the nitrogen atom at the 2-position is double bonded to the carbon atom at the 3-position of the pyrazole while the nitrogen atom at the 1-position of the pyrazole is available for substitution with hydrogen or other substituents.


The 5-position substitutent and the 1- or 2-position substituent of the pyrazole can be selected so as to improve the physical characteristics, especially aqueous solubility and drug delivery performance, of the substituted pyrazole. Preferably, however, these substituents each have a molecular weight less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight less than about less than about 250 atomic mass units. Still more preferably, these substituents have a combined molecular weight less than about 360 atomic mass units.


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


R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and


R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and


R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and


R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;


provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


In this embodiment of the invention, one or more of R1, R2, R3 and R4 preferably are selected from the corresponding groups of the compounds of Formula I and/or IA. More preferably, R3 is an optionally substituted pyridinyl or pyrimidinyl, R4 is a halo substituted phenyl, and R1 and R2 have the definitions set forth immediately above.


A class of substituted pyrazoles of particular interest consists of those compounds of Formula XI wherein


R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and


R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys52, Glu69, Leu73, Ile82, Leu84, Leu101, and Thr103 sidechains at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site; and


R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N—H backbone of Met106 of p38 kinase; and


R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units.


The present invention also comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I and/or IA.


For example, in one embodiment the present invention comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I
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wherein


R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or

    • R1 has the formula
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wherein:


i is an integer from 0 to 9;


R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and


R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and


R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or


R27 is —CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or


R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and


R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or

    • R2 has the formula:
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wherein:


j is an integer from 0 to 8; and


m is 0 or 1; and


R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and


R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;


R33 is selected from hydrogen, alkyl, —C(O)R35, —C(O)OR35, —SO2R36, —C(O)NR37R38, and —SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and


R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or


R2 is —CR41R42 wherein R41 is aryl, and R42 is hydroxy; and


R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl,
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wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and arylcxyalkyl; and


wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or —NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and


R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;


provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided Ra is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or


a pharmaceutically-acceptable salt or tautomer thereof.


The present invention also is directed to the use of the compounds of Formula I and/or IA in the preparation of medicaments useful in the treatment and/or prophylaxis of p38 kinase mediated conditions and disorders.


Also included in the family of compounds of Formulae I and/or IA are the pharmaceutically-acceptable salts and prodrugs thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formulae I and/or IA may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I and/or IA include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formulae I and/or IA by reacting, for example, the appropriate acid or base with the compound of Formulae I and/or IA.


The present invention additionally comprises a class of compounds defined by Formula XX:
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wherein R3 and R4 are as defined for the compounds of Formulae I and/or IA. Also included in the family of compounds of Formula XX are the pharmaceutically-acceptable salts and prodrugs thereof.


The compounds of Formula XX are useful as intermediates in the preparation of the compounds of Formulae I and/or IA. In addition, the compounds of Formula XX themselves have been found to show usefulness as p38 kinase inhibitors. These compounds are useful for the prophylaxis and treatment of the same p38 kinase mediated disorders and conditions as the compounds of formulae I and/or IA. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula XX or a pharmaceutically acceptable salt or prodrug thereof.


The present invention further comprises a pharmaceutical composition for the treatment of a TNF mediated disorder, a p38 kinase mediated disorder, inflammation, and/or arthritis, comprising a therapeutically-effective amount of a compound of Formula XX, or a therapeutically-acceptable salt or prodrug thereof, in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.


The compounds of the invention can be prepared according to the following procedures of Schemes I-XXIX wherein R1, R2, R3, R4, R5 and Ar1 are as previously defined for the compounds of Formula I, IX, X and XI except where expressly noted.
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Scheme I shows the synthesis of pyrazole 5 by two routes. Condensation of the pyridylmethyl ketone 1 with aldehyde 2 in the presence of a base, such as piperidine, in a solvent, such as toluene or benzene, either in the absence or the presence of acetic acid at reflux, provides the α,β-unsaturated ketone 3. In route 1, ketone 3 is first converted to epoxide 4, such as by treatment with hydrogen peroxide solution at room temperature, in the presence of base such as sodium hydroxide. Treatment of epoxide 4 with hydrazine in ethanol or other suitable solvent at a temperature ranging up to reflux, yields pyrazole 5. In route 2, ketone 3 is condensed directly with tosyl hydrazide in the presence of an acid such as acetic acid, at reflux, to provide pyrazole 5. Alternatively, the intermediate tosyl hydrazone 6 may be isolated, conversion of it to pyrazole 5 is effected by treatment with a base, such as potassium hydroxide, in a suitable solvent, such as ethylene glycol, at a temperature ranging from 25° C. up to 150° C.
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Scheme II shows the synthesis of pyrazole 12 of the present invention. The treatment of 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, gives ketone 9. Treatment of ketone 9 or a hydrohalide salt of ketone 9 with a halogenating agent, such as bromine, N-bromosuccinimide or N-chlorosuccinimide, in suitable solvents, such as acetic acid, methylene chloride, methanol, or combinations thereof, forms the a-halogenated ketone 10 (wherein X is halo). Examples of suitable hydrohalide salts include the hydrochloride and hydrobromide salts. Reaction of haloketone 10 with thiosemicarbazide 11 (where R6 and R7 can be hydrido, lower alkyl, phenyl, heterocyclyl and the like or where R6 and R7 form a heterocyclyl ring optionally containing an additional heteroatom) provides pyrazole 12. Examples of suitable solvents for this reaction are ethanol and dimethylformamide. The reaction may be carried out in the presence or absence of base or acid at temperatures ranging from room temperature to 100° C.


Thiosemicarbazides which are not commercially available may be conveniently prepared by one skilled in the art by first reacting an appropriate amine with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide. Treatment of the resultant alkyl dithiocarbamate with hydrazine results in the desired thiosemicarbazide. This chemistry is further described in E. Lieber and R. C. Orlowski, J. Org. Chem., Vol. 22, p. 88 (1957). An alternative approach is to add hydrazine to appropriately substituted thiocyanates as described by Y. Nomoto et al., Chem. Pharm. Bull., Vol. 39, p.86 (1991). The Lieber and Nomoto publications are incorporated herein by reference.


Where Compound 12 contains a second derivatizable nitrogen atom, a wide range of substituents may be placed on that atom by methods known to those skilled in the art. For examlple, in cases where R6 and R7 together with the nitrogen atom to which they are attached comprise a piperazine ring, the distal nitrogen of that ring may be, for example, (i) methylated by reaction with formic acid and formaldehyde; (ii) propargylated by reaction with propargyl bromide in a suitable solvent such as dimethylformamide in the presence of a suitable base such as potassium carbonate; (iii) acylated or sulfonylated by reaction with a suitable acyl or sulfonyl derivative in pyridine; or (iv) cyclopropanated by reaction with [1(1-ethoxycyclopropyl)oxy]trimethylsilane using sodium cyanoborohydride in the presence of acetic acid.


Additionally, one of the nitrogen atoms of the pyrazole ring optionally may be alkylated by reaction with an alkyl halide, such as propargyl bromide, in the presence of a strong base such as sodium hydride.
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Scheme III shows the synthesis of pyrazole 19 in more general form by three routes. In Route 1, ketone 13 is condensed with hydrazine 14 to give the substituted hydrazide 16, which is then reacted with acyl halide or anhydride 17 at low temperature to provide acyl hydrazone 18. Upon heating at a temperature up to 200° C., acyl hydrazone 18 is converted to pyrazole 19. In Route 2, acyl hydrazone 18 is formed directly by reaction of ketone 13 with acyl hydrazide 15, formed by reaction of hydrazine with a carboxylic acid ester, at room temperature. Heating acyl hydrazone 18 as above then provides pyrazole 19. In Route 3, ketone 13 is treated with acyl hydrazide 15 at a suitable temperature, ranging from room temperature to about 200° C., to give pyrazole 19 directly. Alternatively, this condensation may be carried out in an acidic solvent, such as acetic acid, or in a solvent containing acetic acid.
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Synthetic Scheme IV describes the preparation of pyrazole 19.
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Scheme V shows the two step synthesis of the 3-substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclization of hydrazone dianions with carboxylates. In step 1, the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as later described in Scheme IX) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32. 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 generate dianions. This reaction may be carried out at temperatures of about 0° C. or lower. In the same step, the dianions then are condensed with esters such as methyl isonicotinate, methyl cyclopropanecarboxylate, to give the desired pyrazoles 33. It may be necessary to treat the product from this step with a dehydrating agent, such as a mineral acid, to produce the target pyrazole in some instances.
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Scheme VI shows an alternative method for synthesizing pyrazoles which are unsubstituted at the 5 position of the ring. In accordance with this method, a heteroarylmethyl ketone 34 is synthesized by first treating a 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 species is then reacted with a substituted benzoate ester to produce ketone 34. Examples of suitable benzoate esters are methyl and ethyl p-fluorobenzoate and ethyl and methyl p-chlorobenzoate. Ketone 34 is converted to the aminomethylene derivative 35 by reaction with an aminomethylenating agent such as dimethylformamide dimethyl acetal or tert-butoxybis(dimethylamino)methane. Ketone 35 is converted to pyrazole 36 by treatment with hydrazine.


A modification of this synthetic route serves to regioselectively synthesize pyrazole 38 which contains a substituted nitrogen at position 1 of the ring. Ketone 34 is first converted to hydrazone 37 by reaction with the appropriate substituted hydrazine. Examples of suitable hydrazines are N-methylhydrazine and N-(2-hydroxyethyl)hydrazine. Reaction of hydrazone 37 with an aminomethylenating agent produces pyrazole 38. Examples of suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tert-butoxybis(dimethylamino)methane.


In cases where the R3 substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen, subsequent treatment with an amine produces an amino-substituted heteroaromatic derivative. Examples of such amines include benzylamine, cyclopropylamine and ammonia. The leaving group may also be replaced with other nucleophiles such as mercaptides and alkoxides. Examples of substitutable R3 groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl groups.
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Scheme VII describes the preparation of derivatives from pyrazole 5 (prepared in accordance with Scheme I) when R2=CH3. Oxidation of pyrazole 5 gives carboxylic acid 39, which is then reduced to hydroxymethyl compound 40, or coupled with amine NR10R11 (wherein R10 and R11 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42.
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Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole 43. The alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished using conventional techniques. Treatment of pyrazole 43 with an appropriate base (for example, sodium hydride) followed by treatment with an alkyl halide (for example, CH3I)yields a mixture of isomers 44 and 45.
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Scheme IX illustrates the synthesis of 3-aryl-4-pyridyl-pyrazoles of the present invention. Benzoate 46 is reacted with pyridine 47 in the presence of a strong base, such as an alkali metal hexamethyldisilazide (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give desoxybenzoin 48. Desoxybenzoin 48 is then converted to ketone 49 by treatment with an excess of dimethylformamide dimethyl acetal. Ketone 49 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to yield pyrazole 50. In Scheme IX, R12 represents one or more radicals independently selected from the optional substituents previously defined for R4. Preferably, R12 is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy.


The 3-aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized in the manner of Scheme IX by replacing pyridine 47 with the corresponding pyrimidine. In a similar manner, Schemes X through XVII can be employed to synthesize 3-aryl-4-pyrimidinyl-pyrimidines corresponding to the 3-aryl-4-pyrimidinyl-pyrazoles shown in those schemes.
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Scheme X illustrates one variation of Scheme IX that can be used to synthesize 3-aryl-4-pyridyl-pyrazoles that are further substituted on the nitrogen atom at position 1 of the pyrazole ring. If desoxybenzoin 48 (prepared in accordance with Scheme IX) instead is first converted to hydrazone 51 by treatment with hydrazine and hydrazone 51 is then treated with dimethylformamide dimethyl acetal, then the resulting product is pyrazole 52.


Schemes XI through XVIII illustrate further modifications that can be made to Scheme IX to synthesize other 3-aryl-4-pyridyl-pyrazoles having alternative substituents.
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In Scheme XII, X is chloro, fluoro or bromo; R13 is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino; and R20 is, for example, hydrogen or alkyl.
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In Scheme XV, n is 1, 2, 3, 4 or 5; and R14 and R15 are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
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In Scheme XVI, R16 is selected, for example, from hydrogen, alkyl and phenyl.
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In Scheme XVII, R17 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.
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Compounds wherein the 2-position of the pyridine ring is substituted by a carboxyl group or a carboxyl derivative may be synthesized according to the procedures outline in Scheme XVIII. The starting pyridyl pyrazole 67 is converted to the 2-cyano derivative 68 by first conversion to its pyridine N-oxide by reaction with an oxidizing agent such as m-chloroperoxybenzoic acid. Treatment of the pyridine N-oxide with trimethylsilyl cyanide followed by dimethylcarbamoyl chloride produces the 2-cyano compound 68. Compound 68 is converted to its carboxamide 69 by reaction with hydrogen peroxide in the presence of a suitable base. Examples of suitable bases include potassium carbonate and potassium bicarbonate. Carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethyl acetal in methanol. The ester 70 is converted to its carboxylic acid 71 by saponification. Typical saponification conditions include reaction with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or ethanol and water or methanol and water or the like. Ester 70 is also convertible to substituted amide 72 by treatment with a desired amine, such as methylamine at a suitable temperature. Temperatures may range from room temperature to 180° C. In Scheme XVIII, R18 and R19 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
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The synthesis of compound 77, wherein the amino group is extended two methylene units from the pyrazole ring is illustrated in Scheme XIX above. Reaction of pyrazole 73 with a protecting reagent such as 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) in the presence of a base such. as sodium hydride yields protected pyrazole 74. This reaction results in a mixture of regioisomers wherein the 2-(trimethylsilyl)-ethoxymethyl (SEM) group may be attached to either of the nitrogen atoms of the pyrazole ring. Alternatively, protecting reagents such as 2-methoxyethoxymethyl chloride (MEMCl) also may be used.


Reaction of compound 74 with a suitable derivative of dimethyl formamide, followed by exposure to water, leads to aldehyde 75. Examples of suitable derivatives of dimethylformamide include tert.-butoxybis(dimethylamino)methane and dimethylformamide dimethyl acetal. One skilled in the art will understand that this leads to the formation of a reactive vinyl amine as an intermediate. The reaction may be carried out in the reagent itself or in the presence of dimethylformamide as solvent. Suitable reaction temperatures range from about 50° C. to about 153° C. The contacting of the intermediate vinyl amine with water may be carried out in solution in a suitable solvent such as methanol, ethanol, acetone, or dioxane. Alternatively, a solution of the vinyl amine in a suitable solvent may be contacted with hydrated silica gel.


Aldehyde 75 may be reductively aminated to amine 76 by reaction with the desired amine in the presence of a reducing agent. Typical reducing agents include sodium cyanoborohydride, sodium borohydride or hydrogen in the presence of a catalyst, such as a palldium/carbon catalyst or a Raney nickel catalyst, either at atmospheric pressure or in a pressurized system. An acid catalyst such as acetic acid or dilute hydrochloric acid may also be employed. The reaction may be run at ambient temperature or may be heated.


Pyrazole 77 is obtained by removal of the pyrazole nitrogen protecting group. The deprotection reaction employed will depend upon the specific protecting group removed. A 2-(trimethylsilyl)ethoxymethyl group can be removed, for example, by reaction of amine 76 with tetrabutylammonium fluoride while a 2-methoxyethoxymethyl group can be removed, for example, by acid hydrolysis.
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Scheme XX shows the syntheses of pyrazole 82 and its derivatives 83 and 85. A substituted 4-picoline 78 is condensed with ethyl ester derivative 79 in the presence of a base such as lithium diisopropylamide to give ketone derivative 80. An example of a suitable picoline is 4-picoline. Suitable ethyl ester derivatives include ethyl 4-piperidinylacetate (Compound 79, n=1). Ester 79 may be synthesized, for example, by hydrogenation of ethyl 4-pyridylacetate and protection of the resulting piperidine nitrogen as the tert.-butoxycarbonyl (Boc) derivative by reaction with tert.-butoxycarbonyl chloride. The hydrogenation may be carried out, for example, at pressures from atmospheric to 100 psi. Suitable catalysts include 5% platinum on carbon. The presence of an acid such as hydrochloric acid may also improve reaction performance.


Treatment of 80 with a substituted benzaldehyde provides unsaturated ketone 81. Pyrazole 82 may be synthesized by treatment of 81 with p-toluenesulfonylhydrazide in the presence of acetic acid. During this reaction, the protecting tert.-butoxycarbonyl group is removed. Derivatization of pyrazole 82 by appropriate methods as described in Scheme II for analogous piperazine derivatives gives various pyrazole derivatives 83.


Alternatively, unsaturated ketone 81 can be converted to pyrazole 84 by first reaction with hydrogen peroxide in the presence of sodium or postassium hydroxide, followed by reaction with hydrazine. Using trifluoroacetic acid, the tert.-butoxycarbonyl group may be removed from pyrazole 84 to give pyrazole 82.


Alternatively, the tert.-butoxycarbonyl group of 84 may be reduced with a reagent such as lithium aluminum hydride to provide the methyl derivative 85.
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Scheme XXI shows the synthesis of pyrazoles 92. Treatment of compound 86 with ester 87 in the presence of a base, such as sodium bis(trimethylsilyl)amide, in a suitable solvent such as tetrahydrofuran, gives ketone 88. Substituent R3 is typically heteroaryl, preferably pyridinyl or pyrimidinyl, and more preferably 4-pyridinyl. Substituent R4 is typically aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl or aralkyl, and is preferably a substitued phenyl. R103 can be, for example, lower alkyl.


Treatment of ketone 88 with carbon disulfide, dibromomethane, and a base such as potassium carbonate in a suitable solvent such as acetone gives dithietane 89. Other suitable bases include, but are not limited to, carbonates such as sodium carbonate, tertiary amines such as triethylamine or diazabicycloundecane (DBU), and alkoxides such as potassium tert-butoxide. Other suitable solvents include, but are not limited to, low molecular weight ketones, methyl ethyl ketone, tetrahydrofuran, glyme, acetonitrile, dimethylformamide, dimethylsulfoxide, dichloromethane, benzene, substituted benzenes and toluene.


Dithietane 89 may be reacted with an appropriate amine, with or without heating, in an acceptable solvent such as toluene or acetonitrile to make thioamide 90. Thioamide 90 is treated with hydrazine or a substituted hydrazine in an appropriate solvent such as tetrahydrofuran or an alcohol, with or without heating, to produce pyrazole 92 and/or its tautomer.


Alternatively, thioamide 90 can be reacted with an alkyl halide or a sulphonic acid ester to yield substituted thioamide 91. Substituted thioamide 91 is treated with hydrazine or a substituted hydrazine in an appropriate solvent such as tetrahydrofuran or an alcohol, with or without heating, to produce pyrazole 92 or its tautomer.


R104 and R105 can be independent radicals or can form a heterocyclyl ring that is optionally substituted and/or contains an additional heteroatom.
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Scheme XXII shows the synthesis of substituted 5-amino pyrazoles 98 and 99. Desoxybenzoin 93 (prepared, for example, as illustrated in Scheme IX, supra, or Example C-1, infra) is reacted with an aminomethylenating agent, such as N,N-dimethylformamide dimethyl acetal, to form aminomethylene ketone 94. Aminomethylene ketone 94 is converted to isoxazole 95 by treatment with a hydroxylamine in a suitable solvent such as ethanol. Isoxazole 95 is treated with a base, such as dilute aqueous sodium hydroxide, to form cyanoketone 96. Cyanoketone 96 is then reacted with a chlorinating agent, such as phosphorous trichloride, to form a vinyl chloride which is then treated with hydrazine hydrate (or a substituted hydrazine hydrate) to form amino pyrazole 97. Amino pyrazole 97 can be reacted further with a variety of alkyl halides, such as methyl bromoacetate, bromoacetonitrile, and chloroethylamine, to form the appropriate mono- or disubstituted, cyclic or acyclic amino pyrazole 98. Typical R106 and R107 substituents include, for example, hydrogen and alkyl. In addition, amino pyrazole 97 can be reacted further with a variety of acylating agents, such as benzyliminodiacetic acid and N,N-dimethylglycine, to give the corresponding mono- or disubstituted, cyclic or acyclic amide or imide 99. Typical R108 and R109 substituents include, for example, hydrogen, alkyl and acyl.
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Scheme XXIII shows the synthesis of sulfoxide/sulfone 103. Ketone 100, wherein X is preferably halo such as fluoro or chloro, in a solvent, such as tetrahydrofuran, is treated with a suitable base, such as sodium hydride or potassium t-butoxide, to yield an enolate intermediate. The enolate intermediate is reacted with carbon disulfide and then alkylated with an appropriate alkylating agent, such as methyl iodide, benzyl bromide, or trimethylsilylchloride, to form dithioketene acetal 101. Dithioketene acetal 101 can be cyclized to pyrazole 102 using hydrazine, or its hydrate (or a substituted hydrazine or its hydrate), in a suitable solvent, such as tetrahydrofuran or ethanol. Pyrazole 102 is then treated with an oxidizing agent, such as potassium peroxymonosulfate, ammonium persulfate, or 3-chloroperoxybenzoic acid, to generate sulfoxide 103 (n=1) and/or sulfone 103 (n=2).
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Scheme XXIV shows the synthesis of pyrazole 106. Dithioketene acetal 104 in a suitable solvent, such as toluene, is combined with a secondary amine, wherein Z is preferably S or —NCH3, and heated to about 80-110° C. After the solution has been heated for several hours, any insoluble bis substituted material may be removed by filtration. Mono substituted product 105 is then reacted with hydrazine, or its hydrate (or a substituted hydrazine or its hydrate), in a solvent, such as tetrahydrofuran or ethanol, at ambient up to reflux temperatures, to form pyrazole 106.
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Scheme XXV shows the synthesis of pyrazole 109. Dithietane 107 is added to a solution of a sodium or potassium alkoxide in tetrahydrofuran. The alkoxide may be generated by treating an alcohol, in tetrahydrofuran, with a suitable base, such as sodium hydride, sodium hexamethyldisilazide, or potassium hexamethyldisilazide. The reaction mixture is stirred from 4 to 72 hours at room temperature. The resulting thionoester 108 is reacted with hydrazine, or its hydrate (or a substituted hydrazine or its hydrate), in ethanol, methanol, or tetrahydrofuran at room temperature for about 2-18 hours to generate pyrazole 109.
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Scheme XXVI shows the synthesis of pyrazole 112. To dithietane 107 in a suitable solvent, such as toluene, is added an amine, such as thiomorpholine and heated to about 80-110° C., to form thioamide 110. Thioamide 110 may be isolated or used directly in the next reaction step. To thioamide 110 in tetrahydrofuran is added a suitable base, such as potassium t-butoxide, and the resulting thiol anion alkylated with iodomethane to form alkylated thioamide 111. Alkylated thioamide 111 can be cyclized with hydrazine (or substituted hydrazine), in a solvent, such as tetrahydrofuran or ethanol, to generate pyrazole 112.
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Scheme XXVII shows the synthesis of pyrazole 114. Dithietane 107 in a suitable solvent, such as tetrahydrofuran or ethanol, is reacted with hydrazine, or its hydrate (or a substituted hydrazine or its hydrate), at room temperature up to the reflux temperature of the solvent to generate thiopyrazole 113. The thiol group of thiopyrazole 113 may be alkylated with a variety of alkylating agents, such as alkyl halides or Michael acceptors, including, but not limited to, methyl chloroacetate, ethyl acrylate, and benzyl bromide, in the presence of a suitable base such as potassium carbonate, sodium ethoxide or triethylamine, in a solvent such as dimetliylformainide or ethanol to generate pyrazole 114.
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Scheme XXVIII shows the synthesis of pyrazole 117. Pyrazoles containing acid labile amine protecting groups, such as pyrazole 115, may be treated with a suitable acid catalyst, such as trifluoroacetic acid in dichloromethane or HCl in ethanol or dioxane to yield amine 116. Amine 116 can then be acylated or alkylated by methods known to one of ordinary skill in the art, such as reacting amine 116 with a reagent such as acetyl chloride or methyl iodide in the presence of a suitable base, such as potassium carbonate or triethylamine. In addition, N-methylation can be performed directly, using formaldehyde and formic acid in ethanol/water at reflux to give pyrazole 117 wherein R114 is methyl.
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Scheme XXIX shows the synthesis of pyrazole 120. Pyrazoles containing base labile esters, such as pyrazole 118, may be treated with a suitable base, such as, sodium hydroxide to generate free acid 119. Acid 119 can then be aminated by methods known to one of ordinary skill in the art, such as treating acid 119 with a suitable coupling reagent, such as 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate, with or without catalysts, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, and an appropriate amine. In addition, amidation can be performed directly, by treating the methyl ester with an appropriate amine, for example N-methylpiperazine, in a suitable solvent such as dimethylformamide or methanol, at a temperature from room temperature up to reflux to generate pyrazole 120.


The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I, IA, XI, X, XI, and XX. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by nuclear Overhauser effect (NOE) experiments.


The following abbreviations are used:




  • HCl—hydrochloric acid

  • MgSO4—magnesium sulfate

  • Na2SO4—sodium sulfate

  • NaIO4—sodium periodate

  • NaHSO3—sodium bisulfite

  • 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

  • KMnO4—potassium permanganate

  • NaHMDS—sodium hexamethyldisilazide

  • DMF—dimethylformamide

  • EDC—1-(3-dimethylaminopropyl)3-ethylcarbodiiminde

  • hydrochloride

  • HOBT—1-hydroxybenzotriazole

  • mCPBA—3-chloroperoxybenzoic acid

  • Ts—tosyl

  • TMSCN—trimethylsilyl cyanide

  • Me2NCOCl—N,N-dimethylcarbamoyl chloride

  • SEM-Cl—2-(trimethylsilyl)ethoxymethyl chloride

  • h—hour

  • hr—hour

  • min—minutes

  • THF—tetrahydrofuran

  • TLC—thin layer chromatography

  • DSC—differential scanning calorimetry

  • b.p.—boiling point

  • m.p.—melting point

  • eq—equivalent

  • RT—room temperature

  • DMF DMA—dimethylformamide dimethyl acetal

  • TBAF—tetrabutylammonium fluoride

  • Boc—tert.-butoxycarbonyl

  • DBU—diazabicycloundecane

  • DMF(OMe)2—N,N-dimethylformamide dimethyl acetal

  • Et3N—triethylamine

  • TMSCl—trimethylsilylchloride

  • TFA—trifluoroacetic acid

  • TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate

  • psi—pounds per square inch

  • ESHRMS—electron spray high resolution mass spectroscopy



EXAMPLE A-1



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

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


A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one 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-methoxylphenyl)-3-butene-2-one (step 1) (0.99 g, 3.65 mmol) in acetic acid (25 ml), p-toluenesulfonyl hydrazide (0.68 g, 3.65 mol) was added. The reaction solution was heated to reflux for 6 hours. Acetic acid was removed by distillation from the reaction solution. The resulting residue was diluted with CH2Cl2 (150 ml), washed with H2O (2×100 ml), dried (Na2SO4), 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%): Anal. Calc'd for C16H14N3OF.0.1 H2O: C, 67.41; H, 5.02; N, 14.74. Found: C, 67.37; H, 4.88; N, 14.35.


EXAMPLE A-2



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4-(3-methyl-5-phenyl-1H-pyrazol-4-y1) pyridine

Step 1: Preparation of 4-pyridylacetone


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


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


Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78%) was obtained as a crystalline solid: m. p. 101-103° C. Anal. Calc'd for C15H13NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.


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


Using the procedure of Example A-1, step 2, a solution of 4-phenyl-3-(4-pyridyl)-3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated 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 procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and 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: m. p. 212-214° C. Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.


EXAMPLE A-3



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4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-y1]pyridine

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


A solution of 4-pyrridylacetone (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. Water generated during the reaction was removed by a Dean-Stark trap. After heating at reflux for 5 hours, the reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated to an orange color oily residue. The crude ketone was purified by chromatography to give 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one: Anal. Calc'd for C16H15NO (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-butene-2-one (step 1) (1.0g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H202 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2SO4, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil 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, 0.868 mmol) in ethyl alcohol (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: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.


EXAMPLE A-4



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

By following the method of Example A-3 and substituting p-fluorobenzaldehyde for o-tolualdehyde, the titled compound was prepared: Anal. Calc'd for C15H12N3F+0.1 H2O: (249.32): C, 70.63; H, 4.82; N. 16.47. Found: C, 70.63; H, 4.78; N, 16.40.


EXAMPLE A-5



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4-[5-methyl-3-(4-methylphenyl)-1H-pyrazol-4-y1]pyridine

By following the method of Example A-3 (with one minor modification: in Step 2, the preparation of the intermediate epoxide was accomplished at 0-10° C. for 1 hour, and the reaction was quenched by being partitioned between water, containing 2 eq. sodium bisulfite, and ethyl acetate) and substituting p-tolualdehyde for o-tolualdehyde, the titled product was isolated: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.97; H, 6.09; N; 16.90.


EXAMPLE A-6



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4-[5-methyl-3-[4-(methylthio)phenyl]-1H-pyrazol-4-y1]pyridine

By following the method of Example A-5 and substituting 4-(methylthio)benzaldehyde for p-tolualdehyde, the titled product was prepared: Anal. Calc'd for C16H15N3S (281.38): C, 68.30; H, 5.37; N, 14.93. Found: C, 68.34; H, 5.09; N. 14.78.


EXAMPLE A-7



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4-[3-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-y1]pyridine

By following the method of Example A-5 and substituting p-chlorobenzaldehyde for p-tolualdehyde, the titled product was obtained. Anal. Calc'd for C15H12N3Cl (269.77): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.43; H, 4.44; N, 15.78.


EXAMPLE A-8



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4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-y1]pyridine

By following the method of Example A-5 and substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C16H15N3+0.2 H2O: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, 6.05; N, 16.38.


EXAMPLE A-9



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4-[5-(2,5-dimethylphenyl)-3-methyl-1H-pyrazol-4-y1]pyridine

By following the method of Example A-5 and substituting 2,5-dimethylbenzaldehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C17H17N3+0.1 H2O: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51.


EXAMPLE A-10



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4-[5-(1,3-benzodioxol-5-y1)-3-methyl-1H-pyrazol-4-y1]pyridine

4-Pyridylacetone (1.5 9, 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 for 2 hours at reflux in a flask equipped with a Dean-Stark trap. The solution was cooled to room temperature, and ethyl acetate was added to precipitate a solid, which was collected on a filter plate (1.25 g). A sample (500 mg) of this solid was heated with p-toluensulfonyl hydrazide (348 mg, 1.81 mmol) in acetic acid (5 mL) at 80° C. for 1 hour. The reaction was heated to reflux for 1 hour. The reaction was cooled to room 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 (MgSO4), filtered and evaporated to obtain a yellow solid. This solid was triturated with methylene chloride, yielding 4-[5-(1,3-benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine which was collected on a filter plate (220 mg, 42% yield). Anal. Calc'd for C16H13N3O2: C, 68.81; H, 4.69; N. 15.04. Found: C, 68.02; H, 4.54; N, 14.76. MS (M+H): 280 (base peak).


EXAMPLE A-11



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4-[3-methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-y1]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 for 2 hours at reflux in a flask equipped with a Dean-Stark trap. The solution was cooled to room temperature and ethyl acetate was added to precipitate a solid, which was collected on a filter plate. A sample (223 mg) of this solid was heated with p-toluensulfonyl hydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium hydroxide (77 mg) at 110° C. for 0.5 hour. The work up procedure was the same as that in Example A-10. 4-[3-Methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-yl]pyridine was obtained (100 mg, 66% yield): Anal. Calc'd for C21H17N3O+0.1 H2O: C, 76.62; H, 5.27; N, 12.76. Found: C, 76.37; H, 5.19; N, 12.64. MS (M+H): 328 (base peak).


EXAMPLE A-12



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4-[5-[[1,1-biphenyl]-4-y1]-3-methyl 1H-pyrazol-4-y1]pyridine

The same procedure as for the preparation of Example A-10 was used, substituting 4-formylbiphenyl in place of piperonal, to give 4-[5-[(1,1′-biphenyl)-4-yl]-3-methyl-1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 312 (base peak).


EXAMPLE A-13



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4-[3-methyl-5-[3-(phenoxyphenyl)-1H-pyrazol-4-y1]pyridine

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


EXAMPLE A-14



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4-[3-methyl-5-[3-(phenylmethoxy)phenyl]-1H-pyrazol-4-y1]pyridine

The same procedure for the preparation of Example A-10 was used, substituting 3-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[3-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 342 (base peak).


EXAMPLE A-15



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4-[3-methyl-5-[2-(phenylmethoxy)-phenyl]-1H-pyrazol-4-y1]pyridine

The same procedure for the preparation of Example A-10 was used, substituting 2-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[2-(phenylmethyloxy)phenyl]-1H-pyrazol-4-yl]pyridine. MS (M+H): 342 (base peak).


EXAMPLE A-16



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2-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-y1]phenol

The same procedure for the preparation of Example A-10 was used, substituting 2-hydroxybenzaldehyde in place of piperonal, to give 2-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol: MS (M+H): 252 (base peak).


EXAMPLE A-17



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3-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-y1]phenol

The same procedure for the preparation of Example A-10 was used, substituting 3-hydroxybenzaldehyde in place of piperonal, to give 3-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol: MS (M+H): 252 (base peak).


EXAMPLE A-18



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1-hydroxy-4-[3-methyl-5-phenyl-1H-pyrazol-4-y1]pyridinium

To a solution of 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (Example A-2) (2.06 g, 8.76 mmol) in a mixture of CH2Cl2 (10 mL) and MeOH (20 mL), was added 3-chloroperoxybenzoic acid (57-86%) (2.65 g, 8.76 mmol). The reaction was stirred at room temperature for 2 h, quenched with K2CO3 solution (25%, 15 mL), and concentrated. The resulting residue was partitioned between EtOAc (2.0 L) and H2O (500 mL). The organic layer was separated, washed with H2O (500 mL), dried over MgSO4, filtered and concentrated to give 1-hydroxy-4-[3-methyl-5-phenyl-1H-pyrazol-4-yl]pyridinium (1.12 g, 54.5%): MS (M+H): 252 (base peak).


EXAMPLE A-19



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5-(4-fluorophenyl)-N,N-dimethyl-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 dry THF (200 mL) over 30 minutes. The reaction mixture was stirred at 0-10° C. for another 30 minutes, then was added to a solution of ethyl 4-fluorobenzoate (16.8 g, 0.10 mol) in dry THF (200 mL) at such a rate that the internal temperature didn't exceed 15° C. After the addition, the resulting yellow suspension was stirred at room temperature for 3 hours. Water (600 mL) was added and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-fluoro-4-(4′-pyridylacetyl)benzene (19.9 g, 92%) as an oil which solidified upon standing: m.p.: 90-91 IC; Anal. Calc'd for C13H10FNO: 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) was added a solution of bromine (8.2 g, 0.052 mol) in acetic acid (20 mL) dropwise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air-dried to give 1-fluoro-4-(41 -pyridylbromoacetyl)benzene (14.5 g). The compound was used in next step without further purification.


Step 3: Preparation of 5-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-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). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by chromatography (silica gel, ethyl acetate) to give 0.3 g 5-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine (0.3 g, 11%) as a light yellow solid: m.p.: 245-247° C. Anal. Calc'd for C16H15FN4: C, 68.07; H, 5.36; N, 19.84. Found: C, 68.00; H, 5.37; N, 19.61.


EXAMPLE A-20



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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 by the same procedure as described for Example A-19: m.p. 218-219° C. Anal. Calc'd for C20H15FN4+0.1 H2O: C, 72.33; H, 4.61; N, 16.87. Found: C, 72.16; H, 4.56; N, 16.77.


EXAMPLE A-21



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4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrizol-4-y1]pyridine

Step 1: Preparation of 1-fluoro-4-(4Õ-pyridylacetyl) benzene 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 of conc. HCl. The reaction mixture was stirred at room temperature overnight. There was white precipitate formed, which was filtered, washed with ether and air-dried to give 1-fluoro-4-(4′-pyridylacetyl)benzene N-benzoylhydrazone (2.90 g, 79%) as a mixture of cis and trans (ratio, 1:9) isomers.


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 N2 for 15 minutes, then cooled. The resulting solid was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazol-4-yl]pyridine (0.25 g, 53%) as a pale yellow solid: m.p.: 265-267° C. Anal. Calc'd for C20H14FN3+0.25 H2O: C, 75.10; H, 4.57; N, 13.14. Found: C, 74.98; H, 4.49; N, 12.87.


EXAMPLE A-22



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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 by the same method as described for 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. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96%) as a clear oil which solidified upon standing.


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 at 200° C. under N2 for 15 minutes. The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine (0.56 g) as a white solid: m.p. 237-239° C. Anal. Calc'd for C16H12F3N3: C, 63.36; H, 3.99; N, 13.85. Found: C, 63.6; H, 4.00; N, 13.70.


EXAMPLE A-23



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A mixture of l-fluoro-4-(4′-pyridylacetyl)benzene (1.0 9, 4.6 mmol) and isonicotinic 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 caused a phase change, and subsequently melted on further heating until 180° C. whereupon a solid crystallized out. The reaction was immediately cooled, diluted with 10% HCl (50 mL) and washed with chloroform. The aqueous layer was neutralized with bicarbonate and a tan colored solid was precipitated out. 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-pyrazol-5-yl]pyridine (1.05 g, 69%) as a shiny tan solid: m.p. 304° C. (DSC). Mass (MH+) 137 (100%). Anal. Calc'd for C19H13N4F.1/4H2O: C, 71.13; H, 4.24; N. 17.46. Found: C, 70.88; H, 3.87; N, 17.38.


EXAMPLE A-24



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4-(5-cyclohexyl)-3-methyl-1H-pyrazol-4-y1)pyridine

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


4-Cyclohexyl-3-pyridyl-3-butene-2-one was prepared by the method of Example A-1, step 1 by replacing of 3-fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde.


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 by the method for Example A-1, step 2, by replacing 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one with 4-cyclohexyl-3-pyridyl-3-butene-2-one (step 1): Anal. Calc'd for C15H19N3: C, 73.56; H, 7.98; N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98.


EXAMPLE A-25



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

4-{5-(3-Fluoro-5-methoxyphenyl)-3-methyl-3-methyl-1H-pyrazol-4-yl}pyridine was prepared by the method of Example A-1, steps 1 and 2 by replacing 3-fluoro-p-anisaldehyde with 3-fluoro-m-anisaldehyde: Anal. Calc'd for C16H14N3OF: C, 67.83; H, 4.98; N, 14.83. Found: C, 67.68, H, 4.92; N, 14.92.


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

Nom.p. orAnal.Calc'dAnal. Calc'd (calcd/found)A-R1R2R3R4DSC(° C.)FormulaCHN44Hembedded imageembedded imageembedded image175.6C16H15N3O.0.15H2O71.70/71.925.75/5.7615.68/15.2945Hembedded imageembedded imageembedded imageC17H19N377.54/77.136.51/6.2815.96/15.6946Hembedded imageembedded imageembedded image412.1C15H11N3F266.42/66.124.09/3.8615.49/15.2547Hembedded imageembedded imageembedded image168.5C17H17N3O.0.15H2O72.40/72.396.18/5.8714.90/14.5048Hembedded imageembedded imageembedded image211.2C16H12N3F3.0.2H2O62.62/62.644.07/4.0613.69/13.3549Hembedded imageembedded imageembedded imageC13H11N3S64.71/64.444.59/4.5817.41/17.2750Hembedded imageembedded imageembedded image189.2C15H11N3Cl259.23/59.223.65/3.2413.81/13.8151Hembedded imageembedded imageembedded image211.7C15H12N3Cl.0.15H2O66.13/66.334.55/4.6215.42/15.0552Hembedded imageembedded imageembedded image219.8C16H14N3Cl64.11/63.854.71/4.6914.02/13.9353Hembedded imageembedded imageembedded image163.4C19H17N3O2Cl64.32/63.984.83/5.0811.84/11.8054embedded imageembedded imageembedded imageHC15H12N3F.0.2H2O70.15/70.184.86/4.6016.35/16.4755Hembedded imageembedded imageHC14H10N3F70.28/69.974.21/3.8417.56/17.53


The following pyrazoles could be prepared by the procedures described above:

  • Example A-56 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • Example A-57 5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • Example A-58 5-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • Example A-59 5-[5-(4-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
  • Example A-62 5-5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)pyridin-2-amine;
  • Example A-63 4-[5-(3-chlorophenyl)-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 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • Example A-66 4-[5-(4-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
  • Example A-69 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • Example A-70 2-methoxy-5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • Example A-71 2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-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 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
  • Example A-77 2-methoxy-4-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • Example A-78 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • Example A-79 4-[5-(3-chlorophenyl)-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-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • Example A-82 4-[5-(4-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
  • Example A-85 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • Example A-86 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • Example A-87 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • Example A-88 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • Example A-89 4-[5-(4-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
  • Example A-92 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • Example A-93 4-[5-(3-chlorophenyl)-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-chlorophenyl)-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
  • Example A-99 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-100 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-101 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-102 4-[5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-1H-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-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-106 4-[5-(1-cyclohexyen-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-107 4-[5-(1,3-cyclohexadien-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-108 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-109 4-(5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine;
  • Example A-110 4-[5-(4-methoxy-3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-111 4-[5-(3-methoxy-4-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-112 4-[5-(3-methoxy-5-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-113 4-[5-(3-furanyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-114 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
  • Example A-115 2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
  • Example A-116 methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-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-1H-pyrazol-4-yl)pyridine-3-carboxamide;
  • Example A-124 1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-3-yl]ethanone;
  • Example A-125 3-bromo-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
  • Example A-126 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-1H-pyrazol-4-yl)pyrimidin-2-amine;
  • Example A-131 N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
  • Example A-132 4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5-phenyl-1H-pyrazole;
  • Example A-133 3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazole;
  • Example A-134 4-(3-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 4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
  • Example A-138 4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
  • Example A-139 4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
  • Example A-140 4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
  • Example A-141 3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazole;
  • Example A-142 3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazole;
  • Example A-143 2-methyl-4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
  • Example A-144 4-(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-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
  • Example A-148 4-[3-(4-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
  • Example A-149 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • Example A-150 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
  • Example A-151 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2-methylpyridine;
  • Example A-152 4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
  • Example A-153 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine; and
  • Example A-154 4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]-2-methylpyridine.


The compounds of Examples A-155 through A-172 were synthesized in accordance with the chemistry described above (particularly Scheme II) and illustrated by many of the previously disclosed Examples by selection of the corresponding starting reagents:


EXAMPLE A-155



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5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 261 ° C. Anal. Calc'd for C20H15ClN4+0.25 H2O (MW 351.32): C, 68.38, H, 4.30, N, 15.95. Found: C, 68.25, H, 4.41, N, 15.74.


EXAMPLE A-156



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5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 260° C. Anal. Calc'd for C15H13ClN4+0.125 H2O (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



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5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine dihydrate: DSC 230 ° C. Anal. Calc'd for C16H15ClN4+2 H2O (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



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5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 227 ° C. Anal. Calc'd for C16H15FN4+0.125 H2O (MW 284.57): C, 67.53, H, 5.31, N, 19.69. Found: C, 67.60, H, 5.20, N, 19.84.


EXAMPLE A-159



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N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 222 ° C. Anal. Calc'd for C17H18N4+0.25 H2O (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



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N-methyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 226 ° C. Anal. Calc'd for C16H16N4+0.125 H2O (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



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N-ethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 227° C. Anal. Calc'd for C17H18N4+0.125 H2O (MW 280.61): C, 72.77, H, 6.47, N, 19.97. Found: C, 72.63, H, 6.40, N, 19.73.


EXAMPLE A-162



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N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 234° C. Anal. Calc'd for C19H22N4 (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



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5-(4-chlorophenyl)-N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: m.p. 260-261° C. Anal. Calc'd for C18H19ClN4 (MW 326.83): C, 66.15, H, 5.86, N, 17.14. Found: C, 66.03, H, 5.72, N, 17.23.[ text missing or illegible when filed


EXAMPLE A-164



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine: DSC 279 ° C. Anal. Calc'd for C16H17ClN4O+0.25 H2O (MW 345.32): C, 62.61, H, 4.96, N, 16.23. Found: C, 62.52, H, 4.77, N, 16.52.


EXAMPLE A-165



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5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 244° C. Anal. Calc'd for C17H17ClN4+0.125 H2O (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



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Isolated as 5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine hydrate (2:1): DSC 237° C. Anal. Calc'd for C21H17ClN4+0.5 H2O (MW 369.86): C, 68.20, H, 4.63, N, 15.15. Found: C, 68.09, H, 4.55, N, 15.15.


EXAMPLE A-167



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Isolated as 5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine monohydrate: DSC 223° C. Anal. Calc'd for C17H17ClN4O+H2O (MW 346.82): C, 58.87, H, 4.94, N, 16.15. Found: C, 58.59, H, 4.79, N, 16.02.


EXAMPLE A-168



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1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-i-piperazinecarboxylate: DSC 251° C. Anal. Calc'd for C23H26ClN5O (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



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Isolated as 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride: DSC 99° C. Anal. Calc'd for C18H18ClN4+3 HCl (MW 449.21): C, 48.13, H, 4.71, N, 15.59. Found: C, 47.76, H, 5.07, N, 15.51.


EXAMPLE A-170



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1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine: m.p. 247-249° C. Anal. Calc'd for C19H20ClN5+0.75 H2O (MW 367.33): C, 62.12, H, 5.49, N, 19.06. Found: C, 62.45, H, 5.86, N, 19.32.


EXAMPLE A-171



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1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate: m.p. 243-244° C. Anal. Calc'd for C23H26FN5O2+0.5 CH3CH2CO2CH2CH3 (MW 467.55): C, 64.22, H, 6.47, N, 14.98. Found: C, 63.90, H, 6.61, N, 4.88.


EXAMPLE A-172



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1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride: m.p. 204-206° C. Anal. Calc'd for C18H18Fn5+3 HCl+0.5 H2O (MW 441.77): C, 48.94, H, 4.79, N, 15.85. Found: C, 48.66, H, 4.88, N, 15.50.


1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine: m.p. 264-265° C. Anal. Calc'd for C18H18ClN5+0.125 H2O (MW 342.08): C, 63.20, H, 5.30, N, 20.47. Found: C, 63.04, H, 5.36, N, 20.33.


Additional compounds that were synthesized in accordance with the chemistry described in Scheme II by selection of the corresponding starting reagents further include the compounds disclosed in Table 2.

TABLE 2GeneralMicroanalysisDSCExampleProcedureFormulaC calcC foundH calcH foundN calcN founddeg C.A-173Sch. IIC24H25ClN6.3HCl.1.5H2O50.6350.584.965.0314.7614.68182A-174Sch. IIC25H24ClN5.0.125H2O69.4769.335.605.5616.2016.11259A-175Sch. IIC17H17FN6.1.25H2O48.6448.454.564.8620.0220.24 82A-176Sch. IIC22H26ClN5O261.7561.576.126.0416.3716.34217A-177Sch. IIC17H18ClN5.3HCl.H2O44.8544.964.654.8715.3815.17220A-178Sch. IIC21H24ClN5O2.0.125H2O60.6160.515.815.8116.8316.64232A-179Sch. IIC25H30ClN5O362.0461.766.256.2514.4714.37220A-180Sch. IIC22H25FN6O2.0.5H2O60.9660.865.816.2119.3919.47N.D.A-181Sch. IIC22H25ClFN5O259.2658.985.655.5515.7115.36210A-182Sch. IIC20H22ClN5.0.75H2O62.9862.975.815.6418.3617.83271A-183Sch. IIC16H19Cl4N5.3HCl45.4145.374.534.74120


EXAMPLE A-173



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


EXAMPLE A-174



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


EXAMPLE A-175



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


EXAMPLE A-176



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


EXAMPLE A-177



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


EXAMPLE A-178



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


EXAMPLE A-179



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1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate


EXAMPLE A-180



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


EXAMPLE A-181



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


EXAMPLE A-182



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


EXAMPLE A-183



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


The compounds of Examples A-184 through A-189 were synthesized in accordance with the chemistry described above (particularly in Schemes I and IV) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents:


EXAMPLE A-184



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4-[3-(2,6-difluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C15H11F2N3: C, 66.42; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; m.p. 236.67° C.


EXAMPLE A-185



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4-[3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C17H17N3: C, 77.54; H. 6.51; N, 15.96. Found; C, 77.16; H. 6.27; N. 15.69. m.p. (DSC): 189.25° C.


EXAMPLE A-186



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4-[3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine: Anal Calc'd for C16H14ClN3.0.1 mole H2O: C, 67.15; H, 4.91; N, 14.33. Found: C, 66.95; H, 5.00; N, 14.36. DSC: 176.18° C.


EXAMPLE A-187



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4-[3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C18H19N3.0.1 mole H2O: C, 77.44; H, 6.93; N, 15.05. Found: C, 77.39; H, 6.94; N, 14.93. m.p. (DSC): 192.66° C.


EXAMPLE A-188



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4-[3-(4-chlorophenyl)-5-(1-methylethyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C17H16ClN2.0.4M EtOAc: C, 67.08; H, 5.81; N, 12.62. Found: C, 67.40; H, 6.15; N, 12.34.


EXAMPLE A-189



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4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C17H14FN3: C, 73.1; H, 5.05; N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63; m.p.: 239-240° C.


The compound of Example A-190 was synthesized in accordance with the chemistry described above (particularly in Scheme III) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents:


EXAMPLE A-190



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

This compound was prepared by the same procedure as described for Example A-22 by replacing 3-(4′-pyridylacetyl)toluene with 1-fluoro-4-(4′-pyridylacetyl) benzene (prepared as set forth in Example A-19).


Anal. Calc'd for C15H9F4N3: C, 58.64; H, 2.95; N, 13.68. Found: C, 58.57; H, 3.07; N, 13.31. m.p. (DSC): 281.94° C.


The compounds of Examples A-191 through A-198 were synthesized in accordance with the chemistry described above (particularly in Scheme V) by selection of the corresponding starting reagents:


EXAMPLE A-191



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

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

To a solution of 4-fluorobenzoyl-4′-pyridinyl methane (8.60 g, 0.04 mol) and methyl hydrazine (2.14 g, 0.044 mol) in 50 mL of ethanol was added two drops of concentrated sulfuric acid. The reaction mixture was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium carbonate solution, washed with brine, and dried over magnesium sulfate. The filtrate was concentrated and the crude product was recrystallized from diethyl ether and hexane to afford 7.5 g of a yellow solid product (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 a solution of the compound prepared in step 1 (0.67 g, 0.0028 mol) in 10 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl cyclopropanecarboxylate (0.34 g, 0.0034 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane/acetone, 10:9:1) to give 0.45 g of product, 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl -1H-pyrazol-4-yl]pyridine, as a light yellow solid (55% yield), mp: 129-130° C.; 1H NMR (CDCL3): δ8.53 (m, 2H), 7.32 (m, 2H), 7.14 (m, 2H), 6.97 (m, 2H), 4.00 (s, 3H), 1.83 (m, 1H), 0.95 (m, 2H), 0.36 (m, 2H); Anal. Calc'd For C18H16FN3: C, 73.70; H, 5.50; N, 14.32. Found: C, 73.63; H. 5.57; N, 14.08.


EXAMPLE A-192



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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
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1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-hydroxyethyl)hydrazone

To a flask containing hydroxyethyl hydrazine (3.4 g, 0.04 mol) at 80° C. was added 4-fluorobenzoyl-4′-pyridinyl methane (8.6 g, 0.04 mol) portionwise. The yellow oil was stirred at this temperature overnight. The cooled reaction mixture was dissolved with hot ethyl acetate and then triturated with hexane to give 8.9 g of product, 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-hydroxyethyl)hydrazone, as a yellow crystal (81%), mp: 122-123° C.


Step 2: Preparation of 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone [2-[[(1.1-dimethylethyl)dimethylsilyl]oxy]ethyl]hydrazone
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1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]hydrazone

To a solution of the 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 (1.5 g, 0.01 mol) in 25 mL of DMF was added imidazole portionwise. The reaction mixture was stirred at room temperature overnight. Water was added and 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 that 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
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3: 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 dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl cyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.30 g of product, 5-cyclopropyl-1-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]ethyl)-3,4-diphenyl-1H -pyrazole, as a light yellow oil (35% yield), 1H NMR (CDCL3): δ8.53 (m, 2H), 7.32 (m, 2H), 7.14 (d, J=5.6 Hz, 2H), 6.97 (m, 2H), 4.47 (t, J=4.8 Hz, 2H), 4.14 (t, J=4.8 Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H), 0.41(m, 2H); Anal. Calc'd For C25H32FN3OSi: C, 68.61; H, 7.37; N, 9.60. Found: C, 68.39; H, 7.81; N, 9.23.


Step 4: Preparation of 5-cyclopropyl-3-(4-fluorophenyl) -4-(4-pyridinyl)-1H-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 1.0 M THF solution) at room temperature. After 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 9:1) to give 0.16 g of product, 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol, as a pale yellow solid, mp: 155-157° C.; 1H NMR (CDCL3): δ8.53 (br s, 2H), 7.32 (m, 2H), 7.14 (d, J=5.6 Hz, 2H), 6.97 (m, 2H), 4.42 (t, J=4.8 Hz, 2H), 4.14 (t, J=4.8 Hz, 2H), 1.83 (m, 1H), 0.93 (m, 2H), 0.35 (m, 2H); Anal. Calc'd For C19H18FN3O: C, 70.57; H, 5.61; N. 12.99. Found: C, 70.46; H, 5.87; N, 12.84.


EXAMPLE A-193



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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 a solution of the compound prepared in step 2 of Example A-192 (1.25 g, 0.0034 mol) in 15 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl 4-(2-methoxy)pyridinecarboxylate (0.0.59 9, 0.0035 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.28 g of product, 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol, as a yellow solid, mp: 168-169° C.; 1H NMR (CDCL3): δ8.42 (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); Anal. Calc'd for C22H19FN4O2: C, 67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03.
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4-[1-[2-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2-methoxypyridine

A second compound, 4-[l-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2-methoxypyridine also was isolated from the above reaction as a yellow oil by chromatography. 1H NMR (CDCL3): δ8.45 (m, 2H), 8.20 (m, 1H), 7.40 (m, 2H), 7.04 (m, 2H), 6.93 (m, 2H), 6.81 (m, 2H), 4.24 (m, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 0.83 (s, 9H), 0.02 (s, 6H).


EXAMPLE A-194



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

To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48% hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. 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 chromatography on silica gel (MeOH/CH2Cl2/NH4OH, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone, as a yellow solid (32% yield), mp: 250-251° C; 1H NMR (DMSO-d6): δ11.74 (s, 1H), 8.45 (d, J=5.0 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 ( d, J=5.0 Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C21H17FN4O2.0.2 H2O: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27.


EXAMPLE A-195



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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 in the form of a yellow solid (38% yield), mp: 220-221° C.; 1H NMR (CDCl3): δ8.50 (m, 2H), 7.39 (m, 3H), 7.02 (m, 4H), 6.59 (m, 1H) 6.08 (dd, J=1.4, 5.2 Hz, 1H), 4.52 (t, J=6.0 Hz, 2H), 4.43 (t, J=6.0 Hz, 2H), 2.04 (s, 3H); Anal. Calc'd for C23H19FN4O3.0.3 H2O: C, 65.46; H, 4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99.


EXAMPLE A-196



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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 a solution of the compound prepared in step 1 of Example A-192 (1.37 g, 0.005 mol) in 20 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of diethyl 1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 0.18 9 of product, ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate, as a light yellow oil (35% yield), 1H NMR (CDCL3): δ8.55 (m, 2H), 7.32 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H), 4.38 (m,2H), 4.16 (m, 4H), 2.47 (m, 1H), 1.53 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), (m, 2H), 0.90 (m, 2H); Anal. Calc'd for C22H22FN3O3.0.25 H2O: C, 66.07; H, 5.67; N, 10.51 Found: C, 65.89; H, 5.80; N, 9.95.


EXAMPLE A-197



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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 in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. 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 addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, 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.; 1H NMR (CD3OD):b 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J=5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20.


EXAMPLE A-198



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

Step 1: Preparation of methyl 1-r[2-(trimethylsilyl) ethoxylmethyl]-1H-pyrrole-3-carboxylate
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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 methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room temperature. The mixture was stirred at room temperature for 0.5 hours. Then SEM-CL (4.17 g, 0.025 mol) was added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours and quenched by adding 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 chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 4.0 g of the major 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-imidazole-4-yl]-1H-pyrazol -4-yl]pyridine
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4-[1-[2[[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]-3-(4-fluorophenyl)-5-[1-[[2-trimethylsilyl)ethoxy]methyl]-1H-imidazole-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 of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of the compound prepared in step 1 of the present Example (0.54 g, 0.0021 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 0.98 g of product as a light yellow oil which solidified upon standing (91% yield), mp: 79-80° C.; 1H NMR (CDCL3): δ8.48 (d, J=6.0 Hz, 2H), 7.68 (d, J=1.3 Hz, 1H), 7.38 (d, J=6.0 Hz, 2H), 7.10 (m, 2H), 7.00 (m, 2H), 6.93 (d, J=1.3 Hz , 1H), 5.25 (s, 2H), 4.53 (t, J=6.0 Hz, 2H), 4.12 (t, J=6.0 Hz, 2H), 3. 84 (t, J=8.0 Hz , 2H), 0.92 (t, J=8.0 Hz, 2H), 0.84 (s, 9H), 0.021 (s, 18H); Anal. Calc'd For C31H44FN5O2Si2: C, 62.70; H, 7.47; N, 11.79. Found: C, 62.98; H, 7.74; N, 11.88.


Step 3: 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 the present Example (0.54 g, 0.001 mol) in 10 mL of THF was added a solution of tetrabutylammonium fluoride (1.0M 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)-1H -pyrazole-1-ethanol, as a white solid (63% yield), mp: 227-228° C; 1H NMR (DMSO-d6): δ8.45 (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); Anal. Calc'd 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 in accordance with the chemistry described above (particularly in Scheme VI) by selection of the corresponding starting reagents:


EXAMPLE A-199



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

Anal. Calc'd for C15H12N3Cl (269.74): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.57; H, 4.15; N, 15.54. m.p. (DSC): 198.17° C.


The compounds of Examples A-200 through A-202 were synthesized in accordance with the chemistry described above (particularly in Scheme VII) by selection of the corresponding starting reagents:


EXAMPLE A-200



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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 as set forth in Example A-4 (5.83 g, 24.0909 mmol) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 ml) and tert-butanol (10 ml) was heated at reflux for 6 hours (or until all the potassium permanganate was consumed). The mixture was then stirred at room temperature overnight and then diluted with water (150 ml). Manganese dioxide was removed from the mixture by filtration. The filtrate was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HCl to increase 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 the monohydrate salt)(2.9777 g, 43.7 %). Anal. Calc'd for C15H10N3FO2. H2O (283+18): C, 59.80; H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH+): 284 (base peak).


EXAMPLE A-201



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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 accordance with Example A-200 (0.526 g, 2.0 mmol) in dry THF (15 ml) at reflux under nitrogen, a solution of 1N lithium aluminum hydride in THF (4.0 ml, 4.0 mmol) was added dropwise over 15 minutes. A precipitate formed. The mixture was boiled for an additional hour. Excess lithium aluminum hydride was then decomposed by cautiously adding a solution of 4N potassium hydroxide in water (0.5 ml). Upon hydrolysis, a white salt precipitated. After the addition was complete, the mixture was heated at reflux for 15 minutes. The hot solution was filtered by suction through a Buchner funnel, and remaining product was extracted from the precipitate by refluxing with THF (15 ml) for 1 hour, followed again by suction filtration. The combined filtrates were concentrated under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, dried over MgSO, to give a crude product (0.45 g). Recrystallization of the crude product from methanol gave 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol (0.2808 g, 56.5%). DSC: 260.26° C.; Anal. Calc'd for C15H12N3FO (269): C, 66.91; H, 4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20. MS (MH+): 270 (base peak).


EXAMPLE A-202



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

Step 1: Preparation of 1,1-dimethylethyl 4-E r5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate
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To a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.9905 g, 3.5 mmol) and 1-hydroxybenzotriazole (0.4824 g, 3.57 mmol) in DMF (20 ml) at 0° C. under nitrogen, 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride (0.6984 g, 3.57 mmol, Aldrich Chemical Co.) was added. The solution was stirred at 0° C. under nitrogen for 1 hour then 1-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) was added followed by N-methylmorpholine (0.40 ml, 3.6 mmol). The reaction was stirred from 0° C. to room temperature overnight. After 19 hours, the solvent was removed under reduced pressure, and resulting residue was diluted with ethyl acetate, washed with saturated NaHCO3 solution, water and brine, and dried over MGSO4. After filtration, the solvent was removed under reduced pressure to give a 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. Anal. Calc'd for C24H26N5O3F. (451): C, 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MH+): 452 (base peak).


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 room temperature under nitrogen for 2 hours. The solvent was removed under reduced pressure and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was dried in a vacuum oven overnight to give 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine (isolated as the bis(trifluoroacetate), monohydrate salt) (0.2400 g, 100%) as a white solid. Anal. Calc'd for C19H18N5OF.2CF3COOH.H2O(351+228+18): C, 46.24; H, 3.71; N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH+) 352 (base peak).


The compounds of Examples A-203 through A-206 were synthesized in accordance with the chemistry described above (particularly in Scheme VIII) by selection of the corresponding starting reagents:


EXAMPLE A-203



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



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


A 60% dispersion of sodium hydride (41 mg, 0.00172 moles)(prewashed with hexane) in mineral oil (69 mg) was added with 5 ml of dioxane to a stirred solution of 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (200 mg, 0.00086 moles) (prepared as set forth in Example A-2) in 50 ml of dioxane. After 3 hours a solution of CH3I (122 mg, 0.00086 mole) in 10 ml dioxane was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated to a solid. The products were partitioned between water (15 ml) and ethyl acetate (50 ml). The organic layer was dried over Na2SO4, filtered and concentrated to a solid. The products were purified and separated by radial chromatography. NMR (NOE experiments) showed that the first component off the column (the minor component) was 4-(1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl]pyridine, and the second material off 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): m.p.: 94-99° C. Anal. calc'd for C16H15N3.0.1MH2O: C, 77.08; H, 6.06; N, 16.85. Found: C, 76.59; H, 5.70; N, 16.62.


EXAMPLE A-204



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



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4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine (the compound of Example A-32)

4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine and 4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine were prepared by the same procedure as described for Example A-203 by replacing 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine with 4-(3-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyridine (prepared as set forth in Example A-7).


Major Isomer (4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine): Anal. calc'd for C16H14N3Cl (283.76): C, 67.72; H, 4.97; N, 14.81; Found: C, 67.45; H, 4.71; N, 14.63. m.p. (DSC): 190.67° C.


Minor Isomer (4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine): m.p.: 82-88° C. Anal. calc'd for C16H14N3Cl: C, 67.72; H, 4.97; N, 14.81; Found: C, 67.56; H, 4.96; N, 14.73.


EXAMPLE A-205



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



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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 by the same procedure as described for Example A-203 by replacing 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine with 4-(3-(4-methylphenyl)-5-ethyl-1H-pyrazol-4-yl)pyridine (prepared as set forth in Example A-45).


Major Isomer (4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine): Anal. Calc'd for C18H19NO3.0.45 MH2O: C, 75.73; H, 7.03; N, 14.77. Found: C, 76.03; H, 6.87 N, 14.28.


Minor Isomer (4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine): Anal. Calc'd for C18H19NO3.0.3MH2O: C, 76.46; H, 6.99; N, 14.86. Found: C, 76.58; H, 6.98; N, 14.63.


EXAMPLE A-206



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4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C17H16N3Cl (297.79): C, 68.57; H. 5.42; N, 14.11. Found: C, 68.33; H, 5.27; N, 14.08; m.p. (DSC) 164.36° C.
EXAMPLE A-207



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4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C17H16N3Cl (297.79): C, 68.57; H, 5.42; N, 14.11. Found: C, 68.25; H, 5.36; N, 13.74; m.p. (DSC) 153.46° C.

The compounds of Examples A-208 and A-209 were prepared in accordance with the chemistry described above (particularly in Scheme IX):


EXAMPLE A-208



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

Step 1: Preparation of 4-fluorobenzoyl-4′-pyridyl methane


To a mixture of 4-picoline (32.6 g, 0.35 moles) and ethyl-4-fluorobenzoate (50.45 g, 0.3 moles), maintained at 20° C., was added lithium bis(trimethylsilylamide) (600 mL (1M)) in a steady but rapid stream so as to maintain ambient temperature. The initial yellow solution turned into a suspension which was then stirred for an additional 2 hours. Toluene (250 mL) was added and the mixture cooled to 0° C. The reaction mixture was quenched with concentrated HCl at 0° C. to lower the pH to about 7. The organic layer was separated and the aqueous layer re-extracted with of toluene (100 mL). The organic layer was dried (sodium sulfate) and concentrated, to furnish a yellow solid which on trituration with hexanes (200 mL) provided the pure desoxybenzoin, 4-fluorobenzoyl-4′-pyridyl methane, in 90% yield (58 g). 1H NMR was consistent with the proposed structure.


Step 2:


To a suspension of the desoxybenzoin prepared in step 1 (30 g, 0.14 moles) in tetrahydrofuran (50 mL) was added dimethylformamide dimethyl acetal (50 mL) and the mixture stirred at ambient temperature for two days. The solution was then concentrated to dryness and the solid paste obtained was triturated with hexanes (150 mL) to furnish a yellow solid which was of sufficient purity (as determined by NMR) and was used for the next step without additional purification. Yield: 33.9 g (90%). 1H NMR was consistent with the proposed structure.


Step 3:


The vinyl amine prepared in step 2 (33.9 g, 0.1255 moles) was dissolved in 125 mL of ethanol and cooled to 0° C. Hydrazine hydrate (8.0 g of anhydrous or 16.0 g. of hydrate, 0.25 moles) was then added in one portion. The mixture was stirred well and allowed to warm up to ambient temperature for 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% HC1. The water layer was then treated with 0.5 g of activated charcoal at 70° C. for 10 minutes, filtered through celite and neutralized cautiously to pH 7-8 with vigorous stirring and cooling (20% sodium hydroxide was used). The fine off-white precipitate was filtered and dried to give 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)pyridine. Yield: 27.3 g. (91%). Mass spectrum: m/z=240. 1H NMR was consistent with the proposed structure. Anal. calc'd for C14H10FN3: C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H, 4.33; N, 17.61.


EXAMPLE A-209



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

This compound was prepared by the same procedure described for Example A-208 using the corresponding starting reagents.


Anal. Calc'd for C14H10ClN3: C, 65.76; H, 3.94; N, 16.43. Found: C, 65.22; H, 3.91; N, 16.50. m.p. (DSC): 208.46° C.


The compounds of Examples A-210 and A-211 illustrate were prepared in accordance with the chemistry described above (particularly in Scheme X):


EXAMPLE A-210



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

The desoxybenzoin prepared in step 1 of Example A-208, 4-fluorobenzoyl-4′-pyridyl methane, (12.79, 0.059 moles) was mixed with 90% hydroxyethyl hydrazine (5.3 g, 0.062 moles) in 30 mL of ethanol containing 0.5 mL of acetic acid in a 500 mL Erlenmeyer flask. After gentle boiling (1 hour), a small sample was evacuated at high vacuum and examined by 1H NMR to confirm completion of hydrazone formation. On cooling to ambient temperature, the reaction mass solidified to a yellow cake. DMF dimethylacetal (36 mL, 0.27 moles) was then added and the mixture heated to 80° C. for 10 min, at which point all the 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, at which point a cloudy yellow oily suspension was obtained. The solution was now warmed to approximately 50-60° C., whereupon the solution turned clear yellow. Slow cooling to ambient temperature with stirring (a crystal seed if available speeds up the process) results in a copious formation of crystals. Suction filtration followed by washing with 10% ethanol-water (50 mL), followed by drying, furnishes 3(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol as a light yellow crystalline solid. Re-heating the filtrate to clarity as before, followed by cooling, yields additional product. The third and fourth recovery from the mother liquor on standing overnight furnishes 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. 1H NMR was consistent with the proposed structure. Anal. calc'd for C16H14FN3O+H2O: C, 63.78; H, 5.35; N, 13.95. Found: C, 63.55; H, 5.07; N, 13.69.


EXAMPLE A-211



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3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol

This compound was prepared by the same procedure as described for Example A-210 except that the 4-picoline used to synthesize the desoxybenzoin was replaced with 4-methyl-pyrimidine.


The compound of Example A-212 was prepared in accordance with the chemistry of Scheme XI:


EXAMPLE A-212



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

The vinyl amine 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. Methyl hydrazine (1.7 g, 0.037 moles) in ethanol (75 mL) was added in one portion while maintaining the temperature at 0 to 10° C. After 3 hours at ambient temperature the solvent was removed and the residue taken up in methylene chloride (150 mL) and water (100 mL). The organic layer was separated, dried and concentrated to provide the crude regio-isomeric mixture as a light tan colored 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 water layer treated with activated charcoal (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) and allowed to cool slowly, first to ambient temperature and then to 15° C. Scratching the sides of the flask starts the crystallization process. After 2 hours of standing, the solids formed were filtered, washed with cold 50% toluene/heptane (25 mL) followed by hexane (25 mL) and dried to yield the pure title compound. 1H NMR confirmed the structure (including regiochemistry using NOE experiments). Yield: 2. 1 g. (45%). Mass spectrum, m/z=254 (base peak). Anal. calc'd for C15H12FN3+0.2 H2O: 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 in accordance with the chemistry of Scheme XII:


EXAMPLE A-213



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

An intimate mixture of 2-fluoro-pyridinyl pyrazole (0.2 g, (prepared by the same procedure as described for Example A-210 except that the 4-picoline used to synthesize the desoxybenzoin was replaced with 2-fluoro-4-methylpyridine) and (R,S)-2-amino-1-butanol (4 fold molar excess) was heated to 210-220° C. in a sealed vial for 1.5 hours. After cooling to 100° C. the vial was cautiously opened and 5 mL of toluene and 5 mL of water were added and stirred well for 1 hour. The solid obtained, 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-butanol, was suction-filtered and washed with an additional 5 mL of water followed by toluene and dried. Yield: 190mg. (71%). Mass spectrum, m/z 343. 1H NMR was consistent with the proposed structure.


The compound of Example A-214 was prepared in accordance with the chemistry of Scheme XIII:


EXAMPLE A-214



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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 in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80° C. overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with K2CO3 (25 g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50 mL×5) to give 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (1.24 g, 35%): mp 174.38° C.; Mass spectrum m/z=332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H11N3FBr.0.2 H2O: 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 in accordance with the chemistry of Scheme XIV:


EXAMPLE A-215



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

Step 1:


To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine (4.3 g, 17.97 mmol) (prepared in accordance with 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. for overnight. The mixture was concentrated. K2CO3 (10%, 100 mL) was added to the residue. A precipitate was formed, filtered and washed with water (30 mL×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 indicated that the starting materials were gone. The mixture was partitioned into ethyl acetate:water (100 mL:20 mL). The organic layer was washed with K2CO3 (10%, 20 mL), water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to give 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile (0.23 g, 56 % yield): mp 209.22° C ; Mass spectrum (chemical ionization): m/z=265; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C15H9N4Fe.0.2 H2O: C, 67.26; H, 3.54; N, 20.92. Found: C, 67.44; H, 3.40; N, 20.69.


The compound of Example A-216 was prepared in accordance with the chemistry of Scheme XV:


EXAMPLE A-216



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

Step 1:



3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (prepared in accordance with Example A-210) (10.0 g, 0.0353 moles) was suspended in pyridine (100 mL) and cooled to 0° C. Methane sulfonyl chloride (4.4 g, 0.0388 moles) was added slowly while maintaining the temperature at 0° C. After stirring overnight at 10° C., chilled water (100 mL) and methylene chloride (150 mL) was added and the two layers separated. The water layer was re-extracted with 100 mL of methylene chloride and the organic layer dried and concentrated to a paste. After drying at high vacuum, a light tan colored cake was obtained which was triturated with ether (75 mL), filtered and dried to furnish a cream colored solid in 79% yield (10.1 g). 1H NMR was consistent with the proposed structure. The compound was used as such for step 2.


Step 2:


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 to 4 hours. After an NMR sample confirmed completion, the mixture was concentrated and taken up in methylene chloride (150 mL) and washed with water (100 mL) and then with 75 mL of 5% HCl. The water layer was neutralized to pH 8 and extracted with methylene chloride (100 mL). On drying and concentration a light yellow pasty solid was obtained which was triturated with 25 mL of ether to furnish a solid. Re-crystallization from toluene/hexane provided 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine as a solid. Yield: 4.5 g (86%). Mass spectrum, m/z=353. 1H NMR was consistent with the proposed structure. Anal. calc'd for C20H21FN4O: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.20; H, 6.21; N, 15.80.


The compound of Example A-217 was prepared in accordance with the chemistry of Scheme XVI:


EXAMPLE A-217



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

To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with 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 to 45° C. for 2 hours. It was quenched with HCl (10 mL, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give a residue. The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z=360 (M+1); 1H NMR was consistent with the proposed structure. Anal. Calc'd for C22H18N2OF.0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.


The compound of Example A-218 was prepared in accordance with the chemistry described above (particularly Scheme XVII):


EXAMPLE A-218



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

The starting desoxybenzoin prepared in step 1 of EXAMPLE A-208, 4-fluorobenzoyl-4′-pyridyl methane, (1.0 g, 0.0046 moles) was dissolved in 10 mL of DMF and cooled to −10° C. (dry ice-aqueous isopropanol). N-chlorosuccinimide (0.62 9, 0.0046 moles) was added in one portion while maintaining the temperature at −10° C. After 5 minutes the thiosemicarbazide (0.0046 moles) was added in one portion at 0° C. and allowed to warm to ambient temperature slowly over 1 hour. After stirring overnight, the solvent was removed at high vacuum and water and toluene (25 mL each) added and stirred well. The toluene layer was separated and the water layer (starting pH of 5.5) treated with bicarbonate to pH 8. The fine precipitate formed was filtered and washed with water, toluene and ether. A final trituration with ether (25 mL) furnished an off white solid, N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine, which was re-filtered and dried. Yield: 0.95 g. (56%). Mass Spec. m/z: 368 (base peak). Anal. Calc'd for C20H22FN5O. C, 65.38; H, 6.04; N, 19.06. Found: C, 64.90; H, 5.92; N, 18.67.


EXAMPLE A-219



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

Step 1: Preparation of (E)-2-(2-bromo-4-pyridinyl)-N,N-dimethylethenamine
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4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t-butoxybis(dimethylamino)methane (5 ml) were heated to 150° C. for 16 hours. 4-Methyl-2-bromopyridine was prepared as set forth in B. 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 solvent 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
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The product from 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 the addition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol). The mixture was stirred under nitrogen for 16 hours. Solvent was evaporated in vacuo and the residue was dissolved in ether (25 ml), stirred with magnesium sulfate (500 mg) and silica gel (500mg), and filtered. Ether was evaporated and the residue was chromatographed on silica gel using mixtures of acetone and methylene chloride as eluents to give 670 mg of the product, (Z)-2-(2-bromo-4-pyridinyl)-1-(3-chlorophenyl)-3-(dimethylamino)-2-propen-1-one, as a glass which was used in step 3 without further purification.


Step 3: Preparation of 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine
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A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C14H9BrClN3: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.


Continued elution with mixtures of ethyl acetate and methanol gave 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl)-2(1H)-pyridinone hydrazone (190 mg, 36%) as a crystalline solid: m.p. 163-164° C.; MS (M+H)=286. Anal. Calc'd for C14H12N5Cl: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87.


EXAMPLE A-220



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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. mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179-180° C.


Anal. Calc'd For C21H17ClN4: C, 69.90; H, 4.75; N, 15.53. Found: C, 69.69; H, 4.81; N, 15.11.


EXAMPLE A-221



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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 removal of solvent, the residue was chromatographed on silica gel with mixtures of ethyl acetate and 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.


Anal. Calc'd For C22H19ClN4: C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66.


EXAMPLE A-222



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4-[3-(3-chlorophenyl)-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) as heated at 150° C. in a sealed tube 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, m.p. 186-187° C. Anal. Calc'd For C16H15ClN4: C, 64.32; H, 7.06; N, 18.75. Found: C, 64.42; H, 7.01; N, 18.45.


The compounds of Examples A-223 through A-226 were synthesized in accordance with the chemistry described above (particularly in Scheme XVIII) by selection of the corresponding starting reagents:


EXAMPLE A-223



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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 as set forth in Example A-208) (8.8 9, 0.037 mol) in methylene chloride was added m-chloroperoxybenzoic acid (mCPBA) in one portion at room temperature. After stirring for 16 hours, 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 a product as a white solid (87%), mp: 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 of DMF at room temperature. After stirring overnight, the reaction mixture was basified by 200 mL of 10% potassium carbonate water solution. 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 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, mp: 238-239° C.


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


To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of 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 while allowing it to warm to room 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), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.


EXAMPLE A-224



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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 as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4 hours. After cooling, the precipitate was collected 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: 239-241° C. Anal. Calc'd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.


EXAMPLE A-225



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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 as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous 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 afford 0.4 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88-89° C. Anal. Calc'd for C16H13FN4O+0.4 H2O: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.


EXAMPLE A-226



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4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid

To a solution of 4-[3-(4-fluorophenyl)-!H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 9, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude was, purified by treating with ether to give 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). Anal Calc'd for C15H10FN3O+0.2 H2O: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14,58.


Additional compounds of the present invention which were prepared according to one or more of above reaction schemes (particularly Schemes IX through XVIII) are disclosed in Table 3. The specific synthesis scheme or schemes as well as the mass spectroscopy and elemental analysis results for each compound also are disclosed in Table 3.

TABLE 3MicroanalysisGeneralMSwaterEtOAcExampleProcedureM + 1C calcC foundH calcH foundN calcN foundaddedaddedA-227IX24069694.34.617.216.80.25A-228IX26665.6965.694.414.3315.3214.98A-229XI25470.670.64.84.516.516.30.1A-230IX25665.7665.483.943.7816.4316.52A-231XI28064.1863.954.394.3113.8613.90A-232XI27166.7966.794.484.2415.5815.32A-233XI28466.966.85514.614.90.2A-234XI27065.965.64.64.615.415.40.2A-235XI2647776.76.56.515.815.70.1A-236IX22175.3875.445.065.118.84190.1A-237IX29061.5261.673.583.5114.3514.32A-238XI30463.3663.283.993.9113.8513.83A-239IX25865.3765.393.533.5216.3316.31A-240IX27461.4461.143.313.0115.3514.95A-241IX30056.0255.993.363.2614.0014.01A-242XI27266.4266.414.094.0415.4915.32A-243XI31457.3457.223.853.6813.3713.27A-244IX34276.3976.164.814.5112.3112.050.25A-245XII34164.8964.656.366.1715.9315.820.6A-246XII39166.0866.185.045.5614.0112.260.5A-247XII36264.4664.164.654.3418.7918.650.6A-249XII25864.9164.843.583.6316.2215.980.1A-250IX34848.4448.072.92.8212.112.01A-251XI36249.8849.893.353.5111.6311.54A-252XI30463.3663.343.993.9613.8513.81A-253XII37768.2468.1754.7114.4714.340.6A-254XII36366.3166.124.774.3114.7314.61A-215XIV26567.367.43.53.420.920.70.2A-255XII29864.6364.645.425.4123.5523.32A-256XI27266.4266.584.094.2615.4914.78A-257IX27660.1160.43.063.1815.0214.730.25A-258IX254A-259XI26871.8971.635.285.2415.7215.84A-260X29062.2862.413.483.4814.5314.51A-261X, XV31169.2669.26.26.2517.9517.890.1A-262XI37672.7172.55.174.9811.0610.990.25A-263XII42870.8170.596.286.4515.8815.080.75A-264XII32663.7963.766.396.0920.6620.450.75A-265IX40066.1866.774.14.2316.7815.831A-266XII36862.3262.386.286.518.1717.561A-267XI30262.6662.854.474.3413.713.530.4A-268XII34962.963.25.24.822.722.50.750.1A-269XI, XV37161.8561.845.715.2414.4214.171A-270XI, XV40470.6670.74.824.6110.310.150.25A-271XI, XV32965.865.35.55.617.116.8A-272XI40669.9570.135.355.2810.149.890.5A-273XI35466.967.26.96.619.118.70.20.1A-274XI, XII,43463.663.16.35.814.41420.2XVA-275XI, XV43370.4470.746.186.312.6412.050.6A-276XI, XII,47665.966.26.16.113.313.60.50.5XVA-277XII33861.1163.026.486.3918.7516.61A-278XI, XV35764.263.86.561514.81A-279XI, XII,46267.467.16.76.213.613.70.60.5XVA-280XII29961.2761.475.375.1117.8617.210.9A-281XII31364.6364.945.555.6317.7317.480.2A-282XII31364.6364.815.555.4317.7317.380.3A-283XI, XII40767.26755.213.613.20.25A-284XI, XV3397070.36.96.916.316.20.25A-285XI, XII,47668.268.55.76.214.713.6XVA-286XVII38259.7759.696.816.5616.616.652.25A-287XVII34056.0756.267.317.117.2117.273.75A-288XVII29369.4269.44.524.619.0519.090.1A-289XI, XII4076867.554.513.813.5A-290XI, XII4076464.55.34.91312.41.4A-291IX29074.774.94.24.214.514.5A-292XVII32661.2261.464.774.5316.816.970.4A-293XVII31355.7555.984.854.0216.2516.371.8A-294XI27873.673.24.44.215.215A-295XI27867.967.74.94.31413.71.3A-296IX70.370.44.54.725.225.4A-297IX57.957.73.12.914.514.5


EXAMPLE A-227



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4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-228



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4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-229



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



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EXAMPLE A-230



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4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-231
4-[3-(1,3-benzodioxol-5-y)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-232
4-[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-233



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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



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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



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2-methyl-4-[1-methyl-3 (or 5)-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-236



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4-(3-phenyl-1H-pyrazol-4-yl)pyridine
EXAMPLE A-237



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4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine
EXAMPLE A-238



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4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine
EXAMPLE A-239



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4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-240



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4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl)-2-fluoropyridine
EXAMPLE A-241



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4-[3-(4-bromophenyl)-1H-pyrazol-4yl]pyridine
EXAMPLE A-242



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4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-243



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4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-244



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(E)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-phenylethenyl)pyridine
EXAMPLE A-245



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(S)-4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(2-methylbutyl)-2-pyridinamine
EXAMPLE A-246



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4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyridinamine
EXAMPLE A-247



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N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine
EXAMPLE A-248



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N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine

Anal Calc'd: C, 41.12; H, 3.58; N, 9.22. Found: C, 41.74; H, 5.05; N, 11.11.


EXAMPLE A-249



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2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-250



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4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-251



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4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-252



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4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine
EXAMPLE A-253



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N-[1-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine
EXAMPLE A-254



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N-[(3-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine
EXAMPLE A-255



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4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine
EXAMPLE A-256



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2-fluoro-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-257



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4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine
EXAMPLE A-258



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4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine
EXAMPLE A-259



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4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methylpyridine
EXAMPLE A-260



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4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-fluoropyridine
EXAMPLE A-261



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3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine
EXAMPLE A-262



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2-[2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine
EXAMPLE A-263



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4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine
EXAMPLE A-264



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N′-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N,N-dimethyl-1,2-ethanediamine
EXAMPLE A-265



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2,4-bis[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-266



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N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine
EXAMPLE A-267



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3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanol
EXAMPLE A-268



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4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(2-(1H-imidazol-1-yl)ethyl]-2-pyridinamine
EXAMPLE A-269



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4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine
EXAMPLE A-270



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(E)-3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethenyl]-4-pyridinyl]-1H-pyrazole-1-ethanol
EXAMPLE A-271



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3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-1H-pyrazole-1-ethanamine
EXAMPLE A-272



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3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-1H-pyrazole-1-ethanol
EXAMPLE A-273



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4-[1-[(2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine
EXAMPLE A-274



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4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine
EXAMPLE A-275



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3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-N,N-dimethyl-1H-pyrazole-1-ethanamine
EXAMPLE A-276



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N-[(4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-1-[[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine
EXAMPLE A-277



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4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-4-piperadinyl-2-pyridinamine
EXAMPLE A-278



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N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine
EXAMPLE A-279



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4-[1-[2-(diethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine
EXAMPLE A-280
2-[[4-[3-(4-(fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethanol
EXAMPLE A-281



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2-[[4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethanol
EXAMPLE A-282



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3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol
EXAMPLE A-283



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3 (or 5)-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol
EXAMPLE A-284



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N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine
EXAMPLE A-285



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N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine
EXAMPLE A-286



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N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholinepropanamine
EXAMPLE A-287



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N′-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-1,3-propanediamine
EXAMPLE A-288



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5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine
EXAMPLE A-289



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3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol
EXAMPLE A-290



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5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol
EXAMPLE A-291



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4-[3-[(4-fluorophenyl)-1H-pyrazol-4-yl]quinoline
EXAMPLE A-292



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N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine methyl ester
EXAMPLE A-293



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N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine
EXAMPLE A-294



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4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-295



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4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-296



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4,4′-(1H-pyrazole-3,4-diyl)bis[pyridine]
EXAMPLE A-297



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4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine
EXAMPLE A-298



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

The pyrimidine-substituted compounds of Examples A-299 through A-312 were synthesized in accordance with the chemistry described in Schemes I-XVIII by selection of the corresponding starting reagents:


EXAMPLE A-299



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

Step 1:
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A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g, 0.031 mol), triethylamine (6.23 g, 0.062 mol) and catalytic amount of 5% Pd/C in 100 mL of THF was hydrogenated on a Parr apparatus under 40 psi at room temperature. After 0.5 hour, the catalyst was filtered and the filtrate was concentrated. The crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 2.36 g of product as a pale yellow crystal (50% yield); mp: 47-49° C.


Step 2: Preparation of 2-(2-chloro-4-pyrimidinyl)-1-(4-fluorophenyl)ethanone
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2-(2-chloro-4-pyrimidinyl)-1-(4-fluorophenyl)ethanone

To a solution of lithium diisopropylamide (generated from BuLi (0.045 mol) and diisopropylamine (0.048 mol) in THF) at −78° C. was added a solution of the compound prepared in step 1 (5.5 g, 0.037 mol) in THF slowly over 30 minutes. After 1 hour, a solution of ethyl 4-fluorobenzoate (7.62 g, 0,045 mol) in THF was added and the reaction mixture was stirred overnight and allowed to warm up to room temperature. Water was added and the aqueous phase was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 4.78 g of a yellow solid (51% yield), mp: 112-113° C.


Step 3: Preparation of (E)-2-(2-chloro-4-pyrimidinyl)-3-(dimethylamino)-1-(4-fluorophenyl)-2-propen-1-one
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(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 room temperature overnight. Excess dimethylformamide dimethyl acetal was removed under vacuum to give 4.5 g of crude product as a thick brown oil, which was used without further purification.


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 room temperature for 6 hours. The 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.; Anal. Calc'd for C13H8ClFN4: 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



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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 reaction mixture was cooled, 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 product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone, as a pale yellow solid (38% yield), mp: 149-150° C.; Anal. Calc'd for C13H11FN6: C, 57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N, 30.73.


EXAMPLE A-301



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

Step 1: Preparation of
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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. overnight. After the solvent was removed under vacuum, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by recrystallization from ethyl acetate and hexane to give 1.23 g of a yellow solid product (32% yield), mp: 76-77° C.; Anal. Calc'd for C10H16N4: C, 62.47; H, 8.39; N, 29.14. Found: C, 62.19; H, 8.58; N, 29.02.


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 the present Example (1.2 g, 0.0064 mol) and triethylamine (0.65 g, 0.0064 mol) in 10 mL of toluene was added 4-fluorobenzoyl chloride dropwise. The mixture was 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 (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 heated at reflux for 2 hours. After ethanol was removed, 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 was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.6 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine, as a yellow solid (33% yield), mp: 155-156° C.; Anal. Calc'd for C15H14FN5: C, 63.59; H, 4.98; N, 24.72. Found: C, 63.32; H, 4.92; N, 24.31.


EXAMPLE A-302



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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 in accordance with Example A-299 (0.3 g, 0.0011 mol) in 10 mL of methylamine (40% water solution) was heated in a sealed tube at 100° C. overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried to give 0.2 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine, as a white solid (68% yield), mp: 217-218° C.; Anal Calc'd for C14H12FN5: C, 62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N, 25.90.


EXAMPLE A-303



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

This compound was synthesize by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217° C.; Anal. Calc'd for C20H16FN5: C, 69.55; H, 4.67; N, 20.28. Found: C, 69.73; H, 4.69; N, 19.90.


EXAMPLE A-304



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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 in accordance with Example A-299 with 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.; Anal. Calc'd for C16H14FN5: C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23.58.


EXAMPLE A-305



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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 in accordance with 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 a off-white solid in 80% yield, mp: 183-185° C.; Anal. Calc'd for C21H18FN5O: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.


EXAMPLE A-306



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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 in accordance with Example A-305 (0.35 g, 0.00093 mol) in 15 mL of trifluoroacetic acid was heated at reflux for 16 hours. Solvent was removed and the residue was partitioned between ethyl acetate and 1 N ammonia hydroxide. Organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.14 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, as a pale yellow solid (59% yield), mp: 273-274° C.; Anal. Calc'd for C13H10FN5.0.25H2O: C, 60.11; H, 4.07; N, 26.96. Found: C, 60.15; H, 3.82; N, 26.38.


EXAMPLE A-307



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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 in accordance with 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 was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, 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.; Anal. Calc'd for C22H18FN5: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.


EXAMPLE A-308



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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 in accordance with Example A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine was added ethyl chloroformate dropwise. After the addition, the clear solution was stirred at room temperature for 6 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was trituated with ether to give 0.15 g of product, ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163-165° C.; Anal. Calc'd for C16H14FN5O2: C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.


EXAMPLE A-309



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

This compound was prepared by the same procedure as described for Example A-208 except that 1-methyl-3-(4′-pyrimidinylacetyl)benzene (prepared as set forth in Step 1 of Example A-19 from 4-methyl-pyrimidine and methyl 3-methylbenzoate) was used in place of 4-fluorobenzoyl-4-pyridinyl methane.


Anal. Calc'd for C14H12N4 (236.27): C, 71.17; H, 5.12; N, 23.71. Found C, 70.67; H, 5.26; N, 23.53. m.p. (DSC); 151.67° C.


EXAMPLE A-310



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

This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.


Anal. Calc'd for C13H9N4Cl.25MH2O: C, 59.78; H, 3.67; N, 21.45. Found: C, 59.89; H, 3.32; N, 21.56. m.p. (DSC): 218.17° C.


EXAMPLE A-311



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

This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.


Anal. Calc'd for C13H9N4F (240.24): C, 64.99; H, 3.78; N, 23.22. Found: C, 64.78; H, 3.75; N, 23.31. m.p. (DSC): 168.58° C.


EXAMPLE A-312



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

This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.


Anal. Calc'd for C13H9N4F (240.24): C, 64.99; H, 3.78; N, 23.32. Found: C, 64.94; H, 3.56; N, 23.44. m.p. (DSC): 191.47° C.


EXAMPLE A-313

The compound 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine was prepared in accordance with general synthetic Scheme VII:
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Step 1: Preparation of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate
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A mixture of 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl)pyridine (5.8 g, 24.0909 mmol; prepared as set forth in Example A-4) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 mL) and tert-butanol (10 mL) was heated to reflux at 95 to 100° C. for 6 hours (or until all the potassium permanganate was consumed) and stirred at room temperature overnight. The mixture was diluted with water (150 mL) and filtered to remove manganese dioxide. The aqueous filtrate (pH >10) was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HCl to a pH of about 6.5. A white precipitate was formed. This precipitate was collected by filtration, dried in air, and then dried in a vacuum oven overnight at 50° C. to give 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate (2.7677 g, 40.6%). The remaining product (0.21 g, 3.1%) was isolated from the mother liquid by reverse phase chromotograhpy. The total isolated yield of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate was 43.7%. Anal. Calc'd for C15H10N3FO2.H2O: C, 59.80; H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS (MH+): 284 (base peak).


Step 2: Preparation of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate
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In a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate (0.9905 g, 3.5 mmol) from step 1 and 1-hydroxybenzotriazole hydrate (0.4824 g, 3.57 mmol) in dimethylformamide (20 mL) at 0° C. under N2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6983 g, 3.57 mmol) was added. The solution was stirred at 0° C. under N2 for 1 hour, then was added 1-tert.-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) followed by N-methyl morpholine (0.40 mL, 3.6 mmol). The reaction was stirred from 0° C. to room temperature overnight. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution, extracted. The organic layer was washed with water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure, and crude product was obtained (1.7595 g). The desired product 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (1.2375 g, 78.4%) was isolated by chromatography (silica gel, 10:90 isopropyl alcohol/toluene). Anal. Calc'd for C24H26N5FO3: C, 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MH+): 452 (base peak).


Step 3: Preparation of 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine


To a suspension of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (0.451 g, 1.0 mL) in dry tetrahydrofuran (8 mL), 1.0N LiAlH4 in tetrahydrofuran (2.5 mL, 2.5 mmol) was added dropwise at such a rate as to maintain reflux over 15 minutes. Upon the addition, the suspension became a clear light yellow solution, which was kept boiling for an additional 1.5 hours. Excess LiAlH4 was decomposed by cautious addition of a solution of KOH (0.5611 g, 10.0 mmol) in water (3.5 mL). Upon hydrolysis, a white salt precipitated. After the addition was completed, the mixture was heated to reflux for 1 hour. The hot solution was filtered by suction through a buchner funnel. Any remaining product was extracted from the precipitate by refluxing with tetrahydrofuran (10 mL) for 1 hour, followed again by suction filtration. The combined filtrates were concentrated under reduced pressure to give a crude residue, which was then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure, and a crude product was obtained. The desired product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine (0.1509 g, 50.1%) was obtained by chromatography (silica gel, 70:30:1 methanol/ethyl acetate/NH4OH). Anal. Calc'd for C20H22N5F.0.6H2O: C, 66.32; H, 6.46; N, 19.33; Found: C, 66.31; H, 5.96; N, 18.83. MS (MH+): 352 (base peak).


EXAMPLE A-314

The compound 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperazine was prepared in accordance with general synthetic Scheme VII:
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Step 1: Preparation of 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monhydrate
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A solution of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (0.6349 g; 1,4077 mmol; prepared as set forth in step 2 of Example A-313) in methylene chloride (3.5 mL) and TFA (1.1 mL, 14.077 mmol) was stirred at room temperature under N2 for 2 hours. The solvents were removed under reduced pressure, and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was triturated with methanol. The resulting solid was collected by filtration and dried in a vacuum oven overnight to give the desired product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate (0.7860 g, 96.4%). Anal. Calc'd for C19H18N5OF.2TFA.H2O: C, 46.24; H, 3.71; N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH+): 352 (base peak).


Step 2: Preparation of 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperazine


By following the method of Example A-313, step 3 and substituting of 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate (prepared in step 1 of this Example) for 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate, the title product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperazine was obtained. Anal. Calc'd for C19H20N5F.0.75H2O: C, 65.03, H, 6.18, N, 19.96. Found: C, 65.47, H, 5.83, N, 19.35. MS (MH+): 338 (base peak).


EXAMPLE A-315

The compound 4-[3-(4-fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine was prepared in accordance with general synthetic Scheme XX:
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Step 1: Preparation of ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate
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Ethyl 4-pyridyl acetate was converted to 2-(4-piperidinyl)ethyl acetate hydrochloride by hydrogenation (60 psi H2) catalyzed by 5% Pt/C at 40° C. in ethanol and HCl solution. To a solution of 2-(4-piperidinyl)ethyl acetate hydrochloride (21.79 g, 0.105 mol) in tetrahydrofuran (500 mL) at 0° C., triethylamine (32.06 mL, 0.230 mL) was added followed by di-tert-butyldicarbonate (23.21 g, 0.105 mol). The reaction mixture was stirred under N2 from 0° C. to room temperature overnight. After removing tetrahydrofuran, the reaction mixture was diluted with ethanol, washed with saturated NaHCO3, 10% citric acid, water and brine, and dried over MgSO4. After filtration, the solvent was removed under reduced pressure. The resulting oily product was dried under vacuum to give ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate (27.37 g, 95.9%). The structure of this product was confirmed by NMR.


Step 2: Preparation of 1,1-dimethylethyl 4-[2-oxo-3-(4-pyridinyl)propyl]-1-piperidinecarboxylate
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To a solution of diisopropylamide (6.15 mL, 43.91 mmol) in dry tetrahydrofuran (40 mL) at 0° C. was added 2.5 M butyl lithium solution in hexane (16.22 mL, 40.53 mmol) dropwise over 10 minutes. After the addition, the lithium diisopropylamide solution was stirred at 0° C. for 20 minutes, then cooled to −78° C. 4-Picoline (3.98 mL, 40.53 mmol) was added to the above lithium diisopropylamide solution under N2 dropwise over 10 minutes. The resulting solution was stirred at −78° C. under N2 for 1.5 hours, then transfered into a suspension of anhydrous cerium chloride (10.0 g, 40.53 mmol) in tetrahydrofuran (40 mL) at −78° C. under N2. The mixture was stirred at −78° C. under N2 for 2 hours, then a solution of ethyl 1-[(1,1-dimethylethoxy)carbonyl]-4-piperidineacetate (from step 1 of this Example) (10.98 g, 40.53 mmol) in tetrahydrofuran (40 mL) was added slowly for 1 hour. The mixture was stirred under N2 from −78° C. to room temperature overnight. The reaction was quenched with water, diluted with ethyl acetate, and washed with a pH 7 buffer. The organic layer was washed with water and brine. After filtration, the solvent was removed under reduced pressure to give a crude product mixture. The desired product 1,1-dimethylethyl 4-[2-oxo-3-(4-pyridinyl)propyl]-1-piperidinecarboxylate (3.19 g, 25%) was isolated by chromatography (silica gel, 50:50-75:25-100:0 ethyl acetate/hexane).


Step 3: Preparation of 1.1-dimethylethyl 4-[4-(4-fluorophenyl)-2-oxo-3-(4-pyridinyl)-3-butenyl]-1-piperidinecarboxylate
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1,1-Dimethylethyl 4-[4-(4-fluorophenyl)-2-oxo-3-(4-pyridinyl)-3-butenyl]-1-piperidinecarboxylate was prepared by the same method as described for step 1 of Example A-1 by replacing 4-pyridylacetone and 3-fluoro-p-anisaldehyde with the ketone of step 2 of the present Example and 4-fluorobenzaldehyde, respectively.


Step 4: Preparation of 1,1-dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate
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1,1-Dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate was prepared by the same method as described for step 3 of Example A-2 by replacing 4-phenyl-3-(4-pyridyl)-3-butene-2-one with the α,β unsaturated ketone of step 3 of the present Example.


Step 5: Preparation of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate
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To a solution of 1,1-dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate prepared in step 4 of this Example (3.45 g, 7.8409 mmol) in ethanol (15 mL), anhydrous hydrazine (0.50 mL, 15.6818 mmol) was added. The reaction was heated to reflux overnight. The reaction solution was cooled to room temperature and ethanol was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, and dried over MgSO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by chromatography (silica gel, 2:1-1:1-1:2 hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4,5-dihydro-4-hydroxy-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (1.9187 g, 53.9%). This intermediate (1.8611 g, 4.0993 mmol) was dissolved in dry methylene chloride (40 mL) and treated with Martin sulfurane dehydrating reagent (4.13 g, 6.1490 mmol). The reaction solution was stirred at room temperature under N2 overnight, then diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over MgSO4. After filtration the solvents were removed. The resulting crude pruduct mixture was purified by flash chromatoghaphy (silica gel, 2:1-1:1-1:2 Hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (0.6964 g, 39%).


Step 6: Preparation of 4-[3-(4-fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine


4-[3-(4-Fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine was prepared using the same method as described for Example A-314, step 1 by replacing 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate with the pyrazole of step 5 of the present Example. Anal. Calc'd for C20H21N4F.2TFA.1.25H2O: C, 49.11; H, 4.38; N, 9.54; Found: C, 48.74; H, 4.02; N, 9.57. MS (MH+): 337 (base peak).


EXAMPLE A-316



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4-[3-(4-fluorophenyl)-5-[(1-methyl-4-piperidinyl)methyl]-1H-pyrazol-4-yl]pyridine was prepared by the same method as described for step 3 of Example A-313 by replacing 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate with the pyrazole of step 5 of the present Example. Anal. Calc'd for C21H23N4F.0.2H2O: C, 71.24; H, 6.66; N, 15.82; Found: C, 71.04; H, 6.54; N, 15.56. MS (MH+): 351 (base peak).


EXAMPLE A-317

The compound 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, dihydrate was prepared in accordance with general synthetic Scheme II:
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2-(4-Pyridyl)-1-(4-fluorophenyl)ethanone hydrochloride (5.9 g, 0.023 moles) was dissolved in a methylene chloride/methanol solution (70/15) at room temperature and N-chlorosuccinimide (3.25 g, 0.024 moles) was added as a solid. The mixture was stirred at room temperature for 2.5 hours.


N-methylpiperazinylthiosemicarbazide (4.1 g, 0.023 moles) was added as a solid and the mixture was stirred for 3 days at room temperature. The mixture was diluted with 100 mL of methylene chloride and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and solvent removed using a rotary evaporator. The residue was treated with ethyl acetate with stirring while cooling in an ice bath. The solid formed was filtered and recrystallized from ethyl acetate with a small amount of methanol to give 1.7 g (22%) of 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, dihydrate. Anal. Calc'd. for C19H20FN5.2H2O: C, 61.11; H, 6.48; N, 18.75. Found: C, 60.59; H, 6.41; N, 18.44. M.p. (DSC) 262-264° C.; MH+=338.


EXAMPLE A-318

The compound 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-(2-propynyl)-1H-pyrazol-3-yl]piperazine, trihydrochloride monohydrate was prepared in accordance with general synthetic Scheme VII:
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To a mixture of sodium hydride (30 mg, 1.5 mmol) in dimethylformamide (25 mL) stirred under a nitrogen atmosphere at room temperature was added 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-N-tert.-butoxycarbonylpiperazinyl)pyrazole (500 mg, 1.1 mmol; prepared as set forth in Example A-169). After stirring for 1 hour, propargyl bromide (225 mg, 1.5 mmol, 80% solution in toluene) was added. After stirring for an additional 2 hour at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using 70% ethyl acetate/hexane as the eluent to give 110 mg of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-N-tert.-butoxycarbonyl-piperazinyl)pyrazole (24%), m. p. 204-205° C. Anal. Calc'd. for C26H28ClN5O2: C, 65.33; H, 5.90; N, 14.65. Found: C, 65.12; H, 5.81; N, 14.70.


A solution of HCl in methanol (5 mL) was generated by addition of acetyl chloride (200 mg) to methanol while cooling (5° C.). 3-(4-Chlorophenyl)-4-(4-pyridyl)-5-(4-N-tert. -butoxycarbonylpiperazinyl)pyrazole (100 mg, 0.2 mmol) prepared above was added and the reaction stirred in the cold for one hour. The reaction mixture was concentrated in vacuo and the residue azeotroped with toluene to give 100 mg of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1-(2-propynyl)-1H-pyrazol-3-yl]piperazine, trihydrochloride monohydrate (90%), m.p.=231-233° C. (dec.). Anal. Calc'd. for C21H20N5Cl.3HCl.H2O: C, 49.92; H, 4.99; N, 13.86. Found: C, 49.71; H, 4.89; N, 13.61.


EXAMPLE A-319

The compound methyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate, monohydrate was prepared in accordance with general synthetic Scheme II:
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Methyl chloroformate (55 mg) was added to a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (200 mg, 0.54 mmol; prepared as set forth in Example A-169) and 4-dimethylaminopyridine (5 mg) in pyridine (10 mL). The mixture was stirred at room temperature for 3 hours. Additional methyl chloroformate (30 mg) was added and stirring was continued for 24 hours. The solvent was removed in vacuo. The residue was treated with water and extracted with ethyl acetate. After drying the organic layer (MgSO4), the solvent was blown down to a volume of 10 mL and refrigerated. The resultant crystalline solid was filtered and air dried to give 103 mg (48%) of methyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate, monohydrate, mp 264-265° C. Anal. Calc'd. for C20H20ClN5O2.H2O: C, 57.76; H, 5.33; N, 16.84. Found: C, 57.98; H, 4.89; N, 16.44.


EXAMPLE A-320

The compound 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(methylsulfonyl)piperazine, monohydrate was prepared in accordance with general synthetic Scheme II:
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A solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (200 mg; 0.54 mmol; prepared as set forth in Example A-169), methanesulfonyl chloride (75 mg) and 4-dimethylaminopyridine (5 mg) in pyridine was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was treated with water. The resultant crystalline solid was filtered, air dried and recrystallized from methanol and water to give 118 mg (37%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(methylsulfonyl)piperazine, monohydrate, m.p. 245-248° C. Anal. Calc'd. for C19H20ClN5SO2.H2O: C, 52.35; H, 5.09; N, 16.07. Found: C, 52.18; H, 5.31; N, 16.00.


EXAMPLE A-321

The compounds 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate, and 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, monosodium salt dihydrate, were prepared in accordance with general synthetic Scheme II:
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A solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperzinyl)pyrazole (200 mg; 0.54 mmol; prepared as set forth in Example A-169), succinic anhydride (60 mg, 0.55 mmol) and 4-dimethylaminopyridine (5 mg) was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue treated with methanol and water (1:1). The resultant crystalline solid was filtered and air dried to give 170 mg (58%) of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate, m. p. 281-283° C. (dec.). Anal. Calc'd. for C22H22ClN5O3.2H2O: C, 55.52; H, 5.51; N, 14.72. Found: C, 55.11; H, 5.20; N, 14.44.


A slurry of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, dihydrate (150 mg, 0.31 mmol) from above in methanol (10 mL) was treated with a solution of sodium hydroxide (12 mg, 0.31 mmol) in methanol (2 mL). The reaction was stirred at room temperature for 15 minutes until dissolution was completed. The solvent was removed in vacuo. The residue was treated with tetrahydrofuran and filtered and air dried to give 150 mg (97%) of 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-γ-oxo-1-piperazinebutanoic acid, monosodium salt dihydrate as a solid. Anal. Calc'd. for C22H21ClN5O3Na.2H2O: C, 53.07; H, 5.06; N, 14.07. Found: C, 52.81; H, 5.11; N, 13.90.


EXAMPLE A-322

The compound 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine was prepared in accordance with general synthetic Scheme II:
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To a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (1.95 g; 5.8 mmoles; prepared as set forth in Example A-169) and acetic acid (3.6 g, 60 mmol) containing 5A molecular sieves (6 g) was added [(1-ethoxycyclopropyl)oxy]trimethylsilane (6 g, 35 mmol). After stirring for 5 minutes, sodium cyanoborohydride (1.7 g, 26 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 6 hours. The reaction mixture was filtered hot and the filtrate concentrated in vacuo. Water (50 mL) was added and the solution made basic with 2N sodium hydroxide. The resultant gel was extracted with dichloroethane and the combined organic extracts dried (MgSO4). Evaporation again yielded a gel which was treated with hot methanol. Upon cooling, the product crystallized to give 1.4 g (63%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine, m. p. 264-265° C. Anal. Calc'd. for C21H22ClN5.1.5H2O: C, 61.99; H, 6.19; N, 17.21. Found: C, 62.05; H, 5.81; N, 16.81.


EXAMPLE A-323

The compound 4-[3-(4-fluorophenyl)-5-(1H-imidazol-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]pyridine was prepared in accordance with general synthetic Scheme V:
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To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 mL of dimethylformamide was added methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room temperature. The mixture was stirred at room temperature for 0.5 hour. Then 2-(trimethylsilyl)ethoxymethyl chloride (4.17 g, 0.025 mol) was added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours and quenched by cautiously adding 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 chromatography on silica gel using ethyl acetate/hexane (8:2) as the eluent to give 4.0 g of the major regioisomer as a clear oil.


To a solution of 4-fluorobenzoyl-4′-pyridyl methane (8.6 g, 0.04 mol, prepared as set forth in Step 1 of Example A-208) in 150 mL of ethanol was added p-methoxyphenylhydrazine hydrochloride (7.34 g, 0.042 mol), followed by triethylamine (4.05 g, 0.04 mol). The reaction mixture was refluxed for 16 hours. After the removal of solvent, the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the crude residue was purified by recrystallization from ethyl acetate and hexane to give 8.45 g of the product hydrazone as a yellow solid. To a solution of sodium hexamethyldisilazide (9 mL of 1.0 M tetrahydrofuran solution, 0.009 mol) was added a solution of this hydrazone (1.35 g, 0.004 mol) in 10 mL of dry tetrahydrofuran at 0° C. After stirring for 30 minutes at this temperature, a solution of the regioisomer prepared above (1.1 g, 0.0042 mol) in 5 mL of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred for 3 hours at room temperature. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by chromatography on silica gel using ethyl acetate as the eluent to give 0.74 g of the desired product as an orange solid (34%). Deprotection of the above solid by using tetrabutylammonium fluoride afforded 0.37 g of 4-[3-(4-fluorophenyl)-5-(1H-imidazol-4-yl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]pyridine as a yellow solid (75%), mp: 124-126° C. Anal. Calc'd. for C24H18FN5O.0.5H2O: C, 68.56; H, 4.55; N, 16.66. Found: C, 68.44; H, 4.39; N, 16.00.


EXAMPLE A-324

The compound 4-[3-(4-fluorophenyl)-1H-pyazol-4-yl]-N-2-propynyl-2-pyrimidinamine was prepared in accordance with general synthetic Scheme XII:
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A mixture of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine (0.28 g; 0.001 mol; prepared as set forth in Example A-299) and 10 mL propargylamine was heated at reflux for 16 hour. Excess amine was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by chromatography on silica gel using ethyl acetate/hexane (1:1) as the eluent to give 0.21 g of 4-[3-(4-fluorophenyl)-1H-pyazol-4-yl]-N-2-propynyl-2-pyrimidinamine as a pale yellow solid (68% yield), mp: 186-187° C. Anal. Calc'd. for C16H12FN5: C, 65.52; H, 4.12; N, 23.88. Found: C, 64.99; H, 4.15; N, 23.91.


EXAMPLE A-325

The compound N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine was prepared in accordance with general synthetic Scheme XII:
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A mixture of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine (0.37 g; 0.0013 mol; prepared as set forth in Example A-299), 7 mL of 2-fluoroaniline and 2 drops of methanol was heated at 180° C. in a sealed tube for 16 hours. Excess amine was removed by vacuum distillation and the residue was treated with ethyl acetate to give 0.35 g of N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine as a yellow solid (77%), mp: 239-240° C. Anal. Calc'd. for C19H13F2N5: C, 65.33; H, 3.75; N, 20.05. Found: C, 64.95; H, 3.80; N, 19.77.


EXAMPLE A-326

The compound 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(2-methoxyphenyl)-2-pyrimidinamine was prepared in accordance with general synthetic Scheme XII:
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4-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-N-(2-methoxyphenyl)-2-pyrimidinamine was synthesized in 41% yield using the same method described for the preparation of N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine in Example A-325 using 2-methoxyaniline in place of 2-fluoroaniline; mp: 265° C. (dec.). Anal. Calc'd. for C20H16FN5O: C, 66.47; H, 4.46; N, 19.38. Found: C, 66.70; H, 4.53; N, 19.20.


EXAMPLE A-327

The compound 1-[5-(3-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine was prepared in accordance with general synthetic Scheme II:
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1-[5-(3-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine was synthesized in 12% yield as a pale yellow solid using the same method described for the preparation of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine in Example A-170 using 2-(4-pyridyl)-1-(3-chlorophenyl)ethanone in place of 2-(4-pyridyl)-1-(4-chlorophenyl)ethanone; mp: 229-231° C. Anal. Calc'd. for C19H20ClN5.0.4H2O: C, 63.21; H, 5.81; N, 19.40. Found: C, 62.85; H, 5.57; N, 19.77.


Additional aminopyrazole compounds that were synthesized in accordance with the chemistry described in Scheme II by selection of the corresponding starting reagents include the compounds disclosed in Table 3-1 below.

TABLE 3-1TheoreticalFoundEXAMPLEFORMULAMWCHNCHNDSC (mp)A-328C18H18ClN5.1/8H2O342.0863.205.3020.4763.045.3620.33199° C.A-329C23H33ClN6O2533.0865.346.2415.7764.986.1115.58(168-171° C.)A-330C23H25ClN5O2457.9460.335.5015.2959.975.5215.17(253-255° C.)A-331C22H24ClN5O2425.9262.045.6816.4461.645.9416.29(273-275° C.)A-332C19H23Cl4N5.H2O481.2647.424.8214.3547.665.1113.74(217-219° C.)A-333C21H20ClN5.2.5H2O422.9259.644.7716.5659.674.8815.96(247° C.) (d)A-334C20H22ClN5.1/4H2O372.3964.515.9618.8164.795.9718.95242° C.A-335C24H22ClN5.3/4H2O429.4467.135.1616.3167.045.3116.32230° C.A-336C25H24ClN5O.1/4H2O450.4666.665.3715.5566.645.1115.69(270-271° C.)A-337C22H24FN5O2.H2O427.4861.815.6616.3861.885.9616.41249° C.A-338C20H22FN5.1/2H2O360.4466.656.1519.4366.746.5919.37241° C.A-339C19H20FN5.3HCl.1/2H2O455.7950.075.0915.3049.875.4715.30(237-239° C.)


EXAMPLE A-328



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1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine
EXAMPLE A-329



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1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-[(phenylmethyl)amino]-4-pyridinyl-1H-pyrazol-3-yl]amino]propyl]carbamate
EXAMPLE A-330



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


EXAMPLE A-331



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ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate
EXAMPLE A-332



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-3H-pyrazol-3-yl]-4-piperidineamine, trihydrochloride, monohydrate
EXAMPLE A-333



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The compound 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-propynyl)piperazine was prepared in accordance with general synthetic Scheme II. To a suspension of of 1-[5-(4-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine (92 mg, 0.27 mmole) in 2 mL of dimethylformamide was added 75 mg (0.54 mmole) of anhydrous potassium carbonate and then 60 microliters of 80% propargyl bromide solution in toluene (containing 64 mg, 0.54 mmole). The resulting mixture was stirred for 30 minutes and then partitioned betwen ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate, and the combined organic extracts filtered through silica gel using 10% methanol-ethyl acetate as eluent to give, after evaporation of the appropriate fractions, 34 mg of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-propynyl)piperazine as a pale yellowish solid, m.p. 247° C. (decomp.). Anal. Calc'd. for C21H20ClN5.2.5H2O (MW 422.92): C, 59.64, H, 4.77, N, 16.56. Found: C, 59.67, H, 4.88, N, 15.96.


EXAMPLE A-334



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine
EXAMPLE A-335



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1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-phenylpiperazine
EXAMPLE A-336



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1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(2-methoxyphenyl)piperazine
EXAMPLE A-337



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Ethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate, monohydrate
EXAMPLE A-338



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N-[5-(4-fluorophenyl)-4-(pyridinyl)-1H-pyrazol-3-yl]-1-methyl-4-piperidinamine
EXAMPLE A-339



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N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine, trihydrochloride
EXAMPLE A-340

The compound of Example A-170 was also synthesized in the following manner. 1-[5-(4-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine (12.2 g, 36 mmol, prepared as set forth in Example A-169), 88% formic acid (20 mL), and formaldehyde (37% formalin solution; 44 g, 540 mmol) were combined and stirred at 60° C. for 16 hours under a nitrogen atmosphere. Excess solvent was removed on the rotary evaporator and the residue was dissolved in water (150 mL). The pH was adjusted to 8-9 by addition of solid sodium bicarbonate. The resulting precipitate was filtered and air dried. It was then treated with hot methanol (400 mL), filtered and blown down to a volume of 75 mL, cooled and filtered. After drying in a vacuum oven at 80° C. overnight, there was obtained 8.75 g (68%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, m. p. 262-264° C. Anal. Calc'd. for C19H20N5Cl: C, 64.49; H, 5.70; N, 19.79. Found: C, 64.04; H, 5.68; N, 19.63.


The compounds of Examples A-341 through A-345 were synthesized, for example, in accordance with the chemistry described in Scheme XXI by selection of the corresponding starting reagents.


EXAMPLE A-341

The compound of Example A-170 was also synthesized in the following manner:


Step 1: Preparation of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone


To a solution of 2-(4-pyridyl)-1-(4-chlorophenyl)ethanone (70.0 g, 0.3 mol) prepared in a similar manner as the compound of Step 1 of Example A-19, dibromomethane (200 mL) and carbon disulfide (25.9 g, 0.34 mol) in acetone (800 mL) was added potassium carbonate (83.0 g, 0.6 mol). The reaction mixture was stirred at room temperature for 24 hours. An additional two equivalents of potassium carbonate and one equivalent of carbon disulfide was added and the stirring was continued for another 24 hours. Solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was stirred with 1000 mL of a mixture of ethyl acetate and ether (1:9) to give 78.4 g of pure product, 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone, as a yellow solid (82%), mp: 177-179° C. Anal. Calc'd. for C15H10ClNOS2: C, 56.33; H, 3.15; N, 4.38. Found: C, 55.80; H, 2.84; N, 4.59.


Step 2: Preparation of 1-[3-(4-chlorophenyl)-3-oxo-2-(4-pyridinyl)-1-thiopropyl]-4-methylpiperazine
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A mixture of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (78.3 g, 0.24 mol) and 1-methylpiperazine (75.0 g, 0.73 mol) in 800 mL of toluene was heated at reflux for 2 hours. Solvent and excess 1-methylpiperazine was removed under vacuum and the residue was triturated with a mixture was ethyl acetate and ether (1:3) to give 53.0 g of product, 1-[3-(4-chlorophenyl)-3-oxo-2-(4-pyridinyl)-1-thiopropyl]-4-methylpiperazine, as yellow crystals (60%), mp: 149-151° C. Anal. Calc'd. for C19H20ClN3OS: C, 61.03; H, 5.39; N, 11.24. Found: C, 60.74; H, 5.35; N, 11.14.


Step 3: Preparation of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine


To a suspension of 1-[3-(4-chlorophenyl)-3-oxo-2-(4-pyridinyl)-1-thiopropyl]-4-methylpiperazine (52.0 g, 0.14 mol) in 500 mL of dry tetrahydrofuran was added anhydrous hydrazine (8.9 g, 0.28 mol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. The pale yellow precipitate was filtered and recrystallized from hot methanol to give 30.2 g of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine as a white powder (60%), mp: 267-268° C. Anal. Calc'd. for C19H20ClN5: C, 64.49; H, 5.70; N, 19.79. Found: C, 64.89; H, 5.55; N, 19.99.


EXAMPLE A-342



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

A mixture of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (3.2 g, 0.01 mol; prepared as set forth in Step 1 of Example A-341) and 2,6-dimethylpiperazine (3.43 g, 0.03 mol) in 35 mL of toluene was heated at reflux for 12 hours. Toluene and excess 2,6-dimethylpiperazine were then removed under vacuum and the crude thiamide produced was used without purification. A solution of the crude thiamide and anhydrous hydrazine (0.65 g, 0.02 mol) in 40 mL of dry tetrahydrofuran was stirred at room temperature overnight. After the removal of tetrahydrofuran, the residue was stirred with a mixture of ethyl acetate and ammonium hydroxide for one hour. The precipitate was filtered and air dried to give 1.6 g of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3,5-dimethylpiperazine as a white solid (43% overall yield), mp: 236-238° C. Anal. Calc'd. for C20H22ClN5.0.25H2O: C, 64.51; H, 6.09; N, 18.81; Cl, 9.52. Found: C, 64.28; H, 5.85; N, 18.70; Cl, 9.67.


EXAMPLE A-343



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

1-[5-(4-Chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-3-methylpiperazine was prepared according to the same procedure set forth above in Example A-342 except that 2-methylpiperazine was used in place of 2,6-dimethylpiperazine (4% overall yield), mp: 235-237° C. Anal. Calc'd. for C19H20ClN5.0.75H2O: C, 62.12; H, 5.90; N, 19.06. Found: C, 62.23; H, 5.53; N, 18.80.


EXAMPLE A-344

The compound of Example A-317 was also synthesized in the following manner:


Step 1: Preparation of 1-(4-pyridyl)-1-(methylenedithioketene)-2-(4-fluorophenyl)-ethanone


To a solution of 4-fluorobenzoyl-4′-pyridyl methane (70.0 g, 0.3 mol, prepared as set forth in Step 1 of Example A-208) and dibromomethane (125 mL) was added solid anhydrous potassium carbonate (55.0 g, 0.4 mol) portionwise over five minutes. Carbon disulfide (17 g, 0.22 mol) was added dropwise over 15 minutes at room temperature. After stirring for 16 hours under a nitrogen atmosphere, the reaction was incomplete. Additional carbon disulfide (15 g) was added and the reaction mixture was stirred for an additional 24 hours. The reaction mixture was filtered and the potassium carbonate was washed on the filter with methylene chloride. The filtered solid was dissolved in water and extracted with methylene chloride. The extract was combined with the filtrate and dried over magnesium sulfate. The drying agent was filtered and the filtrate concentrated in vacuo. The residue was treated with ethyl acetate/ether (1:1), filtered and air dried to give 1-(4-pyridyl)-1-(methylenedithioketene)-2-(4-fluorophenyl)-ethanone (26 g, 86%) as a solid, m.p. 182-183° C.; Anal. Calc'd. for C15H10FNOS2: C, 59.39; H, 3.32; N, 4.62. Found: C, 59.18; H, 3.41; N, 4.49.


Step 2: Preparation of 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, dihydrate


A mixture of the 1-(4-pyridyl)-1-(methylenedithioketene)-2-(4-fluorophenyl)-ethanone (3 g, 0.01 mol) prepared in Step 1 and 1-methylpiperazine (3 g, 0.03 mol) in 30 mL of toluene was refluxed under a nitrogen atmosphere for three hours. The mixture was cooled and solvent was removed under vacuum. The residue was dissolved in dry tetrahydrofuran (30 mL) and anyhydrous hydrazine (640 mg, 0.02 mol) was added. The reaction mixture was stirred at room temperature for 16 hours and the resulting precipitate was filtered. The precipitate was warmed in methanol and a few drops of concentrated ammonium hydroxide were added. The mixture was filtered hot and the filtrate blown down to half the volume. As the filtrate cooled, a product crystallized and was filtered to give 1.5 g (42%) of 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine, dihydrate, mp: 238-240° C.; Anal. Calc'd. for C19H20FN5.2H2O: C, 61.11; H, 65.48; N, 18.75. Found: C, 60.79; H, 6.21; N, 18.98.


EXAMPLE A-345



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-N,1-dimethyl-4-piperidinamine, dihydrate

Step 1: Preparation of 1-methyl-4-methylaminopiperidine


A mixture of 1-methyl-4-piperidone (20 g, 0.18 mol) in methanol:tetrahydrofuran (100 mL, 1:1) and methyl amine (2 M in tetrahydrofuran, 3 mole excess) was placed in a Parr shaker with 5% Pd/C and hydrogenated for two hours at 60 psi and 70° C. The catalyst was filtered and the filtrate concentrated on the rotary evaporator. The crude material was distilled at 44-45° C. at 0.3 mm Hg to give 20 g (87%) of 1-methyl-4-methylaminopiperidine. Anal. Calc'd for C7H16N2: C, 65.57; H, 12.58; N, 21.85. Found: C, 65.49; H, 12.44; N: 21,49.


Step 2: Preparation of N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-N,1-dimethyl-4-piperidinamine, dihydrate


A solution of 1-(4-chlorophenyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridinyl)ethanone (3.2 g, 0.01 mol; prepared as set forth in Step 1 of Example A-341) and 1-methyl-4-methylaminopiperidine (3.8 g, 0.03 mol) in 30 mL of toluene refluxed for six hours under nitrogen. The mixture was cooled and solvent was removed under vacuum. The residue was dissolved in dry tetrahydrofuran (30 mL) and anyhydrous hydrazine (650 mg, 0.02 mol) was added. The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The resulting precipitate was filtered and warmed in methanol and a few drops of concentrated ammonium hydroxide. The mixture was filtered hot and the filtrate blown down to half the volume. As the filtrate cooled, a product separated and was filtered to give 395 of pure N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-N,1-dimethyl-4-piperidinamine, dihydrate, m.p. 260-261° C. Anal. Calc'd for C21H24ClN5.2H2O: C, 60.35; H, 6.75; N, 16.76. Found: C, 59.89; H, 6.56; N: 16.40.


Additional compounds of the present invention that were prepared according to one or more of above reaction schemes (particularly Schemes IX through XVIII) are disclosed in Table 3-2. The specific synthesis scheme or schemes as well as the mass spectroscopy and elemental analysis results for each compound also are disclosed in Table 3-2.

TABLE 3-2MicroanalysisMSCCHHNNWaterEtOAcCHCl3TolueneHClExampleGeneralM+FoundFoundCalcFoundCalcFoundAddedAddedAddedAddedAddedA-346XIIA-347XII32959.3359.595.655.4715.5515.410.80.2A-348XII43968.4666.598.048.4819.1616.17A-349XII39761.8561.997.797.5217.4517.391.30.7A-350XII44966.2966.757.607.6817.8417.001.25A-351XII35268.3657.516.317.3119.9317.17A-352XII36669.0266.276.626.5919.1618.22A-353XII43069.2671.507.406.9118.3614.87A-354XII35570.4870.126.807.1513.9913.910.5A-355XII34166.7367.096.296.7716.0415.780.1A-356XVII41063.4263.616.006.0616.8116.630.4A-357XVII39254.3753.935.916.3213.7814.680.4A-358XII39470.2068.507.177.6817.8016.58A-359XVII39669.2169.337.688.0117.5517.610.2A-360XVII36650.8150.745.975.8014.1114.001.23A-361XII38971.1268.675.455.6414.4212.90A-362XII37570.5768.545.125.3914.9613.90A-363XII38971.1268.865.455.5814.4213.09A-364XVII36868.3168.397.157.4918.9718.930.1A-365XVII33848.7248.575.475.4514.9514.791.23A-366XII39756.3456.217.317.0317.9217.8921A-367XVII32170.2569.835.435.6217.2517.820.25A-368XII31364.6664.285.735.6216.7616.930.25A-369XII41266.7666.607.367.6116.9316.740.1A-370XII31364.6664.365.735.5916.7616.820.25A-371XVII63.7863.636.376.0917.7117.241A-372XII68.6368.807.267.5317.4017.140.5A-373XVII38958.1057.995.004.8817.8317.480.25A-374XII35467.9767.236.846.8119.8119.38A-375XII36668.1868.066.676.8018.9318.560.25A-376XII37570.5768.195.126.0614.9613.13A-377XII39664.1464.446.996.7816.0216.020.35A-378XVII33766.4266.445.224.9116.3116.270.4A-379XVII33962.7662.806.045.4315.4115.171.4A-380XVII38163.3163.405.195.8214.0613.8411A-381XVII30770.5769.694.945.0018.2917.68A-382XVIIA-383XVIIA-38432055.4853.445.645.0017.0321.60A-385XI28052.6552.515.985.1710.8311.121A-386XII35164.9664.775.825.3414.8515.0310.1A-387XII35365.2965.626.326.1414.6414.470.70.2A-38839454.9355.346.216.7913.9314.013


EXAMPLE A-346



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N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-methyl-1-piperazinepropanamine(2E)-2-butenedioate (1:1)
EXAMPLE A-347



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


EXAMPLE A-348



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N,N,N″-triethyl-N′-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethyl]-1,3-propanediamine;


EXAMPLE A-349



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N-[2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyridinyl]amino]ethyl]-N,N′,N′-trimethyl-1,3-propanediamine;


EXAMPLE A-350



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N-(2-[1,4′-bipiperidin]-1′-ylethyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinamine;


EXAMPLE A-351



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


EXAMPLE A-352



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


EXAMPLE A-353



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N2,N2-diethyl-N1-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1-phenyl-1,2-ethanediamine;


EXAMPLE A-354



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


EXAMPLE A-355



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


EXAMPLE A-356



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


EXAMPLE A-357



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4-[3-(4-fluorophenyl)-5-(4-(1-pyrrolidinyl)-1-piperidinyl]-1H-pyrazol-4-yl]pyridine, trihydrochloride;


EXAMPLE A-358



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


EXAMPLE A-359



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N1,N1,-diethyl-N4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-pentanediamine;


EXAMPLE A-360



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


EXAMPLE A-361



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(βR)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;


EXAMPLE A-362



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


EXAMPLE A-363



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(βS)-β-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]benzene propanol;


EXAMPLE A-364



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


EXAMPLE A-365



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


EXAMPLE A-366



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N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-1,4-pentanediamine;


EXAMPLE A-367



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1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,3,6-hexahydropyridine;


EXAMPLE A-368



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


EXAMPLE A-369



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N4-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N1,N1-diethyl-1,4-pentanediamine;


EXAMPLE A-370



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


EXAMPLE A-371



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


EXAMPLE A-372



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


EXAMPLE A-373



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


EXAMPLE A-374



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N,N-diethyl-N′-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,2-ethanediamine;


EXAMPLE A-375



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


EXAMPLE A-376



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


EXAMPLE A-377



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N1,N1-diethyl-N4-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-1,4-pentanediamine;


EXAMPLE A-378



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


EXAMPLE A-379



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


EXAMPLE A-380



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8-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,4-dioxa-8-azaspiro[4.5]decane;


EXAMPLE A-381



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


EXAMPLE A-382



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


EXAMPLE A-383



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


EXAMPLE A-384



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


EXAMPLE A-385



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4-[3-(4-fluorophenyl)-1-(2-propenyl)-1H-pyrazol-4-yl]pyridine, monohydrochloride;


EXAMPLE A-386



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


EXAMPLE A-387



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


EXAMPLE A-388



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1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-diethyl-4-piperidinamine, trihydrochloride;


EXAMPLE A-389



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1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine:


Step 1. Preparation of 1-tolyl-2-(4-pyridyl)ethanone
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Methyl 3-methylbenzoate (6.0 g, 40 mmol), 20 tetrahydrofuran (50 mL), and 4-picoline (4.1 g, 44 mmol) were stirred at −78° C. under an atmosphere of nitrogen. Sodium (bis)trimethylsilylamide 1.0 M in tetrahydrofuran (88 mL, 88 mmol) was added dropwise. The mixture was allowed to warm to room temperature, stirred for 16 hours and then was poured into saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated. The product was recrystallized from ethyl acetate/hexane to yield a light yellow solid (5.7 g, 67%), mp 118.0-119.0° C.; 1H NMR (acetone-d6/300 MHz) 8.50 (m, 2H), 7.90 (m, 2H), 7.44 (m, 2H), 7.29 (m, 2H), 4.45 (s, 2H), 2.41 (s, 3H); ESHRMS m/z 212.1067 (M+H, C14H13NO requires 212.1075); Anal. Calc'd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.54; H, 6.30; N, 6.56.


Step 2. Preparation of 1-(3-tolyl)-2-(1,3-dithietan-2-ylidene)-2-(4-pyridyl)ethanone
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1-tolyl-2-(4-pyridyl)ethanone (4.22 g, 20 mmol), acetone (100 mL), potassium carbonate (8.3 g, 60 mmol), carbon disulfide 4.56 g, 60 mmol), and dibromomethane (10.43 g, 60 mmol) were stirred at room temperature for 16 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over magnesium sulfate and concentrated. This crude material was purified by either flash column chromatography eluting with ethyl acetate:hexane or crystallization from ethyl acetate/hexane to yield a yellow solid (4.8 g, 80%), mp 178.6-179.2° C.; 1H NMR (acetone-d6/300 MHz) 8.47 (m, 2H), 7.08 (m, 6H), 4.37 (s, 2H), 2.21 (s, 3H); ESHRMS m/z 300.0521 (M+H, C16H13NOS2 requires 300.0517); Anal. Calc'd for C16H13NOS2: C, 64.18; H, 4.38; N, 4.68. Found: C, 64.08; H, 4.25; N, 4.62.


Step 3. Preparation of 1-[3-(3-tolyl)-3-oxo-2-(4-pyridinyl)-1-thiopropyl]-4-methylpiperazine
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The dithietane compound from step 2 above (3.0 g, 10 mmol), N-methylpiperazine (5.0 g, 50 mmol), and toluene (50 mL) were refluxed using a Dean-Stark apparatus for one to three hours. The reaction was allowed to cool to room temperature and was concentrated to dryness under high vacuum. This thick, oily material was crystallized from ethyl acetate/hexane (2.9 g, 82%), mp 124.8-125.8° C.; 1H NMR (acetone-d6/300 MHz) 8.57 (m, 2H), 7.75 (m, 2H), 7.54 (m, 2H), 7.37 (m, 2H) 6.54 (s, 1H), 4.27 (m, 2H), 4.19 (m, 1H), 3.83 (m, 1H), 2.47-2.28 (m, 6H), 2.22 (9, 3H), 2.17 (m, 1H); ESHRMS m/z 354.1669 (M+H, C20H23N3OS requires 354.1640); Anal. Calc'd for C20H23N3OS: C, 67.96; H, 6.56; N, 11.89. Found: C, 67.79; H, 6.66; N, 11.88.


Step 4. Preparation of 1-[5-(3-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl-4-methylpiperazine.


The thioamide compound from step 3 above (1.06 g, 3 mmol), tetrahydrofuran (50 mL), and hydrazine (15 mL, 15 mmol, 1.0 M) in tetrahydrofuran were stirred at room temperature for 16 hours. A white solid was collected by filtration. Purification when necessary was by trituration or recrystallization (0.98 g, 97%), mp 261.9-262.0° C.; 1H NMR (DMSO-d6/300 MHz) 12.6 (brs, 1H), 8.42 (m, 2H), 7.2 (m, 4H), 7.12 (s, 1H), 7.0 (m, 1H), 2.86 (m, 4H), 2.34 (m, 4H) 2.25 (s, 3H), 2.16 (5, 3H); ESHRMS m/z 334.2049 (M+H, C20H23N5 requires 334.2032); Anal. Calc'd for C20H23N5: C, 72.04; H, 6.95; N, 21.00. Found: C, 71.83; H, 7.06; N, 20.83.


Additional dithietanes and pyrazoles that were synthesized by selection of the corresponding starting reagents in accordance with the chemistry described in Scheme XXI and further illustrated in Example 389 above include compounds A-390 through A-426 disclosed below.


EXAMPLE A-390



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mp 185.3-185.4° C.; 1H NMR (acetone-d6/300 MHz) 8.49 (m, 2H), 7.31 (m, 4H), 7.09 (m, 2H), 4.39 (s, 2H); ESHRMS m/z 319.9981 (M+H, C15H10ClNOS2 requires 319.9971); Anal. Calc'd for C15H10ClNOS2: C, 56.33; H, 3.15; N, 4.38. Found: C, 56.47; H, 3.13; N, 4.44.


EXAMPLE A-391



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1-(4-chloro-3-methylphenyl)-2-1,3-dithietan-2-ylidene-2-pyridin-4-yl-ethanone

mp 164.0-165.0° C.; 1H NMR (acetone-d6/300 MHz) 8.49 (m, 2H), 7.25 (m, 2H), 7.0 (m, 3H), 4.38 (s, 2H), 2.24 (s, 3H); ESHRMS m/z 334.0130 (M+H, C16H12ClNOS2 requires 334.0127); Anal. Calc'd for C16H12ClNOS2: C, 57.56; H, 3.62; N, 4.20. Found: C, 57.68; H, 3.67; N, 4.17.


EXAMPLE A-392



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mp 126.5-126.6° C.; 1H NMR (acetone-d6/300 MHz) 8.40 (m, 2H), 7.17 (m, 2H), 7.0 (m, 4H), 4.39 (s, 2H), 2.85 (s, 3H); ESHRMS m/z 300.0483 (M+H, C16H13NOS2 requires 300.0517); Anal. Calc'd for C16H13NOS2: C, 64.18; H, 4.38; N, 4.68. Found: C, 64.05; H, 4.27; N, 4.59.


EXAMPLE A-393



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mp 159.6-159.7° C.; 1H NMR (acetone-d6/300 MHz) 8.52 (m, 2H), 7.6 (m, 1H), 7.50 (s, 1H), 7.21 (m, 2H), 7.13 (m, 2H), 4.40 (s, 2H); ESHRMS m/z 363.9503 (M+H, C15H10BrNOS2 requires 363.9465); Anal. Calc'd for C15H10BrNOS2: C, 49.46; H, 2.77; N, 3.84. Found: C, 49.51; H, 2.68; N, 3.74.


EXAMPLE A-394



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mp 198.8-198.9° C.; 1H NMR (acetone-d6/300 MHz) 8.45 (m, 2H), 7.05 (m, 3H), 6.95 (m, 1H), 6.82 (m, 1H), 4.29 (s, 2H), 2.14 (s, 3H), 2.08 (s, 3H); ESHRMS m/z 314.0691 (M+H, C17H15NOS2 requires 314.0673).


EXAMPLE A-395



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mp 182.6-183.0° C. 1H NMR (acetone-d6/300 MHz) 8.50 (m, 2H), 7.42 (d, 2H, J=8.5 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.10 (m, 2H), 4.40 (s, 2H). ESHRMS m/z 370.0173 (M+H, C16H10F3NO2S2 requires 370.0183).


EXAMPLE A-396



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mp 193.3-193.4° C. 1H NMR (acetone-d6/300 MHz) 8.49 (m, 2H), 7.69 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.01 (m, 2H), 4.43 (s, 2H). ESHRMS m/z 311.0327 (M+H, C16H10N20S2 requires 311.0313).


EXAMPLE A-397



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mp 191.5-192.5° C.; 1H NMR (CDCl3/300 MHz) 8.55 (dd, 2H, J=4.6, 1.6 Hz), 7.4 (m, 1H), 7.09-7.03 (m, 3H), 6.67 (d, 1H, J=8.7 Hz), 4.17 (s, 2H), 3.86 (s, 3H); ESHRMS m/z 350.0090 (M+H, C16H12ClNO3S2 requires 350.0076); Anal. Calc'd. for C16H12ClNO2S2: C, 54.93; H, 3.60; N, 4.00; Cl, 10.13; S, 18.33. Found: C, 54.74; H, 3.60; N, 3.89; Cl, 10.45; S, 18.32.


EXAMPLE A-398



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mp 172.1-173.1° C.; 1H NMR (CDCl3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.23-7.21 (m, 4H), 7.04 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 1.25 (s, 9H); ESHRMS m/z 342.1004 (M+H, C19H19NOS2 requires 342.0986); Anal. Calc'd for C19H19NOS2: C, 66.83; H, 5.61; N, 4.10; S, 18.78. Found: C, 66.97; H, 5.89; N, 4.02; S, 18.64.


EXAMPLE A-399



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mp 203.0-204.1° C.; 1H NMR (CDCl3/300 MHz) 8.52 (dd, 2H, J=4.4, 1.6 Hz), 7.29 (d, 1H, J=6.8 Hz), 7.28 (d, 1H, J=7.0 Hz), 7.05 (dd, 2H, J=4.4, 1.6 Hz), 6.70 (d, 1H, J=6.8 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.17 (s, 2H), 3.79 (s, 3H); ESHRMS m/z 316.0475 (M+H, C16H13NO2S2 requires 316.0466); Anal. Calc'd. for C16H13NO2S2: C, 60.93; H, 4.15; N, 4.44; S, 20.33. Found: C, 60.46; H, 4.17; N, 4.37; S, 19.84.


EXAMPLE A-400



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mp 209.1-215.1° C.; 1H NMR (CDCl3/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz), 7.20 (d, 2H, J=8.0 Hz), 7.03-6.99 (m, 4H), 4.18 (s, 2H), 2.30 (s, 3H); ESHRMS m/z 300.0517 (M+H, C16H13NOS2 requires 300.0517); Anal. Calc'd. for C16H13NOS2: C64.18; H, 4.38; N, 4.69; S, 21.42. Found: C, 64.02; H, 4.62; N, 4.54; S, 21.24.


EXAMPLE A-401



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mp 257.6-257.7° C.; 1H NMR (CDCl3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.57 (d, 2H, J=8.5 Hz), 7.27-6.99 (m, 4H), 4.18 (s, 2H); ESHRMS m/z 411.9348 (M+H, C15H10NIOS2 requires 411.9327); Anal. Calc'd. for C15H10NIOS2: C, 43.81; H, 2.45; N, 3.41. Found: C, 43.71; H, 2.27; N, 3.41.


EXAMPLE A-402



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mp 197.3-202.2° C.; 1H NMR (CDCl3/300 MHz) 8.53 (dd, 2H, J=4.4, 1.6 Hz), 7.26 (d, 2H, J=9.3 Hz), 7.09 (dd, 2H, J=4.4, 1.6 Hz), 6.43 (d, 2H, J=9.3 Hz), 4.14 (s, 2H), 2.97 (s, 6H); ESHRMS m/z 329.0789 (M+H, C17H16N2OS2 requires 329.0782); Anal. Calc'd. for C17H16N2OS2: C, 62.17; H, 4.91; N, 8.53; S, 19.53. Found: C, 61.93; H, 5.12; N, 8.46; S, 19.26.


EXAMPLE A-403



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mp 176.6-176.7° C.; 1H NMR (CDCl3/300 MHz) 8.51 (dd, 2H, J=4.4, 1.6 Hz), 7.29-7.22 (m, 4H), 7.03 (dd, 2H, J=4.4, 1.6 Hz), 6.64 (dd, 1H, J=17.5, 10.9 Hz), 5.76 (d, 1H, J=17.7 Hz), 5.31 (d, 1H, J=10.9 Hz), 4.19 (s, 2H); ESHRMS 312.0513 (M+H, C17H13NOS2 requires 312.0517); Anal. Calc'd. for C17H13NOS2: C, 65.56; H, 4.21; N, 4.50. Found: C, 65.75; H, 4.11; N, 4.46.


EXAMPLE A-404



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mp 174.8-175.0° C.; 1H NMR (CDCl3/300 MHz) 8.50 (dd, 2H, J=4.4, 1.6 Hz), 7.23-7.20 (m, 4H), 7.03 (dd, 2H, J=4.6, 1.6 Hz), 4.17 (s, 2H), 2.59 (q, 2H, J=7.6 Hz), 1.17 (t, 3H, J=7.7 Hz); ESHRMS m/z 314.0677 (M+H, C17H15NOS2 requires 314.0673); Anal. Calc'd. for C17H15NOS2: C, 65.14; H, 4.82; N, 4.47. Found: C, 64.90; H, 4.62; N, 4.45.


EXAMPLE A-405



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mp 167.1-167.5° C.; 1H NMR (CDCl3/300 MHz) 8.52 (dd, 1H, J=4.4, 1.6 Hz), 7.33 (d, 1H, J=8.3 Hz), 7.02-7.00 (m, 3H), 6.87-6.83 (m, 1H), 4.19 (s, 2H), 2.28 (s, 3H); ESHRMS m/z 379.9577 (M+H, C16H12BrNOS2 requires 379.9622); Anal. Calc'd. for C16H12BrNOS2: C, 50.80; H, 3.20; N, 3.70. Found: C, 50.69; H, 3.19; N, 3.71.


EXAMPLE A-406



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mp 168.6-168.7° C.; 1H NMR (CDCl3/300 MHz) 8.54 (dd, 2H, J=4.6, 1.8 Hz), 7.68-7.62 (m 2H), 7.43-7.39 (m, 1H), 7.33-7.28 (m, 1H), 6.99 (dd, 2H, J=4.4, 1.6 Hz), 4.22 (s, 2H); ESHRMS m/z 311.0330 (M+H, C16H10N2OS2 requires 311.0313); Anal. Calc'd. for C16H10N2OS2: C, 61.91; H, 3.25; N, 9.02. Found: C, 61.45; H, 3.18; N, 8.91.


EXAMPLE A-407



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


mp 236.7-239.3° C.; 1H NMR (DMSO-d6/300 MHz) 12.6 (brs, 1H), 8.45 (m, 2H), 7.41 (m, 1H), 7.26 (m, 3H), 7.0 (m, 1H), 2.86 (m, 4H), 2.35 (m, 4H), 2.27 (s, 3H), 2.16 (s, 3H); ESHRMS m/z 368.4653 (M+H, C20H22ClN5 requires 368.1642).


EXAMPLE A-408



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1-[5-(2-tolyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine

mp 244.0-244.2° C.; 1H NMR (acetone-d6/300 MHz) 11.6 (brs, 1H), 8.35 (m, 2H), 7.35 (m, 2H), 7.25 (m, 4H), 3.05 (m, 4H), 2.47 (m, 4H), 2.25 (s, 3H), 2.00 (s, 3H); ESHRMS m/z 334.2018 (M+H, C20H23N5 requires 334.2032); Anal. Calc'd for C20H23N5: C, 72.04; H, 6.95; N, 21.00. Found: C, 72.03; H, 7.00; N, 20.85.


EXAMPLE A-409



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

mp 222.5-223.4° C.; 1H NMR (acetone-d6/300 MHz) 11.8 (brs, 1H), 8.51 (m, 2H), 7.55 (m, 2H), 7.34 (m, 4H), 3.0 (m, 4H), 2.41 (m, 4H), 2.22 (s, 3H); ESHRMS m/z 398.0982 (M+H, C19H20BrN5 requires 398.0980).


EXAMPLE A-410



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

mp 270.9-272.7° C.; 1H NMR (DMSO-d6/300 MHz) 12.5 (brs, 1H), 8.41 (m, 2H), 7.24 (m, 2H), 7.26 (m, 3H), 7.10 (m, 2H), 6.92 (m, 1H), 2.86 (m, 4H), 2.38 (m, 4H), 2.21 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H); ESHRMS m/z 348.2183 (M+H, C21H25N5 requires 348.2188).


EXAMPLE A-411



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

mp 221.0-221.2° C.; 1H NMR (DMSO-d6/300 MHz) 12.7 (brs, 1H), 8.45 (m, 2H), 7.38 (s, 4H), 7.24 (m, 2H), 2.86 (m, 4H), 2.34 (m, 4H), 2.16 (s, 3H); ESHRMS m/z 404.1698 (M+H, C20H20F3N5O requires 404.1698).


EXAMPLE A-412



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

mp >300° C.; 1H NMR (DMSO-d6/300 MHz) 12.8 (brs, 1H), 8.47 (m, 2H), 7.83 (m, 2H), 7.42 (m, 2H), 2.88 (m, 4H), 2.39 (m, 4H), 2.20 (s, 3H); ESHRMS m/z 345.1848 (M+H, C20H20N6 requires 345.1828).


EXAMPLE A-413



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

mp 272.7-276.4° C.; 1H NMR (DMSO-d6/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6 Hz), 7.32-7.13 (m, 5H), 3.84 (s, 3H), 2.90-2.85 (m, 4H), 2.38-2.35 (m, 4H), 2.16 (s, 3H); ESHRMS m/z 384.1580 (M+H C20H22ClN5O requires 384.1591).


EXAMPLE A-414



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

mp 243.6-244.3° C.; 1H NMR (DMSO-d6/300 MHz) 8.44 (dd, 2H, J=4.6, 1.6, Hz), 7.40 (d, 2H, J=8.3 Hz), 7.28-7.18 (m, 4H), 2.90-2.85 (m, 4=H), 2.38-2.34 (m, 4H), 2.16 (s,3H), 1.26 (s, 9H); ESHRMS m/z 376.2491 (M+H, C23H29N5 requires 376.2501).


EXAMPLE A-415



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

mp 259.0-260.2° C.; 1H NMR (DMSO-d6/300 MHz) 8.53 (dd, 2H, J=4.4, 1.6 Hz), 7.24 (dd, 2H, J=4.4, 1.6 Hz), 7.18 (d, 2H, J=8.9 Hz), 6.94 (d, 2H, J=8.9 Hz), 3.75 (s, 3H), 2.90-2.85 (m, 4H), 2.39-2.35 (m, 4H), 2.16 (s, 3H); ESHRMS m/z 350.1991 (M+H, C20H23N5O requires 350.1981); Anal. Calc'd. for C20H23N5O+3.93%H2O: C, 66.04; H, 6.81; N, 19.25. Found: C, 66.01; H, 6.62; N, 19.32.


EXAMPLE A-416



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

mp 243.0-246.8° C.; 1H NMR (DMSO-d6/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.24 (m, 6H), 2.91-2.86 (m, 4H), 2.40-2.35 (m, 4H), 2.29 (s, 3H), 2.16 (s, 3H); ESHRMS m/z 334.2041 (M+H, C20H23N5 requires 334.2032); Anal. Calc'd for C20H23N5+4.09%H2O: C, 69.10; H, 7.13; N, 20.14. Found: C, 69.10; H, 7.08; N, 20.13.


EXAMPLE A-417



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

mp 265.2-265.8° C.; 1H NMR (CD3OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.76-7.74 (m, 2H), 7.41-7.39 (m, 2H), 7.08-7.05 (m, 2H), 3.08-3.04 (m, 4H), 2.61-2.58 (m, 4H), 2.35 (s, 3H); ESHRMS m/z 446.0847 (M+H, C19H20IN5 requires 446.0842); Anal. Calc'd. for C19H20IN5+12.09%H2O: C, 44.60; H, 5.39; N, 13.69. Found: C, 44.50; H, 4.56; N, 13.66.


EXAMPLE A-418



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

mp >300° C.; 1H NMR (CD3OD/300 MHz) 8.49 (dd, 2H, J=4.6, 1.6 Hz), 7.4.7-7.44 (m, 4H), 7.26 (d, 2H, J=8.4 Hz), 6.75 (dd, J=17.7, 11.1 Hz), 5.83 (d, 1H, J=17.5 Hz), 5.28 (d, 1H, J=11.1 Hz), 3.07-3.03 (m, 4H), 2.58-2.53(m, 4H), 2.31 (s, 3H); ESHRMS m/z 346.2034 (M+H, C21H23N5 requires 346.2032); Anal. Calc'd. for C21H23N5+2.83 %H2O: C, 70.95; H, 6.84; N, 19.70. Found: C, 70.97; H, 6.49; N, 19.54.


EXAMPLE A-419



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

mp 221.6-222.6° C.; 1H NMR (CD3OD/300 MHz) 8.38 (dd, 2H, J=4.6, 1.6 Hz), 7.44-7.40 (m, 2H), 7.26-7.19 (m, 4H), 3.06-3.02 (m, 4H), 2.66 (q, 2H, J=7.5 Hz), 2.59-2.54 (m, 4H), 2.32 (s, 3H), 1.23 (t, 3H, J=7.5 Hz); ESHRMS m/z 348.2188 (M+H, C21H25N5 requires 348.2188); Anal. Calc'd for C21H25N5+2.59%H2O: C, 70.71; H, 7.35; N, 19.63. Found: C, 70.76; H, 7.40; N, 19.46.


EXAMPLE A-420



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1-[5-(4-bromo-3-methylphenyl)-4-(4-pyrdinyl)-1H-pyrazol-3-yl]-4-methylpiperazine

mp 294.7° C. decomp.; 1H NMR (CD3OD/300 MHz) 8.41 (dd, 2H, J=4.6, 1.6 Hz), 7.55 (d, 1H, J=8.2 Hz), 7.45-7.42 (m, 2H), 7.27-7.25 (m, 1H), 7.00-6.97 (m 2H), 3.08-3.03 (m, 4H), 2.59-2.54 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H); ESHRMS m/z 412.1124 (M+H, C20H22BrN5 requires 412.1137).


EXAMPLE A-421



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

mp >300° C. (decomposed); 1H NMR (CD3OD/300 MHz) 8.37 (d, 2H, J=4.6 Hz), 7.44 (d, 2H, J=4.8 Hz), 7.12, (d, 2H, J=8.9 Hz), 6.73 (d, 2H, J=8.7 Hz), 3.04-3.02 (m, 4H), 2.96 (s, 6H), 2.54-2.49 (m, 4H), 2.31 (s, 3H); ESHRMS m/z 363.2266 (M+H, C21H26N6 requires 363.22972).


EXAMPLE A-422



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1-[5-(3-cyanophenyl)-4-(4-pyrdinyl)-1H-pyrazol-3-yl]4-methylpiperazine

mp 223.4-224.3° C.; 1H NMR (CD3OD/300 MHz) 8.44 (dd, 2H, J=4.6, 1.4 Hz), 7.75-7.69 (m, 2H), 7.56-7.54 (m, 2H), 7.40-7.38 (m, 2H), 3.05-3.03 (m, 4H), 2.54-2.49 (m, 4H), 2.53 (s, 3H); ESHRMS m/z 345.1840 (M+H, C20H20N6 requires 345.1828).


EXAMPLE A-423



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

mp 275.6-281.9° C.; 1H NMR (CD3OD/300 MHz) 8.44-8.40 (m, 2H), 7.46-7.41 (m, 2H), 7.28-7.23 (m, 4H), 3.04-3.00 (m, 4H), 2.59-2.53 (M, 4H), 2.48 (s, 3H), 2.31 (s, 3H); ESHRMS m/z 366.1777 (M+H, C20H23N5S requires 366.1752).


EXAMPLE A-424



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

mp 212.6-213.7° C.; 1H NMR (CD3OD/300 MHz) 8.43 (d, 2H, J=4.8 Hz), 7.69-7.56 (m, 4H), 7.41 (s, 2H), 3.07-3.04 (m, 4H), 2.56-2.53 (m, 4H), 2.32 (s, 3H); ESHRMS m/z 388.1764 (M+H, C20H20F3N5 requires 388.1749).


EXAMPLE A-425



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

mp 240.5° C. (decomposed); 1H NMR (CD3OD/300 MHz) 8.43 (dd, 2H, J=4.6, 1.6 Hz), 7.70-7.67 (m, 2H), 7.51-7.48 (m, 2H), 7.42-7.38 (m 2H), 3.09-3.04 (m, 4H), 2.59-2.53 (m, 4H), 2.31 (s, 3H); ESHRMS m/z 388.1768 (M+H, C20H20F3N5 requires 388.1749).


EXAMPLE A-426



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1-[5-(2-thienyl)-4-(4-pyridinyl-1H-pyrazol-3-yl]-4-methylpiperazine

mp 199.7° C. (decomposed); 1H NMR (CD3OD/300 MHz) 8.44 (d, 2H, J=5.8 Hz), 7.47 (d, 2H, J=5.6 Hz), 7.13-7.07 (m, 3H), 3.04-3.00 (m, 4H), 2.53-2.49 (m, 4H), 2.30 (s, 3H); ESHRMS m/z 326.1454 (M+H, C17H19N5S requires 326.1439).


EXAMPLE A-427



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Step 1: Preparation of 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propene-1-one


A solution of 4-chlorophenyl-2-(pyridin-4-yl)ethan-1-one (20.0 g, 86.4 mmol) and N,N-dimethylformamide dimethylacetal (57.6 mL, 0.43 mole) was heated at 100° C. for 3½ hours. The reaction mixture was concentrated in vacuo, and the residue crystallized from methyl butyl ether to give 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 93%). 1H NMR (CDCl3/300 MHz) δ 8.52 (d, 2H), 7.38 (d, 2H), 7.29 (d, 2H), 7.08 (d, 2H), 2.83 (s, 6H).


Step 2: Preparation of 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole


A solution of 3-dimethylamino-1-(4-chlorophenyl)-2-(pyridin-4-yl)-2-propen-1-one (22.80 g, 79.7 mmol), hydroxylamine hydrochloride (18.01 g, 0.26 mole), and 150 mL ethanol was heated to reflux for 30 minutes. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in 1N hydrochloric acid and then treated with an aqueous saturated solution of sodium bicarbonate. The precipitates were collected by filtration, washed with water and ethanol, and dried to yield 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.50 g, 93%). m.p. 120.8-120.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ 8.53 (d, 2H), 8.46(s, 1H), 7.51(d, 2H), 7.41-7.34 (m, 4H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0457 (M+H, C14H9N2OCl requires 257.0482).


Step 3: Preparation of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile:


A solution of 5-(4-chlorophenyl)-4-(pyridin-4-yl)isoxazole (20.5 g, 79.9 mmol) and 150 mL of a 1N sodium hydroxide solution was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature and adjusted to pH 6 with concentrated hydrochloric acid. The precipitates were filtered, washed with water and ethanol, and dried to give 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (20.0 g, quantitative yield). m.p. 225.4-234.9° C. 1H NMR (CDCl3/CD3OD/300 MHz) δ 8.12 (brs, 2H), 7.73-7.59 (m, 5H), 7.30 (d, 3H). ESLRMS m/z 257 (M+H). ESHRMS m/z 257.0481 (M+H, C14H9N20Cl requires 257.0482).


Step 4: 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole


A solution of 3-(4-chlorophenyl)-3-oxo-2-(pyridin-4-yl)propanenitrile (3.50 g, 13.6 mmol) in 40 mL acetonitrile and phosphorous trichloride (14.2 ml, 163 mmol) was stirred at 100° C. for 5 hours. The reaction mixture was concentrated in vacuo, and the residue taken up in toluene and concentrated again. The residue was then taken up in ethanol (150 mL) and treated with anhydrous hydrazine (1.71 mL, 54.4 mmol). The reaction mixture was heated to reflux for 3 hours, cooled, and concentrated in vacuo. The residue was triturated with a mixture of ethanol and dichloromethane (1:4), and filtered. The solid was washed with the ethanol/dichloromethane mixture, and dried to give 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (2.0 g, 54%): m.p. >300° C. 1H NMR (DMSO/300 MHz) δ 8.40 (d, 2H), 7.40 (d, 2H), 7.29 (d, 2H), 7.11 (d, 2H), 5.05 (s, 2H). ESLRMS m/z 271 (M+H). ESHRMS m/z 271.0752 (M+H, C14H11N4Cl requires 271.0750).


EXAMPLE A-428



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A solution of 1,1′-carbonyldiimidazole (1.19 g, 7.38 mmol) and N-benzyliminodiacetic acid (0.824 g, 3.69 mmol) in dimethylformamide was heated at 75° C. for 30 minutes. To this mixture the 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (1.0 g, 3.69 mmol) was added, and heating was continued at 75° C. overnight. The white solid was filtered, was washed with diethyl ether, methylene chloride, 5% methanol/methylene chloride, and ethanol, and was dried to give the desired imide as an off-white solid (0.9 g, 53%): m.p. >300° C. 1H NMR (DMSO/300 MHz) δ 8.53 (m, 2H), 7.5(d, 2H), 7.44-7.16 (m, 7H), 6.98(m, 2H), 3.64 (m, 4H), 3.48 (m, 2H). ESLRMS m/z 458 (M+H). ESHRMS m/z 458.1380 (M+H, C25H20N5O2Cl requires 458.1384).


EXAMPLE A-429



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Methyl 2-{[3-94-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]amino}acetate

A solution of 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (1.0 g, 3.7 mmol) in dimethylformamide (30 mL) was heated to 95° C. and methyl bromo acetate (0.34 mL, 3.7 mmol) was added dropwise. The resulting solution was stirred at 95° C. for 4 hours, cooled, and concentrated in vacuo to an orange viscous oil (1.79 g). A portion of this product mixture (1.20 g) was crystallized from ethanol and diethyl ether to give methyl 2-{[3-4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]amino}acetate as a bright yellow solid (805 mg): m.p. 195.4-196.8° C. 1H NMR (CD3OD/300 MHz) δ 8.49 (d, 2H), 7.68 (d, 2H), 7.44 (m, 4H), 5.37 (s, 2H), 3.84 (s, 3H). ESLRMS m/z 343 (M+H). ESHRMS m/z 343.0975 (M+H, C17H16N4O2Cl requires 343.0962).


EXAMPLE A-430



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Lithium 2-{[3-4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]amino}acetate

To a solution of methyl 2-{[3-4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]amino}acetate (500 mg, 1.5 mmol) in 15 mL of methanol and 5 mL of water was added lithium hydroxide (189 mg, 4.5 mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue taken up in ethanol. The precipitate was filtered and washed with methanol, and the filtrate was concentrated to give lithium 2-{[3-4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]amino}acetate as a yellow/orange solid (479 mg, 95%). mp >300° C. 1H NMR (CD3OD/300 MHz) δ 8.06 (d, 2H), 7.43 (d, 2H), 7.37 (m, 4H), 3.34 (s, 2H). ESLRMS m/z 329 (M+H), 335 (M+Li), 351 (M+Na). ESHRMS m/z 329.0772 (M+H, C16H14N4O2Cl requires 329.0805).


EXAMPLE A-431



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The above 4-chlorophenylketone was prepared according to the procedure used in Step 1 of Example C-1, infra, substituting methyl 4-chlorobenzoate for ethyl 4-fluorobenzoate. Yield; (74%), yellow solid, mp=95.5-97.3° C.; 1H-NMR (DMSO-d6/300 MHz) 8.57 (br d, 2H), 7.92 (d, 2H), 7.46 (d, 2H), 7.20 (d, 2H), 4.28 (s, 2H); ESLRMS m/z 232 (M+H).


EXAMPLE A-432



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To the ketone (1.0 gm, 4.7 mmol) from Step 1 of Example C-1, infra, in anhydrous tetrahydrofuran (10 mL) was added 1M potassium t-butoxide in tetrahydrofuran (10 mL, 10 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then carbon disulfide (0.31 mL, 5.1 mmol) was added. After several minutes, methyl iodide (0.64 mL, 10.3 mmol) was added and the reaction allowed to stir for 4 hours. The reaction mixture was diluted with saturated sodium bicarbonate solution (25 mL) and extracted twice with ethyl acetate (35 mL). The combined ethyl acetate layers were washed with water (25 mL) and brine (25 mL). The organic solution was dried (MgSO4), filtered and concentrated to an orange oil. The oil solidified on standing. Yield 1.4 gm (94%), mp 80.2-82.1° C.; 1H-NMR (CDCl3/300 MHz) 8.59 (d, 2H), 7.96 (m, 2H), 7.38 (m, 2H), 7.14 (m, 2H), 2.33 (s, 3H), 2.23 (s, 3H); Anal. Calc'd for C16H14FNOS2: C, 60.16; H, 4.42; N, 4.39; S, 20.08. Found: C, 59.89; H, 4.09; N, 4.31; S, 20.14.


EXAMPLE A-433



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The above compound was prepared in a manner analogous to Example A-432 starting with the product of Example A-431. Crude yield: 100%; mp 87.6-88.2° C.; 1H-NMR (CDCl3/300 MHz) 8.60 (d, 2H), 7.87 (d, 2H), 7.44 (d, 2H), 7.37 (m, 2H), 2.33 (s, 3H), 2.22 (s, 3H); ESHRMS m/z 336.0297 (M+H, C16H15ClNOS2 requires 336.0283); Anal. Calc'd for C16H14ClNOS2: C, 57.22; H, 4.20; N, 4.17. Found: C, 57.44; H, 3.97; N, 4.04.


EXAMPLE A-434



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To the compound of Example A-432 (1.4 gm, 4.4 mmol) in ethanol (15 mL) was added 1M hydrazine in acetic acid (5 mL, 5 mmol). The reaction was stirred at room temperature for 18 hours. No reaction had occurred, so additional hydrazine hydrate (1.08 mL, 22 mmol) was added and the reaction heated to reflux for 6 hours. The product began to precipitate from the reaction mixture. The reaction was cooled to room temperature and water was added to precipitate the product. The solid was collected by suction filtration and air dried. Yield: 675 mg (53%). The product was recrystallized from ethanol: 494 mg; mp 249.9-249.9° C.; 1H-NMR (DMSO-d6/300 MHz) 13.51 (br s, 1H), 8.50 (d, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.16 (m, 2H), 2.43 (s, 3H); ESHRMS m/z 286.0807 (M+H, C15H13FN3S requires 286.0814); Anal. Calc'd for C15H12FN3S: C, 63.14; H, 4.24; N, 14.73. Found: C, 63.01; H, 4.43; N, 14.81.


EXAMPLE A-435



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The above compound was made in an analogous manner to Example A-434 starting with the compound of Example A-433. Yield: 750 mg (33%); mp 250.2-250.2° C.; 1H NMR (DMSO-d6/300 MHz) 13.57 (br s, 1H), 8.51 (m, 2H), 7.45 (br s, 2H), 7.32 (m, 2H), 7.17 (m, 2H), 2.43 (s, 3H); ESHRMS m/z 302.0537 (M+H, C15H13ClN3S requires 302.0518); Anal. Calc'd for C15H12ClN3S: C, 59.70; H, 4.01; N, 13.92. Found: C, 59.56; H, 3.96; N, 13.96.


EXAMPLE A-436



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3-(4-fluorophenyl)-4-(methylsulfinyl)-4-pyridin-4-yl-1H-pyrazole

To the compound of Example A-434 (150 mg, 0.52 mmol) in ethanol (15 mL) was added ammonium persulfate (450 mg, 1.97 mmol). The reaction mixture was stirred at ambient temperature. After several hours an additional amount of ammonium persulfate (450 mg) was added. The reaction mixture was monitored by TLC (silica) using 5% methanol in dichloromethane as the eluting solvent. When the stating material had been consumed, the reaction mixture was quenched with saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (2×25 mL). The ethyl acetate layers were combined, washed with brine (25 mL) and dried (MgSO4). Filtration and concentration produced a white solid. The solid was triturated with diethyl ether, collected by suction filtration, and air dried.


Yield 150 mg (96%), mp 262.9-262.9° C.; 1H NMR (DMSO-d6/300 MHz) 14.22 (br s, 1H), 8.56 (d, 2H), 7.42-7.23 (br m, 6H), 2.94 (s, 3H); Anal. Calc'd for C15H12FN3OS.0.25 H2O: C, 58.91; H, 4.12; N, 13.74; Found: C, 58.88; H, 4.17; N, 13.39.


EXAMPLE A-437



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3-(4-fluorophenyl)-5-(methylsulfonyl)-4-pyridin-4-yl-1H-pyrazole

To the compound of Example A-434 (285 mg, 1 mmol) in ethanol (10 mL) was added potassium peroxymonosulfate (2.45 gm, 4 mmol) and water (5 mL). The reaction mixture was stirred at ambient temperature. After 6 hours the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The ethyl acetate layers were combined, washed with brine (25 mL) and dried (MgSO4). The ethyl acetate did not efficiently extract the product from the aqueous phase, so the aqueous layer was saturated with sodium chloride and extracted with acetonitrile (50 mL). The acetonitrile solution was dried (MgSo4), filtered, and combined with the filtered ethyl acetate solution. The solvents were evaporated and the resulting solid was triturated with a small amount of acetonitrile, collected by suction filtration, and air dried. Yield: 203 mg (64%); mp 297.1->300° C.; 1H NMR (DMSO-d6/300 MHz) 14.37 (br s, 1H), 8.54 (m, 2H), 7.29 (m, 6H), 3.26 (s, 3H); Anal. Calc'd for C15H12FN3O2S: C, 56.77; H, 3.81; N, 13.24. Found: C, 56.52; H, 4.03; N, 13.11.


EXAMPLE A-438



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To the compound of Example A-432 (638 mg, 2 mmol) in toluene (6 mL) was added thiomorpholine (502 uL, 5 mmol). The reaction mixture was heated to between 80 and 110° C. After about three hours the bis-thiomorpholine substituted product began to precipitate from the reaction mixture. When the dithioketene acetal had been completely consumed, the reaction mixture was cooled to room temperature and the insoluble bis-thiomorpholine compound removed by filtration. To the toluene solution was added hydrazine hydrate (1 mL) and sufficient ethanol to create a homogeneous solution. The reaction mixture was then stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted twice with water (25 mL) and once with brine (25 mL). The organic solution was dried (MgSO4), filtered and concentrated to a reddish solid. The solid was triturated with acetonitrile, collected by suction filtration, and dried in-vacuo. The solid was then suspended in acetonitrile and heated to reflux. Ethyl acetate was then added until the solid almost completely dissolved. A small amount of ethanol was then added and the homogeneous yellow solution concentrated until a solid began to form. Allow to cool to room temperature. Collected a white solid by suction filtration. Yield: 63 mg, (7%); 1H NMR (DMSO-d6/300 MHz) 12.65 (br s, 1H), 8.45 (d, 2H), 7.27 (m, 6H), 3.14 (m, 4H), 2.63 (m, 4H). ESLRMS m/z 341 (M+H); ESHRMS m/z 341.1241 (M+H, C18H18FN4S requires 341.1236).


EXAMPLE A-439



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The above compound was prepared in a similar manner to Example A-438 starting with the appropriate dithioketene acetal and N-methylpiperazine. A white solid was obtained, mp 270.2-270.7° C.; 1H NMR (DMSO-d6/300 MHz) 12.7 (br s, 1H), 8.47 (m, 2H), 7.57 (m, 2H), 7.21 (m, 2H), 2.85 (m, 4H), 2.34 (m, 4H) 2.15 (s, 3H); ESHRMS 398.0993 (M+H, C19H21BrN5 requires 398.0980).


EXAMPLE A-440



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To N-(2-hydroxyethyl)morpholine (363 uL, 3 mmol) in anhydrous tetrahydrofuran (7 mL), under nitrogen, was added 1M sodium hexamethyldisilamide (3 ml, 3 mmol) in tetrahydrofuran at ambient temperature. The reaction mixture was stirred for 15 minutes, then the dithietane prepared as set forth in Step 1 of Example A-341 (636 mg, 2 mmol) was added as a solid. The reaction mixture gradually became dark orange. After about 18 hours at ambient temperature, the reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted twice with ethyl acetate (30 mL). The organic solutions were combined and washed with saturated NaCl solution (20 mL), then dried (MgSO4), filtered, and concentrated to an orange oil. The oil was taken up in methanol (10 mL) and reconcentrated to remove any remaining ethyl acetate. The oil was then taken up in methanol (5 mL) and anhydrous hydrazine (69 uL) was added. The reaction mixture was allowed to stir at ambient temperature 18 hours, then quenched with saturated sodium bicarbonate solution (30 mL) and extracted twice with ethyl acetate (30 mL). The organic solutions were combined and washed with water (20 mL) and saturated NaCl solution (20 mL), then dried (MgSO4), filtered, and concentrated to an orange semi-solid. The solid was triturated with acetonitrile (5 mL), collected by suction filtration, washed with acetonitrile and dried in-vacuo. Yield: off-white solid, 114 mg (14.8%); mp 198.9-199.9° C.; 1H-NMR (DMSO-d6/300 MHz) 12.61 (br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.33 (t, 2H), 3.54 (m, 4H), 2.70 (t, 2H), 2.44 (m 4H); ESHRMS m/z 385.1444 (M+H, C20H22ClN4O2 requires 385.1431).


EXAMPLE A-441



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The above compound was prepared in an analogous manner to that of Example A-440, starting with 4-hydroxy-N-t-boc piperidine. Recrystallized from acetone/methanol. Yield: white solid 263 mg (29%); mp 230.1-231.8° C.; 1H-NMR (DMSO-d6/300 MHz) 12.61 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.20 (d, 2H), 4.88 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H), 1.93 (m, 2H), 1.65 (m, 2H), 1.39 (s, 9H); Anal. Calc'd for C24H27ClN4O3: C,63.36; H, 5.98; N, 12.31; Found: C, 63.34; H, 5.97; N, 12.22.


EXAMPLE A-442



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Example A-441 (130 mg, 0.28 mmol) was treated with concentrated HCl (0.5 mL) in ethanol (5 mL) for two hours. The solvent was removed in-vacuo and the resulting residue dissolved in ethanol and reconcentrated twice. The resulting solid was triturated with acetonitrile to afford a white solid. Yield: 119 mg (91%) tri-hydrochloride salt; mp 220.6-222.1° C.; 1H-NMR (DMSO-d6/300 MHz) 13.25 (br s, 1H), 9.10 (br s, 2H), 8.67 (d, 2H), 7.75 (d, 2H), 7.60 (d, 2H), 7.50 (d, 2H), 5.04 (m, 1H), 3.17 (br d, 4H), 2.21 (m, 2H), 2.03 (m, 2H); Anal. Calc'd for C19H19ClN4O.3 HCl: C, 49.16; H, 4.78; N, 12.07. Found: C, 49.24; H, 4.72; N, 12.02.


EXAMPLE A-443



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The above compound was prepared in a manner analogous to Example A-440 starting with (+/−)3-hydroxytetrahydrofuran. Recrystallized from ethanol.


Yield: white crystalline solid, 57 mg (8%); mp >300° C.; 1H-NMR (DMSO-d6/300 MHz) 12.65 (br s, 1H), 8.42 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.18 (d, 2H), 5.28 (m, 1H), 3.86 (m, 2H), 3.82 (m, 1H), 3.75 (m, 1H), 2.26-2.01 (br m, 2H); Anal. Calc'd for C18H16ClN3O2: C, 63.25; H, 4.72; N, 12.29. Found: C, 63.12; H, 4.51; N, 12.31.


EXAMPLE A-444



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The above compound was prepared in a manner analogous to Example A-440 starting with p-methoxybenzyl alcohol. Yield: off-white solid, 252 mg (21%); mp=229.1-229.2° C.; 1H-NMR (acetone-d6/300 MHz) 11.62 (br s, 1H), 8.40 (br s, 2H), 7.76 (s, 2H), 7.39 (m, 4H), 7.30 (br s, 2H), 6.87 (d, 2H), 5.27 (s, 2H), 3.77 (s, 3H); Anal. Calc'd for C22H18ClN3O2.0.25H2O: C, 66.67; H, 4.70; N, 10.60. Found: C, 66.79; H, 4.95; N, 10.54.


EXAMPLE A-445



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The above compound was prepared in a manner analogous to Example A-440 starting with N-tert-butoxycarbonyl-ethanolamine. Recrystallized from ethyl acetate/methanol. Yield: white solid, 75 mg (4%); mp >300° C.; 1H-NMR (DMSO-d6/300 MHz) 12.60 (br s, 1H), 8.38 (d, 2H), 7.53 (d, 2H), 7.38 (d, 2H), 7.22 (d, 2H), 7.02 (t, 1H), 4.20 (t, 2H), 3.34 (m, 2H), 1.36 (s, 9H); ESHRMS m/z 415.1551 (M+H, C21H24ClN4O3 requires 415.1537)


EXAMPLE A-446



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The above compound was prepared in a manner analogous to Example A-440 starting with methanol.


Yield: off-white solid, 119 mg (14%); mp=265.3-265.3° C.; 1H-NMR (DMSO-d6/300 MHz) 12.61 (br s, 1H), 8.41 (d, 2H), 7.52 (d, 2H), 7.38 (d, 2H), 7.17 (d, 2H), 3.90 (s, 3H); ESHRMS m/z 286.0766 (M+H, C15H13ClN3O requires 286.0747); Anal. Calc'd for C15H12ClN3O, 0.25H2O: C, 62.08; H, 4.34; N, 14.48. Found: C, 62.24; H, 4.11; N, 14.16.


EXAMPLE A-447



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To the dithietane of Step 1 of Example A-341 (638 mg, 2 mmol) in toluene (15 mL) was added thiomorpholine (800 uL, 8 uL). The reaction mixture was heated to reflux for 6 hours, then cooled to room temperature and diluted with toluene (20 mL). The reaction mixture was then extracted twice with water (20 mL) and brine (20 mL). The organic solution was dried (MgSO4), filtered, and concentrated to an oil. Hexane was added to the residue and heated to reflux, then decanted. The oil became semi-solid. The semi-solid was dissolved in tetrahydrofuran (10 mL) and potassium t-butoxide 1M in tetrahydrofuran (2 mL, 2 mmol) was added. This was followed by iodomethane (125 uL, 2 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water (20 mL). The reaction mixture was extracted with ethyl acetate (2×30 mL). The organic layers were pooled, washed with brine (20 mL) and dried (MgSO4). Filtration and concentration produced an oil which was chased once with toluene to remove any ethyl acetate. The residue was dissolved in ethanol (10 mL) and hydrazine hydrate (97 uL, 2 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours then partitioned between ethyl acetate and saturated sodium bicarbonate solution (30 mL each). The layers were separated and the aqueous layer extracted again with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL) and dried (MgSO4). Filtration and concentration produced an orange residue which was triturated with acetonitrile to generate a tan solid. Yield: 295 mg (43%); mp >300° C.; 1H NMR (DMSO-d6/300 MHz) 12.70 (br s, 1H), 8.47 (d, 2H), 7.46 (d, 2H), 7.26 (m, 4H), 3.13 (m, 4H), 2.62 (m, 4H); ESHRMS m/z 357.0942 (M+H, C18H18ClN4S requires 357.0941); Anal. Calc'd for C18H17ClN4S: C, 60.58; H, 4.80; N, 15.70. Found: C, 60.32; H, 4.96; N, 15.60.


EXAMPLE A-448



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3-(4-chlorophenyl)-5-[(1-methylpiperidin-4-yl)-oxy]-4-pyridin-4-yl-1H-pyrazole

The compound of Example A-441 (455 mg, 1.5 mmol) was combined with 98% formic acid (6 mL) and heated to 100° C. After three hours, 37% formaldehyde (1.22 mL, 15 mmol) was added and the reaction was heated for an additional five hours at 100° C. The reaction mixture was allowed to cool to room temperature and filtered. The solution was diluted with water (15 mL) and extracted once with ethyl acetate (30 mL). The aqueous solution was then basified with 2.5 N sodium hydroxide to pH 8. The cloudy mixture was then extracted twice with 1:1 tetrahydrofuran:ethyl acetate (30 mL). The organic layers were pooled and washed once with brine (25 mL), dried (MgSO4), filtered and concentrated to an oil which solidified on standing. The solid was triturated with acetonitrile and collected by suction filtration. The solid was suspended in ethanol:water 2:1 (15 mL) and 1 mL of concentrated HCl was added. The solution was allowed to stir at room temperature for one hour, then filtered and concentrated. The residue was combined with ethanol (10 mL) and reconcentrated twice. The resulting solid was triturated with acetonitrile (10 mL) containing a small amount of ethanol (0.5 mL) to remove some colored impurities. The solid was collected by suction filtration, washed with acetonitrile and dried in-vacuo.


Yield: 490 mg (88%); mp 255.9-256.8° C.; 1H NMR (D2O/DMSO-d6/NaOD/300 MHz) 7.93 (d, 2H), 7.09 (s, 4H), 7.00 (d, 2H), 4.42 (m, 1H), 2.26 (br m, 2H,) 2.12 (br m, 2H), 1.92 (s, 3H), 1.68 (br m, 2H), 1.57 (br m , 2H); ESLRMS m/z 369 (M+H).


EXAMPLE A-449



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To the compound of Example C-1, infra, (4′-fluoro-1-(4-pyridyl)acetophenone, 14.0 g, 0.065 mol) in anhydrous tetrahydrofuran (200 mL) was added dropwise potassium t-butoxide (1M in tetrahydrofuran, 150 mL). The mixture was stirred 30 minutes. Carbon disulfide (4.2 mL, 0.07 mol) in tetrahydrofuran (25 mL) was added dropwise and stirred 15 minutes. 2-Bromomethyl-1,3-dioxolane (25.0 g, 0.15 mol) in tetrahydrofuran (25 mL) was added dropwise and contents were refluxed 10 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MGSO4 and concentrated in vacuo leaving a red oil (29.3 g). Chromatography on silica gel eluting with 25% ethyl acetate/hexanes gave the desired compound as a red oil, (5.5 g, 18% yield). 1H NMR (CDCl3) 8.62-8.52 (m, 2H); 8.07-7.95 (m, 2H); 7.48-7.40 (m, 2H); 7.20-7.05 (m, 2H); 5.15-5.05 (m, 1H); 4.98-4.90 (m, 1H); 4.00-3.77 (m, 8H); 3.08 (d, J=6 Hz, 2H); 3.03 (d, J=6 Hz, 2H); ESHRMS m/z 464.0966 (M+H, C22H23FNO5S2 requires 464.1001); Anal. Calc'd for: C22H22FNO5S2 (0.1 H2O): C, 56.79; H, 4.81; N, 3.01. Found: C, 56.45; H, 4.71; N, 3.02.


EXAMPLE A-450



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To the compound of Example C-1, infra, (4′-fluoro-1-(4-pyridyl)acetophenone, 7.0 g, 0.0325 mol) in anhydrous tetrahydrofuran (200 mL) was added dropwise potassium t-butoxide (1M in tetrahydrofuran, 75 mL). The mixture was stirred 30 minutes. Carbon disulfide (2.1 mL, 0.035 mol) in tetrahydrofuran (25 mL) was added dropwise and stirred 15 minutes. 4-Methoxybenzyl chloride (10.2 mL, 0.075 mol) in tetrahydrofuran (10 mL) was added dropwise and contents were stirred overnight. The contents were partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo leaving a red oil (19.1 g). Chromatography on silica gel eluting with 25% ethyl acetate/hexanes gave the desired as a white solid (11.8 g, 68% yield). Recrystallization from ethyl acetate/hexanes gave the desired as colorless crystals: mp 118.5-120.6° C.; 1H NMR (CDCl3) 8.43 (d, J=7 Hz, 2H); 7. 62-7.52 (m, 2H); 7.20-6.72 (m, 12H); 3.98 (d, J=6 Hz, 4H); 3.83 (s, 3H); 3.81 (s, 3H); ESHRMS m/z 532.1408 (M+H, C30H27FNO3S2 requires 532.1416); Anal. Calc'd for: C30H26FNO3S2 (0.5 H20): C, 66.65; H, 5.03; N, 2.59. Found: C, 66.34; H, 4.96; N, 2.55.


EXAMPLE A-451



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The compound of Example A-449 (4.0 g, 9.2 mmol) and hydrazine monohydrate (2.2 mL, 46 mmol) were refluxed in ethanol (100 mL) for three hours. The mixture was allowed to cool and stand overnight. A yellow precipitate was filtered to give the desired product as a yellow solid, (1.34 g, 41% yield); mp 202.1-205.4° C.; 1H NMR (DMSO-d6) 13.5 (br s, 1H); 8.55-8.45 (m, 2H); 7.40-7.12 (m, 6H); 5.01 (s, 1H); 3.92-3.70 (m, 4H); 3.13 (s, 2H); ESHRMS m/z 358.1025 (M+H, C16H17FN3O2S requires 358.1025); Anal. Calc'd for: C18H16FN3O2S: C, 60.49; H, 4.51; N, 11.76. Found: C, 60.26; H, 4.55 N, 11.87.


EXAMPLE A-452



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The above compound was prepared similarly to the compound of Example A-451 starting with the compound prepared in Example A-450. The desired product was obtained as a white solid (2.15 g, 49% yield); mp 214.7-215.8C; 1H NMR (DMSO-d6+approx. 10%TFA) 8.70 (d, 2H); 7.60 (d, 2H); 7.42-7.38 (m, 2H); 7.30-7.20 (m, 2H); 6.70 (d, 2H); 4.10 (s, 2H); 3.68 (s, 3H); ESHRMS m/z 392.1225 (M+H, C22H19FN3OS requires 392.1232); Anal. Calc'd for: C22H18FN3OS: C, 67.50; H, 4.63; N, 10.73. Found: C, 67.46; H, 4.67 N, 10.77.


EXAMPLE A-453



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The compound prepared in step 1 of Example A-341 (50 g, 0.156 mol) and anhydrous hydrazine (25 mL, 0.8 mol) were refluxed in ethanol (500 mL) for five hours. The mixture was allowed to cool and the precipitate filtered to afford the desired product as a yellow-orange solid (21.8 g). The filtrate was diluted with water (200 mL) and a second crop was obtained as a yellow-orange solid (18.0 g). The pH of the filtrate was adjusted to pH 8 with 3N HCl and the precipitated solid filtered to give more desired as a yellow-orange solid (2.0 g). The product was obtained in 93% yield. mp 266.3-268.9° C.; 1H NMR (DMSO-d6) 13.80 (br, 1H); 12.20 (br s, 1H); 8.32 (s, 4H); 7.50-7.30 (m, 4H); ESHRMS m/z 288.0358 (M+H, C14H11ClN3S requires 288.0362); Anal. Calc'd for: C14H10ClN3S (0.4 H2O): C, 57.01; H, 3.69; N, 14.25. Found: C, 56.95; H, 3.50 N, 14.14.


EXAMPLE A-454



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The above compound was prepared similarly to the compound of Example A-453. mp 261.3-263.9° C.; 1H NMR (DMSO-d6) 11.55 (br s, 1H); 8.25-8.13 (m, 2H); 7.61-7.50 (m, 2H); 7.36-7.20 (m, 2H); 7.19-7.05 (m, 2H); ESHRMS m/z 272.0691 (M+H, C14H11FN3S requires 272.0657); Anal. Calc'd for: C14H10FN3S (0.25 H2O): C, 60.97; H, 3.84; N, 15.24. Found: C, 61.05; H, 3.64 N, 15.12.


EXAMPLE A-455

To the compound prepared in Example A-453 (100 mg, 0.35 mmol) in methanol (2 mL) was added 0.5 M sodium methoxide (0.7 mL, 0.35 mmol). The mixture was stirred for 15 minutes and filtered to remove some small particles. The filtrate was concentrated in vacuo, dissolved in water and concentrated in vacuo leaving the desired product as a white solid. 1H NMR (DMSO-d6) 11.60 (br s, 1H); 8.20 (d, 2H); 7.60-7.50 (m, 2H); 7.40-7.20 (m, 4H); Anal. Calc'd for: C14H9ClN3NaS (2.5 H2O): C, 47.40; H, 3.98; N, 11.84. Found: C, 47.39; H, 3.33; N, 11.50.


EXAMPLE A-456



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[3-(4-chlorophenyl)-4-pyridin-4-yl-1H-pyrazole-5-yl]thio]-acetonitrile

To the compound prepared in Example A-453 (584 mg, 2.0 mmol) and bromoacetonitrile (140 ul, 2.0 mmol) in dimethylformamide (5 mL) was added anhydrous potassium carbonate (276 mg, 2.0 mmol). The contents were stirred overnight, then partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo leaving a tan solid. The solid was triturated with methanol and filtered to give the desired as a off-white solid (369 mg, 56% yield). mp 230.0-230.5° C.; 1H NMR (DMSO-d6) 13.90 (br s, 1H); 8.58 (d, 2H); 7.60-7.13 (m, 6H); 4.10 (s, 2H); ESHRMS m/z 327.0482 (M+H, C16H12ClN4S requires 327.0471); Anal. Calc'd for: C16H11C11N4S (0.3 H2O): C, 57.85, H, 3.52; N, 16.87. Found C, 57.88; H, 3.31; N, 16.77.


EXAMPLE A-457



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The above compound was prepared similarly to the compound of Example A-456 except that when the contents were partitioned between ethyl acetate and water, an insoluble solid was filltered to give the desired product as a white solid (2.16 g). A second crop (1.68 g) of desired product gave a total yield of 61% . mp 192.8-195.2° C.; 1H NMR (DMSO-d6+approximately 10%TFA) 9.80 (d, 2H); 7.80 (d, 2H); 7.52-7.34 (m, 4H); 3.92 (s, 2H); 3.57 (s, 3H); ESHRMS m/z 360.05735 (M+H, C17H14ClNl3O2S requires 360.05732); Anal. Calc'd for: C17H14ClN3O2S (0.25 H2O): C, 56.05, H, 4.01; N, 11.53. Found C, 56.10; H, 3.72; N, 11.51.


EXAMPLE A-458



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The compound prepared in Example A-453 (1.2 g, 4.2 mmol), potassium carbonate (630 mg, 4.6 mmol), N-tert-butoxycarbonyl-4-bromo piperidine (1.2 g, 4.5 mmol) were heated in dimethylformamide (15 mL) at 105° C. for three hours. Contents were allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo. The residue was triturated with ethyl acetate and filtered to give the desired as a white solid (1.2 g, 61% yield). mp 220.9-221.0° C.; 1H NMR (DMSO-d6) 13.70 (br, 1H); 8.60-8.50 (m, 2H); 7.58-7.10 (m, 6H); 3.80-3.60 (m, 2H); 3.40-3.20 (m, 1H); 3.00-2.63 (m, 2H); 2.00-1.53 (m, 2H); 1.50-1.05 (m, 2H); 1.40 (S, 9H); ESHRMS m/z 471.1605 (M+H, C24H28ClN4OS requires 471.1622); Anal. Calc'd for: C24H27ClN4OS (0.5 H2O): C, 60.05; H, 5.88; N, 11.67. Found: C, 60.04; H, 5.57; N, 11.31.


EXAMPLE A-459



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3-(4-chlorophenyl)-5-[(piperidin-4-yl)-thio]-4-pyridin-4-yl-1H-pyrazole

The compound prepared in Example A-458 (5.0 g, 11 mmol), and TFA (30 mL) were mixed in methylene chloride (50 mL) and stirred overnight. The mixture was concentrated in vacuo leaving a pale yellow oil which was dissolved in water. The pH was adjusted with 2.5 N sodium hydroxide to pH 9, precipitating a white solid which was filtered to give the desired product as a white solid (3.7 g, 93% yield). mp 211.1-211.2° C.; 1H NMR (DMSO-d6) 13.80 (br, 1H); 8.55 (d, 2H); 8.40 (br, 1H); 7.50-7.15 (m, 6H); 3.50-3.00 (m, 3H); 3.00-2.80 (m, 2H); 2.05-1.80 (m, 2H); 1.65-1.42 (m, 2H); ESHRMS m/z 371.1103 (M+H, C19H20ClN4S requires 371.1097); Anal. Calc'd for: C19H19ClN4S (H2O): C, 58.68; H, 5.44; N, 14.41. Found: C, 58.86; H, 5.28; N, 14.25.


EXAMPLE A-460



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To 1-(2-chloroethyl)pyrrolidine hydrochloride (306 mg, 1.8 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide (7.0 mL, 3.6 mmol). The mixture was stirred 10 minutes and the compound of Example A-453 (500 mg, 1.8 mmol) added. The contents were refluxed one hour, allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo leaving a light amber solid. The solid was recrystallized from methanol (15 mL) to give the desired product as a white solid (213 mg, 33% yield). mp 189.9-190.1° C.; 1H NMR (DMSO-d6) 13.65 (br, 1H); 8.52 (d, 2H); 7.42 (d, 2H); 7.38-7.10 (m, 4H); 3.10-2.93 (m, 2H); 2.63-2.51 (m, 2H); 2.38 (br s, 4H); 1.70-1.52 (m, 4H); ESHRMS m/z 385.1262 (M+H, C20H22ClN4S requires 385.1254); Anal. Calc'd for: C20H21ClN4S: C, 62.41, H, 5.50; N, 14.56. Found C, 62.22; H, 5.62; N, 14.48.


EXAMPLE A-461



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Method A: The compound prepared in Example A-457 (1.3 g, 3.6 mmol) in methanol (10 mL), 2.5N sodium hydroxide (4 mL) and water (10 mL) were stirred overnight. The mixture was concentrated in vacuo to remove the methanol and the aqueous solution left was made acidic to pH 6 with 3N HCl, precipitating a solid. The solid was extracted into ethyl acetate, dried over MgSO4 and concentrated in vacuo leaving light tan crystals (205 mg). Brine was added to the aqueous layer precipitating more solid. The solid did not extract into ethyl acetate, but was filtered to give more desired product as a light tan powder (529 mg). Total yield was 61% yield. 1H NMR (DMSO-d6+10%TFA) 8.80 (d, 2H); 7.83 (d, 2H); 7.55-7.35 (m, 4H); 3.87 (s, 2H).


Method B: The compound prepared in Example A-457 (3.8 g, 11 mmol) and 3N HCl (30 mL) were reluxed for three hours. The mixture was allowed to cool and concentrated in vacuo. The residue was mixed with CH3CN (50 mL). Upon standing overnight, pale yellow crystals grew and were filtered to give the desired product as the HCl salt (2.9 g, 69% yield). 1H NMR (DMSO-d6) 8.79 (d, 2H); 7.75 (d, 2H); 7.51-7.38 (m, 4H); 3.88 (s, 2H); ESHRMS m/z 346.0435 (M+H, C17H16ClN4OS requires 346.0417); Anal. Calc'd for: C16H12ClN3O2S (HCl, 0.5 H2O): C, 49.12; H, 3.61; N, 10.74. Found: C, 49.36; H, 3.48; N, 10.72.


EXAMPLE A-462



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The compound prepared in Example A-457 (400 mg, 11 mmol) and a 2M solution of methyl amine in tetrahydrofuran (25 mL) were refluxed for three hours. The mixture was stirred overnight at room temperature before filtering to give the desired as a light amber solid (335 mg, 85% yield). mp 284.0-288.4° C.; 1H NMR (DMSO-d6) 13.58 (br, 1H); 8.60-8.45 (m, 2H); 7.98 (br s, 1H); 7.55-7.12 (m, 6H); 3.60 (s, 2H); 2.46 (s, 3H); ESHRMS m/z 359.0733 (M+H, C17H16ClN114OS requires 359.0745); Anal. Calc'd for: C17H15ClN4OS: C, 56.90; H, 4.21; N, 15.61. Found: C, 56.74; H, 4.11; N, 15.17.


EXAMPLE A-463



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The compound prepared in Example A-457 (415 mg, 12 mmol) and N,N-dimethylaminopropylamine were refluxed in methanol (25 mL) for three hours. The mixture was stirred overnight at room temperature before concentrating in vacuo leaving a solid. The solid was triturated with ethyl acetate and filtered to give the desired as a white solid (256 mg, 50% yield). mp 168.8-169.5° C.; 1H NMR (DMSO-d6) 13.80 (br, 1H); 8.55-8.50 (m 2H); 8.02 (t, 1H); 7.50-7.40 (m, 6H); 3.61 (s, 2H); 3.30-2.98 (m, 2H); 2.14-2.10 (m, 2H); 2.04 (s, 6H); 1.50-1.40 (m, 2H); ESHRMS m/z 430.1472 (M+H, C21H24ClN125OS requires 430.1468); Anal. Calc'd for: C21H24ClN5OS (0.5 H2O): C, 57.46; H, 5.74; N, 15.95. Found: C, 57.71; H, 5.56; N, 16.12.


EXAMPLE A-464



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To the compound prepared in Example A-458 (1.0 g, 2.1 mmol) in methylene chloride (25 mL) was added meta-chloroperbenzoic acid (425 mg, 2.1 mmol). The mixture was stirred 15 minutes and chromatographed on silica gel (20 g) eluting with ethyl acetate. The desired product precipitated out of the ethyl acetate elutant upon standing and was filtered to give the desired product as a white solid (958 mg, 93% yield). mp 215.8-215.9° C.; 1H NMR (DMSO-d6) 14.34 (br s, 1H); 8.57-8.54 (m, 2H); 7.51-7.25 (m, 6H); 4.00-3.82 (m, 2H); 3.60-3.40 (m, 1H); 2.85-2.70 (m, 2H); 2.10-1.95 (m, 1H); 1.56-1.10 (m, 3H); 1.36 (s, 9H); ESHRMS m/z 487.1580 (M+H, C17H16 ClN4OS requires 487.1571); Anal. Calc'd for: C24H27ClN1224O3S: C, 59.19; H, 5.59; N, 11.50. Found: C, 59.00; H, 5.76; N, 11.46.


EXAMPLE A-465



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To the compound prepared in Example A-458 (320 mg, 0.68 mmol) in ethanol (5 mL) was added an aqueous solution of potassium peroxymonosulfate (420 mg, 0.68 mmol). The mixture was stirred two hours and extracted into ethyl acetate which was dried over MGSO4 and concentrated in vacuo leaving a white solid. The solid was triturated with methanol and filtered to give the desired as a white solid (90 mg, 26% yield). mp 228.0-230.8° C.; 1H NMR (DMSO-d6) 8.61 (d, 2H); 7.48 (d, 2H); 7.31-7.20 (m, 4H); 4.05-3.90 (m, 2H); 3.54-3.35 (m, 1H); 2.85-2.60 (m, 2H); 1.92-1.80 (m, 2H); 1.48-1.25 (m, 2H); 1.32 (s, 9H); ESHRMS m/z 503.1541 (M+H, C24H27ClN4O4S requires 503.1520); Anal. Calc'd for: C24H27ClN4O4S (H2O): C, 56.30; H, 5.51; N, 10.94. Found: C, 56.41; H, 5.78; N, 10.54.


EXAMPLE A-466



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The above compound was prepared similarly to the compound of Example A-464. After chromatography the solid obtained was recrystallized from CH3CN to give the desired product as white crystals (64 mg, 33% yield). mp 189.5-189.5° C.; 1H NMR (DMSO-d6) 14.28 (br s, 1H); 8.50 (d, 2H); 7.40-7.20 (m, 4H); 7.20-7.05 (m, 4H); 6.85 (d, 2H); 4.41 (s, 2H); 3.70 (s, 3H); ESHRMS m/z 408.1168 (M+H, C22H19FN3O2S requires 408.1182); Anal. Calc'd for: C22H18FN3O2S: C, 64.85; H, 4.45; N, 10.31. Found: C, 64.44; H, 4.34; N, 10.70.


EXAMPLE A-467



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To the compound prepared in Example A-466 (1.2 g, 2.5 mmol) in methylene chloride (50 mL) was added meta-chloroperbenzoic acid (1.0 g, 5.0 mmol). The mixture was stirred 1.5 hours and filtered a white solid (620 mg) which was inorganic salts. The filtrate was chromatographed on silica gel (20 g) eluting with ethyl acetate to give the desired product as a white solid (98 mg, 9% yield). mp 241.9-242.0° C.; 1H NMR (DMSO-d6) 8.48-8.40 (m, 2H); 7.33-6.80 (m, 10H); 4.55 (s, 2H); 3.72 (s, 3H); ESHRMS m/z 424.1143 (M+H, C24H27ClN4O4S requires 424.1131); Anal. Calc'd for: C22H18FN3O3S: C, 62.40; H, 4.28; N, 9.92. Found: C, 62.14; H, 4.42; N, 9.68.


EXAMPLE A-468



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3-(4-chlorophenyl)-5-[(1-methylpiperidin-4-yl)-thio]-4-pyridin-4-yl-1H-pyrazole

The compound prepared in Example A-458 (5.0 g, 0.01 mol) and formic acid (96% , 7 mL) were heated at 100° C. for one hour. The mixture was allowed to cool to about 50° C. and formaldehyde (37%, 13 mL) was added. The contents were heated at 80° C. for two hours. The contents were allowed to cool, diluted with water (200 mL) and made basic to pH 11 with 2.5N sodium hydroxide, precipitating a white solid. The solid was filtered and recrystallized from methanol to give the desired as a white solid (174 mg. 33% yield). mp 227.7-227.7° C.; 1H NMR (DMSO-d6) 13.70 (br s, 1H); 8.56-8.48 (m, 2H); 7.50-7.15 (m, 6H); 3.10-2.92 (m, 1H); 2.63-2.50 (m, 2H); 2.05 (s, 3H); 1.95-1.65 (m, 4H); 1.50-1.30 (m, 2H); ESHRMS m/z 385.1233 (M+H, C20H22ClN4S requires 385.1254); Anal. Calc'd for: C20H21ClN4S: C, 62.41; H, 5.50; N, 14.56. Found: C, 62.40; H, 5.80; N, 14.61.


EXAMPLE A-469



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3-(4-chlorophenyl)-5-[(2-methoxyethyl)-thio]-4-pyridin-4-yl-1H-pyrazole

The above compound was prepared similarly to the compound of Example A-456 using bromoethyl methyl ether except contents were heated at 70° C. for one hour before partitioning between ethyl acetate and water. The crude product was recrystallized from methanol/ethyl acetate to give the desired product as a white solid (210 mg, 35% yield). mp 189.2-190.2° C.; 1H NMR (DMSO-d6) 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 3.60-2.85 (m, 7H); ESHRMS m/z 346.0799) M+H, C17H17ClN3OS requires 346.0781); Anal. Calc'd for: C17H16ClN3OS (H2O): C, 58.73; H, 4.70; N, 12.09. Found: C, 58.67; H, 4.86; N, 12.03.


EXAMPLE A-470



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The above compound was prepared similarly to the compound of Example A-456 using 2-chloromethylbenzimidazole except contents were heated at 70° C. for one hour before partitioning between ethyl acetate and water. An insoluble solid was filtered from the two layers and triturated with methanol to give the desired product as a light amber solid (292 mg, 40% yield). mp 257.7-257.7° C.; 1H NMR (DMSO-d6) 13.75 (br s, 1H); 12.30 (br s, 1H); 8.55-8.30 (m, 2H); 7.65-6.90 (m, 10H); 4.40 (br s, 2H); ESHRMS m/z 418.0895 (M+H, C22H17ClN5S requires 418.0893); Anal. Calc'd for: C22H16ClN5S (0.75 H2O): C, 61.25; H, 4.09; N, 16.23. Found: C, 61.27; H, 3.90; N, 15.92.


EXAMPLE A-471



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The above compound was prepared similarly to the compound of Example A-456 using DL-alpha-bromo-beta-(5-imidazolyl)propionic acid except the mixture was heated at 70° C. for one hour. The mixture contained an insoluble solid which was diluted with water and the pH was adjusted with 3N HCl to pH 7. The mixture was filtered and triturated with methanol to give the desired product as a white solid (1.5 g, 81% yield). mp 163.0-165.5° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.92 (d, 1H); 8.83-8.75 (m, 2H); 7.80 (d, 2H); 7.55-7.30 (m, 5H); 4.20-4.05 (m, 1H); 3.25-3.00 (m, 2H). ESHRMS m/z 426.0799 (M+H, C20H17ClN5O2S requires 426.0791); Anal. Calc'd for: C20H16ClN5O2S (1.8 H2O): C, 52.41 H, 4.31; N, 15.28. Found: C, 52.68; H, 4.58; N, 15.37.


EXAMPLE A-472



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To the compound prepared in Example A-453 (264 mg, 0.9 mmol) and alpha-methylenebutyrolactone (0.08 mL, 0.9 mmol) in ethanol was added a drop of triethylamine. The mixture was stirred overnight. The resulting solid was filtered and triturated with methanol to give the desired product as a pale yellow solid (181 mg, 51% yield). mp 224.2-225.9° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.53-7.33 (m, 4H); 4.30-4.05 (m, 2H); 3.50-3.40 (m, 1H); 3.15-2.90 (m, 2H); 2.32-2.20 (m, 1H) 2.10-1.90 (m, 1H); ESHRMS m/z 386.0760 (M+H, C19H17ClN3O2S requires 386.0730); Anal. Calc'd for: c19H16ClN3O2S: C, 59.14 H, 4.18; N, 10.89. Found: C, 58.97; H, 4.21; N, 10.96.


EXAMPLE A-473



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The above compound was prepared similarly to the compound of Example A-456 using 2-bromomethyl-1,3-dioxolane except the mixture was heated at 80° C. for two hours. The mixture was diluted with water and filtered to give a white solid (502 mg). The solid was recrystallized from ethanol to give the desired product as off-white crystals (280 mg, 43% yield). mp 197.0-198.2° C.; 1H NMR (DMSO-d6) 13.60 (br s, 1H); 8.60-8.45 (m, 2H); 7.60-7.10 (m, 6H); 5.15-4.85 (m, 1H); 3.95-3.62 (m, 4H); 3.40-2.95 (m, 2H); ESHRMS m/z 374.0741 (M+H, C18H17ClN3O2S requires 374.0730); Anal. Calc'd for: C18H16ClN3O2S: C, 57.83 H, 4.31; N, 11.24. Found: C, 57.69; H, 4.41; N, 11.15.


EXAMPLE A-474



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The above compound was prepared similarly to the compound of Example A-456 using 2-(2-bromoethoxy)tetrahydro-2H-pyran except that the mixture was heated at 80° C. for four hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo leaving a solid (737 mg). The solid was recrystallized from ethanol to give the desired product as pale yellow crystals (281 mg, 39% yield). mp 163.2-163.5° C.; 1H NMR (DMSO-d6) 13.80-13.70 (m, 1H), 8.60-8.42 (br s, 1H); 7.60-7.10 (m, 6H); 4.60-4.30 (m, 1H); 3.90-2.90 (m, 6H); 1.70-1.20 (m, 6H); ESHRMS m/z 416.1200 (M+H, C21H23ClN3O2S requires 416.1198); Anal. Calc'd for: C21H22ClN3O2S: C, 60.64 H, 5.33; N, 10.10. Found: C, 60.49; H, 5.71; N, 9.96.


EXAMPLE A-475



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The above compound was prepared similarly to the compound of Example A-456 using 4-bromobutyronitrile except the mixture was heated at 55° C. for one hour. The mixture was diluted with water (75 mL) and filtered to give a white solid (567 mg). The solid was recrystallized from methanol to give the desired product as white crystals (333 mg, 54% yield). mp 216.7-216.9° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.80-8.75 (m, 2H); 7.83-7.75 (m, 2H); 7.50-7.35 (m, 4H); 3.10-3.00 (m, 2H); 2.60-2.45 (m, 2H); 1.95-1.80 (m, 2H); ESHRMS m/z 355.0818 (M+H, C18H16ClN4S requires 355.0784); Anal. Calc'd for: C18H15ClN4S (0.5 H2O). C, 59.42 H, 4.43; N, 15.40. Found: C, 59.64; H, 4.11; N, 15.44.


EXAMPLE A-476



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The compound prepared in Example A-461 (416 mg, 1.1 mmol), morpholine (4 mL), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (481 mg, 1.5 mmol) and dimethylformamide (10 mL) were stirred overnight. The mixture was diluted with water (75 mL) and the resulting solid was filtered (363 mg). The solid was recrystallized from ethanol to give the desired product as a white solid (219 mg, 48% yield). mp 215.4-215.5° C.; 1H NMR (DMSO-d6) 13.70-13.60 (m, 1H); 8.60-8.50 (m, 2H); 7.50-7.10 (m, 6H); 3.93-3.80 (m, 2H); 3.60-3.20 (m, 8H); ESHRMS m/z 415.0995 (M+H, C20H20ClN4O2S requires 415.1001); Anal. Calc'd for: C20H19ClN4O2S: C, 57.90 H, 4.62; N, 13.50. Found: C, 57.87; H, 4.86; N, 13.53.


EXAMPLE A-477



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The above compound was prepared similarly to the compound of Example A-456 using 2-bromopropionitrile except the mixture was heated at 70° C. for one hour. The mixture was diluted with water (75 mL) and filtered to give an off-white solid (662 mg). The solid was recrystallized from methanol to give the desired product as a white solid (220 mg, 37% yield). mp 211.1-212.8° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.87-8.80 (m, 2H); 7.90-7.80 (m, 2H); 7.55-7.45 (m, 6H); 4.42 (q, 1H); 1.50 (d, 3H); ESHRMS m/z 341.0628 (M+H, C17H 16ClN4S requires 341.0628); Anal. Calc'dfor: C17H13ClN4S: C, 59.91 H, 3.84; N, 16.44. Found: C, 59.64; H, 4.01; N, 16.18.


EXAMPLE A-478



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The above compound was prepared similarly to the compound of Example A-456 using propargyl bromide. The mixture was diluted with water (75 mL) and filtered to give a pale yellow solid (577 mg). The solid was triturated with methanol to give the desired product as a white solid (388 mg, 68% yield). mp 212.7-213.2° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.80 (d, J=6.8 Hz, 2H); 7.82 (d, J=6.8 Hz, 2H); 7.50-7.35 (m, 4H); 3.81 (d, J=2.6 Hz, 2H); 3.05 (t, J=2.6 Hz, 1H); ESHRMS m/z 326.0533 (M+H, C17H13ClN3S requires 326.0519); Anal. Calc'd for: C17H12ClN3S (0.2 H2O): C, 61.98 H, 3.79; N, 12.76. Found: C, 61.89; H, 3.45; N, 12.67.


EXAMPLE A-479



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The above compound was prepared similarly to the compound of Example A-456 using allyl bromide. The mixture was diluted with water (75 mL) and filtered to give a pale yellow solid (509 mg). The solid was recrystallized from methanol to give the desired product as a pale yellow solid (187 mg, 33% yield). mp 207.3-208.1° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.50-7.30 (m, 4H); 5.90-5.70 (m, 1H); 5.10-4.95 (m, 2H); 3.62 (d, 2H); ESHRMS m/z 328.0693 (M+H, C17H15ClN3S requires 328.0675); Anal. Calc'd for: C17H14ClN3S (0.1 H2O): C, 61.94 H, 4.34; N, 12.75. Found: C, 61.83; H, 4.21; N, 12.76.


EXAMPLE A-480



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The above compound was prepared similarly to the compound of Example A-456 using 2-bromoethylamine except two equivalents of potassium carbonate were used. The mixture was diluted with water (75 mL) and filtered to give a pale yellow solid (509 mg). The solid was recrystallized from methanol to give the desired product as a pale yellow solid (262 mg, 45% yield). mp 186.8-187.8° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.85-8.75 (m, 2H); 8.90 (br s, 2H); 8.85-8.75 (m, 2H); 7.55-7.35 (m, 4H); 3.30-3.00 (m, 4H); ESHRMS m/z 331.0779 (M+H, C16H16ClN4S requires 331.0784); Anal. Calc'd for: C16H15ClN4S (0.5 H2O): C, 56.55; H, 4.75; N, 16.49. Found: C, 56.28; H, 4.38; N, 16.20.


EXAMPLE A-481



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The above compound was prepared similarly to the compound of Example A-456 using 3-(2-bromoethyl)indole. The mixture was diluted with water (75 mL) and filtered to give a pale yellow solid (752 mg). The solid was triturated with methanol to give the desired product as a white solid (682 mg, 91% yield). mp 211.9-213.20C; 1H NMR (DMSO-d6+approx. 10%TFA) 10.80 (s, 1H); 8.72 (d, 2H); 7.71 (d, 2H); 7.55-7.35 (m, 5H); 7.29 (d, 1H); 7.12-6.88 (m, 3H); 3.40-3.30 (m, 2H); 3.05-2.95 (m, 2H); ESHRMS m/z 431.1095 (M+H, C24H20ClN4S requires 431.1097); Anal. Calc'd for: C24H19ClN4S (0.15 H2O): C, 66.47 H, 4.49; N, 12.92. Found: C, 66.44; H, 4.51; N, 12.84.


EXAMPLE A-482



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The compound of Example A-464 (464 mg, 0.95 mmol) and TFA (8 mL) were mixed in methylene chloride (10 mL) and stirred overnight. The mixture was concentrated in vacuo and the residue was partitioned between ether and water. The aqueous layer was made basic to pH 10 with 2.5N sodium hydroxide and extracted with ethyl acetate (2×100 mL). Upon standing overnight, a solid precipitated from the aqueous layer and was filtered to give the desired product as a white solid (183 mg, 50% yield). mp 189.1-190.8° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.85 (d, 2H); 8.80-8.60 (m 1H); 8.45-8.25 (m, 1H); 7.90 (d, 2H); 7.55-7.30 (m, 4H); 3.65-3.20 (m 3H); 3.10-2.80 (m 2H); 2.20-2.00 (m, 1H); 1.90-1.50 (m, 3H); ESHRMS m/z 387.1032 (M+H, C19H20ClN4OS requires 387.1046); Anal. Calc'd for: C19H20ClN4OS (2 H2O): C, 53.96 H, 5.48; N, 13.25. Found: C, 53.75; H, 4.99; N, 13.21.


EXAMPLE A-483



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The above compound was prepared similarly to the compound of Example A-456 using 3-bromopropionitrile. The mixture was diluted with water (75 mL) and extracted into ethyl acetate, which was dried over MGSO4 and concentrated in vacuo leaving an orange waxy solid (523 mg). The solid was dissolved in CH3CN and filtered through a pad of silica gel and eluted with ethyl acetate to give a white solid. The solid was triturated with ethyl acetate and filtered to give the desired product as a white solid (76 mg, 13% yield). mp 205.7-206.5° C.; 1H NMR (DMSO-d6+approx. 10%TFA) 8.80 (d, 2H); 7.80 (d, 2H); 7.55-7.35 (m, 4H); 3.30-3.20 (m, 2H); 2.90-2.80 (m, 2H); ESHRMS m/z 341.0639 (M+H, C19H20ClN4OS requires 341.0628); Anal. Calc'd for: C17H13ClN4S (0.25 H2O): C, 59.13 H, 3.94; N, 16.22. Found: C, 59.03; H, 3.93; N, 15.90.


EXAMPLE A-484



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A solution of 5-amino-3-(4-chlorophenyl)-4-(pyridin-4-yl)-pyrazole (200 mg, 0.74 mmol) and toluene sulfonyl chloride (564 mg, 2.94 mmol, prepared as set forth in Example A-427) in pyridine (5 mL) was stirred at 100° C. for two days. The mixture was concentrated in vacuo to a brown residue. The residue was chromatographed on a silica gel column eluting with 10% methanol/dichloromethane. The fractions containing the desired product were combined and concentrated to a yellow solid which was washed with diethyl ether and filtered to afford 78 mg (25% ) of the desired sulfonamide as a white solid. m.p.284.3-284.4° C. 1H NMR (DMSO/300 MHz) δ 13.33 (brs, 0.8H), 9.94 (brs, 0.75H), 8.48 (brs, 1.75H), 8.22 (brs, 0.3H), 7.63 (d, 1.7H), 7.47 (d, 1.85H), 7.24 (m, 6.45H), 7.02 (brs, 0.25H), 6.81 (brs, 0.20H). ESLRMS m/z 425 (M+H). ESHRMS m/z 425.0848 (M+H, C21H18N4ClS requires 425.0839).


EXAMPLE A-485



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

mp >300° C. (decomposed). 1H NMR (CD3OD/300 MHz) 8.50 (d, 2H, J=6.0 Hz), 7.51 (d, 2H, J=5.8 Hz), 2.99-2.93, (m, 4H), 2.52-2.48 (m, 4H), 3.04-3.02 (m, 4H), 2.96 (s, 3H), 2.54-2.49 (m, 1H), 2.31-2.26 (m, 4H), 1.84-1.33 (m, 10H). FABLRMS m/z 326 (M+H).


Additional compounds of the present invention which could be prepared using one or more of the reaction schemes set forth in this application include, but are not limited to, the following:
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4-[3-(4-chlorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine



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



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



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4-[5-(1-piperazinyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]benzonitrile



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



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



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



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



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



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3-(4-chlorophenyl)-5-(1-piperazinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol



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4-[2-aminoethyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydro-3-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-6-ol



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4-(2-aminoethyl)-2-(4-chlorophenyl)-4,5,6,7-tetrahydro-3-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-6-ol



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3-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol



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5-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-3-ethanamine



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5-(4-chlorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-3-ethanamine



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4-[3-(4-fluorophenyl)-5-(4-piperidinyl)-1H-pyrazol-4-yl]pyrimidine



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4-[3-(4-chlorophenyl)-5-(4-piperidinyl)-1H-pyrazol-4-yl]pyrimidine



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



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N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]acetamide



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N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinylpropanamide



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N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]propanamide



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6-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-1H-purine



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6-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-1H-purine



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



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



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N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)propanamide



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1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine



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1-[2-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine



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1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]piperazine



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1-[2-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]ethyl]-4-methylpiperazine



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



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



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



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



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



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



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine



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



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2,6-trimethylpiperazine



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



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



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-dimethylpiperazine



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



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



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



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



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



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



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



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



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5-(4-chlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine



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5-(4-fluorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-4-(4-pyridinyl)-1H-pyrazol-3-amine



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



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-3-piperidinamine



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



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



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanol



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinemethanamine



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanol



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinemethanamine



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4-[3-(4-chlorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine



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4-[3-(4-fluorophenyl)-5-(4-methyl-1-piperazinyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine



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1-[[5-(4-chliorophlenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-piperidinol



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



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



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



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylic acid



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ethyl 4-[5[-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylate



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylic acid



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ethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylate



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxamide



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4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxamide



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



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ethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxylate



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-2-piperazinecarboxamide



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylic acid



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ethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxylate



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4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-methyl-2-piperazinecarboxamide



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-ethyl-4-piperidinamine



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



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1-acetyl-N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine



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



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-cyclopropyl-4-piperidinamine



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(methoxyacetyl)-4-piperidinamine



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N-[5-(40-chlrophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-(methylethyl)-4-piperidinamine



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N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-propyl-4-piperidinamine



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ethyl 4-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]-1-piperidinecarboxylate



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Additional compounds of specific interest include the compounds of Tables 3-3, 3-4, 3-5 and 3-6:

TABLE 3-3embedded imageR2R5R124-piperidinylmethylm- or p-fluoro4-piperidinylethylm- or p-fluoro4-piperidinylaminom- or p-fluoro4-piperidinylmethylaminom- or p-fluoro4-piperidinyldimethylaminom- or p-fluoro4-piperidinylethylaminom- or p-fluoro4-piperidinyldiethylaminom- or p-fluoro4-piperidinylpropylaminom- or p-fluoro4-piperidinyldipropylaminom- or p-fluoro4-piperidinylhydroxyethylaminom- or p-fluoro4-piperidinyl1-hydroxy-1,1-m- or p-fluorodimethylethyl4-piperidinylmethoxyethylaminom- or p-fluoro4-piperidinylmethylm- or p-chloro4-piperidinylethylm- or p-chloro4-piperidinylaminom- or p-chloro4-piperidinylmethylaminom- or p-chloro4-piperidinyldimethylaminom- or p-chloro4-piperidinylethylaminom- or p-chloro4-piperidinyldiethylaminom- or p-chloro4-piperidinylpropylaminom- or p-chloro4-piperidinyldipropylaminom- or p-chloro4-piperidinylhydroxyethylaminom- or p-chloro4-piperidinyl1-hydroxy-1,1-m- or p-chlorodimethylethyl4-piperidinylmethoxyethylaminom- or p-chloro4-piperidinylmethylm- or p-methyl4-piperidinylethylm- or p-methyl4-piperidinylaminom- or p-methyl4-piperidinylmethylaminom- or p-methyl4-piperidinyldimethylaminom- or p-methyl4-piperidinylethylaminom- or p-methyl4-piperidinyldiethylaminom- or p-methyl4-piperidinylpropylaminom- or p-methyl4-piperidinyldipropylaminom- or p-methyl4-piperidinylhydroxyethylaminom- or p-methyl4-piperidinyl1-hydroxy-1,1-m- or p-methyldimethyl ethyl4-piperidinylmethoxyethylaminom- or p-methyl4-piperazinylmethylm- or p-fluoro4-piperazinylethylm- or p-fluoro4-piperazinylaminom- or p-fluoro4-piperazinylmethylaminom- or p-fluoro4-piperazinyldimethylaminom- or p-fluoro4-piperazinylethylaminom- or p-fluoro4-piperazinyldiethylaminom- or p-fluoro4-piperazinylpropylaminom- or p-fluoro4-piperazinyldipropylaminom- or p-fluoro4-piperazinylhydroxyethylaminom- or p-fluoro4-piperazinyl1-hydroxy-1,1-m-or p-fluorodimethylethyl4-piperazinylmethoxyethylaminom- or p-fluoro4-piperazinylmethylm- or p-chloro4-piperazinylethylm- or p-chloro4-piperazinylaminom- or p-chloro4-piperazinylmethylaminom- or p-chloro4-piperazinyldimethylaminom- or p-chloro4-piperazinylethylaminom- or p-chloro4-piperazinyldiethylaminom- or p-chloro4-piperazinylpropylaminom- or p-chloro4-piperazinyldipropylaminom- or p-chloro4-piperazinylhydroxyethylaminom- or p-chloro4-piperazinyl1-hydroxy-1,1-m- or p-chlorodimethylethyl4-piperazinylmethoxyethylaminom- or p-chloro4-piperazinylmethylm- or p-methyl4-piperazinylethylm- or p-methyl4-piperazinylaminom- or p-methyl4-piperazinylmethylaminom- or p-methyl4-piperazinyldimethylaminom- or p-methyl4-piperazinylethylaminom- or p-methyl4-piperazinyldiethylaminom- or p-methyl4-piperazinylpropylaminom- or p-methyl4-piperazinyldipropylaminom- or p-methyl4-piperazinylhydroxyethylaminom-or p-methyl4-piperazinyl1-hydroxy-1,1-m- or p-methyldimethylethyl4-piperazinylmethoxyethylaminom- or p-methylaminocyclohexylmethylm- or p-fluoroaminocyclohexylethylm- or p-fluoroaminocyclohexylaminom- or p-fluoroaminocyclohexylmethylaminom- or p-fluoroaminocyclohexyldimethylaminom- or p-fluoroaminocyclohexylethylaminom- or p-fluoroaminocyclohexyldiethylaminom- or p-fluoroaminocyclohexylpropylaminom- or p-fluoroaminocyclohexyldipropylaminom- or p-fluoroaminocyclohexylhydroxyethylaminom- or p-fluoroaminocyclohexyl1-hydroxy-1,1-m- or p-fluorodimethylethylaminocyclohexylmethoxyethylaminom- or p-fluoroaminocyclohexylmethylm- or p-chloroaminocyclohexylethylm- or p-chloroaminocyclohexylaminom- or p-chloroaminocyclohexylmethylaminom- or p-chloroaminocyclohexyldimethylaminom- or p-chloroaminocyclohexylethylaminom- or p-chloroaminocyclohexyldiethylaminom- or p-chloroaminocyclohexylpropylaminom- or p-chloroaminocyclohexyldipropylaminom- or p-chloroaminocyclohexylhydroxyethylaminom- or p-chloroaminocyclohexyl1-hydroxy-1,1-m- or p-chlorodimethylethylaminocyclohexylmethoxyethylaminom- or p-chloroaminocyclohexylmethylm- or p-methylaminocyclohexylethylm- or p-methylaminocyclohexylaminom- or p-methylaminocyclohexylmethylaminom- or p-methylaminocyclohexyldimethylaminom- or p-methylaminocyclohexylethylaminom- or p-methylaminocyclohexyldiethylaminom- or p-methylaminocyclohexylpropylaminom- or p-methylaminocyclohexyldipropylaminom- or p-methylaminocyclohexylhydroxyethylaminom- or p-methylaminocyclohexyl1-hydroxy-1,1-m- or p-methyldimethylethylaminocyclohexylmethoxyethylaminom- or p-methyl


Still other compounds of specific interest include those compounds of Table 3-3 modified as follows:


(1) The 4-piperidinyl moiety is replaced with a 1-, 2-or 3-piperidinyl moiety; and/or


(2) The 4-piperidinyl, 3-piperidinyl, 2-piperidinyl or piperazinyl ring is substituted at a nitrogen ring atom with methyl, ethyl, isopropyl, cyclopropyl, propargyl, benzyl, hydroxyethyl, methoxyethyl, or methoxyacetyl; and/or


(3) The 1-piperidinyl ring is substituted at a carbon ring atom with methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, cyclopropylamino, propargylamino, benzylamino, hydroxyethylamino, methoxyethylamino, or methoxyacetylamino; and/or


(4) The amino group of the aminocyclohexyl is replaced with methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, methoxyethylamino, or methoxyacetylamino; and/or


(5) A linking group selected from the group consisting of methylene, —S—, —O—, and —NH— separates the piperidinyl, piperazinyl or cyclohexyl moiety from the pyrazole nucleus.

TABLE 3-4embedded imageR4R3R200R2014-pyridyl4-methylphenylHO4-pyridyl4-methylphenylCH3O4-pyrimidyl4-methylphenylHO4-pyrimidyl4-methylphenylCH3O4-pyridyl4-methylphenylHS4-pyridyl4-methylphenylCH3S4-pyrimidyl4-methylphenylHS4-pyrimidyl4-methylphenylCH3S4-pyridyl3-methylphenylHO4-pyridyl3-methylphenylCH3O4-pyrimidyl3-methylphenylHO4-pyrimidyl3-methylphenylCH3O4-pyridyl3-methylphenylHS4-pyridyl3-methylphenylCH3S4-pyrimidyl3-rnethylphenylHS4-pyrimidyl3-methylphenylCH3S









TABLE 3-5















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R4
n
X













4-chlorophenyl
1
S



4-chlorophenyl
2
SO



4-chlorophenyl
2
SO



4-chlorophenyl
2
CH2



4-chlorophenyl
2
CHCH3



4-chlorophenyl
2
CHOH



4-chlorophenyl
1
CH2



4-chlorobenzyl
2
NCH3



2-chlorophenyl
2
NCH3



3,4-methylenedioxyphenyl
2
NCH3



cyclohexyl
2
NCH3



2-thienyl
2
NCH3



5-chloro-2-thienyl
2
NCH3



4-propynylphenyl
2
NCH3



4-methylsulfoxylphenyl
2
NCH3



4-methylsulfonylphenyl
2
NCH3



2-(1-methyl-5-chloro)indolyl
2
NCH3

















TABLE 3-6















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R4
R3
R400













p-Cl phenyl
4-pyridyl
—SO2CH3



p-Cl phenyl
4-pyridyl
—CH2CN







p-Cl phenyl
4-pyridyl


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p-Cl phenyl


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H










BIOLOGICAL EVALUATION

p38 Kinase Assay


Cloning of Human p38a:


The coding region of the human p38a cDNA was obtained by PCR-amplification from RNA isolated from the human monocyte cell line THP.1. First strand CDNA was synthesized from total RNA as follows: 2 μg of RNA was annealed to 100 ng of random hexamer primers in a 10 μl reaction by heating to 70° C. for 10 minutes followed by 2 minutes on ice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega, Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5× buffer, 2 μl of 100 mM DTT and 1 μl (200 U) of Superscript II™ AMV reverse transcriptase. Random primer, dNTP's and Superscript™ reagents were all purchased from Life-Technologies, Gaithersburg, Mass. The reaction was incubated at 42° C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5 μl of the reverse transcriptase reaction into a 100 μl PCR reaction containing the following: 80 μl dH2O, 2 μl 50 mM dNTP's, 1 μl each of forward and reverse primers (50 pmol/μl), 10 μl of 10× buffer and 1 μl Expand™ polymerase (Boehringer Mannheim). The PCR primers incorporated Bam HI sites onto the 5′ and 3′ end of the amplified fragment, and were purchased from Genosys. The sequences of the forward and reverse primers were 5′-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3′ and 5′GATCGAGGATTCTCAGGACTCCATCTCTTC-3′ respectively. The PCR amplification was carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 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 dNTP's were removed from the amplified fragment with a Wizard TM PCR prep (Promega) and digested with Bam HI (New England Biolabs). The Bam HI digested fragment was ligated into BamHI digested pGEX 2T plasmid DNA (PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The ligation reaction 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 a Promega Wizard™ miniprep kit. Plasmids containing the appropriate Bam HI fragment were sequenced in a DNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.). cDNA clones were identified that.coded for both human p38a isoforms (Lee et al. Nature 372, 739). One of the clones which contained the cDNA for p38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T, 3′ of the GST coding region was designated pMON 35802. The sequence obtained for this clone is an exact match of the cDNA clone reported by Lee et al. This expression plasmid allows for the production of a GST-p38a fusion protein.


Expression of Human p38a:


GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E. coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The next day, 500 ml of fresh LB was inoculated with 10 ml of overnight culture, and grown in a 2 liter flask at 37° C. with constant shaking until the culture reached an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by addition of isopropyl b-D-thiogalactosidse (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for three hours at room temperature, and the cells were harvested by centrifugation. The cell pellets were stored frozen until protein purification.


Purification of p38 Kinase-α:


All chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet collected from five 1 L shake flask fermentations was resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 1.8 mM KH2PO4, pH 7.3) up to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then split equally into five 50 ml Falcon conical tubes. The cells were sonnicated (Ultrasonics model W375) with a 1 cm probe for 3×1 minutes (pulsed) on ice. Lysed cell material was removed by centrifugation (12,000×g, 15 minutes) and the clarified supernatant applied to glutathione-sepharose resin (Pharmacia).


Glutathione-Sepharose Affinity Chromatography:


Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200 ml clarified supernatant and incubated batchwise for 30 minutes at room temperature. The resin was collected by centrifugation (600×g, 5 min) and washed with 2×150 ml PBS/1% Triton X-100, followed by 4×40 ml PBS. To cleave the p38 kinase from the GST-p38 fusion protein, the glutathione-sepharose resin was resuspended in 6 ml PBS containing 250 units thrombin protease (Pharmacia, specific activity >7500 units/mg) and mixed gently for 4 hours at room temperature. The glutathione-sepharose resin was removed by centrifugation (600×g, 5 min) and washed 2×6 ml with PBS. The PBS wash fractions and digest supernatant containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.


Mono Q Anion Exchange Chromatography:


The thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved sample was diluted 2-fold 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 160 ml 0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).


Sephacryl S100 Gel Filtration Chromatography:


The concentrated Mono Q-p38 kinase purified sample was purified by gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 column equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5 ml/minute flowrate and protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at −80° C. Typical purified protein yields from 5 L E. coli shake flasks fermentations were 35 mg p38 kinase.


In Vitro Assay


The ability of compounds to inhibit human p38 kinase alpha was evaluated using two in vitro assay methods. In the first method, activated human p38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I (phosphorylated heat and acid stable protein-insulin inducible), in the presence of gamma 32P-ATP (32P-ATP). PHAS-I was biotinylated prior to the assay and provides a means of capturing the substrate which is phosphorylated during the assay. p38 Kinase was activated by MKK6. Compounds were tested in 10 fold serial dilutions over the range of 100 μM to 0.001 μM using 1% DMSO. Each concentration of inhibitor was tested in triplicate.


All reactions were carried out in 96 well polypropylene plates. Each reaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and 50 μM unlabeled ATP. Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μg per 50 μl reaction volume, with a final concentration of 1.5 μM. Activated human p38 kinase alpha was used at 1 μg per 50 μl reaction volume representing a final concentration of 0.3 μM. Gamma 32P-ATP was used to follow the phosphorylation of PHAS-I. 32P-ATP has a specific activity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reaction volume. The reaction proceeded either for one hour or overnight at 30° C.


Following incubation, 20 μl of reaction mixture was transferred to a high capacity streptavidin coated filter plate (SAM-streptavidin-matrix, Promega) prewetted with phosphate buffered saline. The transferred reaction mix was allowed to contact the streptavidin membrane of the Promega plate for 1-2 minutes. Following capture of biotinylated PHAS-I with 32P incorporated, each well was washed to remove unincorporated 32P-ATP three times with 2M NaCl, three washes of 2M NaCl with 1% phosphoric, three washes of distilled water and finally a single wash of 95% ethanol. Filter plates were air dried and 20 μl of scintillant was added. The plates were sealed and counted. Results are shown in Table 4.


A second assay format was also employed that is based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, a 21 mer) in the presence of 33P-ATP. Compounds were tested in 10 fold serial dilutions over the range of 100 μM to 0.001 μM in 10% DMSO. Each concentration of inhibitor was tested in triplicate. Compounds were evaluated in 50 μl reaction volumes in the presence of 25 mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05 uCi gamma 33P-ATP. Reactions were initiated by addition of 0.09 μg of activated, purified human GST-p38 kinase alpha. Activation was carried out using GST-MKK6 (5:1, p38:MKK6) for one hour at 30° C. in the presence of 50 μM ATP. Following incubation for 60 minutes at room temperature, the reaction was stopped by addition of 150 μl of AG 1×8 resin in 900 mM sodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer). The mixture was mixed three times with pipetting and the resin was allowed to settle. A total of 50 μl of clarified solution head volume was transferred from the reaction wells to Microlite-2 plates. 150 μl of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted.

TABLE 4p38 kinaseExampleIC50 (μM)14.621.58<0.1163.8231.5252.6260.7280.3332.5348.03612.1380.8391.1401.3420.343<0.144<0.145<0.146<0.1473.2481.8502.351<0.1520.1530.9540.7556.4143<0.1


TNF Cell Assays


Method of Isolation of Human Peripheral Blood Mononuclear Cells:


Human whole blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully layered over 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The sample was centrifuged at 450-500×g for 30-35 minutes in a swing out rotor at room temperature. After centrifugation, the top band of cells were removed and washed 3 times with PBS w/o calcium or magnesium. The cells were centrifuged at 400×g for 10 minutes at room temperature. The cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml.


LPS Stimulation of Human PBMs:


PBM cells (0.1 ml, 2 million/ml) were co-incubated with 0.1 ml compound (10-0.41 μM, final concentration) for 1 hour in flat bottom 96 well microtiter plates. Compounds were dissolved in DMSO initially and diluted in TCM for a final concentration of 0.1% DMSO. LPS (Calbiochem, 20 ng/ml, final concentration) was then added at a volume of 0.010 ml. Cultures were incubated overnight at 37° C. Supernatants were then removed and tested by ELISA for TNF-a and IL1-b. Viability was analyzed using MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS was added to remaining 0.1 ml cells. The cells were incubated at 37° C. for 2-4 hours, then the O.D. was measured at 490-650 nM.


Maintenance and Differentiation of the U937 Human Histiocytic Lymphoma Cell Line:


U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2 mM glutamine (Gibco). Fifty million cells in 100 ml media were induced to terminal monocytic differentiation by 24 hour incubation with 20 ng/ml phorbol 12-myristate 13-acetate (Sigma). The cells were washed by centrifugation (200×g for 5 min) and resuspended in 100 ml fresh medium. After 24-48 hours, the 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 μM, final concentration) for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in culture medium to yield a final DMSO concentration of 0.1% in the cell assay. LPS (E coli, 100 ng/ml final concentration) was then added at a volume of 0.02 ml. After 4 hour incubation at 37° C., the amount of TNF-α released in the culture medium was quantitated by ELISA. Inhibitory potency is expressed as IC50 (μM). Results of these TNF Cell Assays are shown in Table 5.


TNF Inhibition: Human Whole Blood Assay


Human peripheral blood is obtained in heparinized tubes. A 190 μL aliquot of blood is placed in each well of a 96 well u-bottom plate. A compound or control vehicle (phosphate buffered saline with dimethylsulfoxide and ethanol) is added to the blood in 10 μL aliquots for serial dilutions providing final concentrations of 25, 5, 1 and 0.25 μM. The final dimethylsulfoxide and ethanol concentrations are 0.1% and 1.5%, respectively. After one hour of incubation at 37° C., 10 mL of lipopolysaccharide (Salmonella typhosa, Sigma) in phosphate buffered saline is added resulting in a final concentration of 10 mg/mL. After four to five hours of incubation at 37° C., the supernatants are harvested and assayed at 1:10 or 1:20 dilutions for human TNF using ELISA.

TABLE 5Human PBM AssayU937 Cell AssayExampleIC50 (μM)IC50 ((μM)10.521.60.57840.10.22250.27470.20.2018<0.190.4100.71.687128.5134.8141.2171.1190.30.484201.089210.077223.2248.226<0.10.029272.7280.1292.2302.6310.81.053322.696330.4340.5350.7361.4371.50.099380.20.208390.70.244400.4411.0420.743<0.10.243440.40.47745<0.10.04460.329472.359482.20.522496.8500.9510.074540.20.1355<0.10.2281430.301


Rat Assay


The efficacy of the novel compounds in blocking the production of TNF also was evaluated using a model based on rats challenged with LPS. Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and was fasted overnight prior to testing. Compound administration was typically by oral gavage (although intraperitoneal, subcutaneous and intravenous administration were also used in a few instances) 1 to 24 hours prior to the LPS challenge. Rats were administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.] intravenously via the tail vein. Blood was collected via heart puncture 1 hour after the LPS challenge. Serum samples were stored at −20° C. until quantitative analysis of TNF-α by Enzyme Linked-Immuno-Sorbent Assay (“ELISA”) [Biosource]. Additional details of the assay are set forth in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated by reference in this application.


Mouse Assay


Mouse Model of LPS-Induced TNF Alpha Production:


TNF alpha was induced in 10-12 week old BALB/c female mice by tail vein injection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline. One hour later mice were bled from the retroorbital sinus and TNF concentrations in serum from clotted blood were quantified by ELISA. Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour after LPS injection.


The compounds tested 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 hour or 6 hours prior to LPS injection. The 1 hour protocol allowed evaluation of compound potency at Cmax plasma levels whereas the 6 hour protocol allowed estimation of compound duration of action. Efficacy was determined at each time point as percent inhibition of serum TNF levels relative to LPS injected mice that received vehicle only.


Additional results obtained using the above-described assays are set forth in Table 6 below. p38 assay and U937 cell assay results are expressed as IC50 (μm). Mouse-LPS assay results are expressed as percent inhibition.

TABLE 6mLPSmLPSmLPSExamplep381p382U9378 h6 h dose1 h, 30 mpkA-2120.490.740.0967201093A-2080.1040.0490.1896983097A-2270.0696A-2280.760.3390.4173323092A-2291.40.46227691A-2300.420.17896A-2310.1740.3225863094A-2320.04896A-2330.04453A-2340.103A-2350.10456A-2360.23794A-2370.0930.08760A-2380.1770.4016A-2390.034513087A-2400.961783085A-2410.338793087A-2420.047953087A-2430.72982A-2440.099A-245<.0010.033765A-2460.4030.5920.4952A-247<0.010.166A-2490.432733086A-2502.873A-2510.6373287A-2520.7741.197483075A-253<.0010.004461A-2540.0810.1411A-2152.340.2976383080A-2560.8130.4562A-2571.081<.010.5167A-2130.2257A-2580.481.208368A-2590.170.757462A-2100.160.1983853093A-2600.231.2821473079A-2140.061.400670A-2610.0080.2542483092A-2160.0181.8287273091A-262<0.10.326745A-263<0.01<0.10.543449A-2640.259461A-265<0.10.601632A-2660.53930A-2670.432.668180A-268<0.010.007411A-2170.6970.34869A-269>10 uM51A-2700.0150.346653A-2710.2164.214468A-2720.0730.583−8A-2736.98>1043A-274<0.10.922130A-27510.142>10A-2760.1760.45−2430A-2770.0263330A-2780.2852.36230A-2790.0050.76430A-2800.1341530A-2810.0532230A-2180.0441830A-2820.0450.09733030A-283<0.10.7998−2030A-2840.980.5088−1A-285<0.10.17951130A-2860.0570.092930A-2870.0410.27−2430A-2880.0170.34030A-289<0.10.144430A-2906.0191430A-2910.3881.13093630A-2921.15>10A-2930.73A-2940.0150.56130A-2957.66>109430A-29626A-2970.520.178930
1p38α in vitro assay results based on PHAS-I assay procedure

2p38α in vitro assay results based on EGFRP assay procedure


Induction And Assessment Of Collagen-Induced Arthritis In Mice:


Arthritis was induced in mice according to the procedure set forth in J. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199 (1984), which is incorporated herein by reference. Specifically, arthritis was induced in 8-12 week old DBA/1 male mice by injection of 50 μg of chick type II collagen (CII) (provided by Dr. Marie Griffiths, Univ. of Utah, Salt Lake City, Utah) in complete Freund's adjuvant (Sigma) on day 0 at the base of the tail. Injection volume was 100 μl. Animals were boosted on day 21 with 50 μg of CII in incomplete Freund's adjuvant (100 μl volume). Animals were evaluated several times each week for signs of arthritis. Any animal with paw redness or swelling was counted as arthritic. Scoring of arthritic paws was conducted in accordance with the procedure set forth in Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectibility and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15:180 (1983). Scoring of severity was carried out using a score of 1-3 for each paw (maximal score of 12/mouse). Animals displaying any redness or swelling of digits or the paw were scored as 1. Gross swelling of the whole paw or deformity was scored as 2. Ankylosis of joints was scored as 3. Animals were evaluated for 8 weeks. 8-10 animals per group were used.


Preparation And Administration Of Compounds:


The compounds tested on mice having collagen-induced arthritis were prepared as a suspension in 0.5% methylcelluose (Sigma, St. Louis, Mo.), 0.025% Tween 20 (Sigma). The compound suspensions were administered by oral gavage in a volume of 0.1 ml b. i. d. Administration began on day 20 post collagen injection and continued daily until final evaluation on day 56. Scoring of arthritic paws was conducted as set forth above. Assay results are set forth in Table 7.

TABLE 7Compound% Inhibition of ArthritisA-21058.5 @ 15 mpkA-17249.3 @ 100 mpkA-18951.6 @ 30 mpkA-20897.5 @ 60 mpkA-20875.0 @ 60 mpk


Additional results for selected compounds obtained using the above-described assays are set forth in Tables 8, 9 and 10 below:

TABLE 8Rat LPSTNFAssay %Inhibition-p38α KinaseInhibitionHuman WholeAssay(Dose inBlood AssayIC50 in μMExamplemg/kg)(μM)(% DMSO)A-313, Step 11.34 (1) A-313, Step 396.0 (20.0)0.120.036 (1) 0.37 (10)A-314, Step 10.85 (1) 0.37 (10)A-314, Step 2  0 (1.0)0.470.032 (10) 53.0 (5.0) 85.0 (20.0)A-3151.750.049 (10) A-31758.0 (3.0) 0.450.07 (10)10.0 (3.0) 0.11 (10)69.0 (10.0)A-31854.0 (3.0) 0.1670.29 (1) 0.58 (10)0.37 (10) 0.6 (10)A-31962.0 (3.0) >25.06.06 (1) 0.13 (10)A-3201.0 (3.0)0.27 (1) 0.05 (10)0.15 (10)A-321>25.00.77 (1) (dihydrate)A-32114.0 (3.0) (monosodiumsaltdihydrate)A-32251.5 (3.0) 4.20.15 (10)0.25 (10)A-32340.0 (30.0)0.39 (10)54.0 (30.0)A-32444.0 (3.0) 0.08 (10)A-32525.0 (3.0) 0.0570.021 (1) 11.0 (30.0)<0.1 (10)A-326  0 (10.0)>25.00.97 (10)A-32783.0 (20.0)0.180.15 (10)A-3280.012 (1) A-33113.0 (20.0) >100 (1) 0.64 (10)A-33233.0 (1.0) 0.450.04 (1) 26.0 (3.0) 0.04 (10)25.0 (5.0) 0.015 (10) −85.0 (10.0)  <0.1 (10)A-33369.0 (5.0) 0.5850.052 (10) A-33495.0 (20.0)0.220.07 (10)57.0 (5.0) 36.0 (1.0) A-335>25.089.9 (10)A-3361.16 (10)A-337>25.01.35 (10)A-3380.0590.018 (10) A-3390.0560.052 (10) A-34298.0 (20.0)0.310.012 (10) A-34396.0 (20.0)0.016 (10) 














TABLE 9












Rat LPS
TNF





Assay %
Inhibition-
p38α Kinase




Inhibition
Human Whole
Assay




(Dose in
Blood Assay
IC50 in μM



Example
mg/kg)
(μM)
(10% DMSO)





















A-350
65 (20)





A-351
 0 (20)
0.49
0.27



A-352
36 (20)
9.8
0.13



A-353
49 (20)
5.3
0.037



A-354
 0 (20)
25
0.22



A-355
 0 (20)
0.095
0.05



A-356
73 (20)
5.3
<0.01



A-357
74 (20)
0.25
0.12



A-358
71 (20)
4
0.23



A-359
70 (20)
1
0.3



A-360
95 (20)
0.5
0.06




14 (5) 




0 (1)



A-361
 9 (20)
1



A-362
 0 (20)
5.5
0.69



A-363
 6 (20)
25
1.5



A-364
79 (20)
0.255
0.49



A-365
95 (20)
0.057
0.032




50 (5) 




12 (1) 



A-366
92 (20)
0.29
0.041




DR:

0.06




6 (1)

0.04




45 (5) 




97 (20)



A-368
88 (20)
0.66
0.042




DR:




28 (1) 




41 (5) 




97 (20)



A-369
94 (20)
0.84
0.019




52 (5) 

0.011






0.0027



A-370
90 (20)
1.92
0.16




46 (5) 



A-371
52 (20)
25
7.9



A-372
56 (20)
21
0.53



A-374
88 (20)
0.31
0.38




0 (5)




3 (1)



A-375
43 (20)
28%
2.3



A-376
24 (20)
1
0.032



A-377
84 (20)
0.67
0.004




DR:

0.0019




32 (1) 




67 (5) 




96 (20)



A-378
73 (10)
49%
6.2



A-379
61 (10)
44%
0.19



A-380
85 (30)
32%
0.85




62 (10)




33 (3) 



A-385


0.18






1.25



A-386
91 (20)
0.16
0.016



A-387
83 (20)
0.11
0.005



A-388
97 (20)
0.34
0.21




67 (5) 




















TABLE 10









Rat LPS





Assay %
TNF
p38α Kinase



Inhibition
Inhibition-
Assay IC50



(Dose in
Human Whole
(μm)



mg/kg @ 4.0
Blood Assay
(10% DMSO; @


Example
hours)
(μm)
1.0 hour)


















A-389, Step 4
55.0 (5.0) 

0.16



94.0 (20.0)


A-389, Step 1


1.72


A-390

>25.0
15.1


A-391
53.0 (20.0)
>25.0
4.83


A-392


29.7


A-393


2.32


A-394


9.11


A-395


>100


A-397


30.0


A-398

>25.0
45.6


A-399


22.9


A-400

>25.0
4.77


A-401


21.2


A-402


28.9


A-403

>25.0
4.89


A-404

>25.0
4.13


A-405

>25.0
4.85


A-406

>25.0
7.24


A-407
21.0 (5.0) 
3.86
0.18



82.0 (20.0)


A-408
20.0 (5.0) 
11.7
5.59



49.0 (20.0)


A-409
41.0 (5.0) 
5.27
0.21



89.0 (20.0)


A-410
11.0 (5.0) 

0.21



  0 (20.0)


A-411
40.0 (5.0) 

3.37



  0 (20.0)


A-412
  0 (5.0)

2.15



  0 (20.0)


A-413
45.0 (5.0) 
6.51
0.91



85.0 (20.0)


A-414
3.0 (5.0)
11.2
9.51



14.0 (20.0)


A-415
17.0 (5.0) 

0.51



84.0 (84.0)


A-416

5.07
0.041


A-417
40.0 (5.0) 
12.0
0.19



70.0 (20.0)


A-418


0.12


A-419
24.0 (5.0) 

1.31



58.0 (10.0)


A-420
47.0 (5.0) 

0.32



91.0 (20.0)


A-427
56.0 (5.0) 
24.1
0.19



77.0 (20.0)


A-428

0.68
0.4


A-429


56.3


A-430


>100


A-434


5.84


A-435
10.0 (1.0) 
>25.0
0.35



  0 (5.0)



14.0 (20.0)


A-436

4.61
2.81


A-437

>25.0
7.76


A-438
49.0 (20.0)
>25.0
0.56


A-439
58.0 (5.0) 
5.63
0.15



93.0 (20.0)


A-440


A-441
14.0 (5.0) 
>25.0
1.21



62.0 (20.0)


A-442
51.0 (1.0) 
0.16
0.022



56.0 (5.0) 



92.0 (20.0)


A-443

4.89
0.47


A-444


6.99


A-445

>25.0
1.08


A-446

3.38
0.9


A-447

>25.0
0.77


A-448
73.0 (5.0) 
0.12
0.084



97.0 (20.0)


A-449


59.0


A-450


>100


A-451

15.0
0.078


A-452

0.24
2.87


A-454


8.41


A-453


10.2


A-455


12.9


A-456
36.0 (1.0) 
0.98
0.12



48.0 (5.0) 



53.0 (20.0)


A-457

>25.0
0.4


A-458

>25.0
8.7


A-459
  0 (1.0)
0.26
0.027



54.0 (5.0) 



80.0 (20.0)


A-459 (salt)

0.28
0.1


A-460

8.91
1.84


A-461


30.6


A-462

>25.0
1.66


A-463

>25.0
1.66


A-464


>100


A-465


>100


A-466


20.1


A-467


21.4


A-468
46.0 (1.0) 

0.3



50.0 (5.0) 



94.0 (20.0)


A-469
51.0 (5.0) 
7.17
0.095



68.0 (20.0)


A-470


10.4


A-471


4.92


A-472

>25.0
0.39


A-473
58.0 (20.0)
0.56
0.17


A-474
59.0 (20.0)
1.47
0.11


A-475

5.11
0.28


A-476
35.0 (20.0)
0.97
1.01


A-477


0.34


A-478

0.49
0.18


A-479

2.97
0.072


A-480

0.16
0.11


A-481

>25.0
0.2


A-482
15.0 (20.0)
0.69
1.62


A-483

0.51
0.3









Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of this invention in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) 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 a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM) or topically. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of the composition may be adjusted, if necessary, with suitable acid, base, or buffer. Suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400, may also be included in the composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection. The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions 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 various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.


All patent documents listed herein are incorporated by reference.


Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.


Description of parallel array synthesis methodology utilized to prepare compounds of Examples B-i, B-ii, and B-iii.


Scheme B-1 describes the parallel array reaction blocks that were utilized to prepare compounds of Examples B-0001 through B-1574, and by analogy could also be used to prepare compounds of Examples B-1575 through B-2269. Parallel reactions were performed in multi-chamber reaction blocks. A typical reaction block is capable of performing 48 parallel reactions, wherein a unique compound is optionally prepared in each reaction vessel B1. Each reaction vessel B1 is made of either polypropylene or pyrex glass and contains a frit B2 toward the base of the vessel. Each reaction vessel is connected to the reaction block valve assembly plate B3 via leur-lock attachment or through a threaded connection. Each vessel valve B4 is either opened or closed by controlling the leur-lock position or by the opening or closing of levers B5 within a valve assembly plate row. Optionally, solutions can be either drained or maintained above the vessel frits by leaving the valves in the opened position and controlling the back pressure beneath the valve assembly plate by control of inert gas flow through the inert gas inlet valve B6. The parallel reactions that are performed in these reaction blocks are allowed to progress by incubation in a jacketed, temperature controlled shaking station. Temperature control of the reaction chambers is effected by passing a heat-transfer liquid through jacketed aluminum plates that make contact with the reaction block mantle B7. Mixing is effected at the shaking station by either vertical orbital shaking of the up-right reaction block or by lateral shaking of the reaction block tilted on its side.


Functionalized resins are optionally added to each reaction vessel B1 during the course of reaction or at the conclusion of the reaction. These functionalized resins enable the rapid purification of each reaction vessel product. Vacuum filtration of the reaction block apparatus by opening of the vacuum valve B8 allows purified products to be separated from resin-sequestered non-product species. Valve B8 is located on the bottom reaction block chamber B10 which houses the quadrant collection vial racks B11. The desired products are obtained as filtrates in unique collection vials B9. Removal of solvent from these collection vials affords desired products.
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Scheme B-2 illustrates the various utilizations of functionalized resins to purify reaction vessel products B22 prior to filtration from the fritted vessels B1into


collection vials B9. Said functionalized resins perform as 1) resin-bound reagents B12, which give rise to resin-bound reagent byproducts 313; 2) sequestrants B14 or B15 of excess solution-phase reactants B16 or B17, respectively. Solution-phase reactants B16 and B17 contain inherent reactive functionality -rf1 and -rf2 which enable their chemoselective sequestration by the complementary reactive functionality -Crf1 and -Crf2 attached to resins B14 and B15; 3) sequestrants B18 of solution-phase byproducts B19. Byproduct B19 contains molecular recognition functionality -mr2 which enables its chemoselective sequestration by the complementary functionality -Cmr2 attached to resin B18; 4) reaction-quenching resins B20 which give rise to quenched resins 321. Resin B30 contains functionality -Q which mediates reaction quenching (for instance, proton transfer) of product B22 to form a desired isolable form of, product B22. Upon performing reaction quench, the resin B20 is converted to resin B21 wherein -q represents the spent functionality on resin B21 ; 5) secuestrants B23 of chemically-tagged reagents B24 and their corresponding reagent byproducts B25. The soluble reagent B24 contains a bifunctional chemical group, -tag, which is inert to the reaction conditions but is used to enable the post-reaction sequestration of B24 by the complementary functionality -Ctag attached to resin B23. Additionally, the soluble reagent byproduct B25, formed during the course of reaction, contains the same chemical function -tag that also enables its sequestration by resin B23. Additionally, some reactants B16, particularly sterically-hindered reactants and/or electron deficient nucleophiles, contain poorly sequestrable functionality (rf1 in this case is a poorly sequestable functionality). These poorly sequestable reactants B16 can be transformed in situ to more robustly sequestrable species B27 through their reaction with sequestration-enabling-reagents B26. B26 contain highly reactive, complementary functionality Crf1 which reacts with B16 to form B27 in situ. The bifunctional molecular recognition functionality, mr, contained within B26 is also present on the in situ derivatized B27. Both B26 and 327 are sequestered by the complementary molecular recognition functionality attached to resin B28. By analogy, some reactions contain poorly sequestable byproducts B19, wherein the molecular recognition functionality mr2 in this case is not able to mediate the direct sequestration of B19 by the complementary functionality attached to resin B18. Similar use of the bifunctional sequestration-enabling-reagent B29 transforms B19 into the more readily sequestrable species B30. The imparted molecular recognition functionality, mr, present in B30 is readily sequestered by the complementary functionality, Cmr, attached to resin B31. In some reactions, multiple sequestration resins are utilized simultaneously to perform reaction purifications. Even resins containing incompatible (mutually reactive) functional groups can be used simultaneously because these resins scavenge complementary functionalized solution phase reactants, reagents, or byproducts from solution phase faster than resin cross-neutralization. Similarly, resins containing mutually reactive or neutralizing reaction-quenching functionality are able to quench solution phase reactants, products, or byproducts faster than resin cross-neutralization.
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Scheme B3 describes the modular robotics laboratory environment that was utilized to prepare compounds of Examples B0001 through Bxxxx. Chemicals that are utilized in the robotics laboratory are weighed and then dissolved or suspended into solvents at Station #1 (Automated Chemistry Prep Station). Thus, solutions or suspensions of known molarity are prepared for use at the other robotics workstations. Station #1 also optionally bar-code labels each chemical solution so that its identity can be read by bar-code scanning at this and other robotics workstations.


Reactions are initiated at the modular Stations #2 and #2 DUP. Station #2DUP is defined as a duplicate of Station #2 and is used to increase capacity within the robotics laboratory. A reaction block is mounted at Station #2 or #2 DUP. Also, racks containing reactants, reagents, solvents, and resin slurries are also mounted at Station #2 or #2 DUP. Under the control of a chemical informatics mapping file, reactions are initiated by the transfer of reactant solutions, reagent solutions, solvents, and/or resin slurries into each mounted reaction block vessel. The transfer of known volumes of solutions, suspensions, or solvents is mediated by syringes which control a one-up septum piercing/argon purging cannula, a wide-bore resin slurry-despensing cannula, or by a six-up cannula which can simultaneously deliver volumes to a row of six reaction vessels. The reaction block and/or chemical solution racks may be optionally cooled below room temperature during the chemical solution transfer operations. After the transfer of chemical solutions and solvents has been performed by Station #2 or #2DUP, incubation of the reaction block may occur while the reaction block is mounted at the robot station. Preferably, however, the reaction block is removed after all volume transfers are complete and the reaction block is brought to ambient temperature. The reaction block is transferred off-line to either a vertical- or lateral shaking Incubator Station #5.


The Automated weighing/archival Station #3 performs the functions of weighing empty collection vials (to obtain tare weights of collection vials) and also performs the functions of weighing collection vials containing filtered, purified products (to obtain gross weights of collection vials). After product-containing collection vials have been weighed (gross weight determinations) at workstation #3, the collection vial products are optionally redissolved into an organic solvent at workstation #3. Transfer of solvents is accomplished with syringes which control a mounted one-up septum-piercing/argon purging cannula. Each product-containing collection vial is pr epared as a solution of known molarity as directed and recorded by the chemical informatics system. These product solutions may be subsequently mounted at Station #2 or #2DUP for subsequent reaction steps or taken to Station #7 or #7DUP for analytical processing.


Rapid solvent evaporation of product-containing collection vials is accomplished by mounting the collection racks at Savant Automated Solvent Evaporation Stations #4, #4 DUP, or #4 TRIP, wherein 44DUP and #4TRI are defined as a duplicate and a triplicate of Station #4 to increase the capacity for solvent removal within the robotics laboratory. Commercially available solvent removal stations were purchased from the Savant Company (model #SC210A speedvac unit equipped with model #RVT4104 vapor trap and model #VN100 vapornet cryopump).


Stations #7 and #7DUP perform analytical processing functions. Station #7DUP is defined as a duplicate of Station #7 to increase capacity within the robotics laboratory. Product-containing collection racks are mounted at either of these stations. Each product-containing collection vial is then prepared as a solution of known molarity as directed and recorded by the chemical informatics mapping file. Optionally, this dissolution function is performed by prior processing of the collection vial rack at Station #3 as described above. Station #7 or #7DUP, under the control of the chemical informatics mapping file, transfers aliquots of each product vial into unique and identifable microtiter plate wells that are utilized to perform analytical determinations. One such microtiter plate is prepared at. Station #7 or #7DUP for subsequent utilization at the Automated HPLC/Mass Spectrometer Station #8 or #8DUP. Station #8DUP is a duplicate of Station #8 to increase the analytical capacity of the robotics laboratory. Stations #8 and #8DUP are commercially available benchtop LC/Mass spec units purchased from Hewlett Packard (model HP1100 HPLC connected to HP100 MSD (G1946A) mass spectrometer; this unit is also equipped with a model#G1322A solvent degasser, model #1312A binary pump, a model #G1316A column heater, and a model #G1315A diode array detector. The HP unit has been interfaced with a commercially available autosanpler rack (Gilson Company #215 autosampler). Station #8 or #8DUP is utilized for the determination of product purity and identity by performing high performance liquid chromatography (H?LC) and companion atmospheric pressure chemi-ionization (APCI) or electrospray mass spectrometry for molecular weight determination.


Another microtiter plate is prepared at Station #7 or #7DUP for subsequent utilization at a commercially available flow-probe Varian NMR spectrometer Station #10 (Varian Instruments flow probe NMR, 300 MHz, interfaced with a commercially available Gilson 215 autosampler). Proton, 13-Carbon, and/or 19-Fluorine NMR spectra are determined at this Station #10.


Other microtiter plates are optionally mounted at Station #7 or #7DUP for the purpose of preparing product-containing plates for biological assays. Aliquots of product-containing collection vials are transferred to these biological assay microtiter plates under the control of the chemical informatics mapping file. Identity and amount of each transferred product is recorded by the chemical informatics system for retrieval by biologists who perform the biological assaying of products.


The Fourier Transfrom InfraRed (FT-IR) Spectrometer Station #11 is utilized to analyze resins for the identity of organic functional groups chemically attached to these resins. The resins, as mentioned above, contain chemical functionality utilized as reagents, chemoselective sequestrants, or reaction quenching media for the workup and purification of the crude product mixtures contained within reaction block vessels. The robotics laboratory utilizes a commercially available FT-IR spectrometer purchased from Nicolet Instruments (model # MagnaIR 560 interfaced with an InspectIR microscope for resin mounting and positioning).


Scheme B-3

The lines interconnecting the modular Stations denote the transfer of chemical racks, reaction blocks, and/or collection vial racks from one modular Station to another.
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The ChemLib IT system is a composite of software running on the client's desktop and software running on a remote server.


The ChemLib IT system is a client/server software application developed to support and document the data handling flow in the robotics laboratory described above. This IT system integrates the chemist with the robotics synthesis laboratory and manages the data generated by this processes.


The software running on the server warehouses all the electronic data for the robotics chemistry unit. This server, a Silicon Graphics IRIX station v6.2, runs the database software, Oracle 7 v7.3.3.5.0, that warehouses the data. Connection from the client's desktop to the server is provided by Oracle's TCP/IP Adapter v2.2.2.1.0 and SQL*Net v2.2.2.1. OA. SQL*Net is Oracle's network interface that allows applications running on the client's desktop to access data in Oracles' database. The client's desktop is Microsoft Windows 95. The ChemLib IT system client software is composed of Omnis7 v3.5 and Microsoft Visual C++v5.0. This composition on the client side is what is herein referred to as ChemLib. ChemLib communicates with the server for its data via Oracle's PL/SQL v2.3.3.4.0. These PL/SQL calls within ChemLib creates a network socket connection to Oracle's SQL*Net driver and the TCP/IP Adapter thereby allowing access to the data on the server.


A “library” is defined as a composite number of wells, where each well defines a single compound. ChemLib defines a library in a module called the Electronic Spreadsheet. The Electronic Spreadsheet is then a composite of n-number of wells containing the components that are required to synthesize the compound that exist in each these well(s).


The chemist begins by populating the Electronic Spreadsheet with those components required for the compound synthesis. The identity and the availability of these components are defined in the Building Block Catalog module of ChemLib. The Building Block Catalog is a catalog of a listing of all reagents, solvents, peripherals available in the robotics laboratory. Upon selecting the components for each compound we also declare the quantity of each component to be utilized. The quantity of each component can be identified by its molarity and volumetric amounts (μl) or by it's solid state form (mg). Therefore a well in the Electronic Spreadsheet defines a compound that is identified by its components and the quantity of each of these components.


The assembly or the synthesis of these components for each compound in the Electronic Spreadsheet is defined in the WS Sequence module of ChemLib. The Define WS Sequence module identifies the synthesis steps to be performed at the robotics workstations and any activities to be performed manually or off-line from the robotics workstation. With this module we identify which components from the Electronic Spreadsheet and the activity that should be performed with this component in the robotics laboratory. In the Define WS Sequence module the chemist chooses from a list of activities to be performed in the robotics laboratory and assembles them in the order in which they are to occur. The ChemLib system takes these set of activities identified, and with the component data in the Electronic Spreadsheet assembles and reformats these instructions into terminology for the robotics workstation use. This robotics terminology is stored in a ‘sequence’ file on a common server that is accessible by the robotics workstation.


The robotics workstation performs the synthesis in a reaction block apparatus as described. Each well in the Electronic Spreadsheet is tracked and mapped to a unique location in the reaction block apparatus on the robotics workstation. The compound or product synthesized at the robotics workstation in the reaction block is then captured into collection vials.


The collection vials are first tarred then grossed on the robotics workstation after collecting their products from the reaction block. These weights (tare and gross) are recorded into the ChemLib system with the Tare/Gross Session module. The Tare/Gross Session module then calculates the product or compound yields and its final mass.


Preparation of the compound for analytical analysis and screening is defined by 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 the compound's product yield and the desired molar concentration. This identifies the quantity, in μL, to be transferred at the robotics workstation, to a specific location on the MTP (microtiter plate) to be sent for analysis and/or biological assaying. The mass spectrometric and HPLC results for each well are recorded and scored into the ChemLib system.


The Dilute/Archive WS module further identifies each compound by mapping the compounds well from the Electronic Spreadsheet to a specific MX block location for long term storage and archival as part of the registration process.


All communications between ChemLib and the robotics workstations are by ASCII files. These files are placed on a server by the ChemLib system that is accessible by the robotics workstations. Reports generated by the robotics workstations are also placed on the server where the ChemLib system can read these files to record the data generated. Each robotics workstation consists of 5 robotics hardware by Bohdan Automation, Inc. Mundelein, Ill., and a PC currently running Microsoft Windows for Workgroup v3.11 and Ethernet software. The robotics workstation PC is logged into the network for one-way communication that allows the workstation to access the server for file access only.


General Scheme B4

Scaffold C-i with a primary amine functionaliy contained within the R4 substituent is reacted in spatially addressed, parallel array reaction block vessels with excess of electrophiles RJ-Q wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide. RJ-Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-i with RJ-Q is effected in the presence of a tertiary amine base at room temperature in a mixture of a polar aprotic solvent and/or a halogenated solvent. As illustrated in Scheme B-4 the products of the general formulae B-i are isolated in purified form by addition of a carbonyl-functionalized resin B32 which covalently sequesters any unreacted primary amine scaffold C-i as resin-bound adduct B35, and also by the addition of a primary amine-functionalized resin B33 which covalently sequesters any remaining electrophile RJ-Q from each reaction mixture as resin-bound adduct B34. Resin B33 also sequesters the HQ byproduct from the reaction mixture by proton transfer from solution-phase Base-HQ. Incubation at room temperature, filtration, rinsing of the resin cake, and concentration of the filtrates affords purified products B-i filtered away from resin-bound adducts B32, B33, B34, B35, and B36.
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Scheme B-5 specifically illustrates the derivatization of the primary amine-containing scaffold C1 to afford the desired products B-i in a parallel array synthesis format. In a parallel array synthesis reaction block, individual reaction products are prepared in each of multiple reaction block vessels in a spatially addressed format. A solution of the desired primary amine-containing scaffold C1 (limiting amount,) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0 fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added the electrophiles: either a 2.0 fold stoichiometric excess when RJ-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when RJ-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RJ-Q is an isocyanate. Excess electrophiles and N-methylmorpholine were used to effect more rapid and/or more complete conversion of scaffold C1 to products B-0001-B-0048 compared to reactions that do not utilize stoichiometric excesses of electrophiles and N-methylmorpholine. The reaction mixtures are incubated at ambient temperature for 2-3 h. Each reaction vessel is 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-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. The excess electrophiles RJ-Q and any unreacted scaffold amine C1 are removed from the reaction medium as insoluble adducts B34 and B37 respectively. In addition the N-methylmorpholine hydrochloride salt formed during the course of the reaction is also neutralized to its free base form by proton transfer reaction to the amine-functionalized resin B33. Simple filtration of the insoluble resin- adducts B32, B33, B34, B36, and B37, rinsing of the resin cake with dichloroethane, and evaporation of the filtrates affords the desired products B-i in purified form.
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Scheme B-6 illustrates a general synthetic method involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the R4 substituent. Each reaction vessel is charged with the secondary amine-containing scaffold C-ii, followed by the introduction of a stoichiometric excess of an optionally unique electrophile RL-Q into each vessel, wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide. RL-Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-ii with RL-Q is effected in the presence of tertiary amine base at room temperature or elevated temperature in a mixture of a polar aprotics solvent and/or a halogenated solvent. After solution-phase reactions have progressed to afford crude product mixtures in each vessel, the products B-ii are isolated in purified form by the addition of the isocyanate-functionalized resin B38 which covalently sequesters remaining secondary amine scaffold C-ii as resin-bound adduct B39, and also by the addition of the primary amine-functionalized resin B33 which covalently sequesters remaining electrophile RL-Q from each reaction vessel as resin-bound adducts B40. Resin B33 also sequesters the HQ byproduct in each vessel as B36, formed by proton transfer from solution-phase Base-HQ. Incubation with these resins, either simultaneously or sequentially, followed by filtration, rinsing, and concentration of the filtrates affords purified products B-ii filtered away from resin-adducts B33, B36, B38, B39, and B40.
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Scheme B-7 illustrates the conversion of the secondary-amine containing scaffold C-2 to the desired products B-ii. In a parallel array synthesis reaction block, individual reaction products are prepared in each of 48 multiple reaction block vessels. A solution of the scaffold C-2 (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0-fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added an electrophile RL-Q as a dichloroethane (DCE) solution: either a 2.0 fold stoichiometric excess is used when RL-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when RL-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RL-Q is an isocyanate. The reaction mixtures are incubated at ambient temperature for 2-6 h. Each reaction vessel is then charged with a large excess (15-2.0 fold stoichiometric excess) of the amine-functionalized resin B33 and the isocyanate-functionalized resin B32. The resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. The excess electrophiles RL-Q and unreacted scaffold amine C-2 are removed from the reaction medium as insoluble adducts B40 and B39, respectively. Resin B33 also sequesters the HQ byproduct in each vessel as B36, formed by proton transfer from solution-phase Base-HQ. Incubation with these resins, followed by filtration and rinsing with solvent mixtures of DMF and/or DCE, affords purified product solutions in collection vials filtered away from resin-adducts B33, B36, B38, B39, and B40. Concentration of filtrates affords purified products B-ii.
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Scheme B-8 illustrates another general synthetic method involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the R4 substituent. Each reaction vessel is charged with the secondary amine-containing scaffold C-ii, followed by the introduction of a stoichiometric excess of an optionally unique electrophile RL-Q into each vessel. Reaction of scaffold C-ii with RL-Q is effected in the presence of tertiary amine base at room temperature or elevated temperature in a mixture of a polar aprotic solvent and/or a halogenated solvent.


Excess electrophiles and N-methylmorpholine are used to effect more rapid and/or more complete conversion of scaffold C-ii to products B-ii compared to reactions that do not utilize stoichiometric excesses of electrophiles and N-methylmorpholine. The reaction mixtures are incubated at ambient temperature for 2-8 h. Each reaction vessel is then charged with the sequestration-enabling reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine scaffold C-ii, converting C-41 to the in situ-derivatized compound B42. Subsequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequesters the solution-phase species RL-Q, HQ, 341, and B42 as the resin-bound adducts B40, B36, 844, and B43, respectively. The resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B36, B40, B43 and B44 and subsequent rinsing of the vessel resin-bed with DMF and/or DCE affords filtrates containing the purified products B-ii. Concentration of the filtrates affords the purified products B-ii.
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Scheme B-9 illustrates the method of Scheme B-8 using scaffold C-2. A solution of the scaffold C-2 (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0-fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added an electrophile RL-Q as a dichloroethane (DCE) solution: either a 2.0 fold stoichiometric excess is used when RL-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when RL-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RL-Q is an isocyanate. The reaction mixtures are incubated at ambient temperature for 2-6 h. After solution-phase reactions have progressed to afford crude product mixtures, each reaction vessel is then charged with a dichloroethane solution of the sequestration-enabling reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine scaffold C-2, converting C-2 to the in situ-derivatized compound B45. Subsequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequesters the solution-phase species RL-Q, HQ, B41, and B45 as the resin-bound adducts B40, B36, B44, and B46, respectively. The resin-charged reaction block is shaken vertically for 20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B36, B40, B44, and B46 and subsequent rinsing of the vessel resin-bed with DCE affords filtrates containing the purified products B-ii. Concentration of the filtrates affords the purified products B-ii.
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Another general method for the parallel array reaction block synthesis is illustrated in Scheme B-10 for the derivatization of the carboxylic acid-containing scaffold C-iii. Scaffold C-iii with a free carboxylic acid functionality is reacted in spatially addressed, parallel array reaction block vessels with excesses of optionally different primary or secondary amines B47 in the presence of the polymer-bound carbodiimide reagent B48 and a tertiary amine base in a mixture of a polar aprotic solvent and/or a halogenated solvent. After filtration of each crude vessel product misture away from resins B48 and B49, each reaction mixture is purified by treatment with the sequestration-enabling-reagent BSO (tetra-fluorophthalic anhydride). The reagent B50 reacts with remaining excess amine B47 to afford the in situ-derivatized intermediates B51 which contain carboxylic acid molecular recognition functionality. Subsequent incubation of each reaction mixture with a 15-20-fold stoichiometric excess of the primay amine-functonalized resin B33 sequesters B51, BSO, and any remaining acid scaffold C-iii as resin-bound adducts B52, B53, and B54, respectively. Filtration of solution-phase products B-iii away from these resin-bound adducts and rinsing of the resin beds with a polar aprotic solvent and/or halogenated solvent affords filtrates containing purified products B-iii. Concentration of the filtrates affords purified B-iii.
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Scheme B-11 illustrates the conversion of the acid containing scaffold C-49 to the desired amide products B-iii in a parallel synthesis format. A limiting amount of the scaffold C-49 is added as a solution 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 is added to this slurry, followed by addition of an excess amount of a dimethylformamide solution of a unique amine B47 (1.5 fold stoichiometric excess) to each vessel. The parallel reaction block is then agitated vertically on an orbital shaker for 16-18 h at ambient temperature and filtered to separate the solution phase product mixture away from resin-bound reagent B48 and resin-bound reagent byproduct B49. The resulting solutions (filtrates) containing a mixture of the desired amide products B-iii, excess amines B47 and any unreactedacid containing scaffold C-49, are treated with tetrafluorophthalic anhydride B50. B50 converts the excess amines B47 in each filtrate vessel to its respective sequestrable half acid form B51. After two h incubation time, an excess of the amine-functionalized resin B33 and dichloromethane solvent are added to each reaction vessel. The amine-containing resin B33 converts B51, any remaining B50, and any remaining C-49 to their resin-bound adducts B52, B53, and B55, respectively. The resin-charged reaction block is shaken vertically for 16 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B52, B53., and B55 and subsequent rinsing of the vessel resin-bed with dimethylformamide affords filtrates containing the purified products B-iii. Concentration of the filtrates affords the purified products B-iii.
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Although Schemes B-1 through B-11 describe the use of parallel array chemical library technology to prepare compounds of general formulae B-i, B-ii, and B-iii, it is noted that one with ordinary skill in the art of classical synthetic organic chemistry would be able to prepare B-i, B-ii, and B-iii by conventional means (one compound prepared at a time in conventional glassware and purified by conventional means such as chromatography and/or crystallization).


A general synthesis of pyridylpyrazole scaffolds C-i, C-ii, and C-iii is depicted in Scheme C-1.


Step A: Picoline is treated with a base chosen from but not limited to n-butyllithium (n-BuLi), lithium di-iso-propylamide (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 from −78° C. to 50° C. for a period of time from 10 minutes to 3 hours. The metallated picoline solution is then added to a solution of ester B56. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature may range from −20° C. to 120° C. The mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the pyridyl monoketone B57 is isolated as a crude solid which can be purified by crystallization and/or chromatography.


Step B: A solution of the pyridyl monoketone B57 in ether, THF, tBuOH, or dioxane is added to a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH contained in hexane, THF, diethyl ether, t-butyl methyl ether, or t-BuOH from −78° C. to 50° C. for a period of time from ranging from 10 minutes to 3 hours. An appropriately substituted activated ester or acid halide derived from R4—CO2H is then added as a solution in THF, ether, or dioxane to the monoketone anion of B57 while the temperature is maintained between −50° C. and 50° C. The resulting mixture is allowed to stir at the specified temperature for a period of time from 5 minutes to three hours. The resulting pyridyl diketone intermediate B58 is utilized without purification in Step C.


Step C: The solution containing the pyridyl diketone B58 is quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H2SO4, HC1, or HNO3. The temperature during this step is maintained between −20° C. and room temperature. Hydrazine or hydrazine hydrate was then added to the mixture while maintaining the temperature between −20° C. and 40° C. for a period of 30 minutes to three hours. The mixture is then poured into water and extracted with an organic solvent. The pyridyl pyrazole C-i or C-ii is obtained as a crude solid which is purified by chromatography or crystallization.


Step: D In some cases the pyridyl pyrazole C-i or C-ii is alkylated with Q-C(RA)-(CH2)nCO2alkyl wherein Q is halogen. C-i or C-ii is treated with a base chosen from NaH, NaOEt, KOtBu, or NEt3 in an organic solvent such as THF, methylene chloride, dioxane, or DMF at temperatures between 31 20° C. and 150° C. and reaction times between 30 minutes and 12 hours. The resulting alkylated pyridyl pyrazole ester is then hydrolyzed to the acid by treament with NaOH or LiOH in aqueous/alcohol solvent mixtures or in THF/water solvent mixtures. Alternatively, the ester function is removed by treatment with an organic or inorganic acid if the alkyl residue is t-butyl. Acidification, followed by extraction with an organic solvent affords. C-iii which may be purified by chromatography or crystallography. In some cases, regioisomeric alkylated products C-iv are also formed. The desired C-iii can be separated away from C-iv by chromatographic purification or by fractional crystallization.
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A synthesis of pyridylpyrazole scaffold C-1 is depicted in Scheme C-2.


Step A:


Picoline is added to a solution of LiHMDS in THF at room temperature over a time period ranging from 30 minutes to 1 hour. The resulting solution is stirred for an additional 30 minutes to 1 hour at room temperature. This solution is then added to neat ethyl p-fluorobenzoate B60 at room temperature over 1-2 h. The mixture is then allowed to stir at room temperature for 16-24 h. Equal portions of water and ethyl acetate are then added to the reaction and the mixture is partitioned in an extraction funnel. The organic layer is dried, filtered, and evaporated to give an oily solid. Hexanes are then added and the solid is filtered and washed with cold hexanes leaving the pyridyl monoketone B61 for use in Step B.


Step B:


The pyridyl monoketone B61 is added as a solution in THF to a flask maintained at room temperature which contains t-BuOK in a THF/t-BuOH cosolvent. A yellow precipitate forms and stirring at room temperature is continued for 1-3 h. After this time, N-Cbz-protected glycine N-hydroxysuccinimide B62 is added dropwise at room temperature as a solution in THF over 1-3 h. 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 is then added dropwise to the mixture as a solution in water over 30 minutes to 1 h at room temperature. Water and ethyl acetate are then added to the flask and the mixture is then partitioned in a separatory funnel. The organic layer is dried, filtered, and evaported to give a crude oil which is purified by silica gel chromatography, giving rise to purified C-1Cbz.


Step: D


The Cbz protecting group contained in compound C-1Cbz is cleaved using hydrogen gas under pressure and Pd-C in methanol solvent. The resulting amine C-1 is obtained by filtration and concentration.
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A number of pyridyl pyrazole scaffolds of type C-v are prepared as shown in Scheme C-3.


Step A: Picoline is treated with a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in an organic solvent such as THF, ether, t-BUOH or dioxane from −78° C. to 50° C. for a period of time from 10 minutes to 3 hours. The metallated picoline solution is then added to a solution of an appropriately activated ester analog of a carboxylic acid CbzNRH—(CH2) nCRF(RG)—CO2H or BocNRH—(CH2) nCRF(RG)—CO2H, preferably but not limited to the N-hydroxysuccinimide B64. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature may range from −20° C. to 120° C. The mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the pyridyl monoketone B65 is isolated as a crude solid which can be purified by crystallization and/or chromatography.


Step B: A solution of the pyridyl monoketone B65 in ether, THF, tBuOH, or dioxane is added to a base chosen from but not limited to n-BuLi, LDA, LiHNDS, tBuOK, or NaH contained in hexane, THF, ether, dioxane, or tBuOH from −78° C. to 50° C. for a period of time from 10 minutes to 3 hours. The anion sometimes precipitates as a yellow solid. An appropriately substituted activated ester such as the N-hydroxysuccinimide B66 is then added as a solution in THF, ether, or dioxane to the monoketone anion while the temperature is maintained between −50° C. and 50° C. The resulting mixture is allowed to stir at the specified temperature for a period of time from ranging from 5 minutes to 3 hours. The resulting pyridyl diketone intermediate B67 is utilized without further purification in Step C.


Step C: The solution containing the pyridyl diketone B67 is quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H2SO4, HCl, or HNO3. The temperature during this step is maintained between −20° C. and room temperature. Hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between −20° C. and 40° C. for a period of 30 minutes to three hours. The mixture is then poured into water and extracted with an organic solvent. The pyridyl pyrazole C-vBoc or C-vCbz is obtained as a crude solid which is purified by chromatography or crystallization.


Step: D


The carbamate protecting groups from C-vBoc or C-vCbz are removed to afford the scaffolds C-v containing either a free primary amine (RH is hydrogen) or a free secondary amine (RH not equal to hydrogen). The Boc protecting carbamate groups are cleaved utilizing 1:1 trifluoroacetic acid (TFA)/methylene chloride at room temperature for several hours. The CBZ carbamate protecting groups are cleaved using hydrogen gas under pressure and Pd-C in an alcoholic solvent. The resulting amines C-v are then optionally crystallized or purified by chromatography.
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The synthesis of scaffolds C-vi is accomplished as shown in Scheme C-4.


Step A:


A Boc protected pyridylpyrazole B68 is treated with benzaldehyde in methylene chloride at room temperature in the presence of a drying agent for a period of time ranging from 1-24 h. Solvent is then evaporated and the resulting imine B69 is used in step B without further purification.


Step B:


The pyridylpyrazole imine B69 is dissolved in THF and stirred under nitrogen at temperatures 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 h. Two-five equivalents of an alklyating agent RF-Q are then added to the mixture and stirring is continued for several hours. The mixture is then quenched with acid and allowed to warm to room temperature and stirred several hours until cleavage of the Boc and the imine functions 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 give C-vi.
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The synthesis of maleimide-containing scaffolds C-vii is accomplished as shown in Scheme C-5.


The maleimide pyrazole scaffolds C-vii are synthesized as depicted in scheme C-5. Condensation reaction of a primary amine H2N—R with a maleic anhydride B70 that is substituted at position 3 with either a bromo, chloro, or triflate group generates compound B71. The formed maleimide derivative B71 then reacts with an acetophenone derivative B72 in the presence of a Pd(0) catalyst and base to afford compound B73. The methylene position of B73 is then acylated with an acid anhydride B74 or an activated acid ester B75, forming the di-ketone derivative B76. The di-ketone B76 condenses with hydrazine to afford the desired maleimide pyrazole scaffold C-vii.
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Scheme C-6 illustrates the synthesis of the maleimide pyrazole scaffold C-63 wherein R4 is hydrogen. The synthesis starts with the condensation reaction of bromomaleic anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride, giving rise to intermediate B78. The maleimide B78 is then treated with 4′-fluoroacetophenone in the presence of catalytic amount Pd2(dba)3 and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. The B79 is treated with tert-butoxybis(dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is condensed with hydrazine to form the maleimide pyrazole skeleton B81. The 2,4-dimethoxybenzyl group protecting group is optionally removed with ceric ammonium nitrate (CAN) to give compound C-63.
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Scheme C-7 illustrates the synthesis of maleimide-containing scaffolds C-64 and C-65. These scaffolds C-49 and C-50 are synthesized according to the general methods illustrated in Scheme C-5 and exemplified with the utilization of N-hydroxysuccinimides B82 and B83 to afford the maleimide-containing pyrazoles B86 and B87, respectively. Optional removal of the 2,4-dimethoxylbenzyl groups with CAN and subsequent removal of the Boc-protecting groups with trifluoroacetic acid (TFA) affords the scaffolds C-64 and C-65.
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The various functionalized resins and sequestration-enabling-reagents utilized to prepare and purify parallel reaction mixtures are more fully described below, including their commercial source or literature reference to their preparation.
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Experimental procedure for the parallel synthesis of a series of amides, carbaqnates, ureas and sulfonamides B-0001 through B-0048 from scaffold C-1.


EXAMPLES B-0001 THROUGH B-0048

To each reaction vessel (polypropylene syringe tubes fitted with a porous frit, closed at the bottom) of a parallel reaction apparatus was added 200 uL of dimethylformamide. A stock solution of the scaffold amine C-1 in dimethylformamide (0.1 M, 500 uL) was added to each reaction vessel followed by the addition of a stock solution of N-methylmorpholine in dimethylformamide (1.0 M., 200 uL). A stock solution of each of the electrophiles was then added to the appropriate reaction vessels: a) 500 uL of a 0.2 M solution of the acid chlorides in dichloroethane or b) 500 uL of a 0.2 M solution of the chloroformates in dichloroethane or c) 313 uL of a 0.2 M solution of the isocyanates in dichloroethane or d) 375 uL of a 0.2 M solution of the sulfonyl chlorides in dichloroethane. The parallel reaction apparatus was then. orbitally shaken (Labline Benchtop orbital shaker) at 200 RPM at ambient temperature (23-30° C.) for a period of 2-3 h, under a gentle flow of nitrogen. At this time each reaction vessel was treated with approximately 250 mg of polyamine resin B33 (4.0 meq N/g resin) and approximately 100 mg of polyaldehyde resin B32 (2.9 mmol/g resin). Each reaction vessel was diluted with 1 mL dimethylformamide and 1 mL dichloroethane and the orbital shaking was continued at 200 RPM for a period of 14-20 h at ambient temperature. Each reaction vessel was then opened and the desired solution phase products separated from the insoluble quenched byproducts by filtration and collected in individual conical vials. Each vessel was rinsed twice with dichloroethane (1 mL) and the rinsings were also collected. The solutions obtained were then evaporated to dryness in a Savant apparatus (an ultracentrifuge equipped with high vacuum, scalable temperature settings and a solvent trap to condense the volatile solvent vapors). The resulting amide, carbamate, urea and sulfonamide products were then weighed and characterized. The yields and analytical data for the products obtained using this method are shown below.

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By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-0049 through B-1573 were prepared.

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image100442443B-0226embedded imageembedded image88482483B-0227embedded imageembedded image73482483B-0228embedded imageembedded image37452B-0229embedded imageembedded image100476477B-0230embedded imageembedded image94476477B-0231embedded imageembedded image100460461B-0232embedded imageembedded image90440441B-0233embedded imageembedded image99476477B-0234embedded imageembedded image100486487, 489B-0235embedded imageembedded image89486487, 489B-0236embedded imageembedded image100476477B-0237embedded imageembedded image100476477B-0238embedded imageembedded image92438B-0249embedded imageembedded image100516517, 519B-0250embedded imageembedded image72458B-0251embedded imageembedded image100427428B-0252embedded imageembedded image100450451B-0253embedded imageembedded image100472473B-0254embedded imageembedded image100433434B-0255embedded imageembedded image84547548B-0256embedded imageembedded image100484507aB-0257embedded imageembedded image85534535B-0258embedded imageembedded image100491492B-0259embedded imageembedded image100554555B-0260embedded imageembedded image91500501B-0261embedded imageembedded image100486487B-0262embedded imageembedded image100481482B-0263embedded imageembedded image100554555B-0264embedded imageembedded image75375376B-0265embedded imageembedded image71459460B-0266embedded imageembedded image100412413B-0267embedded imageembedded image100386387B-0268embedded imageembedded image89406407B-0269embedded imageembedded image84386387B-0270embedded imageembedded image92440441B-0271embedded imageembedded image98428429B-0272embedded imageembedded image57498499B-0273embedded imageembedded image100440441B-0274embedded imageembedded image94397398B-0275embedded imageembedded image90422423B-0276embedded imageembedded image100408409B-0277embedded imageembedded image88408409B-0278embedded imageembedded image100426427B-0279embedded imageembedded image54440441B-0280embedded imageembedded image79414415B-0281embedded imageembedded image82458459B-0282embedded imageembedded image89426427B-0283embedded imageembedded image90458459B-0284embedded imageembedded image100458459B-0285embedded imageembedded image94458459B-0286embedded imageembedded image100458459B-0287embedded imageembedded image96458459B-0288embedded imageembedded image100458459B-0289embedded imageembedded image96406407B-0290embedded imageembedded image96386387B-0291embedded imageembedded image95440441B-0292embedded imageembedded image94390391B-0293embedded imageembedded image100408409B-0294embedded imageembedded image100440441B-0295embedded imageembedded image91408409B-0296embedded imageembedded image96426427B-0297embedded imageembedded image88390391B-0298embedded imageembedded image95408409B-0299embedded imageembedded image90408409B-0300embedded imageembedded image95406407B-0301embedded imageembedded image99450451, 453B-0302embedded imageembedded image94440441B-0303embedded imageembedded image100378379B-0304embedded imageembedded image100391392B-0305embedded imageembedded image70326327B-0306embedded imageembedded image59340341B-0307embedded imageembedded image59354355B-0308embedded imageembedded image60368369B-0309embedded imageembedded image61352353B-0310embedded imageembedded image61366367B-0311embedded imageembedded image65356357B-0322embedded imageembedded image64474475B-0323embedded imageembedded image58474475B-0324embedded imageembedded image60422423B-0325embedded imageembedded image64422423B-0326embedded imageembedded image58422423B-0327embedded imageembedded image63378379B-0328embedded imageembedded image68389390B-0329embedded imageembedded image63362363B-0330embedded imageembedded image48376377B-0331embedded imageembedded image66424425B-0332embedded imageembedded image61442443B-0333embedded imageembedded image60458459B-0334embedded imageembedded image55502503B-0335embedded imageembedded image60454455B-0336embedded imageembedded image100500501B-0337embedded imageembedded image65458B-0338embedded imageembedded image69502503B-0339embedded imageembedded image68454B-0340embedded imageembedded image77492493B-0341embedded imageembedded image64458459B-0342embedded imageembedded image41438B-0343embedded imageembedded image63430431B-0344embedded imageembedded image96464465B-0345embedded imageembedded image62507508B-0346embedded imageembedded image56497498B-0347embedded imageembedded image61341342B-0348embedded imageembedded image3367B-0349embedded imageembedded image57403404B-0350embedded imageembedded image57481482B-0351embedded imageembedded image31355356B-0352embedded imageembedded image51397398embedded imageCalcd.Observed%MassSpecExample#R2RJYieldSpec(M + H)B-0353embedded imageembedded image71382383B-0354embedded imageembedded image35512513B-0355embedded imageembedded image37352353B-0356embedded imageembedded image57404405B-0357embedded imageembedded image88366367B-0358embedded imageembedded image88410411B-0359embedded imageembedded image100324325B-0360embedded imageembedded image56364365B-0361embedded imageembedded image70350351B-0362embedded imageembedded image100464465B-0363embedded imageembedded image73512513B-0364embedded imageembedded image88377378B-0365embedded imageembedded image70396397B-0366embedded imageembedded image100354355B-0367embedded imageembedded image71416417B-0368embedded imageembedded image100354355B-0369embedded imageembedded image40440441B-0370embedded imageembedded image94364365B-0371embedded imageembedded image88460461B-0372embedded imageembedded image69430431B-0373embedded imageembedded image100430431B-0374embedded imageembedded image75400401B-0375embedded imageembedded image74386387B-0376embedded imageembedded image53378379B-0377embedded imageembedded image71387388B-0378embedded imageembedded image69387388B-0379embedded imageembedded image66387388B-0380embedded imageembedded image85416417B-0381embedded imageembedded image93430431B-0382embedded imageembedded image84382383B-0383embedded imageembedded image74583584B-0384embedded imageembedded image63438439B-0392embedded imageembedded image100440441B-0393embedded imageembedded image75388389B-0394embedded imageembedded image92402403B-0395embedded imageembedded image87374375B-0396embedded imageembedded image86360361B-0397embedded imageembedded image81452453B-0398embedded imageembedded image88428429B-0399embedded imageembedded image99436437B-0400embedded imageembedded image82482483B-0401embedded imageembedded image94367368B-0402embedded imageembedded image73325326B-0403embedded imageembedded image91415416B-0404embedded imageembedded image41379380B-0405embedded imageembedded image88395396B-0406embedded imageembedded image100419420B-0407embedded imageembedded image52353354B-0408embedded imageembedded image83339340B-0409embedded imageembedded image74415416B-0410embedded imageembedded image100419420B-0411embedded imageembedded image94429430B-0412embedded imageembedded image91365366B-0413embedded imageembedded image79367368B-0414embedded imageembedded image85429430B-0415embedded imageembedded image82401402B-0416embedded imageembedded image93429430B-0417embedded imageembedded image97429430B-0418embedded imageembedded image100419420B-0419embedded imageembedded image100431432B-0420embedded imageembedded image36381382B-0421embedded imageembedded image96353354B-0422embedded imageembedded image100461462B-0423embedded imageembedded image100408407B-0424embedded imageembedded image76366367B-0425embedded imageembedded image21368369B-0426embedded imageembedded image100354344B-0427embedded imageembedded image100379380B-0428embedded imageembedded image100379380B-0429embedded imageembedded image86368369B-0430embedded imageembedded image51500501B-0431embedded imageembedded image76479480B-0432embedded imageembedded image90500501B-0433embedded imageembedded image96456457B-0434embedded imageembedded image75496497B-0435embedded imageembedded image52496497B-0436embedded imageembedded image73506B-0437embedded imageembedded image19466B-0438embedded imageembedded image100490491B-0439embedded imageembedded image67464465B-0440embedded imageembedded image96472473B-0441embedded imageembedded image87472473B-0442embedded imageembedded image72481482B-0443embedded imageembedded image66473474B-0444embedded imageembedded image80515516B-0445embedded imageembedded image94490491B-0446embedded imageembedded image84464465B-0447embedded imageembedded image89470471B-0448embedded imageembedded image100490491B-0449embedded imageembedded image100474475B-0450embedded imageembedded image100447445B-0451embedded imageembedded image100454455B-0452embedded imageembedded image95495497B-0453embedded imageembedded image100490491B-0454embedded imageembedded image100500501B-0455embedded imageembedded image96500501B-0456embedded imageembedded image89494495


























Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0457


embedded image




embedded image


93
482
483





B-0458


embedded image




embedded image


100
490
491





B-0459


embedded image




embedded image


100
490
491





B-0460


embedded image




embedded image


93
450
451





B-0461


embedded image




embedded image


84
452
453





B-0462


embedded image




embedded image


96
456
457





B-0463


embedded image




embedded image


66
456
457





B-0464


embedded image




embedded image


69
490
491





B-0465


embedded image




embedded image


86
490
491





B-0466


embedded image




embedded image


78
474
475





B-0467


embedded image




embedded image


78
470
471





B-0468


embedded image




embedded image


91
450
451





B-0469


embedded image




embedded image


85
436
437





B-0470


embedded image




embedded image


99
466
467





B-0471


embedded image




embedded image


100
490
491





B-0472


embedded image




embedded image


37
482
483





B-0473


embedded image




embedded image


92
462
463





B-0474


embedded image




embedded image


99
530
532





B-0475


embedded image




embedded image


55
472
473





B-0476


embedded image




embedded image


89
441
442





B-0477


embedded image




embedded image


79
464
465





B-0478


embedded image




embedded image


92
486
487





B-0479


embedded image




embedded image


97
447
448





B-0480


embedded image




embedded image


75
561
562





B-0481


embedded image




embedded image


74
498
499





B-0482


embedded image




embedded image


57
548
549





B-0483


embedded image




embedded image


83
505
506





B-0484


embedded image




embedded image


100
568
569





B-0485


embedded image




embedded image


100
495
496





B-0486


embedded image




embedded image


100
426
427





B-0487


embedded image




embedded image


32
389
390





B-0488


embedded image




embedded image


100
588
569





B-0489


embedded image




embedded image


91
500
501





B-0490


embedded image




embedded image


40
473
474





B-0491


embedded image




embedded image


73
514
515





B-0492


embedded image




embedded image


89
400
401





B-0493


embedded image




embedded image


100
420
421





B-0494


embedded image




embedded image


100
400
401





B-0495


embedded image




embedded image


100
454
455





B-0496


embedded image




embedded image


100
442
443





B-0497


embedded image




embedded image


50
512
513





B-0498


embedded image




embedded image


100
454
455





B-0499


embedded image




embedded image


98
411
412





B-0500


embedded image




embedded image


100
436
437





B-0501


embedded image




embedded image


100
422
423





B-0502


embedded image




embedded image


100
422
423





B-0503


embedded image




embedded image


92
440
441





B-0504


embedded image




embedded image


67
454
455





B-0505


embedded image




embedded image


68
428
429





B-0506


embedded image




embedded image


98
472
473





B-0507


embedded image




embedded image


82
440
441





B-0508


embedded image




embedded image


99
472
473





B-0509


embedded image




embedded image


100
472
473





B-0510


embedded image




embedded image


96
472
473





B-0511


embedded image




embedded image


100
472
473





B-0512


embedded image




embedded image


100
472
473





B-0513


embedded image




embedded image


100
472
473





B-0514


embedded image




embedded image


100
420
421





B-0515


embedded image




embedded image


100
400
401





B-0516


embedded image




embedded image


100
454
455





B-0517


embedded image




embedded image


100
404
405





B-0518


embedded image




embedded image


99
422
423





B-0519


embedded image




embedded image


100
454
455





B-0520


embedded image




embedded image


98
422
423





B-0521


embedded image




embedded image


99
440
441





B-0522


embedded image




embedded image


88
404
405





B-0523


embedded image




embedded image


100
422
423





B-0524


embedded image




embedded image


100
422
423





B-0525


embedded image




embedded image


100
420
421





B-0526


embedded image




embedded image


100
464
465





B-0527


embedded image




embedded image


100
454
455





B-0528


embedded image




embedded image


100
392
393





B-0529


embedded image




embedded image


94
405
406















embedded image





















Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0530


embedded image




embedded image


67
382
383





B-0531


embedded image




embedded image


66
512
513





B-0532


embedded image




embedded image


37
352
353





B-0533


embedded image




embedded image


56
404
405





B-0534


embedded image




embedded image


100
366
367





B-0535


embedded image




embedded image


100
410
411





B-0536


embedded image




embedded image


41
324
325





B-0537


embedded image




embedded image


100
364
365





B-0538


embedded image




embedded image


29
350
351





B-0539


embedded image




embedded image


70
464
465





B-0540


embedded image




embedded image


50
512
513





B-0541


embedded image




embedded image


61
377
378





B-0542


embedded image




embedded image


61
396
397





B-0543


embedded image




embedded image


59
354
355





B-0544


embedded image




embedded image


45
416
417





B-0545


embedded image




embedded image


100
454
455





B-0546


embedded image




embedded image


44
440
441





B-0547


embedded image




embedded image


64
364
365





B-0548


embedded image




embedded image


89
460
461





B-0549


embedded image




embedded image


100
430
431





B-0550


embedded image




embedded image


100
4.30
431





B-0551


embedded image




embedded image


81
400
401





B-0552


embedded image




embedded image


38
386
387





B-0553


embedded image




embedded image


31
378
379





B-0554


embedded image




embedded image


100
387
388





B-0555


embedded image




embedded image


66
387
388





B-0556


embedded image




embedded image


32
387
388





B-0557


embedded image




embedded image


70
416
417





B-0558


embedded image




embedded image


57
430
431





B-0559


embedded image




embedded image


74
382
383





B-0560


embedded image




embedded image


36
583
584





B-0561


embedded image




embedded image


51
438
439





B-0562


embedded image




embedded image


88
440
441





B-0563


embedded image




embedded image


68
422
423





B-0564


embedded image




embedded image


47
388
389





B-0565


embedded image




embedded image


100
448
449





B-0566


embedded image




embedded image


76
436
437





B-0567


embedded image




embedded image


99
458
459





B-0568


embedded image




embedded image


45
414
415





B-0569


embedded image




embedded image


88
440
441





B-0570


embedded image




embedded image


61
388
389





B-0571


embedded image




embedded image


58
402
403





B-0572


embedded image




embedded image


75
374
375





B-0573


embedded image




embedded image


72
360
361





B-0574


embedded image




embedded image


97
452
453





B-0575


embedded image




embedded image


71
428
429





B-0576


embedded image




embedded image


88
436
437





B-0577


embedded image




embedded image


72
482
483





B-0578


embedded image




embedded image


89
367
388





B-0579


embedded image




embedded image


100
325
326





B-0580


embedded image




embedded image


75
415
416





B-0581


embedded image




embedded image


44
379
380





B-0582


embedded image




embedded image


75
395
396





B-0583


embedded image




embedded image


80
419
420





B-0584


embedded image




embedded image


57
353
354





B-0585


embedded image




embedded image


83
339
340





B-0586


embedded image




embedded image


71
415
416





B-0587


embedded image




embedded image


100
419
420





B-0588


embedded image




embedded image


94
429
430





B-0589


embedded image




embedded image


78
365
386





B-0590


embedded image




embedded image


82
367
368





B-0591


embedded image




embedded image


72
429
430





B-0592


embedded image




embedded image


82
401
402





B-0593


embedded image




embedded image


88
429
430





B-0594


embedded image




embedded image


100
429
430





B-0595


embedded image




embedded image


99
419
420





B-596


embedded image




embedded image


93
431
432





B-597


embedded image




embedded image


40
381
382





B-0598


embedded image




embedded image


93
353
354





B-0599


embedded image




embedded image


100
461
462





B-0600


embedded image




embedded image


98
406
407





B-0601


embedded image




embedded image


66
366
367





B-0602


embedded image




embedded image


25
368
369





B-0603


embedded image




embedded image


90
354
355





B-0604


embedded image




embedded image


86
379
380





B-0605


embedded image




embedded image


87
379
380





B-0606


embedded image




embedded image


72
368
369





B-0607


embedded image




embedded image


34
500
501





B-0608


embedded image




embedded image


100
479
480





B-0609


embedded image




embedded image


82
500
501





B-0610


embedded image




embedded image


100
456
457





B-0611


embedded image




embedded image


76
496
497





B-0612


embedded image




embedded image


69
496
497





B-0613


embedded image




embedded image


61
506





B-0614


embedded image




embedded image


18
466





B-0615


embedded image




embedded image


100
490
491





B-0616


embedded image




embedded image


77
464
465





B-0617


embedded image




embedded image


93
472
473





B-0618


embedded image




embedded image


84
472
473





B-0619


embedded image




embedded image


71
481
482





B-0620


embedded image




embedded image


89
473
474





B-0621


embedded image




embedded image


68
515
516





B-0622


embedded image




embedded image


70
490
491





B-0623


embedded image




embedded image


92
464
465





B-0624


embedded image




embedded image


98
470
471





B-0625


embedded image




embedded image


96
490
491





B-0626


embedded image




embedded image


100
474
475





B-0627


embedded image




embedded image


100
447
448





B-0628


embedded image




embedded image


64
454
455





B-0629


embedded image




embedded image


100
496
497





B-0630


embedded image




embedded image


85
490
491





B-0631


embedded image




embedded image


75
500
501





B-0632


embedded image




embedded image


83
500
501





B-0633


embedded image




embedded image


58
494
495





B-0634


embedded image




embedded image


63
482
483





B-0635


embedded image




embedded image


95
490
491





B-0636


embedded image




embedded image


100
490
491





B-0637


embedded image




embedded image


91
450
451





B-0638


embedded image




embedded image


96
436
437





B-0639


embedded image




embedded image


100
456
457





B-0640


embedded image




embedded image


100
456
457





B-0641


embedded image




embedded image


88
490
491





B-0642


embedded image




embedded image


99
490
491





B-0643


embedded image




embedded image


92
474
475





B-0644


embedded image




embedded image


100
470
471





B-0645


embedded image




embedded image


92
450
451





B-0646


embedded image




embedded image


100
436
437





B-0647


embedded image




embedded image


90
466
467





B-0648


embedded image




embedded image


94
490
491





B-0649


embedded image




embedded image


57
482





B-0650


embedded image




embedded image


82
462
463





B-0651


embedded image




embedded image


100
530
531





B-0652


embedded image




embedded image


53
472





B-0653


embedded image




embedded image


84
441
442





B-0654


embedded image




embedded image


92
464
465





B-0655


embedded image




embedded image


100
486
487





B-0656


embedded image




embedded image


98
447
448





B-0657


embedded image




embedded image


85
561
562





B-0658


embedded image




embedded image


92
498
499





B-0659


embedded image




embedded image


46
548
549





B-0660


embedded image




embedded image


80
505
506





B-0661


embedded image




embedded image


100
568
569





B-0662


embedded image




embedded image


98
495
496





B-0663


embedded image




embedded image


74
426
427





B-0664


embedded image




embedded image


30
389
390





B-0665


embedded image




embedded image


100
568
569





B-0666


embedded image




embedded image


93
500
501





B-0667


embedded image




embedded image


54
473
474





B-0668


embedded image




embedded image


66
514
515





B-0669


embedded image




embedded image


65
400
401





B-0670


embedded image




embedded image


45
420
421





B-0671


embedded image




embedded image


43
400
401





B-0672


embedded image




embedded image


45
454
455





B-0673


embedded image




embedded image


41
442
443





B-0674


embedded image




embedded image


16
512
513





B-0675


embedded image




embedded image


39
454
455





B-0676


embedded image




embedded image


34
411
412





B-0677


embedded image




embedded image


46
436
437





B-0678


embedded image




embedded image


37
422
423





B-0679


embedded image




embedded image


34
422
423





B-0680


embedded image




embedded image


60
440
441





B-0681


embedded image




embedded image


31
454
455





B-0682


embedded image




embedded image


37
428
429





B-0683


embedded image




embedded image


46
472
473





B-0684


embedded image




embedded image


50
440
441





B-0685


embedded image




embedded image


44
472
473





B-0686


embedded image




embedded image


66
472
473





B-0687


embedded image




embedded image


57
472
473





B-0688


embedded image




embedded image


52
472
473





B-0689


embedded image




embedded image


42
472
473





B-0690


embedded image




embedded image


34
472
473





B-0691


embedded image




embedded image


52
420
421





B-0692


embedded image




embedded image


41
400
401





B-0693


embedded image




embedded image


56
454
455





B-0694


embedded image




embedded image


38
404
405





B-0695


embedded image




embedded image


43
422
423





B-0696


embedded image




embedded image


57
454
455





B-0697


embedded image




embedded image


51
422
423





B-0698


embedded image




embedded image


59
440
441





B-0699


embedded image




embedded image


46
404
405





B-0700


embedded image




embedded image


47
422
423





B-0701


embedded image




embedded image


46
422
423





B-0702


embedded image




embedded image


43
420
421





B-0703


embedded image




embedded image


57
464
465





B-0704


embedded image




embedded image


44
454
455





B-0705


embedded image




embedded image


33
392
393





B-0706


embedded image




embedded image


35
405
406















embedded image





















Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0707


embedded image




embedded image


76
516
517





B-0708


embedded image




embedded image


61
498
499





B-0709


embedded image




embedded image


37
464
465





B-0710


embedded image




embedded image


76
524
525





B-0711


embedded image




embedded image


75
512
513





B-0712


embedded image




embedded image


91
534
535





B-0713


embedded image




embedded image


42
490
491





B-0714


embedded image




embedded image


87
516
517





B-0715


embedded image




embedded image


60
464
465





B-0716


embedded image




embedded image


59
478
479





B-0717


embedded image




embedded image


61
450
451





B-0718


embedded image




embedded image


65
436
437





B-0719


embedded image




embedded image


84
528
529





B-0720


embedded image




embedded image


69
504
505





B-0721


embedded image




embedded image


63
512
513





B-0722


embedded image




embedded image


88
558
559





B-0723


embedded image




embedded image


68
443
444





B-0724


embedded image




embedded image


75
401
402





B-0725


embedded image




embedded image


83
491
492





B-0726


embedded image




embedded image


24
455
456





B-0727


embedded image




embedded image


67
471
472





B-0728


embedded image




embedded image


89
495
496





B-0729


embedded image




embedded image


38
429
430





B-0730


embedded image




embedded image


76
415
416





B-0731


embedded image




embedded image


60
491
492





B-0732


embedded image




embedded image


86
495
496





B-0733


embedded image




embedded image


81
505
506





B-0734


embedded image




embedded image


87
441
442





B-0735


embedded image




embedded image


83
443
444





B-0736


embedded image




embedded image


91
505
506





B-0737


embedded image




embedded image


9
477






B-0738


embedded image




embedded image


87
505
506





B-0739


embedded image




embedded image


82
505
506





B-0740


embedded image




embedded image


85
495
496





B-0741


embedded image




embedded image


68
507
508





B-0742


embedded image




embedded image


14
457






B-0743


embedded image




embedded image


77
429
430





B-0744


embedded image




embedded image


88
537
538





B-0745


embedded image




embedded image


82
482
483





B-0746


embedded image




embedded image


74
442
443





B-0747


embedded image




embedded image


83
444
445





B-0748


embedded image




embedded image


94
430
431





B-0749


embedded image




embedded image


100
455
456





B-0750


embedded image




embedded image


100
455
456





B-0751


embedded image




embedded image


48
444
445





B-0752


embedded image




embedded image


84
516
517





B-0753


embedded image




embedded image


67
498
499





B-0754


embedded image




embedded image


31
464
465





B-0755


embedded image




embedded image


85
524
525





B-0756


embedded image




embedded image


77
512
513





B-0757


embedded image




embedded image


57
534
535





B-0758


embedded image




embedded image


36
490
491





B-0759


embedded image




embedded image


79
516
517





B-0760


embedded image




embedded image


53
464
465





B-0761


embedded image




embedded image


50
478
479





B-0762


embedded image




embedded image


60
450
451





B-0763


embedded image




embedded image


75
436
437





B-0764


embedded image




embedded image


43
528
529





B-0765


embedded image




embedded image


75
504
505





B-0766


embedded image




embedded image


67
512
513





B-0767


embedded image




embedded image


43
558
559





B-0768


embedded image




embedded image


78
443
444





B-0769


embedded image




embedded image


76
401
402





B-0770


embedded image




embedded image


57
491
492





B-0771


embedded image




embedded image


14
455
456





B-0772


embedded image




embedded image


72
471
472





B-0773


embedded image




embedded image


100
495
496





B-0774


embedded image




embedded image


41
429
430





B-0775


embedded image




embedded image


91
415
416





B-0776


embedded image




embedded image


64
491
492





B-0777


embedded image




embedded image


90
495
496





B-0778


embedded image




embedded image


19
505
506





B-0779


embedded image




embedded image


79
441
442





B-0780


embedded image




embedded image


40
443
444





B-0781


embedded image




embedded image


93
505
506





B-0782


embedded image




embedded image


57
477
478





B-0783


embedded image




embedded image


99
505
506





B-0784


embedded image




embedded image


100
505
506





B-0786


embedded image




embedded image


91
507
508





B-0787


embedded image




embedded image


15
457
458





B-0788


embedded image




embedded image


48
429
430





B-0789


embedded image




embedded image


91
537
538





B-0790


embedded image




embedded image


93
482
483





B-0791


embedded image




embedded image


76
442
443





B-0792


embedded image




embedded image


96
444
445





B-0793


embedded image




embedded image


54
430
431





B-0794


embedded image




embedded image


100
455
456





B-0795


embedded image




embedded image


100
455
456





B-0796


embedded image




embedded image


94
444
445





B-0797


embedded image




embedded image


90
458
459





B-0799


embedded image




embedded image


82
428
429





B-0800


embedded image




embedded image


92
480
481





B-0801


embedded image




embedded image


82
442
443





B-0802


embedded image




embedded image


95
486
487





B-0803


embedded image




embedded image


89
400
401





B-0804


embedded image




embedded image


87
440
441





B-0805


embedded image




embedded image


100
426
427





B-0806


embedded image




embedded image


99
540
541





B-0807


embedded image




embedded image


96
588
559





B-0808


embedded image




embedded image


82
453
454





B-0809


embedded image




embedded image


92
472
473





B-0810


embedded image




embedded image


98
430
431





B-0811


embedded image




embedded image


88
492
493





B-0812


embedded image




embedded image


81
530
531





B-0813


embedded image




embedded image


98
516
517





B-0814


embedded image




embedded image


100
440
441





B-0815


embedded image




embedded image


100
536
537





B-0816


embedded image




embedded image


99
506
507





B-0817


embedded image




embedded image


98
506
507





B-0818


embedded image




embedded image


86
476
477





B-0819


embedded image




embedded image


90
462
463





B-0820


embedded image




embedded image


91
454
455





B-0821


embedded image




embedded image


69
463
464





B-0822


embedded image




embedded image


79
463
464





B-0823


embedded image




embedded image


79
463
464





B-0824


embedded image




embedded image


82
492
493





B-0825


embedded image




embedded image


100
506
507





B-0826


embedded image




embedded image


97
458
459





B-0827


embedded image




embedded image


100
659
660





B-0828


embedded image




embedded image


97
514
515





B-0829


embedded image




embedded image


63
458
459





B-830


embedded image




embedded image


70
588
589





B-0831


embedded image




embedded image


100
428
429





B-0832


embedded image




embedded image


81
480
481





B-0833


embedded image




embedded image


73
442
443





B-0834


embedded image




embedded image


79
486
487





B-0835


embedded image




embedded image


5
400
401





B-0836


embedded image




embedded image


28
440
441





B-0837


embedded image




embedded image


81
426
427





B-0838


embedded image




embedded image


84
540
541





B-0839


embedded image




embedded image


80
588
589





B-0840


embedded image




embedded image


71
453
454





B-0841


embedded image




embedded image


55
472
473





B-0842


embedded image




embedded image


71
430
431





B-0843


embedded image




embedded image


68
492
493





B-0844


embedded image




embedded image


61
530
531





B-0845


embedded image




embedded image


84
516
517





B-0846


embedded image




embedded image


87
440
441





B-0847


embedded image




embedded image


86
536
537





B-0848


embedded image




embedded image


79
506
507





B-0849


embedded image




embedded image


81
506
507





B-0850


embedded image




embedded image


69
476
477





B-0851


embedded image




embedded image


83
462
463





B-0852


embedded image




embedded image


77
454
455





B-0853


embedded image




embedded image


87
463
464





B-0854


embedded image




embedded image


73
463
464





B-0855


embedded image




embedded image


92
463
464





B-0856


embedded image




embedded image


75
492
493





B-0857


embedded image




embedded image


86
506
507





B-0858


embedded image




embedded image


84
458
459





B-0859


embedded image




embedded image


80
659
660





B-0860


embedded image




embedded image


94
514
515















embedded image





















Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0861


embedded image




embedded image


84
583
584





B-0862


embedded image




embedded image


96
475
476





B-0863


embedded image




embedded image


69
423
424





B-0864


embedded image




embedded image


86
437
438





B-0865


embedded image




embedded image


62
395






B-0866


embedded image




embedded image


81
421
422





B-0867


embedded image




embedded image


100
535
536


































Observed






Calcd.
Mass





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0868


embedded image




embedded image


89
583
584





B-0869


embedded image




embedded image


100
448
449





B-0870


embedded image




embedded image


100
425
426





B-0871


embedded image




embedded image


100
487
488





B-0872


embedded image




embedded image


78
501
502





B-0873


embedded image




embedded image


78
471
472





B-0874


embedded image




embedded image


92
475
476





B-0875


embedded image




embedded image


37
458
459





B-0876


embedded image




embedded image


69
507
508





B-0877


embedded image




embedded image


70
445
446





B-0878


embedded image




embedded image


91
431
432





B-0879


embedded image




embedded image


92
511
512





B-0880


embedded image




embedded image


89
410
411





B-0881


embedded image




embedded image


84
490
491





B-0882


embedded image




embedded image


85
500
501





B-0883


embedded image




embedded image


85
424
425





B-0884


embedded image




embedded image


86
532
533















embedded image



















Observed






Calcd.
Mass





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0885


embedded image




embedded image


51
583






B-0886


embedded image




embedded image


97
475






B-0887


embedded image




embedded image


29
423
424





B-0888


embedded image




embedded image


82
437
438





B-0889


embedded image




embedded image


93
395
396





B-0890


embedded image




embedded image


91
421
422





B-0891


embedded image




embedded image


43
535
536





B-0892


embedded image




embedded image


62
583
584





B-0893


embedded image




embedded image


95
448
449





B-0894


embedded image




embedded image


100
425
426





B-0895


embedded image




embedded image


76
487
488





B-0896


embedded image




embedded image


62
501
502





B-0897


embedded image




embedded image


80
471
472





B-0898


embedded image




embedded image


79
475
476





B-0899


embedded image




embedded image


70
458
459





B-0900


embedded image




embedded image


62
507
508





B-0901


embedded image




embedded image


43
445
446





B-0902


embedded image




embedded image


93
431
432





B-0903


embedded image




embedded image


100
511
512





B-0904


embedded image




embedded image


95
410
411





B-0905


embedded image




embedded image


89
490
491





B-0906


embedded image




embedded image


69
500
501





B-0907


embedded image




embedded image


28
424
425





B-0908


embedded image




embedded image


64
532
533















embedded image






















Observed






Calcd.
Mass





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0909


embedded image




embedded image


83
542
543





B-0910


embedded image




embedded image


80
434
435





B-0911


embedded image




embedded image


91
382
383





B-0912


embedded image




embedded image


100
396
397





B-0913


embedded image




embedded image


94
354
355





B-0914


embedded image




embedded image


95
380
381





B-0915


embedded image




embedded image


98
494
495





B-0916


embedded image




embedded image


84
542
543





B-0917


embedded image




embedded image


79
407
408





B-0918


embedded image




embedded image


89
384
385





B-0919


embedded image




embedded image


91
446
447





B-0920


embedded image




embedded image


99
460
461





B-0921


embedded image




embedded image


84
430
431





B-0922


embedded image




embedded image


81
434
435





B-0923


embedded image




embedded image


76
417
418





B-0924


embedded image




embedded image


70
466
467





B-0925


embedded image




embedded image


64
404
405





B-0926


embedded image




embedded image


47
390
391





B-0927


embedded image




embedded image


89
470
471





B-0928


embedded image




embedded image


53
369
370





B-0929


embedded image




embedded image


100
449
450





B-0930


embedded image




embedded image


14
459
460





B-0931


embedded image




embedded image


41
383
384





B-0932


embedded image




embedded image


94
491
492















embedded image






















Observed






Calcd.
Mass





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-0933


embedded image




embedded image


48
447
448





B-0934


embedded image




embedded image


44
429
430





B-0935


embedded image




embedded image


33
485
486





B-0936


embedded image




embedded image


30
479






B-0937


embedded image




embedded image


68
367
368





B-0938


embedded image




embedded image


72
479
480





B-0939


embedded image




embedded image


76
415
416





B-0940


embedded image




embedded image


36
397
398





B-0941


embedded image




embedded image


41
441
442





B-0942


embedded image




embedded image


27
473
474





B-0943


embedded image




embedded image


55
493
494





B-0944


embedded image




embedded image


53
473
474





B-0945


embedded image




embedded image


82
429
430





B-0946


embedded image




embedded image


100
459
460





B-0947


embedded image




embedded image


60
425
426





B-0948


embedded image




embedded image


100
431
432





B-0949


embedded image




embedded image


98
473
474





B-0950


embedded image




embedded image


64
419
420





B-0951


embedded image




embedded image


100
469
470





B-0952


embedded image




embedded image


61
469
470





B-0953


embedded image




embedded image


67
425
426





B-0954


embedded image




embedded image


62
431
432





B-0955


embedded image




embedded image


39
461
462





B-0956


embedded image




embedded image


66
429
430





B-0957


embedded image




embedded image


93
429
430





B-0958


embedded image




embedded image


86
365
366





B-0959


embedded image




embedded image


73
451
452





B-0960


embedded image




embedded image


98
485
486





B-0961


embedded image




embedded image


100
469
470





B-0962


embedded image




embedded image


100
419
420





B-0963


embedded image




embedded image


83
401
402





B-0964


embedded image




embedded image


38
429
430





B-0965


embedded image




embedded image


90
411
412





B-0966


embedded image




embedded image


76
443
444





B-0967


embedded image




embedded image


100
443
444





B-0968


embedded image




embedded image


100
477
478





B-0969


embedded image




embedded image


77
477
478





B-0970


embedded image




embedded image


38
461
462





B-0971


embedded image




embedded image


95
469
470





B-0972


embedded image




embedded image


98
479
480





B-0973


embedded image




embedded image


96
485
486





B-0974


embedded image




embedded image


74
443
444





B-0975


embedded image




embedded image


100
495
496





B-0976


embedded image




embedded image


70
453
454





B-0977


embedded image




embedded image


100
467
468





B-0978


embedded image




embedded image


91
431
432





B-0979


embedded image




embedded image


54
491
492





B-0980


embedded image




embedded image


65
469
470





B-0981


embedded image




embedded image


78
382
383





B-0982


embedded image




embedded image


82
512
813





B-0983


embedded image




embedded image


94
352
353





B-0984


embedded image




embedded image


81
404
405





B-0985


embedded image




embedded image


84
366
367





B-0986


embedded image




embedded image


80
410
411





B-0987


embedded image




embedded image


85
324
325





B-0988


embedded image




embedded image


91
364
365





B-0989


embedded image




embedded image


88
350
351





B-0990


embedded image




embedded image


68
464
465





B-0991


embedded image




embedded image


86
512
513





B-0992


embedded image




embedded image


79
377
378





B-0993


embedded image




embedded image


81
396
397





B-0994


embedded image




embedded image


100
354
355





B-0995


embedded image




embedded image


75
416
417





B-0996


embedded image




embedded image


65
454
455





B-0997


embedded image




embedded image


64
440
441





B-0998


embedded image




embedded image


81
364
355





B-0999


embedded image




embedded image


79
460
461





B-1000


embedded image




embedded image


84
430
431





B-1001


embedded image




embedded image


78
430
431





B-1002


embedded image




embedded image


85
400
401





B-1003


embedded image




embedded image


53
386
387





B-1004


embedded image




embedded image


87
378
379





B-1005


embedded image




embedded image


57
387
388





B-1006


embedded image




embedded image


80
387
388





B-1007


embedded image




embedded image


54
387
388





B-1008


embedded image




embedded image


64
416
417





B-1009


embedded image




embedded image


81
430
431





B-1010


embedded image




embedded image


81
382
383





B-1011


embedded image




embedded image


66
583
584





B-1012


embedded image




embedded image


69
438
439





B-1013


embedded image




embedded image


53
440
441





B-1014


embedded image




embedded image


61
422
423





B-1015


embedded image




embedded image


47
388
389





B-1016


embedded image




embedded image


74
448
449





B-1017


embedded image




embedded image


63
436
437





B-1018


embedded image




embedded image


82
458
459





B-1019


embedded image




embedded image


41
414
415





B-1020


embedded image




embedded image


100
440
441





B-1021


embedded image




embedded image


100
388
389





B-1022


embedded image




embedded image


74
402
403





B-1023


embedded image




embedded image


76
374
375





B-1024


embedded image




embedded image


73
360
361





B-1025


embedded image




embedded image


100
452
453





B-1026


embedded image




embedded image


95
428
429





B-1027


embedded image




embedded image


98
436
437





B-1028


embedded image




embedded image


100
482
483





B-1029


embedded image




embedded image


98
367
368





B-1030


embedded image




embedded image


88
325
326





B-1031


embedded image




embedded image


97
415
416





B-1032


embedded image




embedded image


64
379
380





B-1033


embedded image




embedded image


83
395
396





B-1034


embedded image




embedded image


67
419
420





B-1035


embedded image




embedded image


73
353
354





B-1036


embedded image




embedded image


79
339
340





B-1037


embedded image




embedded image


78
415
416





B-1038


embedded image




embedded image


100
419
420





B-1039


embedded image




embedded image


95
429
430





B-1040


embedded image




embedded image


91
365
366





B-1041


embedded image




embedded image


88
367
368





B-1042


embedded image




embedded image


78
429
430





B-1043


embedded image




embedded image


79
401
402





B-1044


embedded image




embedded image


93
429
430





B-1045


embedded image




embedded image


100
429
430





B-1046


embedded image




embedded image


94
419
420





B-1047


embedded image




embedded image


100
431
432





B-1048


embedded image




embedded image


58
381
382





B-1049


embedded image




embedded image


97
353
354





B-1050


embedded image




embedded image


100
461
462





B-1051


embedded image




embedded image


88
406
407





B-1052


embedded image




embedded image


82
366
367





B-1053


embedded image




embedded image


21
368





B-1054


embedded image




embedded image


98
354
355





B-1055


embedded image




embedded image


100
379
380





B-1056


embedded image




embedded image


85
379
380





B-1057


embedded image




embedded image


30
368
369





B-1058


embedded image




embedded image


35
500
501





B-1059


embedded image




embedded image


77
479
480





B-1060


embedded image




embedded image


37
500
501





B-1061


embedded image




embedded image


86
456
457





B-1062


embedded image




embedded image


58
496
497





B-1063


embedded image




embedded image


59
496
497





B-1064


embedded image




embedded image


58
506






B-1065


embedded image




embedded image


24
466






B-1066


embedded image




embedded image


100
490
491





B-1067


embedded image




embedded image


74
464
465





B-1068


embedded image




embedded image


79
472
473





B-1069


embedded image




embedded image


97
472
473





B-1070


embedded image




embedded image


54
481
482





B-1071


embedded image




embedded image


67
473
474





B-1072


embedded image




embedded image


35
515
516





B-1073


embedded image




embedded image


100
490
491





B-1074


embedded image




embedded image


100
464
465





B-1075


embedded image




embedded image


100
470
471





B-1076


embedded image




embedded image


93
490
491





B-1077


embedded image




embedded image


100
474
475





B-1078


embedded image




embedded image


80
447
448





B-1079


embedded image




embedded image


85
454
455





B-1080


embedded image




embedded image


100
496
497





B-1081


embedded image




embedded image


100
490
491





B-1082


embedded image




embedded image


100
500
501





B-1083


embedded image




embedded image


93
500
501





B-1084


embedded image




embedded image


81
494
495





B-1085


embedded image




embedded image


93
482
483





B-1086


embedded image




embedded image


92
490
491





B-1087


embedded image




embedded image


100
490
491





B-1088


embedded image




embedded image


97
450
451





B-1089


embedded image




embedded image


100
436
437





B-1090


embedded image




embedded image


100
456
457





B-1091


embedded image




embedded image


100
456
457





B-1092


embedded image




embedded image


96
490
491





B-1093


embedded image




embedded image


100
490
491





B-1094


embedded image




embedded image


100
474
475





B-1095


embedded image




embedded image


81
470
471





B-1096


embedded image




embedded image


77
450
451





B-1097


embedded image




embedded image


100
436
437





B-1098


embedded image




embedded image


93
466
467





B-1099


embedded image




embedded image


100
490
491





B-1100


embedded image




embedded image


47
482






B-1101


embedded image




embedded image


64
462
463





B-1102


embedded image




embedded image


98
530
531





B-1103


embedded image




embedded image


65
472






B-1104


embedded image




embedded image


88
441
442





B-1105


embedded image




embedded image


100
464
465





B-1106


embedded image




embedded image


91
486
487





B-1107


embedded image




embedded image


96
447
448





B-1108


embedded image




embedded image


55
561
562





B-1109


embedded image




embedded image


100
498
499





B-1110


embedded image




embedded image


73
548
549





B-1111


embedded image




embedded image


94
505
506





B-1112


embedded image




embedded image


100
568
569





B-1113


embedded image




embedded image


100
495
496





B-1114


embedded image




embedded image


73
426
427





B-1115


embedded image




embedded image


30
389
390





B-1116


embedded image




embedded image


100
568
569





B-1117


embedded image




embedded image


83
500
501





B-1118


embedded image




embedded image


55
473






B-1119


embedded image




embedded image


70
514
515





B-1120


embedded image




embedded image


84
400
401





B-1121


embedded image




embedded image


86
420
421





B-1122


embedded image




embedded image


90
400
401





B-1123


embedded image




embedded image


100
454
455





B-1124


embedded image




embedded image


91
442
443





B-1125


embedded image




embedded image


50
512
513





B-1126


embedded image




embedded image


85
454
455





B-1127


embedded image




embedded image


93
411
412





B-1128


embedded image




embedded image


87
436
437





B-1129


embedded image




embedded image


78
422
423





B-1130


embedded image




embedded image


96
422
423





B-1131


embedded image




embedded image


84
440
441





B-1132


embedded image




embedded image


77
454
455





B-1133


embedded image




embedded image


62
428
429





B-1134


embedded image




embedded image


91
472
473





B-1135


embedded image




embedded image


85
440
441





B-1136


embedded image




embedded image


82
472
473





B-1137


embedded image




embedded image


95
472
473





B-1138


embedded image




embedded image


100
472
473





B-1139


embedded image




embedded image


100
472
473





B-1140


embedded image




embedded image


92
472
473





B-1141


embedded image




embedded image


100
472
473





B-1142


embedded image




embedded image


88
420
421





B-1143


embedded image




embedded image


90
400
401





B-1144


embedded image




embedded image


87
454
455





B-1145


embedded image




embedded image


93
404
405





B-1146


embedded image




embedded image


90
422
423





B-1147


embedded image




embedded image


100
454
455





B-1148


embedded image




embedded image


87
422
423





B-1149


embedded image




embedded image


87
440
441





B-1150


embedded image




embedded image


90
404
405





B-1151


embedded image




embedded image


82
422
423





B-1152


embedded image




embedded image


85
422
423





B-1153


embedded image




embedded image


90
420
421





B-1154


embedded image




embedded image


78
464
465





B-1155


embedded image




embedded image


79
454
455





B-1156


embedded image




embedded image


95
392
393





B-1157


embedded image




embedded image


81
405
406















embedded image






















Observed






Calcd.
Mass





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-1158


embedded image




embedded image


54
396
397





B-1159


embedded image




embedded image


42
526
527





B-1160


embedded image




embedded image


27
366
367





B-1161


embedded image




embedded image


58
418
419





B-1162


embedded image




embedded image


62
380
381





B-1163


embedded image




embedded image


58
424
425





B-1164


embedded image




embedded image


67
338
339





B-1165


embedded image




embedded image


66
378
379





B-1166


embedded image




embedded image


65
364
365





B-1167


embedded image




embedded image


64
478
479





B-1168


embedded image




embedded image


76
526
527





B-1169


embedded image




embedded image


70
391
392





B-1170


embedded image




embedded image


76
410
411





B-1171


embedded image




embedded image


82
368
369





B-1172


embedded image




embedded image


73
430
431





B-1173


embedded image




embedded image


74
468
469





B-1174


embedded image




embedded image


83
454
455





B-1175


embedded image




embedded image


76
378
379





B-1176


embedded image




embedded image


96
474
475





B-1177


embedded image




embedded image


94
444
445





B-1178


embedded image




embedded image


90
444
445





B-1179


embedded image




embedded image


57
414
415





B-1180


embedded image




embedded image


75
400
401





B-1181


embedded image




embedded image


66
392
393





B-1182


embedded image




embedded image


74
401
402





B-1183


embedded image




embedded image


62
401
402





B-1184


embedded image




embedded image


51
401
402





B-1185


embedded image




embedded image


90
430
431





B-1186


embedded image




embedded image


86
444
445





B-1187


embedded image




embedded image


74
396
397





B-1188


embedded image




embedded image


76
597
598





B-1189


embedded image




embedded image


60
452
453





B-1190


embedded image




embedded image


44
454
455





B-1191


embedded image




embedded image


47
436
437





B-1192


embedded image




embedded image


50
402
403





B-1193


embedded image




embedded image


62
462
463





B-1194


embedded image




embedded image


49
450
451





B-1195


embedded image




embedded image


61
472
473





B-1196


embedded image




embedded image


52
428
429





B-1197


embedded image




embedded image


54
454
455





B-1198


embedded image




embedded image


44
402
403





B-1199


embedded image




embedded image


67
416
417





B-1200


embedded image




embedded image


45
388
389





B-1201


embedded image




embedded image


52
374
375





B-1202


embedded image




embedded image


100
466
467





B-1203


embedded image




embedded image


91
442
443





B-1204


embedded image




embedded image


100
450
451





B-1205


embedded image




embedded image


83
496
497





B-1206


embedded image




embedded image


97
381
382





B-1207


embedded image




embedded image


100
339
340





B-1208


embedded image




embedded image


90
429
430





B-1209


embedded image




embedded image


69
393
394





B-1210


embedded image




embedded image


35
409
410





B-1211


embedded image




embedded image


100
433
434





B-1212


embedded image




embedded image


83
367
368





B-1213


embedded image




embedded image


78
353
354





B-1214


embedded image




embedded image


68
429
430





B-1215


embedded image




embedded image


65
433
434





B-1216


embedded image




embedded image


91
443
444





B-1217


embedded image




embedded image


99
379
380





B-1218


embedded image




embedded image


92
381
382





B-1219


embedded image




embedded image


74
443
444





B-1220


embedded image




embedded image


67
415
416





B-1221


embedded image




embedded image


14
443
444





B-1222


embedded image




embedded image


19
443
444





B-1223


embedded image




embedded image


71
433
434





B-1224


embedded image




embedded image


100
445
446





B-1225


embedded image




embedded image


75
395
396





B-1226


embedded image




embedded image


58
367
368





B-1227


embedded image




embedded image


98
475
476





B-1228


embedded image




embedded image


71
420
421





B-1229


embedded image




embedded image


85
380
381





B-1230


embedded image




embedded image


10
382






B-1231


embedded image




embedded image


66
368
369





B-1232


embedded image




embedded image


100
393
394





B-1233


embedded image




embedded image


96
393
394





B-1234


embedded image




embedded image


66
382
383





B-1235


embedded image




embedded image


50
514
515





B-1236


embedded image




embedded image


100
493
494





B-1237


embedded image




embedded image


91
514
515





B-1238


embedded image




embedded image


100
470
471





B-1239


embedded image




embedded image


71
510
511





B-1240


embedded image




embedded image


27
510
511





B-1241


embedded image




embedded image


73
520





B-1242


embedded image




embedded image


26
480
481





B-1243


embedded image




embedded image


100
504





B-1244


embedded image




embedded image


52
478
479





B-1245


embedded image




embedded image


100
486
487





B-1246


embedded image




embedded image


56
486
487





B-1247


embedded image




embedded image


43
495
496





B-1248


embedded image




embedded image


61
487
488





B-1249


embedded image




embedded image


32
529
530





B-1250


embedded image




embedded image


56
504
505





B-1251


embedded image




embedded image


58
478
479





B-1252


embedded image




embedded image


98
484
485





B-1253


embedded image




embedded image


59
504
505





B-1254


embedded image




embedded image


100
488
489





B-1255


embedded image




embedded image


96
461





B-1256


embedded image




embedded image


79
468
469





B-1257


embedded image




embedded image


63
510
511





B-1258


embedded image




embedded image


100
504
505





B-1259


embedded image




embedded image


95
514
515





B-1260


embedded image




embedded image


92
514
515





B-1261


embedded image




embedded image


98
508
509





B-1262


embedded image




embedded image


97
496
497





B-1263


embedded image




embedded image


100
504
505





B-1264


embedded image




embedded image


100
504
505





B-1265


embedded image




embedded image


100
464
465





B-1266


embedded image




embedded image


79
466
451





B-1267


embedded image




embedded image


100
470
471





B-1268


embedded image




embedded image


87
470
471





B-1269


embedded image




embedded image


100
504
505





B-1270


embedded image




embedded image


100
504
505





B-1271


embedded image




embedded image


56
488
489





B-1272


embedded image




embedded image


98
484
485





B-1273


embedded image




embedded image


90
464
465





B-1274


embedded image




embedded image


87
450
451





B-1275


embedded image




embedded image


94
480
481





B-1276


embedded image




embedded image


100
504
505





B-1277


embedded image




embedded image


60
496
511





B-1278


embedded image




embedded image


68
476
477





B-1279


embedded image




embedded image


100
544
545





B-1280


embedded image




embedded image


68
486






B-1281


embedded image




embedded image


98
455
456

































Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-1282


embedded image




embedded image


100
478
479





B-1283


embedded image




embedded image


58
500
501





B-1284


embedded image




embedded image


58
461
462





B-1285


embedded image




embedded image


65
575
576





B-1286


embedded image




embedded image


87
512
513





B-1287


embedded image




embedded image


79
562
563





B-1288


embedded image




embedded image


100
519
520





B-1289


embedded image




embedded image


77
582
583





B-1290


embedded image




embedded image


100
509
510





B-1291


embedded image




embedded image


91
440
441





B-1292


embedded image




embedded image


35
403
404





B-1293


embedded image




embedded image


73
582
583





B-1294


embedded image




embedded image


49
514
515





B-1295


embedded image




embedded image


48
487






B-1296


embedded image




embedded image


76
528
529





B-1297


embedded image




embedded image


62
447
448





B-1298


embedded image




embedded image


66
452
453





B-1299


embedded image




embedded image


65
479
431





B-1300


embedded image




embedded image


71
444
445





B-1301


embedded image




embedded image


100
472
473





B-1302


embedded image




embedded image


75
410
411





B-1303


embedded image




embedded image


74
424
425





B-1304


embedded image




embedded image


11
430
431





B-1305


embedded image




embedded image


2
424






B-1306


embedded image




embedded image


30
433
434





B-1307


embedded image




embedded image


100
522
523





B-1308


embedded image




embedded image


100
508
509





B-1309


embedded image




embedded image


100
448
449





B-1310


embedded image




embedded image


26
430
431





B-1311


embedded image




embedded image


45
397
398





B-1312


embedded image




embedded image


14
507
508





B-1313


embedded image




embedded image


67
450
451





B-1314


embedded image




embedded image


69
444
445





B-1315


embedded image




embedded image


57
450
451





B-1316


embedded image




embedded image


75
393
394





B-1317


embedded image




embedded image


100
461
462





B-1318


embedded image




embedded image


31
450
451





B-1319


embedded image




embedded image


23
464
465





B-1320


embedded image




embedded image


59
512
513





B-1321


embedded image




embedded image


63
414
415





B-1322


embedded image




embedded image


45
434
435





B-1323


embedded image




embedded image


53
414
415





B-1324


embedded image




embedded image


32
468
469





B-1325


embedded image




embedded image


45
456
457





B-1326


embedded image




embedded image


50
526
527





B-1327


embedded image




embedded image


55
468
469





B-1328


embedded image




embedded image


29
425
426





B-1329


embedded image




embedded image


67
450
451





B-1330


embedded image




embedded image


59
436
437





B-1331


embedded image




embedded image


45
436
437





B-1332


embedded image




embedded image


81
454
455





B-1333


embedded image




embedded image


23
468
469





B-1334


embedded image




embedded image


53
442
443





B-1335


embedded image




embedded image


81
486
487





B-1336


embedded image




embedded image


69
454
455





B-1337


embedded image




embedded image


67
486
487





B-1338


embedded image




embedded image


39
486
487





B-1339


embedded image




embedded image


61
486
487





B-1340


embedded image




embedded image


49
486
487





B-1341


embedded image




embedded image


55
486
487





B-1342


embedded image




embedded image


51
486
487





B-1343


embedded image




embedded image


72
434
435





B-1344


embedded image




embedded image


52
414
415





B-1345


embedded image




embedded image


43
468
469





B-1346


embedded image




embedded image


40
418
419





B-1347


embedded image




embedded image


67
436
437





B-1348


embedded image




embedded image


39
468
469





B-1349


embedded image




embedded image


68
436
437





B-1350


embedded image




embedded image


73
454
455





B-1351


embedded image




embedded image


54
418
419





B-1352


embedded image




embedded image


77
436
437





B-1353


embedded image




embedded image


66
436
437





B-1354


embedded image




embedded image


58
434
435





B-1355


embedded image




embedded image


77
478
479





B-1356


embedded image




embedded image


50
468
469





B-1357


embedded image




embedded image


36
406
407





B-1358


embedded image




embedded image


39
419
420















embedded image





















Calcd.
Observed





%
Mass
Spec


Example#
R2
RJ
Yield
Spec
(M + H)























B-1359


embedded image




embedded image


95
552
553





B-1360


embedded image




embedded image


77
444
445





B-1361


embedded image




embedded image


100
392
393





B-1362


embedded image




embedded image


85
406
407





B-1363


embedded image




embedded image


100
364
365





B-1364


embedded image




embedded image


99
390
391





B-1365


embedded image




embedded image


92
504
505





B-1366


embedded image




embedded image


100
552
553





B-1367


embedded image




embedded image


100
417
418





B-1368


embedded image




embedded image


86
394
395





B-1369


embedded image




embedded image


100
456
457





B-1370


embedded image




embedded image


100
470
471





B-1371


embedded image




embedded image


77
440
441





B-1372


embedded image




embedded image


100
444
445





B-1373


embedded image




embedded image


42
427
428





B-1374


embedded image




embedded image


60
476
477





B-1375


embedded image




embedded image


94
414
415





B-1376


embedded image




embedded image


87
400
401





B-1377


embedded image




embedded image


100
480
481





B-1378


embedded image




embedded image


95
379
380





B-1379


embedded image




embedded image


93
459
460





B-1380


embedded image




embedded image


89
469
470





B-1381


embedded image




embedded image


84
393
394





B-1382


embedded image




embedded image


85
501
502





B-1383


embedded image




embedded image


46
416
417





B-1384


embedded image




embedded image


56
432
433





B-1385


embedded image




embedded image


59
426
427





B-1386


embedded image




embedded image


50
427
428





B-1387


embedded image




embedded image


12
427
428





B-1388


embedded image




embedded image


66
504
505





B-1389


embedded image




embedded image


48
460
461





B-1390


embedded image




embedded image


44
494
495





B-1391


embedded image




embedded image


50
456
457





B-1392


embedded image




embedded image


47
451
452





B-1393


embedded image




embedded image


44
444
445





B-1394


embedded image




embedded image


52
460
461





B-1395


embedded image




embedded image


77
440
441





B-1396


embedded image




embedded image


58
451
452





B-1397


embedded image




embedded image


64
460
461





B-1398


embedded image




embedded image


65
504
505





B-1399


embedded image




embedded image


50
494
495





B-1400


embedded image




embedded image


74
440
441





B-1401


embedded image




embedded image


76
462
463





B-1402


embedded image




embedded image


65
462
463





B-1403


embedded image




embedded image


64
445
446





B-1404


embedded image




embedded image


70
512
513





B-1405


embedded image




embedded image


57
512
513





B-1406


embedded image




embedded image


73
512
513





B-1407


embedded image




embedded image


80
512
513





B-1408


embedded image




embedded image


2
512
513





B-1409


embedded image




embedded image


62
512
513





B-1410


embedded image




embedded image


42
512
513





B-1411


embedded image




embedded image


19
462
463





B-1412


embedded image




embedded image


74
462
463





B-1413


embedded image




embedded image


75
494
495





B-1414


embedded image




embedded image


68
462
463





B-1415


embedded image




embedded image


48
462
463





B-1416


embedded image




embedded image


48
494
495





B-1417


embedded image




embedded image


57
494
495





B-1418


embedded image




embedded image


49
494
495





B-1419


embedded image




embedded image


39
494
495





B-1420


embedded image




embedded image


72
378
379





B-1421


embedded image




embedded image


74
406
407





B-1422


embedded image




embedded image


68
394
395





B-1423


embedded image




embedded image


57
408
409





B-1424


embedded image




embedded image


77
422
423





B-1425


embedded image




embedded image


26
408
409





B-1426


embedded image




embedded image


41
406
407





B-1427


embedded image




embedded image


37
404
405





B-1428


embedded image




embedded image


60
456
457





B-1429


embedded image




embedded image


2
418
419





B-1430


embedded image




embedded image


61
442
443





B-1431


embedded image




embedded image


64
428
429





B-1432


embedded image




embedded image


71
429
430





B-1433


embedded image




embedded image


74
462
463





B-1434


embedded image




embedded image


88
466
467





B-1435


embedded image




embedded image


75
481
482





B-1436


embedded image




embedded image


71
504
505





B-1437


embedded image




embedded image


63
468
469





B-1438


embedded image




embedded image


78
502
503





B-1439


embedded image




embedded image


70
545
546





B-1440


embedded image




embedded image


62
535
536





B-1441


embedded image




embedded image


82
608





B-1442


embedded image




embedded image


79
555
556





B-1443


embedded image




embedded image


28
513
514





B-1444


embedded image




embedded image


75
522
523





B-1445


embedded image




embedded image


74
526
527





B-1446


embedded image




embedded image


70
570
571





B-1447


embedded image




embedded image


73
506
507





B-1448


embedded image




embedded image


76
530
531





B-1449


embedded image




embedded image


82
530
531





B-1450


embedded image




embedded image


83
530
531





B-1451


embedded image




embedded image


74
530
531





B-1452


embedded image




embedded image


76
530
531





B-1453


embedded image




embedded image


73
530
531





B-1454


embedded image




embedded image


81
498
499





B-1455


embedded image




embedded image


83
498
499





B-1456


embedded image




embedded image


78
498
499





B-1457


embedded image




embedded image


74
496
497





B-1458


embedded image




embedded image


82
540
541





B-1459


embedded image




embedded image


80
476
477





B-1460


embedded image




embedded image


78
530
531





B-1461


embedded image




embedded image


82
487
488





B-1462


embedded image




embedded image


71
540
541





B-1463


embedded image




embedded image


78
506
507





B-1464


embedded image




embedded image


83
480
481





B-1465


embedded image




embedded image


84
496
497





B-1466


embedded image




embedded image


80
540
541





B-1467


embedded image




embedded image


79
476
477





B-1468


embedded image




embedded image


79
530
531





B-1469


embedded image




embedded image


75
487
488





B-1470


embedded image




embedded image


80
480
481





B-1471


embedded image




embedded image


74
496
497





B-1472


embedded image




embedded image


75
540
541





B-1473


embedded image




embedded image


77
476
477





B-1474


embedded image




embedded image


81
530
531





B-1475


embedded image




embedded image


70
487
488





B-1476


embedded image




embedded image


54
540
541





B-1477


embedded image




embedded image


79
546
547





B-1478


embedded image




embedded image


87
394
395





B-1479


embedded image




embedded image


41
504
505





B-1480


embedded image




embedded image


87
451
452





B-1481


embedded image




embedded image


18
416
417





B-1482


embedded image




embedded image


77
427
428





B-1483


embedded image




embedded image


74
406
407





B-1484


embedded image




embedded image


82
422
423





B-1485


embedded image




embedded image


85
460
461





B-1486


embedded image




embedded image


64
406
407





B-1487


embedded image




embedded image


71
392
393





B-1488


embedded image




embedded image


82
427
428





B-1489


embedded image




embedded image


87
444
445





B-1490


embedded image




embedded image


81
462
463





B-1491


embedded image




embedded image


87
462
463





B-1492


embedded image




embedded image


69
364
365





B-1493


embedded image




embedded image


53
417
418





B-1494


embedded image




embedded image


17
426
427





B-1495


embedded image




embedded image


79
460
461





B-1496


embedded image




embedded image


80
444
445





B-1497


embedded image




embedded image


82
460
461





B-1498


embedded image




embedded image


72
378
379





B-1499


embedded image




embedded image


70
432
433





B-1500


embedded image




embedded image


68
390
391





B-1501


embedded image




embedded image


63
394
395





B-1502


embedded image




embedded image


78
408
409





B-1503


embedded image




embedded image


55
404
405





B-1504


embedded image




embedded image


39
418
419





B-1505


embedded image




embedded image


69
540
541





B-1506


embedded image




embedded image


69
462
463





B-1507


embedded image




embedded image


70
496
497





B-1508


embedded image




embedded image


65
480
481





B-1509


embedded image




embedded image


56
414
415





B-1510


embedded image




embedded image


62
400
401





B-1511


embedded image




embedded image


30
468
469





B-1512


embedded image




embedded image


50
476
477





B-1513


embedded image




embedded image


44
540
541





B-1514


embedded image




embedded image


42
530
531





B-1515


embedded image




embedded image


68
496
497





B-1516


embedded image




embedded image


27
429
430





B-1517


embedded image




embedded image


92
466
467





B-1518


embedded image




embedded image


33
379
380





B-1519


embedded image




embedded image


50
393
394





B-1520


embedded image




embedded image


82
435
436





B-1521


embedded image




embedded image


86
509
510





B-1522


embedded image




embedded image


12
405
406





B-1523


embedded image




embedded image


59
459
460





B-1524


embedded image




embedded image


81
459
460





B-1525


embedded image




embedded image


57
419
420





B-1526


embedded image




embedded image


73
410
411





B-1527


embedded image




embedded image


66
520
521





B-1528


embedded image




embedded image


91
467
468





B-1529


embedded image




embedded image


73
432
433





B-1530


embedded image




embedded image


91
443
444





B-1531


embedded image




embedded image


74
422
423





B-1532


embedded image




embedded image


68
438
439





B-1543


embedded image




embedded image


82
476
477





B-1544


embedded image




embedded image


76
460
461





B-1545


embedded image




embedded image


77
476
477





B-1546


embedded image




embedded image


76
394
395





B-1547


embedded image




embedded image


58
448
449





B-1548


embedded image




embedded image


83
406
407





B-1549


embedded image




embedded image


67
410
411





B-1550


embedded image




embedded image


37
424
425





B-1551


embedded image




embedded image


55
420
421





B-1552


embedded image




embedded image


23
434
435





B-1553


embedded image




embedded image


83
556
557





B-1554


embedded image




embedded image


84
478
479





B-1555


embedded image




embedded image


93
512
513





B-1556


embedded image




embedded image


83
496
497





B-1557


embedded image




embedded image


62
430
431





B-1558


embedded image




embedded image


45
416
417





B-1559


embedded image




embedded image


67
484
485





B-1560


embedded image




embedded image


16
492
493





B-1561


embedded image




embedded image


84
556
557





B-1562


embedded image




embedded image


74
546
547





B-1563


embedded image




embedded image


72
512
513





B-1564


embedded image




embedded image


57
445
446





B-1565


embedded image




embedded image


64
482
483





B-1566


embedded image




embedded image


71
395
396





B-1567


embedded image




embedded image


54
409
410





B-1568


embedded image




embedded image


76
451
452





B-1569


embedded image




embedded image


70
525
526





B-1570


embedded image




embedded image


79
421
422





B-1571


embedded image




embedded image


60
475
476





B-1572


embedded image




embedded image


77
475
476





B-1573


embedded image




embedded image


65
435
436









proton NMR data for selected members from Examples B-0001 through B-1573 sre shown in the following table.

Plate ID1H NMR(solvent), d ppmB-0120(DMF-d7) d 8.53(bd, J=4.99Hz, 2H), 7.44-7.24(m, 11H), 4.41(s, 2H), 4.31(br, 2H)B-0224(DMF-d7) d 8.56(bd, J=4.98Hz, 2H), 7.78-7.69(m, 4H), 7.39-7.19(m, 6H),4.23(br, 2H)B-0235(DMF-d7) d 8.47(br, 2H), 7.91-7.75(m, 3H), 7.57-7.53(m, 1H), 7.38-7.34(m,2H), 7.21-7.13(m, 4H), 4.20(br, 2H)B-0244(CDCl3/CD3OD) d 8.38(d, J=5.38Hz, 1H), 7.62-7.32(m, 9H), 7.04-6.95(m,4H, 6.86-6.80(m, 2H), 4.52(q, J=6.96Hz, 1H), 1.40(d, J=6.88Hz, 3H)B-0256(DMF-d7) d 8.45(bd, J=2.85, 2H), 7.87(br s, 4H), 7.76-7.75(m, 2H), 7.53-7.33(m,5H), 7.18-7.13(br, 4H)B-0426(DMF-d7), 1.32(br, 3H), 1.67(br, 3H), 4.17(br, 2H), 5.12(br, 1H), 7.50(m, 6H),8.77(m, 2H), 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=34.8Hz, 1H).B-0473(CD3OD), 1.53(d, J=7.2Hz, 3H), 4.59(q, J=7.2Hz, 1H), 6.88(d, J=4Hz,1H), 7.09(m, 3H), 7.15(dd, J=4.4, 1.6Hz, 2H), 7.26(m, 2H), 8.46(d, J=6.0Hz, 2H).B-0477(DMF), 1.80(br, 3H), 2.35(s, 1H), 4.98(br, 1H), 7.38(m, 6H), 7.85(m, 2H),8.45(br, 1H), 8.75(d, J=6.0Hz, 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, 1H), 7.42(br, 2H), 7.54(br, 2H),7.66(br, 3H), 8.82(s, 2H).B-0566(CD3OD), 1.38(d, J=7.2Hz, 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(CD3OD), 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=30.0Hz, 3H), 4.62(br, 1H), 7.25(m, 6H), 7.60(m, 4H),8.59(br, 2H), 13.30(brd, J=12.3Hz).B-06437.18(m, 2H), 7.32(dd, J=6.0, 4.4Hz, 1H), 7.70(dd, J=9.0, 5.8Hz, 1H),8.43(dd, J=4.8, 3.2Hz, 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(CDCl3/CD3OD) d 8.48(d, J=5.30Hz, 2H), 7.72-7.59(m, 4H), 7.14-7.10(m,2H), 7.03-6.97(m, 4H), 4.60(q, J=7.57Hz, 1H), 1.43(d, J=7.26Hz, 3H)B-0663(CD3OD), 1.52(d, J=6.8Hz, 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-1165Hz, 2H), 3.06(m, 1H), 3.43(q, J=6.1Hz, 2H), 7.02(m, 2H), 7.14(m, 2H),7.41(m, 2H), 8.59(d, J=5.6Hz, 2H).B-1169= 1.6Hz, 1H), 7.04(t, J=8.6Hz, 2H), 7.14(m, 2H), 7.36(m, 2H), 8.39(d, J=1.8Hz,1H), 8.60(m, 2H).B-11716.83(br, 1H), 7.02(t, J=8.7Hz, 2H), 7.15(d, J=5.6Hz, 2H), 7.40(m, 2H),8.59(d, J=5.0Hz, 2H).B-1179(CDCl3), 1.94(br, 2H), 2.53(s, 3H), 2.85(t, 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(CDCl3), 2.00(br, 2H), 2.85(br, 2H), 3.64(br, 2H), 7.03(br, 3H), 7.17(br, 2H),7.36(br, 2H), 7.66(br, 2H), 8.60(br, 2H), 8.77(br, 2H).B-1194(DMSO), 1.76(br, 2H), 2.66(br, 2H), 2.91(br, 2H), 4.30(s, 2H), 7.18(br, 5H),7.35(m, 6H), 8.54(d, J=5.8Hz, 2H).B-1200(DMSO), 1.17(br, 3H), 1.76(br, 2H), 2.71(br, 2H), 2.97(br, 4H), 7.18(br, 4H),7.36(br, 2H), 8.54(br, 2H).B-1206(DMSO), 1.03(s, 6H), 1.68(br, 2H), 2.63(br, 2H), 3.00(br, 2H), 3.65(br, 1H),5.69(m, 2H), 7.16(br, 4H), 7.35(br, 2H), 8.54(br, 2H).B-1216(DMSO), 1.75(m, 2H), 2.14(s, 6H), 2.66(br, 2H), 3.10(br, 2H), 7.04(br, 3H),7.18(br, 4H), 7.35(m, 2H), 7.47(br, 1H), 8.54(d, J=4.8Hz, 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-d6), 1.80(br, 4H), 2.82(br, 1H), 2.94(br, 1H), 3.10(br, 1H), 3.60(br, 1H),4.54(br, 1H), 7.18(m, 4H), 7.30(m, 4H), 7.46(m, 2H), 8.54(br, 2H).B-1361(DMSO-d6), 0.99(br, 6H), 1.73(br, 4H), 2.89(br, 2H), 3.03(m, 1H), 4.04(br, 2H),4.44(m, 1H), 7.18(m, 4H), 7.30(m, 2H), 8.57(d, J=4.64Hz, 2H).B-1363(DMSO-d6), 1.78(br, 4H), 2.01(s, 3H), 2.89(br, 1H), 3.05(br, 1H), 3.34(br, 1H),3.85(br, 1H), 4.48(br, 1H), 7.12(br, 2H), 7.21(br, 2H), 7.30(br, 2H), 8.69(br, 2H).B-1364(CDCl3), 0.78(dd, J=3.0, 2.9Hz, 2H), 1.00(s, 2H), 1.78(m, 1H), 1.86(b, 4H),2.64(m, 1H), 2.99(m, 1H), 3.16(m, 1H), 4.33(br, 1H), 4.70(br, 1H), 6.99(m, 2H),7.14(s, 2H), 7.29(m, 2H), 8.64(s, 2H).B-1368(CDCl3), 1.89(s, 4H), 2.65(m, 1H), 2.96(m, 1H), 3.06(m, 1H), 3.43(s, 3H),3.93(d, J=13.2Hz, 1H), 4.09(d, J=13.5Hz, 1H), 4.18(d, J=13.5Hz, 1H),4.68(d, J=12.4Hz, 1H), 7.60(m, 2H), 7.12(s, 2H), 7.26(m, 2H), 8.63(s, 2H).


By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-1574through B-2269 are prepared.

Example #R2RLembedded imageExamples B-1574 through B-1597 are prepared from Scaffold C-27B-1574embedded imageembedded imageB-1575embedded imageembedded imageB-1576embedded imageembedded imageB-1577embedded imageembedded imageB-1578embedded imageembedded imageB-1579embedded imageembedded imageB-1580embedded imageembedded imageB-1581embedded imageembedded imageB-1582embedded imageembedded imageB-1583embedded imageembedded imageB-1584embedded imageembedded imageB-1585embedded imageembedded imageB-1586embedded imageembedded imageB-1587embedded imageembedded imageB-1588embedded imageembedded imageB-1589embedded imageembedded imageB-1590embedded imageembedded imageB-1591embedded imageembedded imageB-1592embedded imageembedded imageB-1593embedded imageembedded imageB-1594embedded imageembedded imageB-1595embedded imageembedded imageB-1596embedded imageembedded imageB-1597embedded imageembedded imageembedded imageExamples B-1598 through B-1621 are prep ared from Scaffold C-28B-1598embedded imageembedded imageB-1599embedded imageembedded imageB-1600embedded imageembedded imageB-1601embedded imageembedded imageB-1602embedded imageembedded imageB-1603embedded imageembedded imageB-1604embedded imageembedded imageB-1605embedded imageembedded imageB-1606embedded imageembedded imageB-1607embedded imageembedded imageB-1608embedded imageembedded imageB-1609embedded imageembedded imageB-1610embedded imageembedded imageB-1611embedded imageembedded imageB-1612embedded imageembedded imageB-1613embedded imageembedded imageB-1614embedded imageembedded imageB-1615embedded imageembedded imageB-1616embedded imageembedded imageB-1617embedded imageembedded imageB-1618embedded imageembedded imageB-1619embedded imageembedded imageB-1620embedded imageembedded imageB-1621embedded imageembedded imageembedded imageExamples B-1622 through B-1645 are prepared from Scaffold C-38B-1622embedded imageembedded imageB-1623embedded imageembedded imageB-1624embedded imageembedded imageB-1625embedded imageembedded imageB-1626embedded imageembedded imageB-1627embedded imageembedded imageB-1628embedded imageembedded imageB-1629embedded imageembedded imageB-1630embedded imageembedded imageB-1631embedded imageembedded imageB-1632embedded imageembedded imageB-1633embedded imageembedded imageB-1634embedded imageembedded imageB-1635embedded imageembedded imageB-1636embedded imageembedded imageB-1637embedded imageembedded imageB-1638embedded imageembedded imageB-1639embedded imageembedded imageB-1640embedded imageembedded imageB-1641embedded imageembedded imageB-1642embedded imageembedded imageB-1643embedded imageembedded imageB-1644embedded imageembedded imageB-1645embedded imageembedded imageembedded imageExamples B-1646 through B-1669 are prepared from Scaffold C-39B-1646embedded imageembedded imageB-1647embedded imageembedded imageB-1648embedded imageembedded imageB-1649embedded imageembedded imageB-1650embedded imageembedded imageB-1651embedded imageembedded imageB-1652embedded imageembedded imageB-1653embedded imageembedded imageB-1654embedded imageembedded imageB-1655embedded imageembedded imageB-1656embedded imageembedded imageB-1657embedded imageembedded imageB-1658embedded imageembedded imageB-1659embedded imageembedded imageB-1660embedded imageembedded imageB-1661embedded imageembedded imageB-1662embedded imageembedded imageB-1663embedded imageembedded imageB-1664embedded imageembedded imageB-1665embedded imageembedded imageB-1666embedded imageembedded imageB-1667embedded imageembedded imageB-1668embedded imageembedded imageB-1669embedded imageembedded imageembedded imageExamples B-1670 through B-1693 are prepared from Scaffold C-65B-1670embedded imageembedded imageB-1671embedded imageembedded imageB-1672embedded imageembedded imageB-1673embedded imageembedded imageB-1674embedded imageembedded imageB-1675embedded imageembedded imageB-1676embedded imageembedded imageB-1677embedded imageembedded imageB-1678embedded imageembedded imageB-1679embedded imageembedded imageB-1680embedded imageembedded imageB-1681embedded imageembedded imageB-1682embedded imageembedded imageB-1683embedded imageembedded imageB-1684embedded imageembedded imageB-1685embedded imageembedded imageB-1686embedded imageembedded imageB-1687embedded imageembedded imageB-1688embedded imageembedded imageB-1689embedded imageembedded imageB-1690embedded imageembedded imageB-1691embedded imageembedded imageB-1692embedded imageembedded imageB-1693embedded imageembedded imageembedded imageExamples B-1694 through B-1717 are prepared from Scaffold C-66B-1694embedded imageembedded imageB-1695embedded imageembedded imageB-1696embedded imageembedded imageB-1697embedded imageembedded imageB-1698embedded imageembedded imageB-1699embedded imageembedded imageB-1700embedded imageembedded imageB-1701embedded imageembedded imageB-1702embedded imageembedded imageB-1703embedded imageembedded imageB-1704embedded imageembedded imageB-1705embedded imageembedded imageB-1706embedded imageembedded imageB-1707embedded imageembedded imageB-1708embedded imageembedded imageB-1709embedded imageembedded imageB-1710embedded imageembedded imageB-1711embedded imageembedded imageB-1712embedded imageembedded imageB-1713embedded imageembedded imageB-1714embedded imageembedded imageB-1715embedded imageembedded imageB-1716embedded imageembedded imageB-1717embedded imageembedded imageembedded imageExamples B-1718 through B-1741 are prepared from Scaffold C-69B-1718embedded imageembedded imageB-1719embedded imageembedded imageB-1720embedded imageembedded imageB-1721embedded imageembedded imageB-1722embedded imageembedded imageB-1723embedded imageembedded imageB-1724embedded imageembedded imageB-1725embedded imageembedded imageB-1726embedded imageembedded imageB-1727embedded imageembedded imageB-1728embedded imageembedded imageB-1729embedded imageembedded imageB-1730embedded imageembedded imageB-1731embedded imageembedded imageB-1732embedded imageembedded imageB-1733embedded imageembedded imageB-1734embedded imageembedded imageB-1735embedded imageembedded imageB-1736embedded imageembedded imageB-1737embedded imageembedded imageB-1738embedded imageembedded imageB-1739embedded imageembedded imageB-1740embedded imageembedded imageB-1741embedded imageembedded imageembedded imageExamples B-1742 through B-1765 are prepared from Scaffold C-70B-1742embedded imageembedded imageB-1743embedded imageembedded imageB-1744embedded imageembedded imageB-1745embedded imageembedded imageB-1746embedded imageembedded imageB-1747embedded imageembedded imageB-1748embedded imageembedded imageB-1749embedded imageembedded imageB-1750embedded imageembedded imageB-1751embedded imageembedded imageB-1752embedded imageembedded imageB-1753embedded imageembedded imageB-1754embedded imageembedded imageB-1755embedded imageembedded imageB-1756embedded imageembedded imageB-1757embedded imageembedded imageB-1758embedded imageembedded imageB-1759embedded imageembedded imageB-1760embedded imageembedded imageB-1761embedded imageembedded imageB-1762embedded imageembedded imageB-1763embedded imageembedded imageB-1764embedded imageembedded imageB-1765embedded imageembedded imageembedded imageExamples B-1766 through B-1789 are prepared from Scaffold C-71B-1766embedded imageembedded imageB-1767embedded imageembedded imageB-1768embedded imageembedded imageB-1769embedded imageembedded imageB-1770embedded imageembedded imageB-1771embedded imageembedded imageB-1772embedded imageembedded imageB-1773embedded imageembedded imageB-1774embedded imageembedded imageB-1775embedded imageembedded imageB-1776embedded imageembedded imageB-1777embedded imageembedded imageB-1778embedded imageembedded imageB-1779embedded imageembedded imageB-1780embedded imageembedded imageB-1781embedded imageembedded imageB-1782embedded imageembedded imageB-1783embedded imageembedded imageB-1784embedded imageembedded imageB-1785embedded imageembedded imageB-1786embedded imageembedded imageB-1787embedded imageembedded imageB-1788embedded imageembedded imageB-1789embedded imageembedded imageembedded imageExamples B-1790 through B-1813 are prepared from Scaffold C-72B-1790embedded imageembedded imageB-1791embedded imageembedded imageB-1792embedded imageembedded imageB-1793embedded imageembedded imageB-1794embedded imageembedded imageB-1795embedded imageembedded imageB-1796embedded imageembedded imageB-1797embedded imageembedded imageB-1798embedded imageembedded imageB-1799embedded imageembedded imageB-1800embedded imageembedded imageB-1801embedded imageembedded imageB-1802embedded imageembedded imageB-1803embedded imageembedded imageB-1804embedded imageembedded imageB-1805embedded imageembedded imageB-1806embedded imageembedded imageB-1807embedded imageembedded imageB-1808embedded imageembedded imageB-1809embedded imageembedded imageB-1810embedded imageembedded imageB-1811embedded imageembedded imageB-1812embedded imageembedded imageB-1813embedded imageembedded imageembedded imageExamples B-1814 through B-1837 are prepared from Scaffold C-73B-1814embedded imageembedded imageB-1815embedded imageembedded imageB-1816embedded imageembedded imageB-1817embedded imageembedded imageB-1818embedded imageembedded imageB-1819embedded imageembedded imageB-1820embedded imageembedded imageB-1821embedded imageembedded imageB-1822embedded imageembedded imageB-1823embedded imageembedded imageB-1824embedded imageembedded imageB-1825embedded imageembedded imageB-1826embedded imageembedded imageB-1827embedded imageembedded imageB-1828embedded imageembedded imageB-1829embedded imageembedded imageB-1830embedded imageembedded imageB-1831embedded imageembedded imageB-1832embedded imageembedded imageB-1833embedded imageembedded imageB-1834embedded imageembedded imageB-1835embedded imageembedded imageB-1836embedded imageembedded imageB-1837embedded imageembedded imageembedded imageExamples B-1838 through B-1861 are prepared from Scaffold C-33B-1838embedded imageembedded imageB-1839embedded imageembedded imageB-1840embedded imageembedded imageB-1841embedded imageembedded imageB-1842embedded imageembedded imageB-1843embedded imageembedded imageB-1844embedded imageembedded imageB-1845embedded imageembedded imageB-1846embedded imageembedded imageB-1847embedded imageembedded imageB-1848embedded imageembedded imageB-1849embedded imageembedded imageB-1850embedded imageembedded imageB-1851embedded imageembedded imageB-1852embedded imageembedded imageB-1853embedded imageembedded imageB-1854embedded imageembedded imageB-1855embedded imageembedded imageB-1856embedded imageembedded imageB-1857embedded imageembedded imageB-1858embedded imageembedded imageB-1859embedded imageembedded imageB-1860embedded imageembedded imageB-1861embedded imageembedded imageembedded imageExamples B-1862 through B-1885 are prepared from Scaffold C-45B-1862embedded imageembedded imageB-1863embedded imageembedded imageB-1864embedded imageembedded imageB-1865embedded imageembedded imageB-1866embedded imageembedded imageB-1867embedded imageembedded imageB-1868embedded imageembedded imageB-1869embedded imageembedded imageB-1870embedded imageembedded imageB-1871embedded imageembedded imageB-1872embedded imageembedded imageB-1873embedded imageembedded imageB-1874embedded imageembedded imageB-1875embedded imageembedded imageB-1876embedded imageembedded imageB-1877embedded imageembedded imageB-1878embedded imageembedded imageB-1879embedded imageembedded imageB-1880embedded imageembedded imageB-1881embedded imageembedded imageB-1882embedded imageembedded imageB-1883embedded imageembedded imageB-1884embedded imageembedded imageB-1885embedded imageembedded imageembedded imageExamples B-1886 through B-1909 prepared from Scaffold C-42B-1886embedded imageembedded imageB-1887embedded imageembedded imageB-1888embedded imageembedded imageB-1889embedded imageembedded imageB-1890embedded imageembedded imageB-1891embedded imageembedded imageB-1892embedded imageembedded imageB-1893embedded imageembedded imageB-1894embedded imageembedded imageB-1895embedded imageembedded imageB-1896embedded imageembedded imageB-1897embedded imageembedded imageB-1898embedded imageembedded imageB-1899embedded imageembedded imageB-1900embedded imageembedded imageB-1901embedded imageembedded imageB-1902embedded imageembedded imageB-1903embedded imageembedded imageB-1904embedded imageembedded imageB-1905embedded imageembedded imageB-1906embedded imageembedded imageB-1907embedded imageembedded imageB-1908embedded imageembedded imageB-1909embedded imageembedded imageembedded imageExamples B-1910 through B-1933 are prepared from Scaffold C-44B-1910embedded imageembedded imageB-1911embedded imageembedded imageB-1912embedded imageembedded imageB-1913embedded imageembedded imageB-1914embedded imageembedded imageB-1915embedded imageembedded imageB-1916embedded imageembedded imageB-1917embedded imageembedded imageB-1918embedded imageembedded imageB-1919embedded imageembedded imageB-1920embedded imageembedded imageB-1921embedded imageembedded imageB-1922embedded imageembedded imageB-1923embedded imageembedded imageB-1924embedded imageembedded imageB-1925embedded imageembedded imageB-1926embedded imageembedded imageB-1927embedded imageembedded imageB-1928embedded imageembedded imageB-1929embedded imageembedded imageB-1930embedded imageembedded imageB-1931embedded imageembedded imageB-1932embedded imageembedded imageB-1933embedded imageembedded imageembedded imageExamples B-1934 through B-1957 are prepared from Scaffold C-41B-1934embedded imageembedded imageB-1935embedded imageembedded imageB-1936embedded imageembedded imageB-1937embedded imageembedded imageB-1938embedded imageembedded imageB-1939embedded imageembedded imageB-1940embedded imageembedded imageB-1941embedded imageembedded imageB-1942embedded imageembedded imageB-1943embedded imageembedded imageB-1944embedded imageembedded imageB-1945embedded imageembedded imageB-1946embedded imageembedded imageB-1947embedded imageembedded imageB-1948embedded imageembedded imageB-1949embedded imageembedded imageB-1950embedded imageembedded imageB-1951embedded imageembedded imageB-1952embedded imageembedded imageB-1953embedded imageembedded imageB-1954embedded imageembedded imageB-1955embedded imageembedded imageB-1956embedded imageembedded imageB-1957embedded imageembedded imageembedded imageExamples B-1958 through B-1981 are prepared from Scaffold C-43B-1958embedded imageembedded imageB-1959embedded imageembedded imageB-1960embedded imageembedded imageB-1961embedded imageembedded imageB-1962embedded imageembedded imageB-1963embedded imageembedded imageB-1964embedded imageembedded imageB-1965embedded imageembedded imageB-1966embedded imageembedded imageB-1967embedded imageembedded imageB-1968embedded imageembedded imageB-1969embedded imageembedded imageB-1970embedded imageembedded imageB-1971embedded imageembedded imageB-1972embedded imageembedded imageB-1973embedded imageembedded imageB-1974embedded imageembedded imageB-1975embedded imageembedded imageB-1976embedded imageembedded imageB-1977embedded imageembedded imageB-1978embedded imageembedded imageB-1979embedded imageembedded imageB-1980embedded imageembedded imageB-1981embedded imageembedded imageembedded imageExamples B-1982 through B-2005 are prepared from Scaffold C-30B-1982embedded imageembedded imageB-1983embedded imageembedded imageB-1984embedded imageembedded imageB-1985embedded imageembedded imageB-1986embedded imageembedded imageB-1987embedded imageembedded imageB-1988embedded imageembedded imageB-1989embedded imageembedded imageB-1990embedded imageembedded imageB-1991embedded imageembedded imageB-1992embedded imageembedded imageB-1993embedded imageembedded imageB-1994embedded imageembedded imageB-1995embedded imageembedded imageB-1996embedded imageembedded imageB-1997embedded imageembedded imageB-1998embedded imageembedded imageB-1999embedded imageembedded imageB-2000embedded imageembedded imageB-2001embedded imageembedded imageB-2002embedded imageembedded imageB-2003embedded imageembedded imageB-2004embedded imageembedded imageB-2005embedded imageembedded imageembedded imageExamples B-2006 through B-2029 are prepared from Scaffold C-60B-2006embedded imageembedded imageB-2007embedded imageembedded imageB-2008embedded imageembedded imageB-2009embedded imageembedded imageB-2010embedded imageembedded imageB-2011embedded imageembedded imageB-2012embedded imageembedded imageB-2013embedded imageembedded imageB-2014embedded imageembedded imageB-2015embedded imageembedded imageB-2016embedded imageembedded imageB-2017embedded imageembedded imageB-2018embedded imageembedded imageB-2019embedded imageembedded imageB-2020embedded imageembedded imageB-2021embedded imageembedded imageB-2022embedded imageembedded imageB-2023embedded imageembedded imageB-2024embedded imageembedded imageB-2025embedded imageembedded imageB-2026embedded imageembedded imageB-2027embedded imageembedded imageB-2028embedded imageembedded imageB-2029embedded imageembedded imageembedded imageExamples B-2030 through B-2053 are prepared from Scaffold C-36B-2030embedded imageembedded imageB-2031embedded imageembedded imageB-2032embedded imageembedded imageB-2033embedded imageembedded imageB-2034embedded imageembedded imageB-2035embedded imageembedded imageB-2036embedded imageembedded imageB-2037embedded imageembedded imageB-2038embedded imageembedded imageB-2039embedded imageembedded imageB-2040embedded imageembedded imageB-2041embedded imageembedded imageB-2042embedded imageembedded imageB-2043embedded imageembedded imageB-2044embedded imageembedded imageB-2045embedded imageembedded imageB-2046embedded imageembedded imageB-2047embedded imageembedded imageB-2048embedded imageembedded imageB-2049embedded imageembedded imageB-2050embedded imageembedded imageB-2051embedded imageembedded imageB-2052embedded imageembedded imageB-2053embedded imageembedded imageembedded imageExamples B-2054 through B-2077 are prepared from Scaffold C-34B-2054embedded imageembedded imageB-2055embedded imageembedded imageB-2056embedded imageembedded imageB-2057embedded imageembedded imageB-2058embedded imageembedded imageB-2059embedded imageembedded imageB-2060embedded imageembedded imageB-2061embedded imageembedded imageB-2062embedded imageembedded imageB-2063embedded imageembedded imageB-2064embedded imageembedded imageB-2065embedded imageembedded imageB-2066embedded imageembedded imageB-2067embedded imageembedded imageB-2068embedded imageembedded imageB-2029embedded imageembedded imageB-2070embedded imageembedded imageB-2071embedded imageembedded imageB-2072embedded imageembedded imageB-2073embedded imageembedded imageB-2074embedded imageembedded imageB-2075embedded imageembedded imageB-2076embedded imageembedded imageB-2077embedded imageembedded imageembedded imageExamples B-2078 through B-2101are prepared from Scaffold C-57B-2078embedded imageembedded imageB-2079embedded imageembedded imageB-2080embedded imageembedded imageB-2081embedded imageembedded imageB-2082embedded imageembedded imageB-2083embedded imageembedded imageB-2084embedded imageembedded imageB-2085embedded imageembedded imageB-2086embedded imageembedded imageB-2087embedded imageembedded imageB-2088embedded imageembedded imageB-2089embedded imageembedded imageB-2090embedded imageembedded imageB-2091embedded imageembedded imageB-2092embedded imageembedded imageB-2093embedded imageembedded imageB-2094embedded imageembedded imageB-2095embedded imageembedded imageB-2096embedded imageembedded imageB-2097embedded imageembedded imageB-2098embedded imageembedded imageB-2099embedded imageembedded imageB-2100embedded imageembedded imageB-2101embedded imageembedded imageembedded imageExamples B-2102 through B-2125 are prepared from Scaffold C-52B-2102embedded imageembedded imageB-2103embedded imageembedded imageB-2104embedded imageembedded imageB-2105embedded imageembedded imageB-2106embedded imageembedded imageB-2107embedded imageembedded imageB-2108embedded imageembedded imageB-2109embedded imageembedded imageB-2110embedded imageembedded imageB-2111embedded imageembedded imageB-2112embedded imageembedded imageB-2113embedded imageembedded imageB-2114embedded imageembedded imageB-2115embedded imageembedded imageB-2116embedded imageembedded imageB-2117embedded imageembedded imageB-2118embedded imageembedded imageB-2119embedded imageembedded imageB-2120embedded imageembedded imageB-2121embedded imageembedded imageB-2122embedded imageembedded imageB-2123embedded imageembedded imageB-2124embedded imageembedded imageB-2125embedded imageembedded imageembedded imageExamples B-2126 through B-2149 are prepared from Scaffold C-56B-2126embedded imageembedded imageB-2127embedded imageembedded imageB-2128embedded imageembedded imageB-2129embedded imageembedded imageB-2130embedded imageembedded imageB-2131embedded imageembedded imageB-2132embedded imageembedded imageB-2133embedded imageembedded 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EXAMPLES B-2270 THROUGH B-2317

In a parallel array reaction block containing 48 fritted vessels, each reaction vessel was charged with 250 mg of polymer bound carbodiimide B48 (1.0 mmol/g resin) and a solution of the acid-containing scaffold C-49 in dimethylformamide (0.1 M, 500 uL). To each slurry was added a solution of pyridine in dichloromethane (0.2 M, 1000 uL) followed by a solution of a unique amine B47 (0.2 M, 375 uL) in dimethylformamide. The reaction mixtures were agitated on a Labline benchtop orbital shaker at 250 RPM for 16-20 h at ambient temperature. The reaction mixtures were filtered into conical vials and the polymer was washed with 1.5 mL of dimethylformamide and 2.0 mL of dichloromethane. The filtrates were evaporated to dryness in a Savant apparatus and dimethylformamide (350 uL) was added to each conical vial to dissolve the residue. A solution of tetrafluorophthalic anhydride (1.0 M, 150 uL) in dimethylformamide was added to the reconstituted conical vials and the mixture incubated for 2 hours at ambient temperature. Polyamine polymer B33 (4.0 meq N/g resin, 250 mg) and 1.0 mL dichloromethane was then added to the reaction mixture in each conical vial. After agitating the reaction mixtures for 16 h at 250 RPM on an orbital shaker at ambient temperature, the mixtures were filtered through a polypropylene syringe tube fitted with a porous frit. The polymers were washed twice with dimethylformamide (1.0 mL. each) and the filtrates and washings collected in conical vials. The filtrates were evaporated to dryness and weighed to afford the desired amide products B-2270 through B-2317 as oils or solids. The analytical data and yields for the products prepared in this manner are listed below.

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By analogy to the procedure identified above for the preparation of Examples B-2270 through B-2317, the following examples B-2318 through B-2461 were prepared.

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EXAMPLE C-1
5-Aminomethyl-4-(4-Pyridyl)-3-(4-Fluorophenyl) Payrazole



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1-(4-fluorophenyl)-2-(4-pyridyl)-1-ethanone. 4-picoline (40 g, 0.43 mol) was added to a LiHMDS solution (0.45 mol, 450 mL of a 1.0 M solution in THF) over 30 minutes at room temperature (a slight exotherm was observed) The resulting solution was stirred for 1 h. This solution was added to ethyl 4-fluorobenzoate (75.8 g, 0.45 mol, neat) over 1 h. The mixture was stirred overnight (16 h). Water (200 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The organic layer was washed with brine (1×200 mL) and dried over Na2SO4. The organic layer was filtered and the solvent was removed to leave oily solid. Hexane was added to the oil and the resulting solid was filtered and washed with hexane (cold). A yellow solid was isolated (50 g, 54%): 1H NMR (CDCl3) δ 8.58 (d, J=5.7 Hz, 2H), 8.02 (dd, J=5.5, 8.0, 2H), 7.12-7.21 (m, 4H), 4.23 (s, 2H); 19F NMR (CDCl3) δ −104.38 (m); LC/MS, tr=2.14 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50° C.), M+H=216; High Resolution MS Calcd for C23H20N4O2F (M+H): 216.0825. Found: 216.0830 (Δmmu=0.5).


N-benzyloxycarbonyl-5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. A 3L round bottom flask fitted with a mechanical stirrer, N2 inlet and an addition funnel was was charged with 557 mL (0.56 mol) of 1 M t-BuOK in THF and 53 mL (0.56 mol) of t-BuOH. The ketone, 1 (60 g, 0.28 mol) was dissolved in 600 mL of THF and added to the stirred mixture at room temperature. A yellow precipitate formed and the mixture was stirred for 1 h. N-benzyloxycarbonyl-glycinyl N-hydroxysuccinimide (128.6 g, 0.42 mol) was dissolved in 600 mL of THF and added dropwise at r.t. over 1 h. The mixture was stirred for another 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 of water) was added via an addition funnel. The mixture was stirred for 1 h and was diluted with 500 mL of water and 500 mL of ethyl acetate. The biphasic mixture was transferred to a sep funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×300 mL). The organic layer was dried (Na2SO4), filtered and evaporated to leave 157 g of a crude reddish oil.


The oil was suspended in CH2Cl2 and filtered to remove any insoluble material (DCU, hydrazone of the monoketone). The solution was split into two portions and each portion was chromatographed (Biotage 75L, 3% EtOH/CH2Cl2 then 6% EtOH/CH2Cl2). The appropriate fractions were concentrated (some contamination from the monoketone and the hydrazone) from each portion to leave a yellow solid. The solid was suspended in ethyl acetate and heated to boiling for 10 minutes. The solution was allowed to cool to R. T. overnight. The precipitate was filtered to give 30 g of a white solid (27% yield of 2): 1H NER (DMF-d7) δ 13.36 (s, 1H), 8.57 (d, J=5.8 Hz, 2H), 7.16-7.52 (m, 11H), 5.11 (s, 2H), 4.48 (d, J=5.4 Hz, 2H); 19F No (DMF-d7) δ −114.9 (m), −116.8 (m) (split fluorine signal is due to the pyrazple tautomers); LC/MS, tr=3.52 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50° C.), M+H=403; High Resolution MS Calcd for C23H20N4O2F (M+H): 403.1570. Found: 403.1581 (Δmmu=1.1).


5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a 1L 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 purged with nitrogen and 1.5 g of 10% Pd/C (wet Degussa type E101) was added. The Parr bottle was pressured to 40 psi (H2) and was agitated. Hydrogen uptake was 5 psi after 5 h. The bottle was repressured to 42 psi and was agitated overnight. The bottle was purged with N2 and was filtered through Celite. The Celite was washed with MeOH (3×50 mL) and the filtrate was concentrated to give 4.5 g of an off-white solid (94%). 1H NMR (DMSO-d6) δ 8.52 (d, J=4.63 Hz, 2H), 7.36 (dd, J=5.64, 8.1 Hz, 2H), 7.16-7.30 (m, 4H), 3.79 (s, 2H); 19F NMR (DMSO-d6) δ −114.56 (m); LC/MS, tr=1.21 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50° C.), M+H=269 m/z; High Resolution MS Calcd for C15H14N4F (M+H): 269.1202. Found: 269.1229 (Δmmu=2.7).


The following pyridylpyrazoles (C-2 through C-21, Table C-1) were prepared according to the experimental procedure described above for example C-1.

TABLE C-1MW, M + HExampleCalculatedNo.StructureFound+H NMR (solvent), ppmC-2 embedded image323.1672 323.1670(DMF-d7): 8.77(t, J=4.4 Hz, 2H), 7.60(m, 2H), 7.44(t, J=4.4 Hz, 2H), 7.35(m, 2H), 3.22(bd, 2H) 3.01(septet, J=5.3 Hz, 1H), 2.74(m, 2H), 1.95(m, 4H)C-3 embedded image282.127 (M) 282.1245 (M, EI)(DMF-d7): 8.77(br s, 2H), 7.64-7.62(m, 2H), 7.50(br s, 2H), 7.38-7.34 (m, 2H), 4.40-4.37(m, 1H), 1.56(br s, 3H)C-4 embedded image282.127 (M) 282.1147 (M, EI)(DMF-7): 8.77(br s, 2H), 7.64-7.62(m, 2H), 7.50(br s, 2H), 7.38-7.35 (m, 2H), 4.40-4.37(m, 1H), 1.57(br s, 3H)C-5 embedded image323.1672 323.1687(DMSO-d6): 8.56(br, 2H), 7.32(m, 2H), 7.18(m, 4H), 2.91(m, 2H), 2.71 (m, 2H), 1.88(m, 1H), 1.65 (m, 2H), 1.40(m, 2H)C-6 embedded image359 359(DMSO-d6): 8.46(d, J=4.6 Hz, 2H), 7.32-7.13(m, 7H), 6.98-6.96(m, 4H), 4.06(t, J=7.0 Hz, 1H), 2.98-2.95(m, 2H)C-7 embedded image359 359(DMSO-d6): 8.46(d, J=5.4 Hz, 2H), 7.32-7.28(m, 2H), 7.20-7.12(m, 5H), 6.98-6.96(m, 4H), 4.06 (t, J=7.0 Hz, 1H), 2.98-2.94(m, 2H)C-8 embedded image313.1465 313.1492(DMSO-d6): 13.83(bs, 1H), 8.61(d, J=5.7 Hz, 2H), 8.33(bs, 1H), 7.33 (m, 6HB), 4.44(m, 1H), 3.63(m, 2H), 3.27(s, 3H)C-9 embedded image313.1465 313.1457(DMSO-d6): 8.55(dd, J=1.5, 4.4 Hz, 2H), 7.37-7.32(m, 2H), 7.26(dd, J=1.6, 4.4 Hz, 2H), 7.22-7.16(m, 2H), 4.06(t, J=6.5 Hz, 1H), 3.49(d, J=6.6 Hz, 2H), 3.20(s, 3H)C-10embedded image354 354(DMSO-d6): 13.03(bs, 1H), 8.50(dd, J=1.6, 2.7 Hz, 2H), 7.58(bq, J=4.3 Hz, 1), 7.3(m, 2H), 7.12-7.21(m, 4H), 3.77 (t, J=6.3Hz, 1H), 2.45 (d, J=4.5 Hz, 3H), 1.97 (t, J=7.4 Hz, 2H), 1.85 (dt, J=7.3, 7.1 Hz, 2H)C-11embedded image354 354(DMSO-d6): 13.03(bs, 1H), 8.50(dd, J=1.6, 2.7 Hz, 2H), 7.58(bq, J=4.3 Hz, 1H), 7.3(m, 2H), 7.12-7.21(m, 4H), 3.77 (t, J=6.3 Hz, 1H), 2.45 (d, J=4.5 Hz, 3H), 1.97 (t, J=7.4 Hz, 2H), 1.85 (dt, J=67.3, 7.1 Hz, 2H)C-12embedded image283.1359 283.1363(DMSO-d6): 8.53(d, J=5.0 Hz, 2H), 7.37-7.32(m, 2H), 7.21-7.17(m, 4H), 2.83(d, J=6.0 Hz, 2H), 2.77(d, J=6.0 Hz, 2H)C-13embedded image297.1515 297.1515(DMSO-d6): 8.53(d, J=5.4 Hz, 2H), 7.34(dd, J=5.8, 8.2 Hz, 2H), 7.18 (dd, J=5.8, 9.8 Hz, 4H), 2.68(t, J=7.3 Hz, 2H), 252(m, 2H), 1.64(m, 2H)C-14embedded image284.0829 284.0806(CD3OD): 8.74(br, 2H), 7.77(br, 2H), 7.45-7.58 (m, 3H), 7.30-7.40(m, 1H), 4.43(s, 2H)C-15embedded image285 285(DMSO-d6): 8.53(br, 2H), 7.56(br, 2H), 7.26(m, 4H), 3.75(br, 2H)C-16embedded image329, 331 329, 331(DMSO-d6): 8.53(d, J=4.4 Hz, 2H), 7.42(d, J=7.9 Hz, 2H), 7.34(d, J=8.5 Hz, 2H), 7.24(d, J=4.6 Hz, 2H), 3.76(bs, 2H)C-17embedded image339 339(DMSO-d6): 8.53(t, J=4.3 Hz, 2H), 7.33(m, 3H), 7.19(t, J=4.6 Hz, 2H), 7.154(d, J=7.3 Hz, 1H), 3.23(m, 2H), 2.88(m, 3H), 1.92, (m, 3H), 1.70 (m, 1H)C-18embedded image339 339(DMSO-d6): 8.57 (d, J=4.6 Hz, 2H), 7.41(d, J=8.3 Hz, 2H), 7.29(d, J=8.5 Hz, 2H), 7.20(d, J=4.8 Hz, 2H), 3.18(bd, 2H), 2.88(m, 1H), 2.76 (m, 2H), 1.82(br, 4H)C-19embedded image383, 385 383, 385(DMSO-d6): 8.56(br, 2H) 7.52(br, 2H), 7.14-7.29 (m, 4H), 2.99(br, 2H), 2.71(br, 1H), 2.51(br, 2H), 1.68(br, 4H)


The following pyridylpyrazoles (C-22 through C-40, Table C-2) are prepared utilizing the general schemes C-1 and C-2 and the experimental procedure described for example C-1 above.

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Step A


The pyrazole (2.60 g, 10.3 mmol) from example C-4 was suspended in 52 mL of dichloroethane and 52 mL of 2.5 M NaOH. Tetrabutylammonium hydroxide (0.5 mL of a 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 room temperature for 4 h. The mixture was poured onto 200 mL of CH2Cl2 and 200 mL of H2O. The phases were separated and the organic phase was washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over Na2SO4 and was filtered. The solvent was removed to leave an off-white solid. This solid was triturated with hexane and the resulting solid isolated by filtration. The solid was washed with hexane to leave 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 room temperature for 4 h. 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 was stirred for 1 h at room temperature. The solvent was removed to leave an oil. The residual solvent was chased with several portions of EtOH. The resulting solid was triturated with Et2O and the title compound Example C-49 was isolated by filtration to afford 3.0 g of an off-white solid (95%). Mass spec: M+H cald: 312; found 312. 1H NMR (DMSO-d6): 8.81 (d, J=6.4 Hz, 2H), 7.73 (d, J=5.8 Hz, 2H), 7.40 (m, 2H), 7.23 (t, J=8.5 Hz, 1H), 5.16 (s, 2H), 2.40 (s, 3H).


EXAMPLE C-50



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According to the procedure described above in Example C-49, Example C-50 was also prepared starting from 4-[3-(4-fluorophenyl)-1H-pyrazole-4-yl]pyridine. Mass spec: M+H cald: 298; found 298. 1H NMR (DMSO-d6): 8.75 (d, J=6.4 Hz, 2H), 8.68 (s, 1H), 7.78 (d, J=6.6 Hz, 2H), 7.52 (dd, J=5.4, 8.5 Hz, 2H), 7.31 (t, J=8.9 Hz, 2H), 5.16 (s, 2H).


EXAMPLE C-51



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Starting with the N-Boc-piperidinyl analog of Example C-2, Example C-51 is also prepared according to the methods described in Scheme C-1.


EXAMPLE C-52



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Step A: Picoline is treated with a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in an organic solvent such as THF, ether, t-BuOH or dioxane from −78° C. to 50° C. for a period of time from 10 minutes to 3 hours. The picoline solution is then added to a solution of N-Cbz-(L)-phenylalaninyl N-hydroxysuccinimide. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature may range from −20° C. to 120° C. The mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the pyridyl monoketone is isolated as a crude solid which could be purified by crystallization and/or chromatography.
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Step B: A solution of the pyridyl monoketone in ether, THF, tBuOH, or dioxane is added to a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH contained in hexane, THF, ether, dioxane, or tBuOH from −78° C. to 50° C. for a period of time from 10 minutes to 3 hours. Formyl acetic anhydride is then added as a solution in THF, ether, or dioxane to the monoketone anion while the temperature is maintained between −50° C. and 50° C. The resulting mixture is allowed to stir at the specified temperature for a period of time from 5 minutes to several hours. The resulting pyridyl diketone intermediate is utilized without purification in Step C.
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Step C: The solution containing the pyridyl diketone is quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H2SO4, HCl, or HNO3. The temperature during this step is maintained between −20° C. and room temperature. Hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between −20° C. and 40° C. for a period of 30 minutes to several hours. The mixture is then poured into water and extracted with an organic solvent. The N-Cbz-protected pyridyl pyrazole is obtained as a crude solid which is purified by chromatography or crystallization.
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Step: D


The CBZ protecting group is cleaved using hydrogen gas under pressure and Pd—C in an alcohol solvent, affording scaffold C-52 after filtration and concentration.
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The following compounds C-53 through C-59 in Table C-3 are prepared according to the general procedure described above for the preparation of C-52.

TABLE C-3Example No.StructureC-53embedded imageC-54embedded imageC-55embedded imageC-56embedded imageC-57embedded imageC-58embedded imageC-59embedded image


EXAMPLE C-60

Step A:


A Boc protected pyridylpyrazole is treated with benzaldehyde in methylene chloride at room temperature in the presence of a drying agent for a period of time ranging from 1-24 h. Solvent is then evaporated and the resulting imine is used in step B without further purification.
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Step B:


The pyridylpyrazole imine is dissolved in THF and stirred under nitrogen at temperatures 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 h. Two equivalents of a methyl iodide are then added to the mixture and stirring is continued for several hours. The mixture is then quenched with acid and allowed to warm to room temperature and stirred several hours until cleavage of the Boc and the imine functions 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 give purified C-60.
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EXAMPLE C-61



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Example C-61 is prepared according to the method described in example C-60, substituting 1,4-dibromobutane for methyl iodide.


EXAMPLE C-62



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Example C-62 is prepared according to the method described in example C-60, substituting 1,3-dibromoethane for methyl iodide.


EXAMPLE C-63

The synthesis of compound C-63 starts with the condensation reaction of bromomaleic anhydride B77 with 2,4-dimethoxybenzylamine in acetic acid and acetic anhydride. The maleimide B78 is then treated with 4′-fluoroacetophenone in the presence of catalytic amount Pd2(dba)3 and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. B79 is then treated with tert-butoxybis(dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is condensed with hydrazine to form the N-protected maleimide pyrazole B81. The 2,4-dimethoxybenzyl group is cleaved with ceric ammonium nitrate (CAN) to give the title compound C-63.
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EXAMPLE C-64



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Using the method described in Schemes C-6 and C-7, Example 64 is prepared.


EXAMPLE C-65



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Using the method described in Schemes C-6 and C-7, Example 65 is prepared.


EXAMPLE C-66



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Using the method described in Schemes C-6 and C-7, Example C-66 is synthesized, substituting N-2,4-dimethoxybenzyl-4-bromopyridone for B78.


EXAMPLE C-67



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Using the method described in Schemes C-6 and C-7, Example C-67 is synthesized, substituting N-2,4-dimethoxybenzyl-4-bromopyridone for B78, and substituting N-Boc-glycyl N-hydroxysuccinimide for B82.


EXAMPLE C-68



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Using the method described in Schemes C-6 and C-7, Example C-68 is synthesized, substituting N-2,4-dimethoxybenzyl-4-bromopyridone for B78.


EXAMPLE C-69



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Using the method described in Schemes C-6 and C-7, Example 69 is prepared, substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.


EXAMPLE C-70



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Using the method described in Schemes C-6 and C-7, Example 70 is prepared, substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.


EXAMPLE C-71



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Using the method described in Schemes C-6 and C-7, Example 71 is prepared, substituting N-methyl-3-bromomaleimide for B78.


EXAMPLE C-72



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Using the method described in Schemes C-6 and C-7, Example 72 is prepared, substituting N-methyl-3-bromomaleimide for B78, and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.


EXAMPLE C-73



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Using the method described in Schemes C-6 and C-7, Example 73 is prepared, substituting N-methyl-3-bromomaleimide for B78 and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.


General Synthetic Procedures

Scheme C-8 illustrates a general method that can be used for the introduction of various groups on an unsubstituted nitrogen atom that is present as part of pyrazole (Cviii) with appropriately substituted aldehydes (R302CHO) or ketones (R302COR303) in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride affords the desired products (Cix). Typical conditions for the reductive alkylation include the use of an alcoholic solvent at temperatures ranging from 20° C. to 80° C. In Scheme C-8, R302 and R303 are selected from but not limited to alkyl, benzyl, substituted benzyl, arylalkyl, heteroarylalkyl.
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Scheme C-9 illustrates another method for introduction of substituents on the unsubstituted nitrogen atom present as part of the C-3 position of the pyrazole (Cviii). Treatment of the pyrazole (Cviii) with a suitable alkylating agent (R304X) such as an alkyl chloride, alkyl bromide, alkyl iodide or with an alkyl methanesulfonate or alkyl p-toluenesulfonate in the presence of a suitable base affords the desired alkylated pyrazoles (Cx). Examples of suitable bases include diisopropylethylamine, triethylamine, N-methylmorpholine, potassium carbonate and potassium bicarbonate.
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Typical conditions for the alkylation include reaction with the suitable base in a polar aprotic solvent such as acetonitrile, dimethylformamide, dimethylacetamide or dimethyl sulfoxide at temperatures ranging from 20° C. to 150° C. Typical R304 substituents are selected from but are not limited to alkyl, substituted benzyl, heteroaromatic, substituted heteroalkyl and substituted heteroarylalkyl groups.


Compounds containing acyl, sulfonyl or ureidyl groups at the nitrogen atom can be prepared as shown in Scheme C-10. Treatment of the pyrazole Cviii with a suitable acylating agent in the presence of a base such as N-methylmorpholine, triethylamine, diisopropylethylamine or dimethylamino pyridine in an organic solvent such as dichloromethane, dichloroethane or dimethylformamide at temperatures ranging from 20° C. to 120° C. affords the desired acylated pyrazoles (Cxi). Suitable acylating agents include acid halides, activated esters of acids such as the N-hydroxysuccinimde esters, p-nitrophenyl esters, pentafluorophenyl esters, sulfonyl halides, isocyanates, and isothiocyanates.
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A general synthesis of 2-substituted pyrimidinylpyrazole compounds of type Cxv is shown in Scheme C-11.


Step A:


4-Methyl-2-methylmercaptopyrimidine is treated with a base selected from but not limited to n-BuLi, LDA, LiHMDS, t-BuOK, NaH in an organic solvent such as THF, ether, t-BuOH, dioxane from −78° C. to 50° C. for a period of time from 30 minutes to 5 hours. The resulting 4-methyl anion is then added to a solution of an appropriate ester B86. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature may range from 0° C. to 100° C. The reaction mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the desired monoketone B89 is isolated as a crude solid which can be recrystallized or purified by chromatography.


Step B:


Monoketone B89 is treated with a base selected from but not limited to n-BuLi, LDA, LiHMDS, t-BuOK, NaH, K2CO3 or Cs2Co3 in an organic solvent such as THF, ether, t-BuOH, dioxane, toluene or DMF from −78° C. to 50° C. for a period of time from 30 minutes to 5 hours. A solution of an appropriately activated ester of a carboxylic acid CbzNRH—(CH2)nCRF(RG)—COOH or BocNRH—(CH2)nCRF(RG)—COOH, preferably but not limited to the N-hydroxysuccinimide ester B90 is then added to the monoketone anion while maintaining the temperature between 0° C. to 100° C. The reaction is allowed to stir at the specified temperature for a period of time ranging from 30 minutes to 48 hours. The resulting pyrimidine diketone intermediate B91 is utilized without further purification in Step C.


Step C:


The solution or suspension containing the diketone intermediate B91 is quenched with water and the pH adjusted to between 4 and 8 using an acid chosen from AcOH, H2SO4, HCl or HNO3 while maintaining the temperature between 0° C. to 40° C. Hydrazine or hydrazine monohydrate is then added to the mixture while maintaining the temperature between 0° C. to 40° C. The mixture is stirred for a period of 30 minutes to 16 hours maintaining the temperature between 20° C. to 50° C., poured into water and extracted with an organic solvent. The pyrimidinyl pyrazole CxiiBoc or CxiiCbz is obtained as crude solid which is purified by chromatography or crystallization.


Step D:


The 2-methylmercapto group in the pyrimidinyl pyrazole (CxiiBoc or CxiiCbz) is oxidized to the 2-methylsulfone (where n=2) or the 2-methylsulfoxide (where n=1) using either Oxone or m-chloroperbenzoic acid as an oxidizing agent in a suitable solvent at temperatures ranging from 25° C. to 100° C. Solvents of choice for the oxidation include dichloromethane, acetonitrile, tetrahydrofuran or hydroalcoholic mixtures. The 2-methylsulfone (n =2) or the 2-methylsulfoxide (n=1) (CxiiiBoc or CxiiiCbz) is purified by crystallization or chromatography.


Step E:


The 2-methylsulfone/2-methylsulfoxide group in CxiiiBoc or CxiiiCBz is conveniently displaced with various amines or alkoxides at temperatures ranging from 20° C. to 200° C. in solvents that include but are not limited to dimethylformamide, acetonitrile, tetrahydrofuran and dioxane. The alkoxides can be generated from their alcohols by treatment with a base selected from but not limited to sodium hydride, lithium hexamethyldisilazide, potassium tertiary-butoxide in solvents such as tetrahydrofuran, dimethylformamide and dioxane at temperatures ranging from 0° C. to 100° C. The resulting 2-amino or 2-oxo derivatives (CxivBOC or CxivCbz) are purified by either chromatography or crystallization.


Step F:


The carbamate protecting groups from CxivBoc or CxivCbz are removed to afford the desired compounds Cxv containing either a free primary amine (RH is hydrogen) or a free secondary amine (RH is not equal to hydrogen). The Boc protecting groups are cleaved utilizing either trifluoroacetic acid in methylene chloride or hydrochloric acid in dioxane at room temperature for several hours. The Cbz protecting groups are cleaved using hydrogen gas at atmospheric or higher pressures and a catalyst (palladium on charcoal) in an alcoholic solvent. The resulting amines Cxv are then crystallized or purified by chromatography.
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The following examples contain detailed descriptions of the methods of preparation of compounds that form part of the invention. These descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All compounds showed NMR spectra consistant with their assigned structures.


EXAMPLE C-74
5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-isonipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as the hydrochloride salt: 1HNMR (d6-DMSO) δ 8.57 (d, J=4.83 Hz, 2H), 7.41 (d, J=8.26 Hz, 2H), 7.29 (d, J=8.26 Hz, 2H), 7.20 (d, J=4.63 Hz, 2H), 3.18 (bd, J=12.08 Hz, 2H), 2.88 (m, 1H), 2.76 (m, 2H), 1.82 (bs, 4H). MS (M+H): 339 (base peak).


EXAMPLE C-75
5-(N-methyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) (25 g, 61 mmol) in 140 mL of formic acid (96%) was added 50 g of formaldehyde (37%). The solution was stirred at 75° C. for 48 h and was cooled to room temperature. The excess formic acid was removed under reduced pressure and the residue was dissolved in 100 mL of water. The solution was added to concentrated NH6OH/H2O and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (1×250 mL) and was dried over Na2SO4. The solution was filtered and concentrated to leave a white solid. The solid was triturated with ether and was filtered to afford the title compound: MS (M+H): 353 (base peak).


EXAMPLE C-76
5-(N-acetyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) (1 g, 2.4 mmol) in 24 mL of CH2Cl2 was added 4-dimethylamino pyridine (0.88 g, 7.2 mmol) and acetyl chloride (0.21 g, 2.6 mmol). The solution was stirred for 3 h and the solvent was removed under reduced pressure. The residue was treated with saturated NH4OH (20 mL) and the suspension was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (1×50 mL), dried over MgSO4, filtered and concentrated to leave a solid. The solid was triturated with ether and was filtered to leave the title compound: MS (M+H): 381 (base peak).


EXAMPLE C-77
5-(N-methoxyacetyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting methoxy acetyl chloride for acetyl chloride the title compound was prepared: 1HNMR (DMSO-d6) δ 8.75 (d, J=6.72 Hz, 2H), 7.70 (d, J=6.72 Hz, 2H), 7.38 (d, J=8.60 Hz, 2H), 7.29 (dd, J=6.72, 1.88 Hz, 2H), 4.40 (d, J=11.8 Hz, 1H), 4.05 (m, 2H), 3.70 (d, J=12.70 Hz, 1H), 3.25 (s, 3H), 3.0 (m, 2H), 2.55 (m, 1H), 1.7 (m, 4H). MS (M+H): 411 (base peak).


EXAMPLE C-78
5-(N-methylsulfonyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting methylsulfonyl chloride (2.0 equivalents) for acetyl chloride the title compound was prepared: 1HNMR (DMSO-d6) δ 8.70 (d, J=6.72 Hz, 2H), 7.72 (d, J=6.72 Hz, 2H), 7.38 (d, J=7.66 Hz, 2H), 7.30 (dd, J=6.72, 1.88 Hz, 2H), 3.58 (bd, J=11.8 Hz, 2H), 2.87 (m, 1H), 2.82 (s, 3H), 2.72 (m, 2H), 1.85 (m, 4H). MS (M+H): 417 (base peak).


EXAMPLE C-79
5-[N-methoxyethyl-4-piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) (500 mg, 1.2 mmol) in 12 mL of DMF was added Hunig's base (790 mg, 6.1 mmol) and 2-bromoethyl methyl ether (850 mg, 6.1 mmol). The solution was stirred at room temperature for 5 days. The solution was poured onto 2.5 N NaOH and was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water (3×100 mL) and brine (1×100 mL). The organic phase was dried over Na2SO4 and was filtered. The solvent was removed under reduced pressure to leave a solid. The solid was triturated and filtered to leave the title compound: 1HNMR (CDCl3) δ 8.63 (d, J=4.23 Hz, 2H), 7.28 (m, 4H), 7.14 (d, J=4.43 Hz, 2H), 3.57 (t, J=5.24 Hz, 2H), 3.38 (s, 3H), 3.14 (bd, J=10.1 Hz, 2H), 2.79 (m, 1H), 2.68 (t, J=5.04, 2H), 2.08 (m, 4H), 1.92 (m, 2H). MS (M+H): 397 (base peak).


EXAMPLE C-80
5-(N-allyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of example C-79 and substituting allyl bromide for 2-bromoethyl methyl ether the title compound was prepared: MS (M+H): 379 (base peak)


EXAMPLE C-81
5-(N-propargyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of example C-79 and substituting propargyl bromide for 2-bromoethyl methyl ether the title compound was prepared: MS (M+H): 377 (base peak)


EXAMPLE C-82



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5-[N-(2-methylthiazolyl)-4-piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole

To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) in 12 mL of MeOH was added trimethyl orthoformate (2.6 g, 24.4 mmol) and 27thiazolecarboxaldehyde (1.4 g, 12.2 mmol). The suspension was stirred at room temperature for 2 h. To this mixture was added NaCNBH, (1.5 g, 24.4 mmol) and the resulting suspension was stirred at room temperature for 7 days. The mixture was poured onto 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to leave a solid. This solid was triturated with ether and filtered to afford the title compound: MS (M+H): 436 (base peak).


EXAMPLE C-83
5-(4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole



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By following the method of Example C-1 and substituting methyl-4-(trifluoromethyl)benzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-isonipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as its hydrochloride salt: MS (M+H):. 373 (base peak).


EXAMPLE C-84
5-(N-methyl-4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl) phenyl] pyrazole



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By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole hydrochloride (Example C-83) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 387 (base peak)


EXAMPLE C-85
5-[N-(2-propyl)-4-piperidyl]-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole



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To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole (Example C-83) (300 mg, 0.7 mmol) in 50 mL of acetone was added 1 mL of ACOH and NaBH(OAc)3 (15 g, 70.8 mmol). The mixture was warmed to reflux and was stirred for 5 days. The reaction mixture was poured onto 100 mL of 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The extracts were combined and washed with brine (1×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the title compound: MS (M+H): 415 (base peak).


EXAMPLE C-86
5-(4-piperidyl)-4-(4-pyridyl)-3-[3-(trifluoromethyl) phenyl] pyrazole



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By following the method of Example C-1 and substituting methyl-3-(trifluoromethyl)benzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-isonipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as its hydrochloride salt: MS (M+H): 373 (base peak).the pyrazole C-3 substituent (Cviii). Treatment of the


EXAMPLE C-87
5-(N-methyl-4-piperidyl)-4-(4-pyridyl)-3-[3-(trifluoromethyl) phenyl] pyrazole



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By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-[3-(trifluoromethyl)phenyl] pyrazole hydrochloride (Example C-86) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 387 (base peak).


EXAMPLE C-88
5-(4-piperidyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-3-chlorobenzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-isonipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 339 (base peak).


EXAMPLE C-89
5-(N-methyl-4-piperdyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole hydrochloride (Example C-88) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 353 (base peak).


EXAMPLE C-90
5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting N-t-butoxycarbonyl-nipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as its hydrochloride salt: MS (M+H): 323 (base peak).


EXAMPLE C-91
5-(N-methyl-3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole hydrochloride (Example C-90) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 337 (base peak).


EXAMPLE C-92
5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate and N-c-butoxycarbonyl-cis-4-aminocyclohexanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: 1HNMR (d6-DMSO) δ 8.56 (d, J=6.04 Hz, 2H), 7.39 (d, J=8.66 Hz, 2H), 7.31 (d, J=8.46 Hz, 2H), 7.17 (d, J=5.84 Hz, 2H), 3.05 (m, 1H), 2.62 (m, 1H), 1.99 (m, 2H), 1.53 (m, 6H). MS (M+H): 353 (base peak).


EXAMPLE C-93
5-cis-(4-N, N-dimetylaminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 381 (base peak).


EXAMPLE C-94
5-[cis-4-N-(2-propyl)aminocyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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To a slurry of 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) (1.0 g, 2.8 mmol, 1.0 eq) in methylene chloride (28 mL) was added acetone (0.5 mL), acetic acid (0.5 mL) and solid sodium triacetoxyborohydride. The slurry was stirred for 5 h and the volatiles were removed. The residue was partitioned between 2.5 M NaOH (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with brine (50 mL), dried over MgSO4 and evaporated. The residue was triturated with ether to yield the title compound as a white powder: 1HNMR (d6-DMSO) δ 8.56 (d, J=5.84 Hz, 2H), 7.40 (d, J=8.26 Hz, 2H), 7.30 (d, J=8.66 Hz, 2H), 7.18 (d, J=5.64 Hz, 2H), 2.95 (m, 2H), 2.72 (m, 1H), 1.90 (m, 2H), 1.73 (m, 2H), 1.55 (m, 4H), 1.07 (d, J=5.64 Hz, 6H). MS (M+H): 395 (base peak).


EXAMPLE C-95
5-cis-[4-N-(acetyl)aminocyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 395 (base peak).


EXAMPLE C-96
5-cis-[4-N-(methoxyacetyl)aminocyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) and methoxy acetyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 425 (base peak).


EXAMPLE C-97
5-cis-[4-N-(methylsulfonyl)aminocyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) and methylsulfonyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 431 (base peak).


EXAMPLE C-98
5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting N-t-butoxycarbonyl-cis-4-aminocyclohexanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 337 (base peak).


EXAMPLE C-99
5-(cis-4-N,N-dimethylaminocyclohexyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-98) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 365 (base peak).


EXAMPLE C-100
5-cis-[4-N-(2-propyl)aminocyclohexyl]-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-94 and substituting cis-5-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-98) for 5-(cis-4-n-(2-propyl)aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-92) the title compound was prepared: MS (M+H): 379 (base peak).


EXAMPLE C-101
5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole



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By following the method of Example C-1 and substituting methyl-4-(trifluoromethyl)benzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-cis-4-aminocyclohexanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 387 (base peak).


EXAMPLE C-102
5-cis-(4-N,N-dimethylaminocyclohexyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole



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By following the method of Example C-75 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl] pyrazole (Example C-101) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 415 (base peak).


EXAMPLE C-103
5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-[3-(trifluoromethyl)phenyl] pyrazole



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By following the method of Example C-1 and substituting methyl-3-(trifluoromethyl)benzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-cis-4-aminocyclohexanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 387 (base peak).


EXAMPLE C-104
5-cis-(4-N,N-dimethylaminocyclohexyl)-4-(4-pyridyl)-3-[3-(trifluoromethyl)phenyl] pyrazole



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By following the method of Example C-75 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(3-(trifluoromethyl)phenyl) pyrazole (Example C-103) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 415 (base peak).


EXAMPLE C-105
5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-3-chlorobenzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-cis-4-aminocyclohexanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 353 (base peak).


EXAMPLE C-106
5-cis-(4-N,N-dimethylaminocyclohexyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-cis-(4-aminocyclohexyl)-4-(4-pyridyl)-3-(3-chlorophenyl) pyrazole hydrochloride (Example C-105) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 381 (base peak).


EXAMPLE C-107
5-(N-acetimido-4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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To a suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-2) (0.11 g, 0.35 mmol) in 2 mL EtOH was added ethyl acetamidate hydrochloride (0.065 g, 0.53 mmol) and the mixture was refluxed for 30 minutes. The solution was left at 5-10° C. for 16 h and filtered to obtain the title compound as a white solid: MS (M+H): 364 (base peak).


EXAMPLE C-108
5-(N-carboxamidino-4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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To a stirred suspension of 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (C-2) (1.5 g, 4.7 mmol) in 47 mL of DMF was added Hunig's base (0.60 g, 4.7 mmol) and pyrazole carboxamide hydrochloride (0.68 g, 4.7 mmol). The slurry was allowed to stir at room temperature for 4 days. The reaction mixture was poured onto 300 mL of ether. The resulting precipitate was filtered to leave the title compound as the hydrochloride salt: MS (M+H): 365 (base peak).


EXAMPLE C-109
5-(N-cyclopropanoyl-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting cyclopropanoyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 407 (base peak).


EXAMPLE C-110
5-[N-(2-fluoro)benzoyl-4-piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting 2-fluorobenzoyl chloride for acetyl chloride the title compound was prepared: MS (M+H) 461 (base peak).


EXAMPLE C-111
5-(N-methylsulfonyl-4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-2) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-74) and methylsulfonyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 401 (base peak).


EXAMPLE C-112
5-(N-methoxyacetyl-4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-2) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-74) and methoxy acetyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 395 (base peak).


EXAMPLE C-113
5-((N-acetyl-4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole Example (C-2) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole Example (C-74) the title compound was prepared: MS (M+H): 365 (base peak).


EXAMPLE C-114
5-[2-(1,1-dimethyl)aminoethyl]-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting N-t-butoxycarbonyl-2-amino-2,2-dimethylpropanoyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as the hydrochloride salt: MS (M+H): 327 (base peak).


EXAMPLE C-115
5-(methoxymethyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate and 2-methoxyacetyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared: MS (M+H): 300 (base peak).


EXAMPLE C-116
5-(4-aminobenzyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate and N-t-butoxycarbonyl-4-aminophenyl acetyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as the hydrochloride salt: MS (M+H): 361 (base peak).


EXAMPLE C-117
5-[4-(N, N-dimethyl)aminobenzyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-(4-aminobenzyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-116) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 389 (base peak).


EXAMPLE C-118
5-[4-(N-acetyl)aminobenzyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(4-aminobenzyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-116) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 403 (base peak).


EXAMPLE C-119
5-(N-methylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a suspension of 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-1) (8.04 g, 30 mmol) in 120 mL dichloromethane was added p-nitrophenylformate (6.01 g, 36 mmol) as a solid. The suspension was stirred for 24 h at room temperature and the solvents removed under reduced pressure. The residue was triturated with ether and filtered to obtain the desired 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole derivative as a white solid: MS (M+H): 297 (base peak).


5-(N-methylaminomethyl)-6-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a suspension of 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (8.74 g, 29.5 mmol) in 90 mL anhydrous tetrahydrofuran was added a 1.0 M solution of borane in tetrahydrofuran (90 mL, 90 mmol) and the mixture was stirred at room temperature for 24 h. 1 N aqueous hydrochloric acid (100 mL) was then added to this mixture and the solution was refluxed for 5 hours and cooled to room temperature. The solution was extracted with ether (2×250 mL) and the pH of the aqueous layer adjusted to 9 by addition of concentrated ammonium hydroxide. The aqueous layers (pH ˜9) were then extracted with ethyl acetate (4×150 mL). The organic extracts were dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was triturated with acetonitrile and filtered to obtain the title compound as a white solid: MS (M+H): 283 (base peak).


EXAMPLE C-120
5-[N-(2-amino-2,2-dimethylacetyl)aminomethyl]-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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5-(N-t-butoxycarbonylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a solution of 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-1) (0.27 g, 1 mmol) in anhydrous dimethylformamide (4 mL) was added N-tert-butoxycarbonyl aminoisobutyric acid N-hydroxysuccinimide ester (0.33 g, 1.1 mmol) and the mixture stirred at 40° C. for 24 h. The resulting solution was evaporated to dryness under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and washed with a saturated solution of sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness to afford 5-(N-t-butoxycarbonylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole as a white solid.


5-(N-(2-amino-2,2-dimethylacetyl)aminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a solution of the above compound in acetonitrile (2 mL) was added 1 mL of a 4.0 M solution of hydrochloric acid in dioxane. The reaction mixture was stirred at room temperature for 6 hours. The suspension was evaporated to dryness under reduced pressure. The resulting residue was stirred in acetonitrile (5 mL), filtered and dried in a vacuum dessicator to afford the title compound as a hydrochloride salt: MS (M+H): 354 (base peak).


EXAMPLE C-121
5-[N-(2-amino-2,2-dimethylacetyl)aminomethyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-120 and substituting 5-aminomethyl-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (Example C-15) for 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-1) the title compound was prepared: MS (M+H): 370 (base peak).


EXAMPLE C-122
5-[4-N-(2-dimethylaminoacetyl)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole



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To a solution of N,N-dimethylglycine hydrochloride (0.28 g, 2 mmol) in dimethylformamide (4 mL) was added hydroxybenzotriazole (0.27 g, 2 mmol), N,N-diisopropylethyl amine (0.7 mL, 4 mmol) and polymer supported ethyl carbodimide (Example B-49) (1 g, 2.39 mmol). To this solution after 30 minutes at room temperature was added 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74), 0.41 g, 1 mmol). The suspension was agitated on a labtop orbital shaker for 24 h. The suspension was filtered, washed with dimethylformamide (2×5 mL) and the filtrates evaporated under high pressure. The residue was dissolved in dichloromethane (30 mL), washed with a saturated solution of sodium bicarbonate (50 mL) and brine (50 mL). The organic layers were dried over sodium sulfate, filtered and evaporated under high vacuum to afford the title compound as a white solid: MS (M+H): 424 (base peak).


EXAMPLE C-123
(S)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting (S)-N-t-butoxycarbonyl-prolinyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4, N HCl in dioxane to afford the title compound: MS (M+H): 309 (base peak).


EXAMPLE C-124
(S)-5-(N-methyl-2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-75 and substituting (S)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-123) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 323 (base peak).


EXAMPLE C-125
(R)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting (R)-N-t-butoxycarbonyl-prolinyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 309 (base peak).


EXAMPLE C-126
(R)-5-(N-methyl-2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-75 and substituting (R)-5-(2-pyrolidinyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-125) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 323 (base peak).


EXAMPLE C-127
(R)-5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-1 and substituting (R)-N- t-butoxycarbonyl-nipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound: MS (M+H): 323 (base peak).


EXAMPLE C-128
(R)-5-(N-methyl-3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-75 and substituting (R)-5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-125) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 337 (base peak).


EXAMPLE C-129
2,2-dimethyl-4-[4-(4-pyridyl)-3-(4-chlorophenyl) pyrazolyl] butyric acid



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate and 2,2-dimethyl glutaric anhydride for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared: MS (M+H): 370 (base peak).


EXAMPLE C-130
4-[4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl] butyric acid



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By following the method of Example C-1 and substituting glutaric anhydride for N-benzyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared: MS (M+H): 326 (base peak).


EXAMPLE C-131
4-[4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl] butyramide



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Methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyrate. To a solution of 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyric acid (Example C-130) (40 g 123 mmol) in 650 mL of MeOH was added 20 mL of concentrated H2SO4. The solution was stirred overnight at room temperature. The solution was concentrated and diluted with 200 mL of water. The solution was cooled with an ice/water bath and to the solution was added 150 mL of saturated NaHCO3. The solution was neutralized further with 50% NaOH to pH 7. The resulting slurry was extracted with CH2Cl2 (3×250 mL). The combined extracts were washed with water (1×300 mL) and saturated NaHCO3 (1×500 mL). The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyrate: MS (M+H): 340 (base peak).


4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyramide. A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated with additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was concentrated to leave a yellow solid. The solid was slurried in ether and filtered to leave the title compound: MS (M+H): 325 (base peak).


EXAMPLE C-132
5-[4-(1-hydroxy)butyl]-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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A stirred suspension of 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyric acid (Example C-130) (2 g, 6.15 mmol) in 100 ml of anhydrous ether was cooled to 0° C. under nitrogen. Lithium aluminum hydride (467 mg, 12.3 mmol) was added to this suspension slowly. After the addition was complete, the mixture was warmed to room temperature and stirred for additional 2 h. The reaction was quenched slowly with 1N KHSO4 (80 ml). The mixture was transferred to a separatory funnel and the aqueous layer was removed. The aqueous layer was then made basic with K2CO3 (pH 8). The aqueous solution was extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (1×100 mL), dried over MgSO4, filtered and concentrated to give the title compound: MS (M+H): 312 (base peak).


EXAMPLE C-133
5-[4-(1,1-dimethyl-1-hydroxy)butyl]-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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A solution of 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyric acid (Example C-130) (200 mg, 0.615 mmol) in 50 ml of MeOH was treated with 10 ml of 4 N HCl/dioxane. The reaction mixture was stirred for 5 hours and evaporated to dryness. To this residue was added 15 ml of 1N methyl magnesium bromide in butyl ether and 5 ml of anhydrous THF. The reaction was heated to reflux under nitrogen for 64 h.


The reaction was quenched with 20 ml of saturated ammonium chloride. This mixture was transferred to a separatory funnel and was extracted with 100 ml ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with water (1×100 mL), dried over MgSO4, filtered and concentrated to afford a crude oil. The crude oil was subjected to column chromatography by using 3.5 % MeOH/CH2Cl2 followed by 6 % MeOH/CH2Cl2 to give the title compound: MS (M+H): 340 (base peak).


EXAMPLE C-134
5-(4-(1-amino)butyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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To a suspension of 4-(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) butyramide (Example C-131) (2 g, 6.2 mmol) in 100 ml of anhydrous ether was added lithium aluminum hydride (467 mg, 12.3 mmol). After the addition was complete, the mixture was warmed to room temperature and stirred for additional 2 h. The reaction was quenched with 20 mL of ethyl acetate and was poured onto 100 mL of 2.5 N NaOH. The mixture was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (1×100 mL), dried over Na2SO4, filtered and concentrated to afford the title compound: MS (M+H): 311 (base peak).


EXAMPLE C-135
4(4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl) propionic acid



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By following the method of Example C-1 and substituting succinic anhydride for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide the title compound was prepared: MS (M+H): 312 (base peak).


EXAMPLE C-136
5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-1 and substituting methyl-4-chlorobenzoate for ethyl-4-fluorobenzoate, N-t-butoxycarbonyl-isonipecotyl N-hydroxysuccinimide for N-benyloxycarbonyl-glycinyl N-hydroxysuccinimide and 4-methylpyrimidine for 4-picoline the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the N-t-butoxycarbonyl intermediate was accomplished with 4 N HCl in dioxane to afford the title compound as the hydrochloride salt: 1H NMR (CDCl3) δ 9.2 (s, 1H), 8.48 (d, J=5.19 Hz, 1H), 7.31 (m, 4H), 6.94 (d, J=4.79 Hz, 1H), (3.69 (m, 3H), 3.12 (m, 2H), 2.3 (m, 3H), 1.24 (m, 2H). MS (M+H): 340 (base peak).


EXAMPLE C-137
5-(N-methyl-4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole



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By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole (Example C-136) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole hydrochloride (Example C-74) the title compound was prepared: 1H NMR (CDCl3) δ 9.2 (d, J=1.2 Hz, 1H), 8.48 (d, J=5.59 Hz, 1H), 7.31 (m, 4H), 6.95 (dd, J=1.2, 5.6 Hz, 1H), 3.39 (m, 1H), 3.03 (d, J=11.6 Hz, 2H), 2.38 (s, 3H), 2.06 (m, 4H), 1.24 (m, 2H). MS (M+H): 354 (base peak).


EXAMPLE C-138
5-(M-acetyl-3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (C-90) for S-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (C-74) the title compound was prepared: MS (M+H): 365 (base peak).


EXAMPLE C-139
5-(N-methoxyacetyl-3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole



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By following the method of Example C-76 and substituting 5-(3-piperidyl)-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (C-90) for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl) pyrazole (C-74) and methoxy acetyl chloride for acetyl chloride the title compound was prepared: MS (M+H): 395 (base peak).


Additional compounds of the present invention which could be prepared using one or more of the reaction schemes set forth in this application include, but are not limited to, the following:


EXAMPLE C-140
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-thiomethyl)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-141
5-(4-piperidinyl)-4-[4-(2-thiomethyl)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-142
5-(4-N-methylpiperidinyl)-4-[4-(2-thiomethyl)pyrimidinyl]-3-4-(chloropbenyl) pyrazole



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EXAMPLE C-143
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-144
5-(4-piperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-145
5-(4-N-methylpiperidinyl)-4-[4-(2-methanesulfonyl)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-146
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-147
5-(4-piperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-148
5-(4-N-methylpiperidinyl)-4-[4-(2-amino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-149
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-150
5-(4-piperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-151
5-(4-N-methylpiperidinyl)-4-[4-(2-methylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-152
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-153
5-(4-piperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-154
5-(4-N-methylpiperidinyl)-4-[4-(2-isopropylamino)pyrimidinyl]-3-(4-chlorophenyl) pyrazole



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EXAMPLE C-155
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-156
5-(4-piperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-157
5-(4-N-methylpiperidinyl)-4-[4-(2-(2-methoxyethylamino))pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-158
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-159
5-(4-piperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-160
5-(4-N-methylpiperidinyl)-4-[4-(2-methoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-161
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-162
5-(4-piperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-163
5-(4-N-methylpiperidinyl)-4-[4-(2-isopropoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-164
5-(4-N-t-butoxycarbonylpiperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-165
5-(4-piperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-166
5-(4-N-methylpiperidinyl)-4-[4-(2-(2-N,N-dimethylamino)ethoxy)pyrimidinyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-167
5-(N-acetylhydroxylimido-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-168
5-(N-benzylhydroxylimido-4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-169
5-(N-phenylacethydroxylimido-4-piperidyl)-4-(4-pyridyl) -3-(4-chlorophenyl)pyrazole



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EXAMPLE C-170
5-[N-methyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-171
5-[N-isopropyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-172
5-[N-benzyl-4-(3,4-dehydro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-173
5-[N-methyl-4-(4-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-174
5-[N-methyl-4-(4-hydroxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-175
5-[N-methyl-4-(4-methoxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-176
5-[N-methyl-4-(2,5-tetramethyl-4-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-177
5-[N-methyl-4-(2,5-tetramethyl-4-hydroxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-178
5-[N-methyl-4-(2,5-tetramethyl-4-methoxy)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-179
5-[4-(3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-180
5-[4-(N-methyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-181
5-[4-(N-isopropyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-182
5-[4-(N-benzyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-183
5-[4-(N-acetyl-3-fluoro)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-184
5-[4-(2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-185
5-[4-(N-methyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-186
5-[4-(N-isopropyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-187
5-[4-(N-benzyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-188
5-[4-(N-acetyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-189
5-[5-(2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-190
5-[5-(N-methyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-191
5-[5-(N-isopropyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-192
5-[5-(N-benzyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-193
5-[5-(N-acetyl-2-oxo)piperidyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-194
5-(N-acethydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-195
5-(N-benzhydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-196
5-(N-phenacethydroxylimido-3-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-197
5-(2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-198
5-(N-methyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-199
5-(N-isopropyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-200
5-(N-benzyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-201
5-(N-acetyl-2-morpholinyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-202
5-[trans-4-(N-t-butoxycarbonylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-203
5-(trans-4-aminomethylcyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-204
5-[trans-4-(N-isopropylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-205
5-[trans-4-(N,N-dimethylamino)methylcyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-206
5-[trans-4-(N-acetylamino)methylcyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-207
5-[trans-4-(N-t-butoxycarbonylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-208
5-(trans-4-aminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-209
5-[trans-4-(N,N-dimethylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-210
5-[trans-4-(N-isopropylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-211
5-[trans-4-(N-acetylamino)cyclohexyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-212
5-[cis-4-(N-t-butoxycarbonyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-213
5-(cis-4-methylaminocyclohexyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-214
5-[cis-4-(N,N-dimethyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-215
5-[cis-4-(N-isopropyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-216
5-[cis-4-(N-acetyl)methylaminocyclohexyl)]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-217
5-[3-(1,1-dimethyl-1-(N-t-butoxycarbonylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-218
5-[3-(1,1-dimethyl-1-amino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-219
5-[3-(1,1-dimethyl-1-(N,N-dimethylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-220
5-[3-(1,1-dimethyl-1-(N-isopropylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-221
5-[3-(1,1-dimethyl-1-(N-acetylamino)propyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-222
5-[4-(1-carboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-223
5-[4-(1-N-methylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-224
5-[4-(1-N-benzylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-225
5-[3-(1-carboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-226
5-[3-(1-N-methylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-227
5-[3-(1-N-benzylcarboxamidino)benzyl-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-228
5-[3-(N-t-butoxycarbonyl)aminobenzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-229
5-(3-aminobenzyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-230
5-8 3-(N,N-dimethylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-231
5-[3-(N-isopropylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-232
5-[3-(N-benzylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-233
5-[3-(N-acetylamino)benzyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-234
5-[4-(2-amino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-235
5-[4-(2-N,N-dimethylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-236
5-[4-(2-N-isopropylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-237
5-[4-(2-N-benzylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-238
5-[4-(2-N-acetylamino)methylimidazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-239
5-[4-(2-amino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-240
5-[4-(2-N,N-dimethylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-241
5-[4-(2-N-isopropylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-242
5-[4-(2-N-benzylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-243
5-[4-(2-N-acetylamino)methyloxazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-244
5-[4-(2-amino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-245
5-[4-(2-N,N-dimethylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-246
5-[4-(2-N-isopropylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-247
5-[4-(2-N-benzylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE C-248
5-[4-(2-N-acetylamino)methylthiazolyl]-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole



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Biological data from compounds of Examples B-0001 through B-1573 and of Examples B-2270 through B-2462 are shown in the following tables.


In vitro P38-alpha kinase inhibitory data are shown in the column identified as:


“P38 alpha kinase IC50, uM or % inhib @ conc. (uM),”


In vitro whole cell assay for measuring the ability of the compounds to inhibit TNF production in human U937 cells stimulated with LPS are shown in the column identified as:


“U937 Cell IC50, uM or % inhib @ conc., (uM)”


In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the mouse is shown in the column identified as:


“Mouse LPS Model, % TNF inhib @ dose @ predose time”


wherein in the dose is milligram per kilogram (mpk) administered by oral gavage and the predose time indicates the number of hours before LPS challenge when the compound is administered.


In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the rat is shown in the column identified as:


“Rat LPS Model, % TNF inhib @ dose @ predose time”


wherein in the dose is milligram per kilogram (mpk) administered by oral gavage and the predose time indicates the number of hours before LPS challenge when the compound is administered.

P38 alpha kinaseU937 Cell IC50, uMMouse LPS Model %Rat LPS Model %IC50, uM or %or %TNF inhib @ doseinhib @ doseExample#inhib@conc. (uM)inhib@conc. (uM)@predose time@predose timeB-000153.0% @1.0uM40.0% @1.0uMB-000271.0% @1.0uM28.0% @10.0uMB-000370.0% @1.0uM76.0% 10.0uMB-000480.0% @1.0uM4.61uMB-000595.0% @1.0uM2.97uMB-000682.0% @1.0uM80% @10.0uMB-000774.0% @1.0uM85.0% @10.0uMB-000842.0% @1.0uM65.0% @10.0uMB-00090.04uM0.72uMB-00100.52uM0.65uMB-00110.03uM4.47uMB-001230.0% @1.0uM44.0% @1.0uMB-001370.0% @1.0uM84.0% @10.0uMB-001479.0% @1.0uM80.0% @10.0uMB-001582.0% @1.0uM80.0% @10.0uMB-001694.0% @1.0uM3.98uMB-001756.0% @1.0uM79.0% @10.0uMB-001860.0% @1.0uM59.0% @10.0uMB-001984.0% @1.0uM100.0% @10.0uMB-002073.0% @1.0uM81.0% @10.0uMB-002168.0% @1.0uM76.0% @10.0uMB-002269.0% @1.0uM44.0@1.0uMB-002390.0% @1.0uM77.0% @10.0uMB-002494.0% @1.0uM52.0% @1.0uMB-002589.0% @1.0uM79.0% @10.0uMB-002696.0% @1.0uM3.27uMB-002794.0% @1.0uM11.0uMB-002869.0% @1.0uM45.0% @10.0uMB-002991.0% @1.0uM58.0% @10.0uMB-003092.0% @1.0uM75.0% @10.0uMB-003194.0% @1.0uM100.0% @10.0uMB-003294.0% @1.0uM78.0% @10.0uMB-003397.0% @1.0uM10.0uMB-003495.0% @1.0uM10.0uMB-003594.0% @1.0uM10.0uMB-003692.0% @1.0uM8.24uMB-003791.0% @1.0uM86.0% @10.0uMB-003871.0% @1.0uM84.0% @10.0uMB-003989.0% @1.0uM72.0% @10.0uMB-004093.0% @1.0uM2.3uMB-004165.0% @1.0uM66.0% @10.0uMB-004294.0% @1.0uM2.76uMB-00430.22uM0.54uMB-00440.14uM0.19uMB-004594.0% @1.0uM1.01uMB-004696.0% @1.0uM54.0% @1.0uMB-004794.0% @1.0uM74.0% @10.0uMB-004894.0% @1.0uM76.0% @10.0uMB-004988% @1.0uM33.0% @1.0uMB-005073% @1.0uM34.0% @1.0uMB-00513.3uM2.15uM47% @100 mpk@-6 h  79% @3 mpk@-4 hB-005292% @1.0uM15.0% @1.0uMB-005395% @1.0uM34.0% @1.0uMB-005490% @1.0uM30.0% @1.0uMB-005593% @1.0uM>1.0uMB-005696% @1.0uM21.0% @1.0uMB-005796% @1.0uM29.0% @1.0uMB-005879% @1.0uM18.0% @1.0uMB-005983% @1.0uM35.0% @1.0uMB-006073% @1.0uM22.0% @1.0uMB-006162% @1.0uM27.0% @1.0uMB-006294% @1.0uM36.0% @1.0uMB-006396% @1.0uM40.0% @1.0uMB-006490% @1.0uM4.0% @1.0uMB-006583% @1.0uM21.0% @1.0uMB-006694% @1.0uM28.0% @1.0uMB-006791% @1.0uM1.0% @1.0uMB-006872% @1.0uM22.0% @1.0uMB-006996% @1.0uM37.0% @1.0uMB-007092% @1.0uM30.0% @1.0uMB-007186% 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@10.0uMB-233582.0% @10.0uM50.0% @10.0uMB-233648.0% @10.0uM35.0% @10.0uMB-233746.0% @10.0uM59.0% @10.0uMB-233873.0% @10.0uM50.0% @10.0uMB-233984.0% @10.0uM>10.0uMB-234035.0% @10.0uM12.0% @10.0uMB-234175.0% @10.0uM50.0% @10.0uMB-234283.0% @10.0uM46.0% @10.0uMB-234343.0% @10.0uM27.0% @10.0uMB-234471.0% @10.0uM50.0% @10.0uMB-234564.0% @10.0uM38.0% @10.0uMB-234645.0% @10.0uM48.0% @10.0uMB-234749.0% @10.0uM50.0% @10.0uMB-234876.0% @10.0uM48.0% @10.0uMB-234975.0% @10.0uM27.0% @10.0uMB-235038.0% @10.0uM56.0% @10.0uMB-235177.0% @10.0uM1.0% @10.0uMB-235237.0% @10.0uM19.0% @10.0uMB-235338.0% @10.0uM33.0% @10.0uMB-235465.0% @10.0uM25.0% @10.0uMB-235584.0% @10.0uM50.0% @10.0uMB-235677.0% @10.0uM45.0% @10.0uMB-235747.0% @10.0uM41.0% @10.0uMB-235817.0% @10.0uM52.0% @10.0uMB-235976.0% @10.0uM35.0% @10.0uMB-236045.0% @10.0uM>10.0uMB-236119.0% @10.0uM46.0% @10.0uMB-236260% @100.0uM39.0% @10.0uMB-236344.0% @10.0uM1.0% @10.0uMB-236447.0% @10.0uM4.0% @10.0uMB-236582.0% @10.0uM43.0% @10.0uMB-236670.0% @10.0uM59.0% @10.0uMB-236746.0% @10.0uM40.0% @1.0uMB-236865.0% @10.0uM55.0% @10.0uMB-236932.0% @10.0uM>10.0uMB-237073% @100.0uM20.0% @10.0uMB-237154.0% @10.0uM36.0% @10.0uMB-237255.0% @100.0uM>10.0uMB-237350.0% @100.0uM6% @10.0uMB-237435.0% @10.0uM20.0% @10.0uMB-237562.0% @100.0uM>10.0uMB-237632.0% @10.0uM17.0% @10.0uMB-237734.0% @10.0uM17.0% @10.0uMB-237848.0% @10.0uM61.0% @10.0uMB-237973.0% @100.0uM45.0% @1.0uMB-238081% @100.0uM53.0% @10.0uMB-238168% @100.0uM2.0% @10.0uMB-238251.0% @10.0uM24.0% @10.0uMB-238363.0% @10.0uM35.0% @10.0uMB-238449% @100.0uM10.0% @10.0uMB-238579.0% @10.0uM19.0% @10.0uMB-238638.0% @10.0uM19.0% @10.0uMB-238750.0% @100.0uM>10.0uMB-238842.0% @10.0uM24.0% @10.0uMB-238939.0% @10.0uM29.0% @10.0uMB-239034.0% @10.0uM27.0% @1.0uMB-239140.0% @10.0uM59.0% @10.0uMB-239263.0% @10.0uM46.0% @10.0uMB-239343.0% @10.0uM>10.0uMB-239437.0% @10.0uM22.0% @10.0uMB-239532.0% @10.0uM28.0% @10.0uMB-239675.0% @10.0uM>10.0uMB-239783.0% @10.0uM22.0% @10.0uMB-239855% @100.0uM10.0% @10.0uMB-239969.0% @10.0uM18.0% @10.0uMB-240060.0% @10.0uM40.0% @10.0uMB-240178.0% @10.0uM44.0% @10.0uMB-240243.0% @10.0uM52.0% @10.0uMB-240372% @100.0uM52.0% @10.0uMB-240458% @100.0uM52.0% @10.0uMB-240547% @100.0uM>10.0uMB-240645.0% @10.0uM24.0% @10.0uMB-240747% @100.0uM27.0% @10.0uMB-240839.0% @10.0uM10.0% @10.0uMB-240978.0% @10.0uM26.0% @10.0uMB-241033.0% @10.0uM32.0% @10.0uMB-241126% @100.0uM13.0% @10.0uMB-241240.0% @10.0uM31.0% @10.0uMB-241375.0% @10.0uM37.0% @10.0uMB-241486.0% @10.0uM38.0% @10.0uMB-241594.0% @10.0uM50.0% @10.0uMB-241685.0% @10.0uM43.0% @1.0uMB-241783.0% @10.0uM18.0% @10.0uMB-241888.0% @10.0uM34.0% @10.0uMB-241986.0% @10.0uM66.0% @10.0uMB-242070.0% @10.0uM34.0% @10.0uMB-242189.0% 210.0uM38.0% @10.0uMB-242290.0% @10.0uM17.0% @10.0uMB-242385.0% @10.0uM>10.0uMB-242486.0% @10.0uM43.0% @10.0uMB-242579.0% @10.0uM42.0% @10.0uMB-242688.0% @10.0uM53.0% @10.0uMB-242787.0% @10.0uM59.0% @10.0uMB-242882.0% @10.0uM50.0% @10.0uMB-242992.0% @10.0uM32.0% @10.0uMB-243090.0% @10.0uM61.0% @10.0uMB-243185.0% 210.0uM68.0% @10.0uMB-243286.0% 210.0uM40.0% @10.0uMB-243394.0% @10.0uM84.0% @10.0uMB-243492.0% @10.0uM63.0% @10.0uMB-243584.0% @10.0uM4.0% @10.0uMB-243680.0% @10.0uM54.0% @10.0uMB-243782.0% @10.0uM41.0% @10.0uMB-243875.0% @10.0uM40.0% @10.0uMB-243981.0% @10.0uM44.0% @10.0uMB-244077.0% @10.0uM78.0% @10.0uMB-244186.0% @10.0uM46.0% @10.0uMB-244286.0% @10.0uM>10.0uMB-244384.0% @10.0uM44.0% @10.0uMB-244489.0% @10.0uM7.0% @10.0uMB-244594.0% @10.0uM15.0% @10.0uMB-244690.0% @10.0uM28.0% @10.0uMB-244794.0% @10.0uM>10.0uMB-244875.0% @10.0uM30.0% @10.0uMB-244986.0% @10.0uM42.0% @10.0uMB-245087.0% @10.0uM46.0% @1.0uMB-245187.0% @10.0uM45.0% @10.0uMB-245289.0% @10.0uM33.0% @10.0uMB-245391.0% @10.0uM>10.0uMB-245488.0% @10.0uM40.0% @10.0uMB-245587.0% @10.0uM54.0% @10.0uMB-245686.0% @10.0uM53.0% @10.0uMB-245790.0% @10.0uM18.0% @10.0uMB-245883.0% @10.0uM36.0% @10.0uMB-245982.0% @10.0uM81.0% @10.0uMB-246080.0% @10.0uM79.0% @10.0uMB-246167.0% @10.0uM59.0% @10.0uM


Biological data from a number of compounds of Examples C-74 through C-139 are shown in the following tables.


In vitro P38-alpha kinase inhibitory data are shown in the column identified as:


“P38 alpha kinase IC50, μM”


In vitro human whole blood assay data for measuring the ability of the compounds to inhibit TNF production in human whole blood stimulated with LPS are shown in the column identified as:


“Human Whole Blood IC50, μM or %Inhib@conc. (μM)”


In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the rat is shown in the column identified as:


“Rat LPS Model % Inhibition@adose@predose time”


wherein the dose is milligram per kilogram (mpk) administered by oral gavage and the predose time indicates the number of hours before LPS challenge when the compound is administered.

Rat LPS ModelP38 alphaHuman Whole Blood% Inhibition@kinaseIC50, μM ordose@predoseExample#IC50, μM% Inhib@conc. (μM)timeC-740.0370.5654% @5 mpk@-4 hC-750.0450.471% @5 mpk@-4 hC-760.073.2466% @5 mpk@-4 hC-770.0718.292% @5 mpk@-4 hC-780.06810.587% @5 mpk@-4 hC-790.0450.5283% @5 mpk@-4 hC-800.00851% @ 5 μMC-810.03740% @ 5 μMC-820.157.31C-830.241.2325% @5 mpk@-4 hC-840.0480.8822% @5 mpk@-4 hC-850.57>25C-860.0070.1966% @5 mpk@-4 hC-870.0270.34C-880.0120.359% @5 mpk@-4 hC-890.0390.1227% @5 mpk@-4 hC-900.0370.48C-910.0542.3163% @5 mpk@-4 hC-920.0240.2866% @5 mpk@-4 hC-930.0090.3850% @5 mpk@-4 hC-940.020.2773% @5 mpk@-4 hC-950.133.9132% @5 mpk@-4 hC-960.0772.138% @5 mpk@-4 hC-970.0253.8321% @5 mpk@-4 hC-980.0160.6478% @5 mpk@-4 hC-990.0620.3836% @5 mpk@-4 hC-1000.0270.2744% @5 mpk@-4 hC-1010.0833.7152% @5 mpk@-4 hC-1020.297.5672% @5 mpk@-4 hC-1050.0330.1346% @5 mpk@-4 hC-1060.0260.4423% @5 mpk@-4 hC-1070.0140.3811% @5 mpk@-4 hC-1080.020.73 0% @5 mpk@-4 hC-1110.216.0539% @5 mpk@-4 hC-1120.546.3689% @5 mpk@-4 hC-1130.0822.7277% @5 mpk@-4 hC-1140.111.7339% @5 mpk@-4 hC-1150.04210.239% @5 mpk@-4 hC-1160.4290.5053% @5 mpk@-4 hC-1173.427.2671% @5 mpk@-4 hC-1180.298>2539% @5 mpk@-4 hC-1200.718.626% @5 mpk@-4 hC-1210.1115.339% @5 mpk@-4 hC-1220.02555% @5 mpk@-4 hC-1230.67>25.0C-1240.174.5651% @20 mpk@-4 hC-1257.22>25.0C-1260.71>25.0 6% @20 mpk@-4 hC-1270.0380.2753% @5 mpk@-4 hC-1280.092.2263% @5 mpk@-4 hC-1320.08644% @ 5 μMC-1330.164.5455% @5 mpk@-4 hC-1356.0C-1360.032C-1370.05158% @5 mpk@-4 hC-1380.280.6826% @5 mpk@-4 hC-1390.23.6646% @5 mpk@-4 h


Additional compounds of interest can be prepared as set forth above and as described below in Scheme D-1, wherein the R1 and R2 substituents are as defined previously.
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The synthesis begins with the treatment of 4-methylpyrimidine 2 with a base such as LiHMDS, LDA or tBuOK in an organic solvent such as THF or ether which is cooled in an ice bath (0-10° C.). To the resulting 4-methylanion is added a solution of a suitably protected (Boc is shown) ethyl ester of isonipecotic acid 1 in THF or ether. The reaction is allowed to warm to room temperature and stirred for a period of 4 hours to 20 hours at which time the desired ketone 3 is isolated after aqueous work up. Condensation of the ketone 3 with tosylhydrazide in toluene or benzene as a solvent at refluxing temperatures for a period of 1 hour to 5 hours affords the hydrazone 4. The hydrazone 4 is reacted with a suitably substituted benzoyl chloride 5, in the presence of a base such as LiHMDS or LDA or tBuOK or triethylamine at temperatures ranging from 0° C. to 70° C. The reaction is stirred for a period of 3-6 hours. Acidic hydrolysis of the protecting groups with an aqueous acid such as HCl or H2SO4 and subsequent neutralization with an aqueous base such as NaOH or KOH affords the desired pyrazole 6. Treatment of the pyrazole 6 with an acid chloride 7 in the presence of base or with an acid 8 under standard peptide coupling conditions (EDC or DCC or PyBrOP with an additive such as HOBt or HATU and base such as N-methylmorpholine or diisopropylethylamine or triethylamine) affords the desired pyrazole amide 9. In most instance the desired products can be obtained pure by direct trituration with solvents such as methanol, ethyl acetate, acetonitrile or ether and/or recrystallization from suitable solvents.


The following examples contain detailed descriptions of the methods of preparation of these additional compounds that form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All compounds showed NMR spectra consistent with their assigned structures.


EXAMPLE D-1
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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Step 1: A 5 L 4-necked round bottom flask fitted with an overhead mechanical stirrer, N2 inlet and a thermocouple was charged with 600 g (2.75 mol) of di-tert-butyl-dicarbonate and 1.5 L of CH2Cl2. The solution was cooled to 0° C. and 428 g (2.73 mol) of ethyl isonipecotate was added dropwise via an addition funnel. The addition took 45 minutes and the temperature rose from 0° C. to 17.4° C. The reaction mixture was stirred for an additional 2 hours at ambient temperature. The solvent was removed in vacuo to afford 725 g of a yellow oil (residual solvent remained).
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Step 2: A 3 L 3-necked round bottom flask fitted with an overhead mechanical stirrer, a N2 inlet, an addition funnel and a thermocouple was charged with 1850 mL (1.85 mol) of a 1.0 M solution of LiHMDS in THF. The flask was cooled to 5° C. and 68 mL (0.74 mol) of 4-methylpyrimidine was added (neat) to the stirred solution. To this solution was added 198 g (0.77 mol) of Ethyl-N-t-butylcarbonyl isonipecotate dissolved in 160 mL of THF. The ice bath was removed and the reaction was allowed to stir for 18 hours. The reaction was quenched with 500 mL of saturated NH4Cl and was extracted with 500 mL of ethyl acetate. The organic phase was washed with 500 mL of brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 235 g of a brown oil.
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Step 3: A 2 L 3-necked round bottom flask fitted with an overhead mechanical stirrer, a Dean-Stark trap and a thermocouple was charged with 1.5 L of toluene, 226 g (0.742 mol) of N-t-butylcarbonyl-1-(4-piperidyl)-2-(4-pyrimidyl)-1-ethanone and 138.4 g (0.743 mol) of tosyl hydrazide. The mixture was warmed to reflux. The solution was allowed to reflux for 2 hours and was cooled to ambient temperature. The reaction was allowed to stand overnight. A fine precipitate formed and was removed by filtration. The filtrate was concentrated in vacuo to afford a brown solid. The solid was suspended in 500 mL of ethyl acetate and the resulting mixture was placed in a sonication bath for 5 hours. The mixture was cooled in an ice bath and was filtered to afford 310 g of a wet solid. The solid was dried in a vacuum oven (40° C., 5 mm) overnight to afford 248 g of the desired hydrazone (71%).



1H NMR (CDCl3) δ 9.03 (d, J=1.2 Hz, 1H), 8.72 (d, J=5.2 Hz, 2H), 7.89 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.26 (dd, J=5.2, 1.0 Hz, 1H), 4.03 (d, J=12.1 Hz, 2H), 3.76 (s, 2H), 2.71 (t, J=12.1 Hz, 2H), 2.43 (s, 3H), 2.34 (m, 1H), 1.66 (d, J=13.5 Hz, 2H), 1.47 (s, 9H), 1.38 (m, 2H); MS (M +H): 474 (base peak).


Step 4:
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Method A. A 2 L 3-necked round bottom flask fitted with an overhead mechanical stirrer, a N2 inlet, an addition funnel and a thermocouple was charged with 400 mL (400 mmol) of a 1.0 M solution of LiHMDS in THF. The solution was cooled to −21.9° C. and a solution of 62 g (131 mmol) of N-t-butylcarbonyl-1-(4-piperidyl)-2-(4-pyrimidyl)-1-ethanone p-toluenesulfonyl hydrazone in 400 mL of THF was added slowly. The temperature never exceeded −11° C. throughout the addition. The solution was re-cooled to −19.6° C. and 23.0 g (131 mmol in 250 mL of THF) of p-chlorobenzoylchloride was added slowly. The temperature never exceeded −13° C. throughout the addition. The cooling bath was removed and the reaction was allowed to warm to ambient temperature. After 3 hours the reaction was quenched with 600 mL of 3 N HCl. The reaction was warmed to reflux and was held at reflux for 2 hours. The reaction was allowed to cool to ambient temperature overnight. The reaction mixture was washed with 1.4 L of Et2O and the aqueous phase was neutralized with 1 L of 2.5 N NaOH. The aqueous phase was extracted with ethyl acetate (2×1000 mL). The combined organic phases were washed with brine (1×500 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 21 g of a yellow solid. The solid was suspended in 500 mL of 2:1 Et2O/hexane. After sonication the solid was isolated by filtration to leave a wet solid. The solid was dried in a vacuum oven to afford 13.8 g of 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole.



1H NMR (DMSO-d6) 9.18 (s, 1H), 8.65 (d, J=5.2, 1H), 7.44 (d, J=8.5, 2H), 7.37 (d, J=7.7 Hz, 2H), 7.15 (d, J=5.2 Hz, 1H), 3.16 (m, 1H), 3.00 (d, J=11.9 Hz, 2H), 2.52 (m, 2H), 1.69 (m, 4H); MS (M +H): 340 (base peak).
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Method B: To a solution of 200 g (423 mmol) of N-t-butylcarbonyl-1-(4-piperidyl)-2-(4-pyrimidyl)-1-ethanone p-toluenesulfonyl hydrazone in 800 mL THF was added 70 mL (500 mmol) of triethylamine in a 3 L three necked flask. The solution was cooled in an ice/salt/water bath to 0-5° C. To this cold solution was added a solution of 4-chlorobenzoyl chloride (74 g, 423 mmol) in 100 mL THF dropwise, maintaining the temperature below 10° C. After the addition was complete the ice-bath was removed and replaced with a heating mantle. 4-N,N-dimethylaminopyridine (5 g, 40 mmol) was added and the reaction mixture was heated to 50° C. for 15-30 minutes. The reaction mixture was filtered and the residue washed with THF (100 mL). The combined filtrates were evaporated under reduced pressure to a semisolid.


The semisolid residue was dissolved in 450 mL THF and 180 mL of 12 N HCl was added to this solution rapidly. The reaction mixture was heated to 65° C. for 1.5-2 hours and transferred to a separatory funnel. The organic layer was discarded and the aqueous phase was washed twice with 200 mL of THF. The aqueous phase was transferred back to a 2 L flask and cooled to 0-10° C. in an ice bath. The pH of the solution was adjusted to between 9-10 by dropwise addition of 15 N ammonium hydroxide (˜180 mL). This mixture was transferred back to a separatory funnel and extracted with warm n-butanol (3×150 mL). The combined n-butanol phases were evaporated under reduced pressure to dryness. The residue was then stirred with methanol (200 mL) filtered and dried to obtain 129 g (90%) of the desired 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole as a off-white solid. This material was identical in all respects to the material prepared by Method A.
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Step 5: A 1 L round bottom flask was charged with 34.2 g (102 mmol) of 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole, 500 mL of CH2Cl2 and 26.6 mL (153 mmol) of Hunig's base. To this suspension was added 16.5 g (122 mmol) of 1-hydroxybenzotriazole and 8.1 g (106 mmol) of glycolic acid. The addition of glycolic acid was followed by the addition of 23.7 g (122 mmol) of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride. The reaction was allowed to stir at ambient temperature overnight. The reaction was concentrated in vacuo to leave an oily residue. The residue was dissolved in 400 mL of methanol and 50 mL of 2.5 N NaOH. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was acidified to pH 5 with 2 N HCl and was extracted with CH2Cl2 (6×200 mL). The combined organic phases were filtered through phase paper and the filtrate was concentrated in vacuo to leave a yellow residue. The residue was treated with 75 mL of acetonitrile. A precipitate formed. The solid was filtered and washed with additional acetonitrile and Et2O to afford 31.4 g of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole. 1H NMR (DMSO-d6) 9.20 (s, 1H), 8.67 (d, J=4.8, 1H), 7.40 (m, 4H), 7.17 (d, J=4.0, 1H), 4.53 (m, 2H), 4.13 (s, 2H), 3.77 (m, 1H), 3.05 (t, J=12.7 Hz, 1H), 2.69 (m, 1H), 1.90 (m, 2H), 1.73 (m, 2H); MS (M+H) 398 (base peak).


EXAMPLE D-2
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride



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A 25 mL round bottom flask was charged with 65 mg (0.164 mmol) of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole and 2.5 mL of dioxane. To this suspension was added 0.082 mL of 4 N HCl in dioxane. The mixture was stirred for 2 hours. The mixture was diluted with 5 mL of Et2O and filtered. The solid was dried over solid CaSO4 under vacuum for 12 h to afford 68 mg of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole hydrochloride. 1H NMR (DMSO-d6) 9.18(s, 1H), 8.63(d, J=5.37 Hz, 1H), 7.40(d, J=8.59 Hz, 2H), 7.33(d, J=8.59 Hz, 2H), 7.15(m, 1H), 4.40(m, 1H), 4.06(m, 2H), 3.72(m, 1H), 3.33(m, 1H), 2.97(m, 1H), 2.62(m, 1H), 1.83(m, 2H), 1.64(m, 2H); MS (M+H): 398.


EXAMPLE D-3
N-(2-Methoxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole (fumarate salt)



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To a suspension of 250 mg (0.74 mmol) of 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole (Example C-1, Step 3) and 180 mg (1.48 mmol) of N,N-dimethylamino pyridine in 20 mL of CH2Cl2 was added 88 mg (0.81 mmol) of 2-methoxyacetyl chloride. The reaction was stirred for 5 hours. The reaction was quenched with 20 mL of saturated NH4Cl. The mixture was extracted with n-butyl alcohol and the organic layer was washed with brine. The solvent was removed to afford 72 mg of an oil. This oil was dissolved in 1 mL of warm MeOH. This solution was combined with a warm solution of 1 equivalent of fumaric acid in warm MeOH. The solution was cooled to ambient temperature and the reaction was allowed to stir for 1 hour. The solvent was removed in vacuo and the residue was triturated with Et2O. The resulting solid was isolated by filtration to yield 56 mg of an off-white powder. 1H NMR (DMSO-d6) 13.23 (bs, 1H), 9.19 (d, J=1.2 Hz, 1H), 8.65 (d, J=5.1 Hz, 1H), 7.41 (m, 4H), 7.16 (dd, J=5.4, 1.2 Hz, 1H), 4.45 (bd, J=11.1 Hz, 1H), 4.11 (qz, J=39.0, 13.8 Hz, 2H), 3.86 (bd, J=12.9 Hz, 1H), 3.32 (m, 4H), 3.04 (bt, J=12.3 Hz, 1H), 2.63 (bt, J=12.0 Hz, 1H), 1.77 (m, 4H); MS (M +H): 411 (base peak).


EXAMPLE D-4
N-(2-Hydroxy-2-methylpropionyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride



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Step 1: To a suspension of 2.05 g (6.1 mmol) of 5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl) pyrazole (Example C-1, Step 3) and 3.7 g (30.5 mmol) of N,N-dimethylamino pyridine in 30 mL of CH2Cl2 was added 1.06 mL (7.3 mmol) of 2-acetoxy-2-methylpropionyl chloride. The reaction was allowed to stir overnight at ambient temperature. The reaction was quenched with saturated NH4Cl and water. The resulting aqueous phase was extracted with CH2Cl2. The combined organic layers were concentrated in vacuo to leave an oily solid. The residue was treated with CH3CN and allowed to stand for 15 minutes. The resulting suspension was diluted with Et2O and was filtered to afford 2.2 g of a solid. Analysis by LC/MS indicated that the solid was a mixture of the hydroxy derivative and the acetoxy derivative. This solid was carried on to the next step without further purification.


Step 2: A solution of 1 g of the solid from step 1 in 10 mL of MeOH was treated with 500 mg of solid K2CO3. The mixture was allowed to stir overnight at ambient temperature. The suspension was treated with water and the resulting solution was extracted with ethyl acetate. The organic phase was filtered through phase separation paper (to remove the residual water) and was concentrated in vacuo to leave an oily solid. The solid was dried under vacuum and was treated with CH3CN. The suspension was filtered to afford 825 mg of an off-white solid. This solid was suspended in 5 mL of dioxane and 0.5 mL of 4 N HCl in dioxane was added. The suspension was stirred for 1 hour and the suspension was filtered to leave a solid. The solid was washed with Et2O and the resulting suspension was filtered to give 900 mg of the title compound. 1H NMR (DMSO-d6) 9.23 (s, 1H), 8.69 (s, 1H), 7.45 (m, 4H), 7.19 (s, 1H), 4.8 (br m, 4H), 3.85 (m, 2H), 3.38 (m, 1H), 1. 89 (m, 2H), 1.72 (m, 2H), 1.37 (s, 6H); MS (M+H): 426 (base peak).


EXAMPLE D-5
(S)-N-(2-Hydroxypropionyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride



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By following the method of Example C-1 and substituting (S)-lactic acid for glycolic acid the title compound was prepared. 1H NMR (DMSO-d6) 13.15 (s, br, 1H), 9.12(d, J=1.07 Hz, 1H), 8.59(d, J=5.37 Hz, 1H), 7.39(d, J=7.79 Hz, 2H), 7.31(d, J=8.33, 2H), 7.10(dd, J=1.34, 5.1 Hz, 1H), 4.76(m, 1H), 4.41(m, 2H), 3.99(m, 1H), 2.97(m, 1H), 2.45(m, 1H), 1.83(m, 2H), 1.64(m, 2H), 1.15(m, 3H); MS (M+H): 412 (base peak).


EXAMPLE D-6
(R)-N-(2-Hydroxypropionyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride



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By following the method of Example C-1 and substituting (R)-lactic acid for glycolic acid the title compound was prepared. 1H NMR (CDCl3) 9.24(s, 1H), 8.52(d, J=5.0 Hz, 1H), 7.32-7.36(m, 4H), 6.98(d, J=5.3 Hz, 1H), 4.72(d, J=10.5 Hz, 1H), 4.55(br, 1H), 3.88(d, J=13.1 Hz, 1H), 3.66(br, 1H), 3.19(br, 1H), 2.82(t, J=12.4 Hz, 1H), 2.10(br, 2H), 1.37(d, J=6.2 Hz, 3H), 1.81-1.90(m, 2H); MS (M+H): 412 (base peak).


EXAMPLE D-7
(R)-N-(2-Hydroxy-2-phenylacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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By following the method of Example C-1 and substituting (R)-phenylacetic acid for glycolic acid the title compound was prepared. 1H NMR (DMSO-d6) 9.15 (d, J=0.9 Hz, 1H), 8.63 (d, J=5.4 Hz, 1H), 7.40 (m, 9H), 7.13 (t, J=6.6 Hz, 1H), 5.43 (d, J=19.5 Hz, 1H), 4.51 (s, 1H), 4.04 (m, 1H), 3.33 (m, 4H), 2.8 (m, 2H), 1.68 (m, 3H); MS (M+H): 474 (base peak).


EXAMPLE D-8
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-fluorophenyl)pyrazole



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By following the method of Example C-1 and substituting 4-fluorobenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared. 1H NMR (DMF-d7) 13.48(s, 1H), 9.40(s, 1H), 8.86(d, J=5.1 Hz, 1H), 7.71(br, 2H), 7.42(bd, J=5.2 Hz, 3H), 4.78(br, 1H), 4.43(s, 2H), 4.04(br, 1H), 3.79(br, 1H), 3.70(s, 1H), 3.34(t, J=12.2 Hz, 1H), 3.0(br, 1H), 2.21(d, J=10.9 Hz, 2H), 2.08(br, 1H); MS (M+H): 382 (base peak).


EXAMPLE D-9
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-trifluoromethylphenyl)pyrazole



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By following the method of Example C-1 and substituting 4-trifluoromethylbenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared.



1H NMR (DMF-d7) 13.47(s, 1H), 9.24(s, 1H), 8.73(d, J=4.0 Hz, 1H), 7.77(bd, J=13.3 Hz, 4H), 7.34(d, J=4.3 Hz, 1H), 4.61(br, 1H), 4.26(s, 2H), 3.87(br, 1H), 3.52(s, 2H), 3.17(t, J=12.0 Hz, 1H), 2.8 (br, 1H), 2.02(br, 2H), 1.91(br, 1H); MS (M+H): 432 (base peak).


EXAMPLE D-10
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-trifluoromethoxyphenyl)pyrazole



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By following the method of Example C-1 and substituting 4-trifluoromethoxybenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared.



1H NMR (DMF-d7) 13.55(s, 1H), 9.40(s, 1H), 8.88(d, J=4.6 Hz, 1H), 7.81(d, J=7.7 Hz, 2H), 7.64(br, 2H), 7.47(d, J=4.4 Hz, 1H), 4.75(br, 1H), 4.42(s, 2H), 4.04(d, J=12.5 Hz, 1H), 3.69(br, 2H), 3.34(t, J=12.0 Hz, 1H), 3.0(br, 1H), 2.20(d, J=11.7 Hz, 2H), 2.05(br, 1H); MS (M+H): 448 (base peak).


EXAMPLE D-11
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(3-chlorophenyl)pyrazole



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By following the method of Example C-1 and substituting 3-chlorobenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared. 1H NMR (DMF-d7) 13.41(s, 1H), 9.24(s, 1H), 8.73(d, J=4.9 Hz, 1H), 7.56(s, 1H), 7.49(br, 2H), 7.41(br, 1H), 7.32(d, J.=4.2 Hz, 1H), 4.60(d, J=11.7 Hz, 1H), 4.25(s, 2H), 3.87(d, J=12.7 Hz, 1H), 3.52(bs, 2H), 3.17(t, J=12.1 Hz, 1H), 2.84(d, J=12.5 Hz, 1H), 2.03(d, J=11.9 Hz, 2H), 1.87(br, 1H); MS (M+H): 398 (base peak).


EXAMPLE D-12
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(3-fluorophenyl)pyrazole



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By following the method of Example C-1 and substituting 3-fluorobenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared. 1H NMR (DMF-d7) 13.38(s, 1H), 9.24(s, 1H), 8.72(d, J=5.2 Hz, 1H), 7.49(dd, J=8.0 and 6.2 Hz, 1H), 7.24-7.32(m, 4H), 4.60(d, J=13.1 Hz, 1H), 4.25 (s, 2H), 3.87(d, J=13.3 Hz, 1H), 3.55-3.60(m, 1H), 3.52(s, 1H), 3.17(t, J=12.2 Hz, 1H), 2.82(d, J=12.9 Hz, 1H), 2.03(d, J=10.9 Hz, 2H), 1.83-1.96(m, 1H); MS (M+H): 382 (base peak).


EXAMPLE D-13
N-(2-Hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(3-trifluoromethylphenyl)pyrazole



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By following the method of Example C-1 and substituting 3-trifluoromethylbenzoyl chloride for 4-chlorobenzoyl chloride the title compound was prepared.



1H NMR (DMF-d7) 13.76(s, 1H), 9.41(s, 1H), 8.91(d, J=5.3 Hz, 1H), 8.02(s, 1H), 7.95(t, J=6.5 Hz, 2H), 7.85(t, J=7.5 Hz, 1H), 7.53(d, J=4.6 Hz, 1H), 4.78(d, J=11.9 Hz, 1H), 4.45(d, J=16.3 Hz, 2H), 4.06(d, J=12.5 Hz, 1H), 3.69(bs, 2H), 3.34(t, J=11.3 Hz, 1H), 3.01(d, J=13.1 Hz, 1H), 2.20(d, J=11.1 Hz, 2H), 2.12(br, 1H); MS (M+H): 432 (base peak).


The following examples can be prepared in a manner similar to that described above for the synthesis of Examples C1-C13.


EXAMPLE D-14
5-[4-N-(2-hydroxy-2-(2-chlorophenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-15
5-[4-N-(2-hydroxy-2-(3-chlorophenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-16
5-[4-N-(1-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-17
5-[4-N-(2-hydroxy-1-cyclohexylacetyl)piperidyll-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-18
5-[4-N-(3-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-19
5-[4-N-(4-hydroxy-1-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-20
5-[4-N-(1-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-21
5-[4-N-(2-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-22
5-[4-N-(3-hydroxy-1-cyclopentylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-23
5-[4-N-(3-hydroxypropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-24
5-[4-N-(2-hydroxy-3,3,3-trifluoropropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-25
5-[4-N-(2-hydroxy-3-methylbutyryl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-26
5-[4-N-(2-hydroxyisocaproyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-27
5-[4-N-(2-hydroxy-2-cyclohexylacetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-28
5-(4-N-(2-hydroxy-2-(4-methoxyphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-29
5-[4-N-(2-hydroxy-2-(3-methoxyphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-30
5-[4-N-(2-hydroxy-2-(4-trifluoromethylphenyl)acetyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-31
5-[4-N-(2-hydroxy-3-phenylpropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-32
5-[4-N-(2-hydroxy-3-(4-hydroxyphenyl)propionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-33
5-[4-N-(2-hydroxy-3-imidazolpropionyl)piperidyl]-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole



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The synthesis of 2-substituted pyrimidinyl pyrazoles is shown in Scheme 2. Reaction of 2-methylmercapto-4-methyl pyrimidine 10 with N-Boc methyl ester of isonipecotic acid (1) under basic (base selected from LiHMDS or LDA or tBuOK) conditions in an anhydrous solvent such as tetrahydrofuran or ether affords the desired ketone 11. Condensation of the ketone 11 with tosyl hydrazine under refluxing conditions in either toluene or benzene affords the hydrazone 12. The hydrazone 12 is deprotonated under basic (base selected from LiHMDS or LDA or tBuOK) conditions in an anhydrous solvent such as tetrahydrofuran or ether and the anion is reacted in situ with a suitably substituted benzoyl chloride 5 to afford, after mild aqueous work up, the desired and fully protected pyrazole 13. Oxidation of the 2-mercaptomethyl group present in 13 with oxidants selected from but not limited to Oxone®, H2O2 or mCPBA in solvents such as dichloromethane, acetonitrile or tetrahyrofuran affords the 2-methane sulfonyl pyrazole 14. The 2-methanesulfone group in 14 is conveniently displaced with various amines, aryloxides or alkoxides in solvents such as tetrahydrofuran, dioxane, dimethylformamide or acetonitrile at temperatures ranging from 20° C. to 200° C. Under these reaction conditions the tosyl protecting group on the pyrazole is also simultaneously deprotected. Aqueous workup affords the desired tosyl deprotected, 2-alkoxy, or 2-aryloxy or 2-amino substituted pyrazoles 15. The alkoxides or aryloxides are generated from their respective alcohols or phenols with suitable bases such as LiHMDS, NaH, LDA or tBuOK in solvents such as tetrahydrofuran, dioxane or dimethylformamide. Deprotection of the remaining N-Boc group in 15 is accomplished with trifluoroacetic acid or hydrochloric acid in solvents such as dichloromethane or dioxane to afford the pyrazole 16. Treatment of the pyrazole 16 with an acid chloride 7 in the presence of base or with an acid 8 under standard peptide coupling conditions (EDC or DCC or PyBrOP with an additive such as HOBt or HATU and base such as N-methylmorpholine or diisopropyl ethylamine) affords the desired final products 17.
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The following 2-substituted pyrimidine compounds can be prepared as set forth above, particularly in a manner similar to that outlined above in Scheme D-2.


EXAMPLE D-34
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-thiomethyl)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-35
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methanesulfonyl)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-36
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-amino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-37
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-38
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-isopropylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-39
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-S-methylbenzylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-40
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-R-methylbenzylamino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-41
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(2-methoxy)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-42
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(p-fluorophenoxy)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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EXAMPLE D-43
5-[4-N-(2-hydroxyacetyl)piperidyl]-4-[4-(p-fluoroanilino)pyrimidyl]-3-(4-chlorophenyl)pyrazole



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In a manner similar to that outlined above in Scheme D-1, for the synthesis of the piperidine analogs 6, the aminocyclohexane analogs are prepared by substitution of 1 in Scheme D-1 with a suitably protected (Boc is shown) methyl or ethyl ester of cis-aminocyclohexane carboxylic acid 10 or trans-aminocyclohexane carboxylic acid 11 or trans-aminomethylcyclohexane carboxylic acid 12, which affords the cis-aminocyclohexane 13, or trans-aminocyclohexane 14 or the trans-aminomethylcyclohexane 15 respectively (Scheme 3). Suitable reductive alkylations on 13, 14 or 15 with 1-1.5 equivalents of aldehydes or ketones in the presence of a reducing agent like sodium cyanoborohydride or sodium triacetoxyborohydride in solvents such as methanol, ethanol, acetic acid, tetrahydrofuran or dichloromethane lead to the desired mono-alkylated derivatives 16, 17 or 18 respectively.
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The dimethyl derivatives 19, 20 or 21 can be prepared by heating a solution of the aminocyclohexanes 13, 14 or 15 respectively in a mixture of formaldehyde and formic acid at temperatures ranging from 40° C. to 110° C.
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An additional group of compounds of interest includes the following:
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Biological data for a number of compounds are shown in the following table. In vitro p38 alpha kinase inhibitory data are shown in the column identified as “p38 alpha IC50 (μM)”. In vitro human whole blood assay data for measuring the ability of the compounds to inhibit TNF production in human whole blood stimulated with LPS are shown in the column identified as: “HWB IC50 (μM)”. In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF-release in the rat is shown in the column identified as: “ratLPS/%Inh@dose (mg/kg)” wherein the dose is in milligram per kilogram (mg/kg) administered by oral gavage, 4 hours before LPS challenge.

ratLPS/ratLPS/% Inh% Inhp38 alphaHWB IC50@1.0@5.0ratLPS/% InhExampleIC50 (uM)(uM)(mg/kg)(mg/kg)@20.0 (mg/kg)D-10.1783.0D-20.0841.7989.095.0D-30.0950.4669.088.091.0D-40.911.5542.383.099.0D-50.144.0965.078.583.0D-60.0831.3382.096.0100D-70.44>25.00D-80.181.36585D-91.6315.8586D-103.9514.880D-110.161.54386D-120.827.067191D-130.338.365387

Claims
  • 1. A compound of Formula IB:
  • 2. A compound of claim 1 wherein: R2 is piperidinyl substituted with one or more substituents selected from hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkylene, alkoxyalkenylene, alkoxyalkynylene, hydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, and hydroxyalkynylcarbonyl, wherein said hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, alkoxyalkylene, alkoxyalkenylene, alkoxyalkynylene, hydroxyalkylcarbonyl, hydroxyalkenylcarbonyl, and hydroxyalkynylcarbonyl substitutents may be optionally substituted with one or more substituents selected from cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl, wherein said cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from alkylene, alkynylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy; or R2 is piperidinyl substituted with one or more substituents selected from hydroxycycloalkyl, alkoxycycloalkyl, and hydroxycycloalkylcarbonyl, wherein said hydroxycycloalkyl, alkoxycycloalkyl, and hydroxycycloalkylcarbonyl substitutents may be optionally substituted with one or more substituents selected from cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl, wherein said cycloalkyl, alkyl, aryl, arylalkyl, haloalkyl, and heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from alkylene, alkynylene, hydroxy, halo, haloalkyl, alkoxy, keto, amino, nitro, cyano, alkylsulfonyl, alkylsulfinyl, alkylthio, alkoxyalkyl, aryloxy, heterocyclyl, and heteroaralkoxy.
  • 3. A compound of claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
  • 4. A compound of claim 1 having Formula XB:
  • 5. A compound of claim 4 wherein R2 is piperidinyl substituted with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine ring.
  • 6. A compound of claim 4 wherein Z represents a carbon atom.
  • 7. A compound of claim 4 wherein Z represents a nitrogen atom.
  • 8. A compound of claim 4 wherein R1 is selected from hydrido, alkyl, hydroxyalkyl and alkynyl.
  • 9. A compound of claim 4 wherein R1 is hydrido.
  • 10. A compound of claim 4 wherein R2 is piperidinyl substituted with at least one substituent selected from lower hydroxyalkyl, lower hydroxyalkylcarbonyl and hydroxycycloalkylcarbonyl.
  • 11. A compound of claim 4 wherein R4 is optionally substituted phenyl.
  • 12. A compound of claim 4 wherein R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from chloro, fluoro, bromo and iodo.
  • 13. A compound of claim 4 wherein R4 is phenyl optionally substituted at the meta or para position with one or more chloro radicals.
  • 14. A compound of claim 4 wherein R5 is hydrido.
  • 15. A compound of claim 1 having Formula XX:
  • 16. A compound of claim 15 wherein: R400 is selected from lower hydroxyalkyl, lower hydroxyalkylcarbonyl and lower alkoxyalkylene, wherein said lower hydroxyalkyl, lower hydroxyalkylcarbonyl and lower alkoxyalkylene may be optionally substituted with one or more substituents selected from cycloalkyl, lower alkyl, phenyl, lower phenylalkyl, lower haloalkyl, and lower heteroarylalkyl, wherein said cycloalkyl, lower alkyl, phenyl, lower phenylalkyl, lower haloalkyl, and lower heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from lower alkylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; or R400 is hydroxycycloalkylcarbonyl that is optionally substituted with one or more substituents selected from cycloalkyl, lower alkyl, phenyl, lower phenylalkyl, lower haloalkyl, and lower heteroarylalkyl, wherein said cycloalkyl, lower alkyl, phenyl, lower phenylalkyl, lower haloalkyl, and lower heteroarylalkyl substituents may be optionally substituted with one or more substituents selected from lower alkylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, aryloxy, heterocyclyl, and lower heteroaralkoxy; and R401a and R401b are independently selected from hydrogen, halo, lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl, wherein said lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl substituents may be optionally substituted with one or more lower alkylene, lower alkenylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; and R402 is selected from hydrogen, phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy, wherein said phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy may be optionally substituted with one or more lower alkylene, lower alkenylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 17. A compound of claim 15 wherein Z represents a carbon atom.
  • 18. A compound of claim 15 wherein Z represents a nitrogen atom.
  • 19. A compound of claim 15 wherein R400 is optionally substituted hydroxyalkylcarbonyl.
  • 20. A compound of claim 15 wherein R400 is optionally substituted hydroxycycloalkylcarbonyl.
  • 21. A compound of claim 15 wherein R400 is optionally substituted alkoxyalkylene.
  • 22. A compound of claim 15 wherein R400 is optionally substituted hydroxyalkyl.
  • 23. A compound of claim 15 wherein R401 represents one or more chloro, fluoro, bromo and iodo.
  • 24. A compound of claim 15 wherein R401 is meta-chloro or para-chloro.
  • 25. A compound of claim 15 wherein R402 is hydrido.
  • 26. A compound of claim 15 wherein: R400 is optionally substituted lower hydroxyalkylcarbonyl; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 27. A compound of claim 15 wherein: R400 is selected from optionally substituted 2-hydroxyacetyl, 2-hydroxy-proprionyl, 2-hydroxy-2-methylpropionyl, 2-hydroxy-2-phenylacetyl, 3-hydroxyproprionyl, 2-hydroxy-3-methylbutyryl, 2-hydroxyisocapropyl, 2-hydroxy-3-phenylproprionyl, and 2-hydroxy-3-imidazolylproprionyl; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 28. A compound of claim 27 wherein R401a is meta-chloro or para-chloro.
  • 29. A compound of claim 27 wherein R401a is para-chloro and R401b is hydrogen.
  • 30. A compound of claim 15 wherein: R400 is optionally substituted lower hydroxycycloalkylcarbonyl; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 31. A compound of claim 15 wherein: R400 is selected from optionally substituted 1-hydroxy-1-cyclohexylacetyl, 2-hydroxy-1-cyclohexylacetyl, 3-hydroxy-1-cyclohexylacetyl, 4-hydroxy-1-cyclohexylacetyl, 1-hydroxy-1-cyclopentylacetyl, 2-hydroxy-1-cyclopentylacetyl, and 3-hydroxy-1-cyclopentylacetyl, 2-hydroxy-2-cyclohexylacetyl; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 32. A compound of claim 31 wherein R401a is meta-chloro or para-chloro.
  • 33. A compound of claim 15 wherein: R400 is optionally substituted lower hydroxyalkyl; R401 is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 34. A compound of claim 15 wherein: R400 is selected from optionally substituted hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxyisopropyl; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 35. A compound of claim 34 wherein R401a is meta-chloro or para-chloro.
  • 36. A compound of claim 15 wherein: R400 is optionally substituted lower alkoxyalkylene; R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 37. A compound of claim 15 wherein: R400 is selected from optionally substituted methoxymethylene, methoxyethylene, methoxypropylene, methoxyisopropylene, ethoxymethylene, ethoxyethylene, ethoxypropylene, and ethoxyisopropylene. R401a is selected from chloro, fluoro, bromo and iodo; and R402 is hydrido.
  • 38. A compound of claim 37 wherein R401a is meta-chloro or para-chloro.
  • 39. A compound of Formula IC:
  • 40. A compound of claim 39 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
  • 41. A compound of claim 39 having Formula XC:
  • 42. A compound of claim 41 wherein R2 is cyclohexyl substituted with at least one substituent attached to the 4-position carbon ring atom of the cyclohexyl ring.
  • 43. A compound of claim 41 wherein Z represents a carbon atom.
  • 44. A compound of claim 41 wherein Z represents a nitrogen atom.
  • 45. A compound of claim 41 wherein R1 is selected from hydrido, alkyl, hydroxyalkyl and alkynyl.
  • 46. A compound of claim 41 wherein R1 is hydrido.
  • 47. A compound of claim 41 wherein R2 is cyclohexyl substituted with one or more substituents selected from optionally substituted lower hydroxyalkyl, lower alkylaminoalkylene and cycloalkylamino.
  • 48. A compound of claim 41 wherein R4 is optionally substituted phenyl.
  • 49. A compound of claim 41 wherein R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from chloro, fluoro, bromo and iodo.
  • 50. A compound of claim 41 wherein R4 is phenyl optionally substituted at the meta or para position with one or more chloro radicals.
  • 51. A compound of claim 41 wherein R5 is hydrido.
  • 52. A compound of claim 41 having Formula XXIA:
  • 53. A compound of claim 52 wherein: R403 is selected from lower hydroxyalkyl, lower alkylaminoalkylene and cycloalkylamino; and R404a and R404b are independently selected from hydrogen, halo, lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl, wherein said lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl substituents may be optionally substituted with one or more lower alkylene, lower alkenylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; and R405 is selected from hydrogen, phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy, wherein said phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy may be optionally substituted with one or more lower alkylene, lower alkenylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 54. A compound of claim 52 wherein Z represents a carbon atom.
  • 55. A compound of claim 52 wherein Z represents a nitrogen atom.
  • 56. A compound of claim 52 wherein R403 is optionally substituted hydroxyalkyl.
  • 57. A compound of claim 52 wherein R403 is optionally substituted alkylaminoalkylene.
  • 58. A compound of claim 57 wherein R403 is optionally substituted dialkylaminoalkylene.
  • 59. A compound of claim 52 wherein R403 is optionally substituted cycloalkylamino.
  • 60. A compound of claim 52 wherein R404a is selected from chloro, fluoro, bromo and iodo.
  • 61. A compound of claim 52 wherein R404a is meta-chloro or para-chloro.
  • 62. A compound of claim 52 wherein R405 is hydrido.
  • 63. A compound of claim 52 wherein: R403 is optionally substituted lower hydroxyalkyl; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 64. A compound of claim 52 wherein: R403 is selected from optionally substituted hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 65. A compound of claim 64 wherein R404a is meta-chloro or para-chloro.
  • 66. A compound of claim 52 wherein: R403 is optionally substituted lower alkylaminoalkylene; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 67. A compound of claim 52 wherein: R403 is selected from optionally substituted methylaminomethylene, methylaminoethylene, methylaminopropylene, ethylaminomethylene, ethylaminoethylene, ethylaminopropylene, propylaminomethylene, propylaminoethylene, propylaminopropylene, dimethylaminomethylene, dimethylaminoethylene, dimethylaminopropylene, diethylaminomethylene, diethylaminoethylene, diethylaminopropylene, dipropylaminomethylene, dipropylaminoethylene, and dipropylaminopropylene; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 68. A compound of claim 67 wherein R404a is meta-chloro or para-chloro.
  • 69. A compound of claim 52 wherein: R403 is optionally substituted cycloalkylamino; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 70. A compound of claim 52 wherein: R403 is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 71. A compound of Formula XXIB:
  • 72. A compound of claim 71 wherein: R403 is selected from lower alkylamino; and R404a and R404b are independently selected from hydrogen, halo, lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl, wherein said lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl substituents may be optionally substituted with one or more lower alkylene, lower alkenylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; and R405 is selected from hydrogen, phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy, wherein said phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy may be optionally substituted with one or more lower alkylene, lower alkenylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 73. A compound of claim 71 wherein Z represents a carbon atom.
  • 74. A compound of claim 71 wherein Z represents a nitrogen atom.
  • 75. A compound of claim 71 wherein R403 is optionally substituted dialkylamino.
  • 76. A compound of claim 71 wherein R404a is selected from chloro, fluoro, bromo and iodo.
  • 77. A compound of claim 71 wherein R404a is meta-chloro or para-chloro.
  • 78. A compound of claim 71 wherein R405 is hydrido.
  • 79. A compound of claim 71 wherein: R403 is optionally substituted lower alkylamino; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 80. A compound of claim 71 wherein: R403 is selected from optionally substituted methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, t-butylamino, isobutylamino, dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-n-butylamino, di-sec-butylamino, di-t-butylamino, and di-isobutylamino; R404a is selected from chloro, fluoro, bromo and iodo; and R405 is hydrido.
  • 81. A compound of claim 80 wherein R404a is meta-chloro or para-chloro.
  • 82. A compound Formula XXII:
  • 83. A compound of claim 82 wherein: R406 is selected from lower alkynyl; and R407a and R407b are independently selected from hydrogen, halo, lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl, wherein said lower haloalkyl, lower haloalkoxy, lower alkoxy, cyano, hydroxy, lower alkyl, lower alkenyl, and lower alkynyl substituents may be optionally substituted with one or more lower alkylene, lower alkenylene, lower alkynylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; and R408 is selected from hydrogen, phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy, wherein said phenyl, lower alkylamino, lower alkylthio, lower alkyloxy, phenyloxy, phenylamino, phenylthio, and phenylalkoxy may be optionally substituted with one or more lower alkylene, lower alkenylene, hydroxy, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, cyano, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, lower alkoxyalkyl, phenyloxy, heterocyclyl, and lower heteroaralkoxy; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 84. A compound of claim 82 wherein Z represents a carbon atom.
  • 85. A compound of claim 82 wherein Z represents a nitrogen atom.
  • 86. A compound of claim 82 wherein R407a is selected from chloro, fluoro, bromo and iodo.
  • 87. A compound of claim 82 wherein R407a is meta-chloro or para-chloro.
  • 88. A compound of claim 82 wherein R408 is hydrido.
  • 89. A compound of claim 82 wherein: R406 is optionally substituted lower alkynyl; R407a is selected from chloro, fluoro, bromo and iodo; and R408 is hydrido.
  • 90. A compound of claim 82 wherein: R406 is selected from optionally substituted ethynyl, propynyl and butynyl; R407a is selected from chloro, fluoro, bromo and iodo; and R408 is hydrido.
  • 91. A compound of claim 82 wherein R406 is propargyl.
  • 92. A compound of claim 82 wherein R407a is meta-chloro or para-chloro.
  • 93. A compound of Formula IA
  • 94. A compound of Formula IXA:
  • 95. A compound of claim 94 wherein R2 is R200-heterocyclyl-R201.
  • 96. A compound of claim 94 wherein R2 is R200-cycloalkyl-R201.
  • 97. A compound of claim 94 wherein: R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R2 is R200-piperidinyl-R201, R200-piperazinyl-R201, or R200-cyclohexyl-R201 wherein: R200 is selected from: —(CR202R203)y—; 13 NR202—; —S—; —O—; or R201 represents a bond; R200 represents one or more radicals selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, methylimidocarbonyl, ethylimidocarbonyl, amidino, methylamidino, methylamidino, benzylamidino, guanidino, guanidinomethylene, guanidinoethylene, and methylsulfonylamino; and R202 and R203 are independently selected from hydrido, methyl, ethyl, propyl, butyl, phenyl and benzyl; and y is 0, 1 or 2; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R5 is selected from hydrido, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, benzyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, ethylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or —NR62R63 wherein R62 is methylcarbonyl or amino, and R63 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 98. A compound of claim 97 wherein R2 is R200-piperidinyl-R201.
  • 99. A compound of claim 97 wherein R2 is R200-pyrazinyl-R201.
  • 100. A compound of claim 97 wherein R2 is R200-cyclohexyl-R201.
  • 101. A compound of claim 94 having the Formula XA:
  • 102. A compound of claim 101 wherein: R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R2 is R200-piperidinyl-R201 wherein: R200 is selected from: methylene; NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, N-benzylamino, methylaminomethylene, aminocarbonyl, methoxycarbonylamino, ethoxycarbonylamino, or methylsulfonylamino; and R202 is selected from hydrido, methyl, ethyl, phenyl and benzyl; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 103. A compound of claim 101 wherein: R1 is hydrido; and R2 is R200-piperidinyl-R201 wherein: R200 is selected from: methylene; —NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxypropyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, amino, aminomethyl, aminoethyl, aminopropyl, N-benzylamino, methylaminomethylene, aminocarbonyl, methoxycarbonylamino, and ethoxycarbonylamino; and R202 is selected from hydrido, methyl phenyl and benzyl; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and R5 is selected from hydrido, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 104. A compound of claim 101 wherein: R1 is hydrido; and R2 is R200-piperidinyl-R201 wherein: R200 is selected from: methylene; —NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of methoxyethyl, methylcarbonyl, hydroxymethylcarbonyl, methoxymethylcarbonyl, and amino; and R202 is selected from hydrido and methyl; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and R5 is selected from hydrido, hydroxypropylamino, hydroxycyclohexylamino, diethylaminoethylamino; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 105. A compound of claim 94 having the Formula XA:
  • 106. A compound of claim 105 wherein: R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R2 is R200-piperazinyl-R201 wherein: R200 is selected from: —(CR202R203)y—; —NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethylene, methoxyethylene, ethoxyethylene, methoxyphenylene, ethoxyphenylene, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, ethoxycarbonylaminomethylene, and methylsulfonylamino; and R202 and R203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl; and y is 0, 1 or 2; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 107. A compound of claim 94 having the Formula XA:
  • 108. A compound of claim 107 wherein: R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R2 is R200-cyclohexyl-R201 wherein: R200 is selected from: —(CR202R203)y—; —NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, (1-hydroxy-1,1-dimethyl)ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethylene, methoxyethylene, methoxypropylene, ethoxyethylene, ethoxypropylene, propoxyethylene, propoxypropylene, methoxyphenylene, ethoxyphenylene, propoxyphenylene, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, benzoyl, chlorobenzoyl, fluorobenzoyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, carboxymethylcarbonyl, carboxyethylcarbonyl, carboxypropylcarbonyl, methoxymethylcarbonyl, methoxyethylcarbonyl, methoxypropylcarbonyl, ethoxymethylcarbonyl, ethoxyethylcarbonyl, ethoxypropylcarbonyl, propoxymethylcarbonyl, propoxyethylcarbonyl, propoxypropylcarbonyl, methoxyphenylcarbonyl, ethoxyphenylcarbonyl, propoxyphenylcarbonyl, piperidinylmethylcarbonyl, piperazinylmethylcarbonyl, morpholinylcarbonyl, methylsulfonylmethylene, amino, aminomethyl, aminoethyl, aminopropyl, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, and ethoxycarbonylaminomethylene; and R202 and R203 are independently selected from hydrido, methyl, ethyl, phenyl and benzyl; and y is 0, 1 or 2; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, ethyl, methoxy and ethoxy; and R5 is selected from hydrido, fluoro, chloro, bromo, hydroxy, methyl, ethyl, cyano, carboxy, methoxy, methoxycarbonyl, aminocarbonyl, acetyl, methylamino, dimethylamino, ethylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminoethylamino, dimethylaminoethylamino, methylaminopropylamino, dimethylaminopropylamino, methylaminobutylamino, dimethylaminobutylamino, methylaminopentylamino, dimethylaminopentylamino, ethylaminoethylamino, diethylaminoethylamino, ethylaminopropylamino, diethylaminopropylamino, ethylaminobutylamino, diethylaminobutylamino, ethylaminopentylamino, methylaminocarbonyl, methylcarbonyl, and ethylcarbonyl; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 109. A compound of claim 107 wherein: R1 is hydrido; and R2 is R200-cyclohexyl-R201 wherein: R200 is selected from: methylene; —NR202—; —S—; —O—; or R200 represents a bond; R201 represents one or more radicals selected from the group consisting of amino, aminomethyl, aminoethyl, aminopropyl, phenylamino, benzylamino, methylaminomethylene, ethylaminomethylene, methylaminoethylene, ethylaminoethylene, aminocarbonyl, methylcarbonylamino, ethylcarbonylamino, methylaminomethylcarbonyl, ethylaminomethylcarbonyl, methylcarbonylaminomethylene, ethylcarbonylaminomethylene, aminomethylcarbonylaminocarbonylmethylene, methoxycarbonylamino, ethoxycarbonylamino, methoxymethylcarbonylamino, methoxyethylcarbonylamino, ethoxymethylcarbonylamino, ethoxyethylcarbonylamino, methoxycarbonylaminomethylene, and ethoxycarbonylaminomethylene; and R202 is selected from hydrido, methyl, phenyl and benzyl; and R4 is phenyl, wherein said phenyl is optionally substituted with one or more radicals independently selected from fluoro, chloro, methyl, and methoxy; and R5 is selected from hydrido, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxycyclopropylamino, hydroxycyclobutylamino, hydroxycyclopentylamino, hydroxycyclohexylamino, (1-ethyl-2-hydroxy)ethylamino, aminomethyl, cyclopropylamino, amino, dimethylaminoethylamino, dimethylaminopropylamino, dimethylaminobutylamino, dimethylaminopentylamino, diethylaminoethylamino, diethylaminopropylamino, diethylaminobutylamino, and diethylaminopentylamino; or a pharmaceutically-acceptable salt or tautomer thereof.
  • 110. A compound of claim 94 wherein R2 comprises a substituted piperidinyl or piperazinyl moiety with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine or piperazine ring.
  • 111. A compound claim 94 wherein R2 comprises a substituted piperidinyl moiety with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperidine ring.
  • 112. A compound of claim 94 wherein R2 comprises a substituted piperazinyl moiety with at least one substituent attached to the distal nitrogen heteroatom or to a carbon ring atom adjacent to the distal nitrogen heteroatom of the piperazine ring.
  • 113. A compound of claim 94 wherein Z represents a carbon atom.
  • 114. A compound of claim 94 wherein Z represents a nitrogen atom.
  • 115. A compound of claim 94 wherein R1 is hydrido.
  • 116. A compound of claim 94 wherein R200 represents a bond.
  • 117. A compound of claim 94 wherein R201 represents one or more radicals selected from the group consisting of lower hydroxyalkyl, lower hydroxyalkylcarbonyl, and lower alkylaminoalkylene.
  • 118. A compound of claim 94 wherein R201 represents one or more radicals selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, methylaminomethylene, ethylaminomethylene, methylaminoethylene, and ethylaminoethylene.
  • 119. A compound of claim 94 wherein R4 is optionally substituted phenyl.
  • 120. A compound of claim 94 wherein R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from chloro, fluoro, bromo and iodo.
  • 121. A compound of claim 94 wherein R4 is phenyl optionally substituted at the meta or para position with one or more chloro radicals.
  • 122. A compound of claim 94 wherein R5 is hydrido.
  • 123. A compound of claim 94 wherein: R1 is hydrido; R200 represents a bond; R201 represents one or more radicals selected from the group consisting of lower hydroxyalkyl, lower hydroxyalkylcarbonyl, and lower alkylaminoalkylene. R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from halo; and R5 is hydrido.
  • 124. A compound of claim 94 wherein: R1 is hydrido; R200 represents a bond; R201 represents one or more radicals selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, (1-hydroxy-1,1-dimethyl)ethyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl, hydroxypropylcarbonyl, methylaminomethylene, ethylaminomethylene, methylaminoethylene, and ethylaminoethylene; R4 is phenyl optionally substituted at a substitutable position with one or more radicals independently selected from chloro, fluoro, bromo and iodo; and R5 is hydrido.
  • 125. A compound selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of:
  • 126. A compound of Formula IA
  • 127. A compound of Formula IA
  • 128. A compound of Formula IA
  • 129. A compound of Formula IA
  • 130. A compound of Formula IA
  • 131. A compound of Formula IA
  • 132. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of any one of claims 1, 39, 71, 82 and 94, or a pharmaceutically acceptable salt thereof.
  • 133. A method of treating a TNF mediated disorder, said method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound, said compound selected from the compounds of any one of claims 1, 39, 71, 82 and 94, or a pharmaceutically acceptable salt thereof.
  • 134. A method of treating a p38 kinase mediated disorder, said method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound, said compound selected from the compounds of any one of claims 1, 39, 71, 82 and 94, or a pharmaceutically acceptable salt thereof.
  • 135. The method of claim 134 wherein the p38 kinase mediated disorder is selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and cachexia.
  • 136. The method of claim 134 wherein the p38 kinase mediated disorder is inflammation.
  • 137. The method of claim 134 wherein the p38 kinase mediated disorder is arthritis.
  • 138. The method of claim 134 wherein the p38 kinase mediated disorder is asthma.
  • 139. A method of treating inflammation, said method comprising treating the subject having or susceptible to inflammation with a therapeutically-effective amount of a compound, said compound selected from the compounds of any one of claims 1, 39, 71, 82 and 94, or a pharmaceutically acceptable salt thereof.
  • 140. A method of treating arthritis, said method comprising treating the subject having or susceptible to arthritis with a therapeutically-effective amount of a compound, said compound selected from the compounds of any one of claims 1, 39, 71, 82 and 94, or a pharmaceutically acceptable salt thereof.
  • 141. A method of preparing pyrazoles of Formula IA
  • 142. The process of claim 141 wherein the process is carried out in an acidic solvent.
  • 143. The process of claim 141 wherein the acidic solvent is acetic acid.
  • 144. The process of claim 141 wherein the acidic solvent is an organic solvent containing an acid.
  • 145. The compound:
  • 146. A compound of claim 71 that is:
  • 147. A compound of claim 39 that is:
  • 148. The compound:
  • 149. A compound of claim 1 that is:
  • 150. The compound:
  • 151. A compound of claim 1 that is:
  • 152. A compound of claim 1 that is:
  • 153. A compound of claim 1 that is:
  • 154. A compound of claim 39 that is:
  • 155. A compound of claim 1 that is:
  • 156. A compound of claim 82 that is:
  • 157. A compound of claim 42 that is:
  • 158. A compound of claim 71 that is:
  • 159. A compound of claim 71 that is:
  • 160. A compound of claim 70 wherein R404a is meta-chloro or para-chloro.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to U.S. Provisional Application Ser. No. 60/047,570 filed May 22, 1997 and U.S. application Ser. No. 09/083,670 filed May 22, 1998.

Divisions (2)
Number Date Country
Parent 10021780 Dec 2001 US
Child 10840734 May 2004 US
Parent 09513351 Feb 2000 US
Child 10021780 Dec 2001 US
Continuation in Parts (1)
Number Date Country
Parent 09196623 Nov 1998 US
Child 09513351 Feb 2000 US